originals - Revista Nefrologia

Transcription

Included in ISI-WOK, MEDLINE, EMBASE, IME, IBECS, SCIELO
V o l u m e
3 1
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N u m b e r
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SUSTAINABILITY OF RENAL REPLACEMENT TREATMENT IN SPAIN
CORTICOSTEROID-RESISTANT IDIOPATHIC FOCAL SEGMENTAL GLOMERULOSCLEROSIS
THE ROLE OF MTOR INHIBITORS IN RENAL DISEASES
MULTICENTRE STUDY OF HAEMODIALYSIS COSTS
CONSENSUS DOCUMENT: RECOMMENDATIONS ON ASSESSING PROTEINURIA
HCV TREATMENT IN CHRONIC KIDNEY DISEASE
PROPHYLAXIS FOR PERMANENT HAEMODIALYSIS CATHETER INFECTION
BLOOD PRESSURE CONTROL IN DIABETIC PATIENTS. PRESDIAB STUDY
TRANSPLANTS IN LATIN AMERICA: THE AGUASCALIENTES DOCUMENT
Sociedad
Española de
Nefrología
Official Publication of the Spanish Society of Nephrology
Versión íntegra inglés y español en www.revistanefrologia.com
Nefrología Journal
Editor-in-Chief: Carlos Quereda Rodríguez-Navarro
Executive editor: Roberto Alcázar Arroyo
Deputy editors: Andrés Purroy Unanua, Ángel Luis Martín de Francisco, Fernando García López
Honorary editors: Luis Hernando Avendaño, David Kerr, Rafael Matesanz Acedos
SUBJECT EDITORS (editors of thematic areas)
Experimental Nephrology
A. Ortiz*
J. Egido de los Ríos
S. Lamas
J.M. López Novoa
D. Rodríguez Puyol
J.M. Cruzado
Clinical Nephrology
M. Praga*
J. Ara
J. Ballarín
G. Fernández Juárez
F. Rivera
A. Segarra
Diabetic Nephropathy
F. de Álvaro*
J.L. Górriz
A. Martínez Castelao
J.F. Navarro
J.A. Sánchez Tornero
R. Romero
Hereditary Nephropathies
R. Torra*
X. Lens
J.C. Rodríguez Pérez
M. Navarro
E. Coto
V. García Nieto
Chronic Kidney Disease
A.L. Martín de Francisco*
A. Otero
E. González Parra
I. Martínez
J. Portolés Pérez
CRF-Ca/P Metabolism
E. Fernández*
J. Cannata Andía
R. Pérez García
M. Rodríguez
J.V. Torregrosa
Arterial Hypertension
R. Marín*
J.M. Alcázar
L. Orte
R. Santamaría
A. Rodríguez Jornet
Nephropathy and
Cardiovascular Risk
J. Díez*
A. Cases
J. Luño
Quality in Nephrology
F. Álvarez-Ude*
M.D. Arenas
E. Parra Moncasi
P. Rebollo
F. Ortega
Acute Renal Failure
F. Liaño*
F.J. Gainza
J. Lavilla
E. Poch
Peritoneal Dialysis
R. Selgas*
M. Pérez Fontán
C. Remón
M.E. Rivera Gorrin
G. del Peso
Haemodialysis
A. Martín Malo*
P. Aljama
F. Maduell
J.A. Herrero
J.M. López Gómez
J.L. Teruel
Renal Transplantation
J. Pascual*
M. Arias
J.M. Campistol
J.M. Grinyó
M.A. Gentil
A. Torres
Paediatric Nephrology
I. Zamora*
N. Gallego
A.M. Sánchez Moreno
R. Vilalta
Nephropathology
J. Blanco*
I.M. García
E. Vázquez Martul
A. Barat Cascante
Evidence-Based Nephrology
Vicente Barrio* (Director of Supplements), Fernando García López (Methodology assessment), Editors: María Auxiliadora Bajo, José Conde, Joan M. Díaz, Mar Espino,
Domingo Hernández, Ana Fernández, Milagros Fernández, Fabián Ortiz, Ana Tato.
Continued Training (journal NefroPlus)
Andrés Purroy*, R. Marín, J.M. Tabernero, F. Rivera, A. Martín Malo.
* Coordinators of thematic area
EDITORIAL BOARD
A. Alonso
J. Arrieta
F.J. Borrego
D. del Castillo
P. Gallar
M.A. Frutos
D. Jarillo
V. Lorenzo
A. Mazuecos
A. Oliet
L. Pallardo
J.J. Plaza
D. Sánchez Guisande
J. Teixidó
J. Alsina
P. Barceló
J. Bustamente
A. Darnell
P. García Cosmes
M.T. González
L. Jiménez del Cerro
J. Lloveras
B. Miranda
J. Olivares
V. Pérez Bañasco
L. Revert
A. Serra
F.A. Valdés
J. Aranzábal
G. Barril
F. Caravaca
C. de Felipe
S. García de Vinuesa
A. Gonzalo
R. Lauzurica
J.F. Macías
E. Martín Escobar
J.M. Morales
R. Peces
J.M. Tabernero
A. Vallo
G. de Arriba
F. Anaya
A. Barrientos
A. Caralps
P. Errasti
F. García Martín
M. González Molina
I. Lampreabe
B. Maceira
J. Mora
J. Ortuño
S. Pérez García
J.L. Rodicio
L. Sánchez Sicilia
A. Vigil
C. Bernis
E. Fernández Giráldez
F.J. Gómez Campderá
P. Gómez Fernández
E. Huarte
E. López de Novales
R. Marcén
J. Montenegro
A. Palma
L. Piera
J. Rodríguez Soriano
A. Tejedor
INTERNATIONAL COMMITEE BOARD
E. Burdmann (Brazil)
B. Canaud (France)
J. Chapman (Australia)
R. Coppo (Italy)
R. Correa-Rotter (Mexico)
F. Cosío (USA)
G. Eknoyan (USA)
A. Felsenfeld (USA)
J.M. Fernández Cean (Uruguay)
J. Frazao (Portugal)
M. Ketteler (Germany)
Levin, Adeera (Canada)
Li, Philip K.T. (Hong Kong, China)
L. Macdougall (United Kingdon)
P. Massari (Argentina)
S. Mezzano (Chile)
B. Rodríguez Iturbe (Venezuela)
C. Ronco (Italy)
J. Silver (Israel)
P. Stevinkel (Sweden)
A. Wiecek (Poland)
C. Zoccali (Italy)
COUNCIL OF THE SPANISH SOCIETY OF NEPHROLOGY
SUBSCRIPTIONS, ADVERTISING AND PUBLISHING
Information and subscriptions:
S.E.N. Secretary: [email protected]
Tel: 902 929 210
Queries regarding of manuscripts:
[email protected]
Avda. dels Vents 9-13, Esc. B, 2.º 1.ª
Edificio Blurbis
08917 Badalona
Tel. 902 02 09 07 - Fax. 93 395 09 95
Rambla del Celler 117-119,
08190 Sant Cugat del Vallès. Barcelona
Tel. 93 589 62 64 - Fax. 93 589 50 77
Distribuido por:
E.U.R.O.M.E.D.I.C.E., Ediciones Médicas, S.L.
© Copyright 2011. Grupo Editorial Nefrología. All rights reserved.
• ISSN: 2013-2514
© Sociedad Española de Nefrología 2011. All international rights
reserved. No part of this publication may be reproduced, stored in
a retrieval system or transmitted in any form or by any means,
mechanical, electronic, photocopying, recording or otherwise,
without the prior written permission of the publisher.
Nefrología is distributed exclusively among medical professionals.
President:
Dr. Alberto Martínez Castelao
Vice-president:
Dr. Isabel Martínez
Secretary:
Dr. José Luis Górriz
Director of Nefrología Publishing Group:
Dr. Carlos Quereda Rodríguez
Chairperson of the Dialysis and
Transplantation Registry:
Dr. Ramón Saracho
Treasurer:
Dr. María Dolores del Pino
Chairpersons of Education
and Research:
Ordinary members:
Dr. Gema Fernández Fresnedo
Dr. Juan Francisco Navarro
Dr. Elvira Fernández Giráldez
Dr. Julio Pascual
Dr. José María Portolés
Web Page of Nefrología:
E-mail Editor-in-Chief:
Dr. Josep Maria Cruzado
Chairperson for selection of the SEN
Congress presentations:
Dr. Rosa Sánchez Hernández
Links:
www.revistanefrologia.com
[email protected]
[email protected]
http://www.revistanefrologia.com
Volume 31 - Number 3 - 2011
RULES OF PUBLICATION IN NEFROLOGIAGÍA
NORMAS PARA LA PUBLICACIÓN DE UN ARTÍCULO
EN NEFROLOGÍA
NEFROLOGÍA is the official publication from the Spanish Society of Nephrology
(SEN) and is a cited reference in the Institute for Scientific Information Web of
Knowledge (ISI-WOK). It is included in the bibliographic databases MEDLINE,
EMBASE, IME, IBECS and SCIELO. The articles’ tables of contents are reproduced
in Current Contents-Clinical Practice, Current Advances in Biological Sciences
and other ISI publications. Full versions of the texts, (including English versions of
regular issues) can be accessed from the NEFROLOGÍA Web site. Some full versions
are also included in SciELO (scielo.isciii.es/scielo.php). The abstracts in English are
found in Excerpta Medica and PubMed. NEFROLOGÍA publishes basic or clinical
research papers associated with nephrology, arterial hypertension, dialysis and
kidney transplantation. All articles undergo a peer revision process, and all
original texts are both assessed internally and proof-read externally. NEFROLOGÍA
endorses the publication rules used by the International Committee of Medical
Journal Editors (ICMJE).
NEFROLOGÍA es la publicación oficial de la Sociedad Española de Nefrología y está
referenciada en la Web of Knowledge del Institute for Scientific Information (ISIWOK). Está incluida en las bases de datos bibliográficas, MEDLINE, EMBASE, IME,
IBECS y SCIELO. Los sumarios se reproducen en Current Contents-Clinical Practice,
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propia Web de NEFROLOGÍA puede accederse a los textos íntegros, incluida la
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están incluidos en SciELO (scielo.isciii.es/scielo.php). En Excerpta Medica y en
PubMed se encuentran los resúmenes en inglés. NEFROLOGÍA publica artículos de
investigación básica o clínica relacionados con nefrología, hipertensión arterial,
diálisis y trasplante renal. Se rige por el sistema de revisión por pares, y todos los
trabajos originales se someten a evaluación interna y a revisiones externas.
NEFROLOGÍA suscribe las normas de publicación del International Committee of
Medical Journal Editors (ICMJE).
The Journal’s main language of publication is Spanish, and articles written in
English by non-Hispanic authors are accepted. All contents of the regular issues
are also available in English, and are easily accessible on the Journal's Web site,
along with the original version. NEFROLOGÍA publishes six issues per year (one every
two months). There is also a Continuing Education edition (NEFROPLUS) and a
series of special editions about topical subjects, such as EVIDENCE-BASED NEPHROLOGY
issues.
El idioma de la Revista es el español, y se admiten artículos en inglés de autores
que no son de habla hispana. Todos los contenidos de los números regulares
disponen también de su versión a texto completo en inglés, de acceso libre en la
Web de la Revista, al igual que la versión original. NEFROLOGÍA publica al año 6
números regulares, cada dos meses, y dispone de una edición de Formación
Continuada (NEFROPLUS) y de una serie de suplementos y números extraordinarios
sobre temas de actualidad, incluyendo los números de NEFROLOGÍA BASADA EN LA
EVIDENCIA.
NEFROLOGÍA belongs to the Grupo Editorial Nefrología publisher, which is a SEN
member that manages printed and digital issues to publish scientific opinions
regarding nephrology and continuing education in this area.
All of the contents and additional material published in NEFROLOGÍA,
NEFROPLUS and other editions from Nefrología or Grupo Editorial Nefrología
are included on the NEFROLOGÍA Web site (www.revistanefrologia.com) (free
access). Information regarding the method for sending papers and the
complete rules of publication in the journal can be easily accessed from
the site.
NEFROLOGÍA se encuadra en el Grupo Editorial Nefrología, órgano de la Sociedad
Española de Nefrología que coordina la producción de ediciones impresas o en
formato digital para transmisión de pensamiento científico nefrológico y
formación continuada en Nefrología.
Todos los contenidos y material complementario publicados en NEFROLOGÍA,
NEFROPLUS y otras ediciones de NEFROLOGÍA o del Grupo Editorial Nefrología, se
incluyen en el sitio Web de NEFROLOGÍA (www.revistanefrologia.com) de acceso
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contents
Volume
31 - Number 3 - 2011
V o l u m e
EDITORIAL
EDITORIALES
241
3 1
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SUSTAINABILITY OF RENAL REPLACEMENT TREATMENT IN SPAIN
CORTICOSTEROID-RESISTANT IDIOPATHIC FOCAL SEGMENTAL GLOMERULOSCLEROSIS
• Sustainability and equity of renal replacement therapy in Spain
THE ROLE OF MTOR INHIBITORS IN RENAL DISEASES
MULTICENTRE STUDY OF HAEMODIALYSIS COSTS
CONSENSUS DOCUMENT: RECOMMENDATIONS ON ASSESSING PROTEINURIA
A.L.M. de Francisco
HCV TREATMENT IN CHRONIC KIDNEY DISEASE
PROPHYLAXIS FOR PERMANENT HAEMODIALYSIS CATHETER INFECTION
BLOOD PRESSURE CONTROL IN DIABETIC PATIENTS. PRESDIAB STUDY
TRANSPLANTS IN LATIN AMERICA: THE AGUASCALIENTES DOCUMENT
EDITORIAL COMMENTS
247
• How to treat corticosteroid-resistant idiopathic focal segmental
glomerulosclerosis?
F. Rivera Hernández
251
• The role of mTOR inhibitors in renal diseases
256
• Establishing and controlling chronic renal failure treatment costs.
A pressing need
Sociedad
Española de
Nefrología
Official Publication of the Spanish Society of Nephrology
Versión íntegra inglés y español en www.revistanefrologia.com
Thrombotic microangiopathy in kidney
transplant patient with antiphospholipid
syndrome. Nephrology and Anatomical
Pathology Department educational archive.
Ramón y Cajal Hospital. Madrid, Spain.
R. Martín Hernández
SHORT REVIEWS
260
• Management of HCV infection in chronic kidney disease
S. Aoufi Rabih, R. García Agudo
268
• Vascular and metabolic properties of manidipine
N. Buset Ríos, F. Rodríguez Esparragón, C. Fernández-Andrade Rodríguez, J.C. Rodríguez Pérez
ESPECIAL ARTICLE
275
• Ethical challenges in transplant practice in Latin America: the Aguascalientes Document
A. Baquero, J. Alberú, representing Documento de Aguascalientes
ORIGINALS
286
• Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with
cyclosporin-resistant focal segmental glomerulosclerosis
A. Segarra Medrano, J. Vila Presas, L. Pou Clavé, J. Majó Masferrer, J. Camps Domenech
292
• Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis
C. Cabrera López, T. Martí, V. Catalá, F. Torres, S. Mateu, J. Ballarín Castán, R. Torra Balcells
299
• Multicentre study of haemodialysis costs
E. Parra Moncasi, M.D. Arenas Jiménez, M. Alonso, M.F. Martínez, A. Gámen Pardo, P. Rebollo, T. Ortega Montoliú,
T. Martínez Terrer, F. Álvarez-Ude, Quality Management Group from the Spanish Society of Nephrology
308
• Prophylaxis with gentamicin locking of chronic tunnelled central venous catheters does not cause
bacterial resistance
J. Fernández-Gallego, M. Martín, E. Gutiérrez, C. Cobelo, P. Frías, C. Jironda, P. Hidalgo, T. Jiménez
313
• Factors associated with blood pressure control in diabetic patients treated in nephrology units.
PRESDIAB Study
N. Serra, A. Oliveras, S. Bergoñon, L. Sans, A. Cobos, P. Martínez, R. Artigas, E. Poch
322
• Impact of an interdisciplinary training program in Counselling and decision-making process in a
nephrology department
H. García-Llana, J. Barbero, E. Remor, L. Díaz-Sayas, R. Rodríguez-Rey, G. del Peso, R. Selgas
contents
Volume
31 - Number 3 - 2011
CONSENSUS DOCUMENT
331
• Consensus Document. Recommendations on assessing proteinuria during the diagnosis and follow-up
of chronic kidney disease
R. Montañés Bermúdez, S. Gràcia García, D. Pérez Surribas, A. Martínez Castelao, J. Bover Sanjuán
A HISTORY OF NEPHROLOGY
346
• Fuller Albright and our current understanding of calcium and phosphorus regulation and primary
hyperparathyroidism
A.J. Felsenfeld, B.S. Levine, C.R. Kleeman
LETTERS TO THE EDITOR
A) Brief papers on basic research and clinical investigation
358
• Prevalence of chronic kidney disease and arteriosclerosis in a non-selected population World Kidney Day
C. Pereira Feijoo, V.E. Martínez Maestro, N. Bretaña Vilanova, L. Queija Martínez, A. Otero González
359
• Monitoring sirolimus levels: How does it affect the immunoassay used?
361
• Good practice guidelines on the use of erythropoiesis-stimulating agents in 2011
M. Marín-Casino, M. Crespo, J. Mateu-de Antonio, J. Pascual
J.F. Pérez-Oliva Díaz
B) Brief case reports
362
• Listeria monocytogenes: an infrequent cause of peritonitis in peritoneal dialysis
O. Benjelloum, J.E. Sánchez Álvarez, C. Rodríguez Suárez, I. González, A. Fernández-Viña, M. Núñez, B. Peláez
365
• Arterial hypertension induced by pyeloureteral stenosis in horseshoe kidney
J.J. Aguilar-García, A.D. Domínguez-Pérez, V. Nacarino-Mejías, C.I. Ruiz-Guerrero, M.A. Iribarren-Marín, C.J. Ortega-Seda
366
• Successful treatment with sodium thiosulfate for calcific uraemic arteriolopathy
368
• Spontaneous remission of nephrotic syndrome in a patient with diabetic nephropathy
and Parkinson’s disease
L. Salanova Villanueva, M.C. Sánchez González, J.A. Sánchez Tomero, P. Sanz
M. Heras, A. Sáiz, M.J. Fernández-Reyes, R. Sánchez, A. Molina, M.A. Rodríguez, F. Álvarez-Ude
369
• Immunotactoid glomerulopathy and tuberculosis: a novel association
A. Gupta, A. Khaira
371
• Sarcoidosis: diagnosis from the renal function and hypercalcaemia study
372
• Membranous glomerulonephritis in a patient with syphilis
O. Ibrik, R. Samon, A. Roda, R. Roca, J.C. González, J. Viladoms, J. Vilaseca, M. Serrano
M.T. Mora Mora, M.S. Gallego Domínguez, M.I. Castellano Cerviño, R. Novillo Santana, J.R. Gómez-Martino Arroyo
374
• Treatment with intravenous daptomycin for a peritonitis relapse caused by Staphylococcus epidermidis
F. Levy, V. Camarero Temiño, A. Blasco Mollá, M.P. Ortega Lafont, P. Abaigar Luquin, M.J. Izquierdo Ortiz, G. Torres Torres
375
• Intraperitoneal daptomycin
376
• Relapses in patients with microscopic polyangiitis with persistently positive antimyeloperoxidase
for 4 years using maintenance immunosuppressants
L. García-López, l. Gómez Sayago, M.J. Fernández-Reyes Luis
M. Heras, M.J. Fernández-Reyes, R. Sánchez, H. Muñoz, M.J. Jiménez, A. Molina
• List of misprints
© 2011 Revista Nefrología. Official Publication of the Spanish Nephrology Society
editorial
Sustainability and equity of renal replacement
therapy in Spain
A.L.M. de Francisco
Nephrology Department. Marqués de Valdecilla University Hospital. President of the S.E.N. 2002-2008. Santander, Cantabria, Spain
Nefrologia 2011;31(3):241-6
doi:10.3265/Nefrologia.pre2011.Apr.10933
U
ntil 1970, Spanish patients with advanced chronic kidney disease died inexorably. Since then, our health
system has undergone immense development in renal
replacement therapy programmes using dialysis and transplants, and currently, these patients can fortunately be treated
with high levels of quality.
The progressive increase in the number of patients requiring
this type of treatment, as well as the costs it entails, has been
the object of several different publications and many special
issues in our NEFROLOGÍA journal. In 1994, we put together a
NEFROLOGÍA supplement based on the conference on
economic and organisational aspects of the treatment of
chronic renal failure, which took place at the summer
Menéndez-Pelayo University in Santander.1 Recently,
another special supplement was published regarding the
sustainability of renal replacement therapy that has served as
information for reflection on several of the socioeconomic
aspects of this type of treatment.2
Finding ourselves in the midst of an economic crisis, and
looking towards the future, what can we nephrologists do in
order to ensure the continuity and equity of renal
replacement therapy in Spain? This is the issue that we will
debate here.
THE SUSTAINABILITY OF THE SPANISH HEALTH
SYSTEM IS AT RISK
The life expectancy at birth from 2006 placed Spain as the
highest country in the 15 member countries of the European
Union, and this came at the lowest health costs as well. With
a mean 81.1 years life expectancy, Spain is at the forefront of
countries such as France, Italy, Sweden, Austria, etc., and the
health costs (public + private) are only 8.4% of the gross
domestic product (GDP), whereas the mean for the 15
countries of the EU is 9.2%, with extreme values in
Luxembourg (7.3%) and France (11.1%) (Sources:
Organisation for Economic Cooperation and Development
[OECD], the World Health Organisation [WHO], and
Instituto Nacional de Estadística (National Institute of
Statistics) [INE]). However, this value rose to 9% for Spain
in 2008.
In the coming 10 years, one in five Spanish citizens will be
older than 65 years, and per person health costs will range
between 4 and 12 times greater than for those younger than
this age. The mean annual cost per capita for the year 2025 is
estimated at €2192 for people younger than 65, €8570 for
those between the ages of 65 and 79, €14 996 for those
between the ages of 80 and 94, and €28 479 for those older
than 95 years (sources: INE [2009], Statistical Office of the
European Communities [EUROSTAT], OECD, and WHO).
Given the current growth rate, health costs could double in
the next 10 years. In other words, in 2020, 50 of every €100
in public spending in the Spanish Autonomous Communities
could be destined to health care, as opposed to the current
amount of €35.3
One of the components in this health cost is renal
replacement therapy. Although these patients make up only
0.1% of the population, they consume 2.5% of the National
Health Service (NHS) budget, i.e., in spite of being a small
proportion of the total population, they consume a
significant amount of resources. This is the problem that
must be resolved, or at least given an in-depth analysis, by
health authorities and with the help of nephrologists.
RENAL REPLACEMENT THERAPY IN SPAIN
Correspondence: ALM de Francisco
Servicio de Nefrología. Presidente de la S.E.N. 2002-2008
Hospital Universitario Valdecilla. Santander, Cantabria. Spain.
[email protected]
According to the most recent dialysis and transplant report
from 2009, from the Spanish registry of renal patients,
developed by the Spanish Society of Nephrology (S.E.N.)
and the Spanish National Transplant Organisation,4 the
241
ALM de Francisco. Sustainability and equity of renal replacement therapy in Spain
editorial
number of new patients has stabilised since 1999, with an
incidence of 129 new patients per million population (pmp)
in the year 2009, as opposed to 126 pmp 10 years earlier. In
this group, 85.1% of new patients are treated using
haemodialysis, 12.1% using peritoneal dialysis, and 2.8%
using renal replacement therapy and a kidney transplant
before initiating dialysis.
This stabilisation in the incidence of the disease has not been
mirrored in the prevalence. In 2001, 885 patients pmp were
treated using renal replacement therapy, and this value
increased to 1039 patients in 2009. Of the patients receiving
treatment, 47.67% are on haemodialysis, 47.51% undergo
kidney transplants, and 4.82% are on peritoneal dialysis.
As we commented on earlier, the general population being
treated with dialysis and transplants is aging. In the report
from 2009, the incidence was 169 (45-64 years), 390 (65-74
years), and 464 (>75 years) pmp.
For example, when comparing the years of 2008 and 2009,
we observe a 4% increase in the number of patients on
peritoneal dialysis, a 3% increase in the number of patients
on haemodialysis, and a 2% increase in the number of
patients living with a functioning kidney transplant.
DIALYSIS TREATMENT IN SPAIN
Using public financing, an offer currently exists for both
public and private sectors to administer replacement
therapy for chronic kidney failure in Spain. According to
Largo, who was the assistant director for contracting health
services in the Spanish Ministry of Health and Consumer
Affairs, it is a sector in which the public-private
collaboration within the NHS has contributed efficiently to
the resolution of a serious health problem.5 In Spain in
2009, there were 363 dialysis centres, attending 21 297
patients on haemodialysis (453 pmp). In 2007, 45% of
dialysis centres were owned by companies such as
Fresenius, FME, Braun, Diaverum, Baxter, etc. Fifteen
percent were managed by private centres, and 40% were
located in public facilities. Between 2005 and 2009, the
number of dialysis centres managed by companies
increased by 3%, the number of private centres decreased
by 3%, and the number of public centres increased by 19%.
The costs for dialysis in Spain during 2010 can be observed
in Table 1 (source: Industry). These prices only include
treatment during the dialysis session, and do not include
medications, which must be considered separately. As we
can see, the cost of basic peritoneal dialysis is the lowest,
although the use of biocompatible supplements, polyglucose,
and automation of the process all raise the price even above
that of haemodialysis. In 2010, 53% (1237 patients) were on
automated peritoneal dialysis, and 47% (1090 patients) on
continuous ambulatory peritoneal dialysis (CAPD).
With this in mind, the presentation of peritoneal dialysis as
an option must be based primarily on aspects of quality
rather than costs, such as the excellent techniques for starting
treatment, the preservation of residual kidney function,
patient independence, nutritional freedom, reduced need for
medication, etc.
Even though renal replacement therapy implies costs during
the first year that are similar to those of dialysis treatment
(including all medical costs), it is the best cost-effective
technique, since the cost in subsequent years is only 20% of
this amount.
Table 1. Mean dialysis costs in 2010 in Spain (€)
Price (€)
Days
CAPD
43.02
360
15 487.20
Biocompatible supplement
11.44
360
4118.40
Polyglucose supplement
Annual cost (
6.29
360
2264.40
60.75
360
21 870.00
APD
73.70
360
26 532.00
Biocompatible supplement
11.44
360
4118.40
Polyglucose supplement
6.29
360
2264.40
91.43
360
32 914.80
Haemodialysis fee
136.9
156
21 356.40
Transportation
10.85
156
1692.60
147.75
156
23 049.00
€)
Source: Industry.
CAPD: Continuous ambulatory peritoneal dialysis; APD: Automated peritoneal dialysis
242
Nefrologia 2011;31(3):241-6
HOW CAN THE DECISIONS
OF THE NEPHROLOGIST IMPACT THIS
INCREASE IN HEALTH COSTS THAT PLACES
THE FUTURE OF RENAL REPLACEMENT THERAPY
IN DANGER?
We can list several different possibilities:
1. Increase the rate of kidney transplants;
2. Increase the percentage of patients on peritoneal
dialysis;
3. An honest reflection regarding the costs and benefits of
prescribing medications;
4. Integrated management contract;
5. Consider the use of non-universal dialysis.
editorial
Increasing the percentage of patients on peritoneal
dialysis
After kidney transplantation, (non-automated) peritoneal
dialysis is the most economically viable option for renal
replacement therapy after the first year. In spite of this, only
4.8% of patients were receiving this type of treatment in
2009. Some Autonomous Communities have reached rates as
high as 25%, but in spite of blatant promotion of this
technique (in our nephrology department, all patients that are
to be treated with dialysis start out with a consultation for
peritoneal dialysis), we have not been able to increase the
overall number. The primary reasons for this failure are that
this technique becomes considerably less effective after 2
years, it is given up by tired patients, is interrupted for
kidney transplantation and, primarily, the lack of patient
dedication to this technique. We must also add to this list the
lack of enthusiasm presented by some physicians for this
technique, which could increase significantly until all of
Spain reaches mean values such as those from Galicia,
Cantabria, and Basque Country.
Increasing the rate of kidney transplants
The actions taken by the Spanish National Transplant
Organisation, consolidating the concepts already put into
place by the Spanish Society of Nephrology in the
development of coordinated kidney transplant
programmes, has elevated our country to become the
leader in cadaveric kidney transplantation. Currently,
based on the transplant and dialysis report from 2009, 4
47% of the patients living with renal replacement
therapy do so through kidney transplants.
The use of cadaveric kidneys probably will not surpass
the current rates. In 2009, 2328 cadaveric kidneys were
transplanted, with 2225 in 2010. It would be difficult to
augment this level, although some programmes do exist
that could facilitate an increase to some degree, such as
implementing kidney transplants from non-heart beating
donors, which has produced very positive results in
some Spanish health centres. 6
Another possibility for increasing the number of kidney
transplants is to promote living-donor transplantations,
which are currently on the rise in Spain, although only
modestly. In 2001, 26 kidneys were transplanted from
living donors, whereas this amount rose to 148 in 2009. 4
The majority of health centres have developed a
sufficiently consolidated protocol for us to hope for a
significant increase in these numbers, as well as new
programmes such as the cross-over kidney
transplantation. However, we must keep in mind that
only 20% of patients receiving dialysis treatment are
also included in waiting lists for kidney transplants, and
so global implementation of this type of treatment is
impossible.
Nefrologia 2011;31(3):241-6
Drug prescriptions
The concept of cost-effectiveness is still far from being
universally adopted by the medical community, and
especially so by nephrologists. The problem we deal with
is not based on whether or not a drug should be financed,
or the financing of drugs that have demonstrated costs and
benefits, but rather the financing of drugs that have not
demonstrated them. 7 A very clear example is that of
phosphate binders. 8 The decision made by a nephrologist
can imply a cost that varies between €61 (calcium
carbonate), €219 (calcium acetate), €410 (calcium
acetate and magnesium carbonate), €2178 (lanthanum
carbonate), and €2512 (Sevelamer). Along with other
authors, 9 we have defended the stance that agents based
on calcium compounds should be the first choice in
binders used for dialysis patients, since these are the
cheapest and best tolerated compounds in the treatment of
hyperphosphataemia, with similar results to other binders.
Sevelamer and lanthanum carbonate have not been shown to
be superior to calcium-based products. They are much more
expensive and are also associated with more side effects. In
the absence of a clear clinical benefit proven by these
compounds, they should not be recommended as an initial
therapy. The calcium issue can be easily resolved using
calcium acetate with or without magnesium carbonate (this
reduces the quantity of calcium with proven efficacy).10 In
2008, we spent many millions of Euros in Spain on noncalcium binders in order to control hyperphosphataemia,
even when other cheaper and more effective options were
available. A recent Cochrane review on phosphate binders
also concluded that the most expensive compounds were no
better than the cheapest ones.11
243
editorial
This is simply one example, and we could also discuss other
concepts such as erythropoietic products, vitamin D
compounds, etc. The point is that there are many ways to
reduce costs. In a study from 2009 with dialysis patients,
the greatest economic burden was erythropoietin (€22.6 per
patient per day), approximately 68% of total drug costs.12 A
more recent estimate from the region of Murcia13 showed
that, from a total cost of €197 per patient per week, 34%
went towards phosphate binders, 25% was for
erythropoietin, 16% for calcimimetics, 3% for iron, 5% for
vitamin D, and 16% for other drugs. These values have
changed somewhat since then, with an increase in
calcimimetics and a decrease in erythropoietin, and there is
room for the nephrologist to manoeuvre, adjusting and
controlling the costs derived from prescribed medications.
Integrated management
This is a new process with as yet undemonstrated results, but
that initially appears to positively influence the costs of renal
replacement therapy. The Health Department of the region of
Murcia is developing this methodology, which requires tight
cooperation between the company in charge of managing
dialysis care and the nephrology department from the
reference hospital.
An integrated management contract would mean statesubsidised treatment with regard to:
1. Dialysis treatment of any kind (haemodialysis, on-line
haemodiafiltration,
peritoneal
dialysis,
daily
haemodialysis),
2. Medications (intra- and extra-dialysis),
DIALYSIS FOR END-STAGE PATIENTS
When dialysis programmes were started, the objective was to
facilitate the return of relatively healthy patients to work and
society. The reality is that many patients older than 75 years with
advanced renal failure have three or more comorbidities and very
low life expectancy. The ethical issues must be approached with
courage and honesty: should dialysis be for everyone?
Currently, developed countries have no limitations in the
application of renal replacement therapy. This situation
frequently implies that the suitability of treatment for each
particular patient may not be adequately evaluated, although
it is evident that not all patients can receive the same benefits
from this treatment. Some studies have retrospectively
analysed the survival of patients older than 75 years with
stage 5 chronic kidney disease in specialised clinics for this
pathology, finding that the advantages provided by dialysis
are substantially reduced by comorbidities in these patients,
and by ischaemic heart disease in particular.14 The study
performed by Couchoud et al15 was a truly practical
assessment of this subject, and using a simple grading
system for comorbidity, they were able to predict the shortterm prognosis of patients older than 75 years starting
dialysis. In many of these cases, conservative treatment
produces equal survival and a better quality of life for the
patient and his/her family. This is not simply a question of
making renal replacement therapy sustainable, but there is
also an ethical issue in protecting a severely incapacitated
sick person and the patient’s family from prolonged agony.
End-stage dialysis should be reconsidered against medical
treatment without dialysis.
SUSTAINABILITY OF THE SPANISH NATIONAL
HEALTH SYSTEM
3. Laboratory analyses,
4. Other diagnostics and tests,
5. Vascular and peritoneal access,
6. Patient transportation.
As we have seen, all types of dialysis are included in this
type of integrated contract, which allows the nephrology
department in the reference hospital to treat the patient being
limited only by the clinical characteristics and condition of
the patient, and keeping in mind the objectives set forth
regarding quality.
Among the benefits provided is the indication of the type of
treatment, a greater ease of administering home treatment
when indicated, which includes better clinical results and
lower overall costs, and an agreement that efficiency is not
attained at the cost of lower quality of treatment.
244
All the measures that nephrologists may take to control the
costs derived from renal replacement therapy will be very
ineffective if not accompanied by a restructuring of our
current NHS model. This restructuring cannot logically be
discussed in this brief editorial, but the Spanish society, and
we especially, the professionals working in the health sector,
must express ourselves clearly regarding the current state of
affairs. We will comment on just a few of these aspects.
Co-payment
Current data indicate that the rate of patients seeking medical
attention in Spain is 40% greater than the mean for the 15
European Union countries.3 The logical consequences are a
saturation of health services and an increase in expenditure.
The Comisión de Análisis y Evaluación del Sistema
Nacional de Salud (analysis and evaluation committee of the
Nefrologia 2011;31(3):241-6
NHS) (Abril’s Committee) from 1991 produced an excellent
report elaborated by all sectors of Spanish society.16 This
report informed that we must adopt measures that limit the
over-prescription of drugs. Acknowledging that these
measures would be unpopular, participation in assuming
these costs and compensation in other sectors such as
pensions and fiscal reimbursements was recommended. The
rule of thumb would be participation in assuming costs,
except for certain groups when deemed necessary. If, for
political reasons, it were not convenient to globally
implement cost participation, expenditure could be analised
and later reimbursements of 40% could ensue.
The majority of European countries use health care copayment and drug payment plans (Germany, Belgium,
France, Italy, Portugal, and Sweden), although with one
exception (United Kingdom). This idea has always been
rejected in Spain with arguments of social protection and
elevated management costs. In our opinion, it would be
unlikely that a political group would assume this idea due to
the impact it would have on elections, but we must abandon
the idea of “political opportunity,” and instead adopt a
concept of “social opportunity.”
editorial
centre within their territory, it is surprising the frivolousness
with which the concept of economies of scale is ignored.
Very wide ranges of prices are charged for the same product,
causing a rupture in the equity of the system.
The existence of different vaccine calendars among
Autonomous Communities is a clear expression of the idiocy
that permeates our health system. There are also different
models for financing certain drugs for particular patient
groups. For example, in Castile and Leon, a decreased
amount is paid for antifungal and antiviral medications in
cancer patients; in Extremadura, the overall cost of drugs is
financed when prescribed to large families and patients with
chronic diseases that are younger than 14 years of age, and
in Valencia, the full cost of treatment for tuberculosis is
financed.18
It would be logical to restructure the system in such a way
that would concentrate resources, make purchases cheaper,
pay for services on time, and ensure equity in the health
services provided to any Spanish citizen. Currently, the
financing of our health system shows major differences
between the Autonomous Communities, with a €560
difference between the territory with the highest per capita
budget (Basque Country) and the lowest (Baleares).18
Government health agreement
Professor Segovia de Arana, one of the main actors in
developing the current excellence provided by the Spanish
health system (founder of the internal medicine residency
programme), has worked along with other very important
representatives of Spanish medicine in the European
Academy of Sciences and Arts to edit a Libro Blanco sobre
el Sistema Nacional de Salud (white paper on the Spanish
health system). They predict that if the political parties in
Spain do not come to an agreement, the Spanish health
system as we know it will be drowned in the sustainability
issues that plague it.
Structural changes that involve the concept of concentration,
such as attempts at synergy, shared diagnostic platforms
(both imaging and laboratory), restructuring of diagnostic
and therapeutic indications, and improved management
(human resources, information, equipment, etc.) could be
implemented in order to save costs.18
In our opinion, a restructuring of the NHS along with a
Government Agreement is necessary for ensuring
sustainability.
Need for leadership
On September 30th 2010, President of the Spanish House of
Commons’ health committee Gaspar Llamazares concluded
that two years of work had been a failure in the attempt to
reach a government agreement in order to safeguard the
viability of the NHS.
Governmental restructuring
The debt for health products and medications on 31
December 2010 was 8.739 billion Euros, of which the
Communities of Andalusia, Valencia, and Castile and Leon
made up more than 35%. Many health care providers have to
wait up to 600 days to receive payment, with the greatest
delays produced in the Communities of Cantabria (709
days), Baleares (645 days), and Murcia (612 days).17
Although some of these areas already have a disbursement
Nefrologia 2011;31(3):241-6
Our NHS has a general lack of leadership, and this is
mirrored in all of the institutions that compose it. Nor does it
have a governmental entity that must be answered to and that
requires proper use of public resources, whether centralised
or autonomic. For this, we must have a government that
ensures the sustainability of our health system, and therefore,
of renal replacement therapy. This government would have
to exert political, economic, and knowledgeable authority for
the management of national affairs.
Conclusion
Although the nephrology service provided in Spain is costeffective and of very high quality, some measures which
have been discussed here could be incorporated by
245
editorial
nephrologists into our daily practice in order to ensure
the sustainability of renal replacement therapy. However,
our compliance with our responsibilities as vectors for
health costs will be for nothing if it is not accompanied
by changes in our NHS. Several of these necessary
changes will not come about simply due to the electoral
interests of politicians. Perhaps the first step we must
take is to demand a global accord to ensure the
sustainability of our NHS, both in its social (equity) and
economic aspects.
9.
10.
11.
REFERENCES
1. Aspectos económicos y organizativos del tratamiento de la
insuficiencia renal crónica permanente. Nefrologia 1994;14 (Supl 1).
2. Selgas R. Calidad y sostenibilidad del tratamiento sustitutivo renal.
Nefrologia 2010 (Suplemento Extraordinario 1).
3. Mc Kindsey and Company. Fundación de estudios de economía aplicada
(FEDEA). Impulsar un cambio posible en el sistema sanitario. Available
at:http://www.cambioposible.es/documentos/sanidad_cambio_posible.pdf
4. Informe de Diálisis y Trasplante del año 2009 perteneciente al Registro Español de Enfermos Renales, realizado por la Sociedad Española
de Nefrología y la Organización Nacional de Trasplantes (página web
SEN website: http://www.senefro.org/modules.php?name=webstructure&idwebstructure=128).
5. Largo F. Oferta pública y privada en el tratamiento sustitutivo de la
IRC en España. Nefrologia 1994;14(Supl 1):36-40.
6. Sánchez Fructuoso A, Prats D, Torrente J, Pérez-Contin, MJ,
Fernández C, Álvarez J, et al. Real transplantation from non-heart
beating donors: a promising alternative to enlarge the donor pool.
J Am Soc Nephrol 2000;11:350-8.
7. Gutiérrez Morlote J. Implicación de los profesionales sanitarios en el
control de gastos. Nefrologia 1994;14(Supl 1):118-33.
8. De Francisco ALM. Debemos considerar el costo efectividad de los
12.
13.
14.
15.
16.
17.
18.
distintos tratamientos al aplicar las recomendaciones sobre los
captores (quelantes) del fosforo? Nefrologia 2008;28(2):129-34.
Tonelli M, Pannu M, Manns B. Oral phosphate binders in patients
with kidney failure. N Engl J Med 2010;362:1312-24.
De Francisco AL, Leidig M, Covic AC, Ketteler M, Benedyk-Lorens
E, Mircescu GM, et al. Evaluation of calcium acetate/magnesium
carbonate as a phosphate binder compared with sevelamer
hydrochloride in haemodialysis patients: a controlled randomized
study (CALMAG study) assessing efficacy and tolerability. Nephrol Dial Transplant 2010 ;25(11):3707-17.
Navaneethan SD, Palmer SC, Vecchio M, Craig JC, Elder GJ, Strippoli GFM. Phosphate binders for preventing and treating bone disease in chronic kidney disease patients. Cochrane Database of
Systematic Reviews 2011;Issue 2.Art. No.: CD006023.
Lorenzo V, Perestelo L, Barroso M, Torres A, Nazco J. Evaluación
económica de la hemodiálisis. Análisis de los componentes del
coste basado en datos individuales. Nefrologia 2010;30(4):40312.
Manuel Molina, comunicación personal.
Murtagh FE, Marsh JE, Donohoe P, Ekbal NJ, Sheerin NS, Harris
FE. Dialysis or not? A comparative survival study of patients over
75 years with chronic kidney disease stage 5. Nephrol Dial Transplant 2007;22(7):1955-62.
Couchoud C, Labeeuw M, Moranne O, Allot V, Esnault V,
French Renal Epidemiology and Information Network (REIN)
registry. A clinical score to predict 6-month prognosis in elderly
patients starting dialysis for end-stage renal disease. Nephrol Dial
Transplant 2009;24(5):1553-61.
Comisión de Análisis y Evaluación del Sistema Nacional de Salud. available
at: http://www.riberasalud.com/ftp/biblio/07102010131536resumen
informe abril.pdf
Observatorio del Medicamento (FEFE). Octubre 2010.
Diez Temas Candentes de la Sanidad Española para 2011. available
at:http://www.pwc.com/es_ES/es/sala-prensa/notas-prensa/2011/
assets/sanidad-espanola-2011-informe.pdf
Sent to review:11 Apr. 2011 | Accepted: 11 Apr. 2011
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Nefrologia 2011;31(3):241-6
editorial comments
See original article on page 286
How to treat corticosteroid-resistant idiopathic focal
segmental glomerulosclerosis?
F. Rivera Hernández
Nephrology Department. General Hospital of Ciudad Real, Spain
Nefrologia 2011;31(3):247-50
INTRODUCTION
Focal segmental glomerulosclerosis (FSGS) is defined as an
increase in the mesangial matrix in some glomeruli with
obliteration of capillary lumens, sclerosis, hyalinosis, foam
cells, and adhesions to the Bowman’s capsule. The damage is
non-specific, and several different causes have been described.
As such, it is essential to distinguish between idiopathic and
secondary forms of the disease (Table 1), since their
pathogenesis, prognosis, and treatment are very different.1
Fortunately, FSGS is an uncommon disease that is found
only in 9% of all kidney biopsies in our country, with stable
rates in recent years. However, it is the third-leading cause of
nephrotic syndrome, preceded only by membranous
nephropathy and minimal change nephropathy.2 Here, we
will only be referring to idiopathic FSGS that presents with
nephrotic syndrome, since this is a major challenge for the
attending physician given the knowledge gaps regarding its
pathogenesis. As with other glomerular diseases, its
treatment must be based on the best evidence available
through controlled clinical trials. However, few studies have
been performed to resolve the current problems with
treatment, and many of them are of poor quality, as reported
by Quereda and Ballarín in an excellent systematic review
published in NEFROLOGÍA in 2007.3 Their conclusions have
not lost their relevance and coincide with the
recommendations soon to be published in the KDIGO
guidelines for the treatment of glomerulonephritis. FSGS is
no exception to this rule of low number and quality of
clinical trials studying glomerular diseases, with even lower
representation than lupus nephritis and membranous
nephropathy.4
Table 1. Causes of focal segmental glomerulosclerosis
INITIAL TREATMENT
Idiopathic or primary disease
Secondary
1. Hereditary (mutations on genes for podocyte proteins)
2. Virus: HIV, parvovirus
3. Medication: heroin, interferon-alpha, lithium, pamidronate
4. Adaptive changes (hyperfiltration)
a. Loss of kidney mass: agenesis, vesicoureteral reflux,
nephrectomy
b. Hypertension, diabetes, obesity, cyanotic cardiopathy
5. Tumours: lymphoma
6. Added to glomerular diseases
a. Focal proliferative glomerulonephritis: IgA, lupus nephritis,
extracapillary proliferative GN
b. Alport’s Syndrome
c. Membranous GN
d. Thrombotic microangiopathy
HIV: Human immunodeficiency virus; GN: glomerulonephritis.
Correspondence: Francisco Rivera Hernández
Sección de Nefrología.
Hospital General de Ciudad Real. Spain.
[email protected]
Patients with idiopathic FSGS that do not develop a
nephrotic syndrome, as well as those with secondary FSGS,
do
not
receive
immunosuppressive
treatment
(recommendation 1C, GRADE system). In these cases, the
standard treatment consists of: 1) maintain blood pressure
below 130/80mm Hg; 2) administer angiotensin-converting
enzyme (ACE) inhibitors, angiotensin II receptor
antagonists, or both; 3) administer statins; 4) administer
antiplatelet or anticoagulation therapy; and 5) diet for renal
protection.5 The initial treatment is based on a prednisone
cycle (1mg/kg/day, maximum of 80mg/day or 2mg/kg/day
on alternate days, maximum of 120mg), which should be
maintained for 16 weeks before the condition is declared
corticosteroid-resistant.6 Treatment with prednisone can
cause remission of the disease in 60%-70% of patients,
according to the studies. These responses depend on the
intensity of the initial proteinuria, the tubular/interstitial
lesions, and the baseline creatinine level, although it is not
possible a priori to separate the patients that will respond to
247
editorial comments
corticosteroid treatment from those that will not. As a rule,
this should not be combined with treatment using other
immunosuppressive drugs, unless there is a risk of toxicity or
intolerance to steroids (obesity, osteoporosis, diabetes,
advanced age, or psychiatric imbalances). If they were to be
used, calcineurin inhibitors are recommended (suggestion 2D),
as will be indicated later when discussing corticosteroidresistant forms of the disease.3 Partial or complete remission of
proteinuria has been associated with a good prognosis, and it is
the most indicative marker of patient evolution, even more than
clinical and histological results.7 Approximately 30%-40% of
patients are corticosteroid-resistant, presenting problems for
developing a treatment plan, since resistance to corticosteroids
is the strongest predictor for the development of chronic kidney
disease: 35% at 5 years and 70% at 10 years. As such, the
current conundrum is: how can we treat idiopathic FSGS that
has not responded to steroids or is corticosteroid-dependent?
Can we modify the patient evolution towards kidney failure?
Here, we will go through the different treatments
recommended in corticosteroid-resistant FSGS according to
the evidence published on the subject (Table 2). Obviously,
each case should be analysed individually, and treated
according to the personal opinion and experience of the
physicians that directly attend to each patient.
F. Rivera Hernández. Corticosteroid-resistant FSGS: treatment
from using tacrolimus (0.15mg/kg/day; levels of 5-10ng/l) and
low-dose steroids (0.15mg/kg/day) in 25 patients with
previous resistance to steroids and CsA. Therefore, its use in
patients that have not responded to CsA is an attractive
treatment option that deserves a try before moving on to other
alternatives. Even so, treatment with calcineurin inhibitors
creates other problems: nephrotoxicity and recurrence after
treatment suspension. The first condition can be avoided by
using the minimum possible dose, monitoring patient levels,
and by performing a kidney biopsy in order to evaluate
vascular and interstitial damage. Recurrence is very common
after reducing the dosage or suspending treatment with this
drug, reaching even 70% in some studies. A study, sponsored
by the GLOSEN (glomerulonephritis study group of the
Spanish Society of Nephrology), has been recently performed
on 5 patients, who were administered calcineurin inhibitors as
an induction therapy, followed by rituximab once remission
was established, with no positive results in avoiding
recurrence after treatment suspension.12 Recurrence is still an
unresolved problem that requires more in-depth studies. On
the other hand, given that approximately 30% of cases do not
respond to calcineurin inhibitors, other treatments have also
been tested.
MYCOPHENOLATE MOFETIL
CALCINEURIN INHIBITORS
Cyclosporin A (CsA) is the best documented method of
treatment in controlled trials and observational studies.3,8 The
recommended dose is 2-5mg/kg/day administered in two
doses (with levels of 125-175ng/ml) during a minimum of 6
months. If at the end of this time there is no response,
treatment must be suspended and the patient should be
considered resistant to CsA. In the case of a partial or
complete response, which appears in 60%-70% of cases,9,10
treatment should be maintained for at least 12 months, and can
then be progressively reduced by 25% every 2 months.
Approximately half of all patients that initially respond to CsA
develop resistance eventually. Fewer studies exist regarding
the use of tacrolimus in the treatment of corticosteroidresistant FSGS, but Segarra et al11 obtained positive results
Table 2. Treatments for idiopathic focal segmental
glomerulosclerosis patients with nephrotic syndrome
1. Initial: steroids or calcineurin inhibitors + steroids at low doses
2. Corticosteroid-resistant disease:
a) Calcineurin inhibitors (cyclosporin or tacrolimus)
b) Mycophenolate mofetil
c) Rituximab
d) Alkylating agents (cyclophosphamide or chlorambucil)
e) Combined treatments
- Tacrolimus and rituximab
- Cyclosporin A and mycophenolate mofetil
248
Experience with this drug is scarce,6 with an approximately
44% of cases showing a partial response, but half of these
patients suffer a recurrence when medication is suspended.7
This is an option when other immunosuppressive drugs
cannot be administered, or when steroid dosage must be
decreased (suggestion 2C).
RITUXIMAB
In a recent study that was also sponsored by GLOSEN,13
involving 8 patients with FSGS resistant to other drug
treatments, rituximab had a positive effect in only 3 cases,
making it an unattractive alternative, at least as a
monotherapy. Therefore, controlled studies are needed,8 but
it still can provide an alternative when nephrotoxicity
develops due to the administration of calcineurin inhibitors.14
ALKYLATING AGENTS
Some experience has been gained in the administration of
cyclophosphamide and chlorambucil, as they were used
before the advent of calcineurin inhibitors. However, they
only produce a complete response in 20% of cases, and a
partial response in 45%. These results, along with the
adverse effects (infections, tumours, leukopenia, infertility),
have severely reduced the role of these drugs,9 with
insufficient evidence to support their use.6,15,16
Nefrologia 2011;31(3):247-50
COMBINED TREATMENTS
Given the limitations presented by the previous drug
treatments, some authors have incorporated the concept of
synergistic effects of immunosuppressive drugs (taken from
the experience gained in transplantations) into the treatment
of glomerular diseases. In this issue of Nefrología, Segarra et
al17 have published on their experience in treating primary
FSGS in 27 adult patients with previously failed treatment
plans using steroids and CsA, combining CsA (4mg/kg/day)
with mycophenolate mofetil (2000mg/day) for 12 months.
This was an observational study with no controls, and it
produced disappointing results. None of the patients in this
study reached complete remission of the disease, and only
one fourth partial remission. Additionally, the glomerular
filtration rate was significantly reduced in all patients, and
59% of cases developed uraemia at the end of the 5-year
follow-up period, which is a similar result to that achieved
by treating patients symptomatically. Lastly, the authors used
a multivariate analysis to show that initial glomerular
filtration rates and mean proteinuria during the follow-up
period were correlated with renal impairment. El-Reshaid et
al18 had already tested a similar combined treatment, with
somewhat better results, but in patients without previous
failure of CsA treatment. The role that this three-part
association may play in the treatment of idiopathic FSGS
resistant to steroids and CsA is still unclear. Although the
authors did not perform a genetic analysis, it is quite
probable that the hereditary forms of the disease were not
present in the study, since the necessary genetic mutations
editorial comments
(NPHS1, NPHS2, alpha-actinin-4, CD2P, TRPC-6 and
others) are very rare in adults.19 With these results, the triple
therapy using steroids, CsA, and mycophenolate mofetil
appears not to decrease proteinuria or slow the development
of kidney disease.
Although the treatment of corticosteroid-resistant idiopathic
FSGS is still an unresolved issue, we must not be
pessimistic. Several different clinical trials have been
initiated20,21 that may help to improve the current results. As
the KDIGO guidelines will state, more controlled clinical
trials are needed to compare the efficacy of calcineurin
inhibitors, mycophenolate mofetil, rituximab, and alkylating
agents in treating corticosteroid-resistant FSGS. Lastly, we
must re-evaluate the use of our current arsenal of
immunosuppressive drugs, whose mechanisms of action are
still unknown and are mostly empirical.22 According to a
recent review by Meyrier,23 the factor or factors that lead to
an increase in capillary permeability must be identified in
order to treat these patients accordingly.
In conclusion, the treatment of idiopathic FSGS patients
with nephrotic syndrome is still unresolved, and clinicians
are faced with a challenge in producing some type of
response in the patient and slowing or halting the
evolution towards kidney failure. In spite of the negative
results obtained by the excellent study by Segarra et al, 17
which inspired this “Editorial Comment,” we must
continue to research ways to improve the current
unsatisfactory results.
KEY CONCEPTS
1. FSGS is a non-specific glomerular lesion that is
classified as idiopathic (primary) or secondary.
not respond to treatment can benefit from the
administration of tacrolimus.
2. Patients with idiopathic FSGS that do not develop nephrotic syndrome and cases of secondary FSGS should not be treated using steroids
or immunosuppressive drugs.
5. Mycophenolate mofetil and rituximab can be
effective alternatives in the case of resistance
to CsA, although little evidence exists.
3. Idiopathic FSGS patients with nephrotic
syndrome should be initially treated with a
cycle of steroids (or steroids and CsA in the case
of intolerance to high levels of steroids) for a
minimum of 4 weeks and a maximum of 16 weeks.
4. Patients with corticosteroid-resistant FSGS
should be treated using CsA and low doses of
steroids for at least 6 months, monitoring blood levels and nephrotoxicity. Patients that do
Nefrologia 2011;31(3):247-50
6. Alkylating agents (cyclophosphamide and chlorambucil) are only barely indicated and their
use is not recommended, except for in very severe cases of dependence on corticosteroids.
7. Until now, combined treatments have not produced any positive results.
8. New treatments are needed based on controlled clinical trials that can induce a response in
proteinuria and avoid the evolution of the disease towards kidney failure.
249
editorial comments
REFERENCES
1. D’Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrology 2003;23:117-34.
2. Registro de Glomerulonefritis de la S.E.N. (Accessed 15/4/2011,
available at http://www.senefro.org/modules.php?name=webstructure&idwebstructure=130.)
3. Quereda C, Ballarín J. Síndrome nefrótico por glomerulosclerosis focal segmentaria del adulto. Nefrologia 2007;27 (Supl 2):56-69.
4. Leaf DE, Appel GB, Radhakrishnan J. Glomerular disease: why is there a dearth of high quality clinical trials? Kidney Int 2010;78:33742.
5. Appel AS, D’Agati VD. Primary and secondary (non-genetic) causes
of focal and segmental glomerulosclerosis. In: Floege J, Johnson RJ,
Feehally J, eds. Comprehensive clinical nephrology (4th ed.). St.
Louis: Elsevier Saunders; 2010:228-40.
6. Meyrier A. Management of idiopathic nephrotic syndrome in adults:
minimal change disease and focal segmental glomerulosclerosis. In:
Molony DA, Craig JC, eds. Evidence-based nephrology (4th ed.). Oxford: Wiley-Blackwell; 2009:149-57.
7. Appel AS, Cattran DC. Treatment of focal segmental glomerulosclerosis. UpToDate 2011.
8. Meyrier A. An update on the treatment options for focal segmental
glomerulosclerosis. Expert Opin Pharmacother 2009;10:615-28.
9. Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, et
al. Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. Cochrane database of systematic reviews
2008:CD003233.
10. Cattran DC, Appel GB, Hebert LA, Hunsicker L, Pohl M, Hoy W, et al.
A randomized trial of cyclosporine in patients with steroid-resistant
focal segmental glomerulosclerosis. Kidney Int 1999;56:2220-6.
11. Segarra A, Vila J, Pou L. Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal
glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up. NDT 2002;17:655-62.
12. Gutiérrez-Solís E, Rivera F, Morales E, Caro J, Gutiérrez-Martínez E, Praga M. Tratamiento secuencial tacrolimus-rituximab en el síndrome nefrótico corticorresistente [abstract]. Nefrologia 2010;30 (Supl 1):11.
13. Fernández-Fresnedo G, Segarra A, González E. Rituximab treatment
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
of adult patients with steroid-resistant focal segmental glomerulosclerosis. CJASN 2009;4:1317-23.
Gulati A, Sinha A, Jordan SC. Efficacy and safety of treatment
with rituximab for difficult steroid-resistant and -dependent
nephrotic syndrome: multicentric report. CJASN 2010;5:220712.
Heering P, Braun N, Mullejans R. Cyclosporine A and chlorambucil
in the treatment of idiopathic focal segmental glomerulosclerosis.
American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation 2004;43:10-8.
Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W.
Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft fur Padiatrische Nephrologie. Pediatr Nephrol 2008;23:1483-93.
Segarra A, Vila J, Pou L, Majó J, Camos J. Eficacia y seguridad del
tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomerulosclerosis segmentaria y focal ciclosporina-resistente. Nefrologia 2011;31:286-91.
El-Reshaid K, El-Reshaid W, Madda J. Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis. Renal Failure
2005;27:523-30.
Nachman PH, Glassock RJ. Vascular, glomerular and interstitial diseases. Focal and segmental glomerulosclerosis (adquired and hereditary). NephSAP 2010;9:126-33.
Focal Segmental Glomerulosclerosis Clinical Trial (FSGS-CT). NCT00135811.
2011.
(Accessed
16/4/2011,
available
at
http://clinicaltrials
.gov/ct2/show/study/NCT00135811.)
Trachtman H, Vento S, Gibson D. Novel therapies for resistant focal
segmental glomerulosclerosis (FONT) phase II clinical trial: study design. BMC Nephrology 2011;12:8.
Ponticelli CE, Glassock RJ. Treatment of focal segmental glomerulosclerosis. Kidney Int 2010;77:259 [author reply].
Meyrier AY. Treatment of focal segmental glomerulosclerosis with
immunophilin modulation: when did we stop thinking about pathogenesis? Kidney Int 2009;76:487-91.
Sent for review: 19 Abr. 2011 | | Accepted: 25 Abr. 2011
250
Nefrologia 2011;31(3):247-50
editorial comments
The role of mTOR inhibitors in renal diseases
Nephrology Department. Dr. Negrín University Hospital, Las Palmas de Gran Canaria, Spain
Nefrologia 2011;31(3):251-5
INTRODUCTION
Signal transduction in different types of cells often
involves conditional or constitutive activation of
receptor tyrosine kinases, which trigger multiple
cytoplasmic kinases. Such signalling pathways can
operate independently, in parallel, and/or through
interconnections that promote different diseases to
develop. The most important signalling pathways are
phosphatidylinositol 3-kinase (PI3K), protein kinase C
(PKC)
and
mitogen-activated
protein
kinase
(MAPK)/Ras. 1
mTOR PROTEIN
mTOR (Mammalian Target of Rapamycin) is a 289-kDa
serine/threonine protein kinase. The TOR family of proteins
has pleiotropic functions, and participates in the regulation
of the initiation of mRNA transcription and protein
translation in response to intracellular concentrations of
amino acids (AA) and other essential nutrients. It is involved
in the organisation of actin cytoskeleton, membrane
trafficking, protein degradation, PKC signalling and
ribosome biogenesis. mTOR regulates essential signalling
pathways and is involved in coupling growth stimuli and
cell-cycle progression.
There are two complexes that contain mTOR: a rapamycinsensitive complex (mTORC1), which is defined by its
interaction with the protein raptor (regulatory-associated
protein of mTOR), and a rapamycin-insensitive complex
(mTORC2), defined by its interaction with rictor
Correspondence: José Carlos Rodríguez Pérez
Servicio de Nefrología.
Hospital Universitario de Gran Canaria Dr. Negrín.
Bco. La Ballena, s/n. 35010. Las Palmas de Gran Canaria. Spain.
[email protected]
(rapamycin-insensitive companion of mTOR). mTOR is a
key kinase which acts downstream of the activation of PI3K.
Much evidence supports the hypothesis that mTOR is the
key for cellular catabolism and anabolism, determining
whether cells, and in particular carcinogenic cells, grow and
proliferate. Furthermore, mTOR regulates apoptosis.
mTOR, in the shape of the two signalling complexes,
cited as mTORC1 and mTORC2 with their two different
proteins, raptor and rictor, establish two different mTOR
pathways. The raptor-mTOR pathway (mTORC1)
regulates cellular growth (cellular mass accumulation)
and proliferation through P70S6K and 4E-BP. It
responds to nutrients and growth factors, partly due to
regulators like TSC1/TSC2 (tuberous sclerosis complex
1: hamartin; tuberous sclerosis complex 2: tuberin) and
Rheb (a Ras family GTPase). mTOR (mTORC1) is
phosphorylated by AKT (also called protein kinase BPKB) through inactivation of the tuberous sclerosis
complex (TSC) and is directly activated by Rheb.2,3
The rictor-mTOR (mTORC2) complex regulates
AKT/PKB, PKCα, Rho/rac, to control cell polarity and
the cytoskeleton. Growth factors and AA activate AKT
and mTOR through PI3K.1
There are transcription factors that could be activated or
inhibited through AKT phosphorylation. AKT activates the
NF-kB transcription factor, which increases the transcription
of antiapoptotic genes. The NF-kB transcription factor is the
central mediator of the immune response, inflammatory
response and cell survival response. Following its activation,
IKK phosphorylates IkB, resulting in their ubiquitination and
degradation in the proteasome. This exposes the NF-kB
nuclear localisation sites and allows it to translocate to the
nucleus to induce antiapoptotic gene expression. Growth
factors, such as the vascular endothelial growth factor
(VEGF), activate NF-kB and protect against apoptosis. On
the other hand, NF-kB inhibition sensitises the cell to a wide
variety of proapoptotic stimuli.3
251
editorial comments
ROLE OF mTOR IN ACUTE RENAL FAILURE
Regeneration and restoration of the morphology and renal
function partly depends on the capacity of the remaining
viable kidney tubule cells to proliferate and restore the
damaged epithelium.4 mTOR is an ubiquitous kinase and its
inhibition by rapamycin also blocks proliferation, including
cells in the kidney.5 mTOR plays an important role in the
regeneration and repair process following an experimental
acute kidney injury. The mTOR activity is low or absent in
the normal kidney, but increases significantly following an
ischaemia-reperfusion process. Inhibition of mTOR by
rapamycin delays renal recovery-repair.5
ROLE OF mTOR IN CHRONIC KIDNEY DISEASE
The mTOR pathway plays an important role in the
mechanisms that are involved in chronic kidney disease
(CKD) progression caused by diabetes, for instance.
Rapamycin reduces interstitial inflammation, fibrosis and
loss of kidney function associated with CKD progression.
Several studies have shown why it is important for mTOR to
be activated in physiological and pathological forms of renal
hypertrophy and other organs, including hypertrophy of the
diabetic nephropathy (DN).6 This phenomenon contributes to
podocyte damage and progressive loss of renal function.7
Furthermore, upon mTOR activation, an increase in matrix
protein synthesis will contribute to glomerular basement
membrane thickening and the accumulation of the mesangial
matrix, which are characteristic of DN.8 mTOR activation in
diabetes is, at least, partly caused by hyperglycaemia via
AKT activation.8 Rapamycin has not only reduced mTOR
activity in in vivo models, but it has also reduced the
characteristic DN changes mentioned above, and it is
associated with a reduction in albuminuria.9
Similar phenomena can be observed in non-diabetic CKD,
with an increase in the proinflammatory and profibrotic
cytokine expression, interstitial inflammatory cell infiltration
and renal fibrosis.10 Rapamycin treatment for membranous
glomerulonephritis in rat models reduces all of these
phenomena.11
ROLE OF mTOR IN AUTOSOMAL DOMINANT
POLYCYSTIC KIDNEY DISEASE
Autosomal dominant polycystic kidney disease (ADPKD) is
a genetic disease characterised by the formation of multiple
cysts within the renal parenchyma, which results in renal
failure. It affects up to one case in every 400-1000
newborns. ADPKD is related to PKD1 and PKD2 gene
mutations, which are located in chromosomes 16 and 4,
respectively. The PKD1 gene codes for the transmembrane
252
J.C. Rodríguez Pérez. The role of mTOR inhibitors in renal diseases
protein polycystin-1 (PC1). It has been reported that this
protein is involved in cell-cell adhesion, cell-matrix
adhesion, transduction of intracellular signals and
polycystin-2 regulation (PC2), as the PKD2 gene codes for
the PC2 protein, which is a calcium channel.2,12 The PC1 and
PC2 complex is essential for maintaining the physiological
phenotype of the tubular epithelial cells.
The polycystin protein complexes are fundamental for
maintaining intracellular calcium homeostasis. All renal
tubular epithelial cells (except the interspersed ones) were
recently found to have a single primary cilium which has
mechanoreceptor and chemoreceptor functions. Stimulation
of these cilia increases the intracellular calcium through the
PC1 and PC2 complex. Intracellular calcium controls many
of the cellular processes, such as proliferation. Therefore,
drugs that reduce cyclic adenosine monophosphate (cAMP)
or which increase intracellular calcium could treat ADPKD.
Calcium is also involved in signalling pathways related
with growth factors, activating signalling cascades for
some protein kinases. Alongside this, PC1 regulates the
mTOR activity (loss of PC1 activity in ADPKD allows
significant mTOR activity inside the cyst epithelial cells in
mouse and human models), which would be a therapeutic
target.2,13
RAPAMYCIN DEVELOPMENT
Rapamycin is also called sirolimus; it is a natural antibiotic
synthesised by S. hygroscopicus. This bacterium was
discovered 30 years ago in earth from Easter Island, Rapa
Nui, which is where the name rapamycin came from. It is a
lactone initially developed as an antifungal agent. In its
purest form, it resembles a white crystalline powder,
insoluble in an aqueous solution, but soluble in organic
solvents. The chemical structure is shown in Figure 1.
Between 1982 and 1988, rapamycin was developed as an
immunosuppressive agent. Thanks to these studies, the
mechanism of action of this molecule was clarified.
Rapamycin interacts with the immunophilin FK506
binding protein (FKBP12) through its methoxy group.
The rapamycin-FKBP12 complex is specifically bound to
the mTOR protein, inhibiting the effector signalling
pathways dependent on said protein.14 Rapamycin inhibits
antigen-induced T cell proliferation and the cytokineinduced proliferative responses, including interleukin-16
(IL-16), immunoglobulin growth factor (IGF), etc. It
follows the cytochrome CYP450 3A4 pathway as the
main system responsible for drug biotransformation,
generating inactive metabolites.
A high level of synergism has been shown for this drug with
cyclosporin,15 both in vivo and in vitro. As such, the dosage
for effective immunosuppression is reduced, decreasing the
Nefrologia 2011;31(3):251-5
editorial comments
proliferation by rapamycin includes, among others, the
binding to protein FKBP12.
FKBP12
binding site
mTOR
binding site
Mod. Biocancer.com
Figure 1. Chemical structure of rapamycin.
probability of kidney graft rejection and minimising
cyclosporine-induced toxicity.16
An important aspect of rapamycin as an immunosuppressant
is that it does not produce secondary effects on renal
haemodynamics. Treatment with rapamycin maintains
glomerular filtration and the renal blood flow both for
normal rats and rats with salt depletion or spontaneous
hypertension.17 The renal tissue seems to be protected during
rapamycin treatment by an inhibition of the intrarenal
angiotensin II cascade. However, rapamycin does produce a
dose-dependent tubular toxicity in rats (including
hypercalcaemia and hypophosphataemia), a phenomenon
linked to delayed recovery of the tubular epithelial function
after injury.18
Rapamycin was approved by the US Food and Drug
Administration (FDA) in 1999 as a preventative
treatment of acute rejection in combination with
cyclosporine and steroids. A year later, the drug was
approved by the European Medicines Agency (EMEA)
as an alternative to calcineurin antagonists in long-term
treatment to prevent graft rejection. Rapamycin, unlike
cyclosporine, does not seem to increase the risk of
malignancy, but reduces the risk of lymphoproliferative
processes after transplantation (reducing AKT levels).
However, rapamycin increases CsA side effects: high
blood pressure, acne and hirsutism and has been
associated with mild secondary effects such as
diarrhoea, tachycardia, oedemas, dyslipidaemia and noninfectious pneumonitis.
In addition to its immunosuppressant capability, rapamycin
has been proven to act as a preventative agent on restenosis
of the coronary arteries.19 The hypothetical mechanism
responsible for the inhibition of vascular smooth muscle cell
Nefrologia 2011;31(3):251-5
In another article published in this issue, Dr Cabrera et al20
discuss the results of rapamycin treatment on the evolution
of angiomyolipomas in a substantial number of patients
suffering from tuberous sclerosis (TS) or PringleBourneville disease (this number is considerable taking into
account the prevalence of the disease).
The TS complex is a systemic disease, which is an
autosomal dominant genetic disorder with a prevalence of
one case for every 6000 live births.21 It is characterised by
benign tumours (hamartomas) in multiple organs and
systems, including brain, skin, kidney, lungs, heart and
retina. Angiomyolipomas are tumours rich in adipose tissue,
muscle and blood vessels that may bleed or infiltrate the
kidneys causing deterioration of kidney function for up to
80% of patients.22
Mutations that may occur in any of the two TS genes, TSC1
(hamartin) or TSC2 (tuberin) is above 85% for TS patients.23
Proteins coded by these two genes form a tumoursuppressive complex, acting through Ras homolog enriched
brain protein (Rheb), which limits mTOR activation
(mTORC1). When TSC1 or TSC2 are deficient, mTORC1 is
overexpressed constitutively, provoking cellular growth,
proliferation and abnormally high protein synthesis.24
The clinical trial in phase 4 which the above mentioned
authors present,20 shows a significant reduction in the
volume of angiomyolipomas after as little as six months of
rapamycin treatment (55.1% average), reaching a reduction
of 66.3% at 12 months. The reduction of volume of
angiomyolipomas seems to be due to the effect of mTOR
inhibition and its effect on VEGF. Another interesting point
that these authors document in this paper is the possibility of
reducing the rapamycin dose once the peak reduction of the
angiomyolipomas volume has been achieved, seemingly
being at between 12 and 24 months.20,25 However, the
treatment must not be withdrawn as that would promote
tumour regrowth.25,26 Whether the effect of rapamycin would
be the same in any type of angiomyolipoma is still unknown,
depending on its size and location (unilateral or bilateral).
Furthermore, as there are no genetic studies, we are still
unaware if the rapamycin response varies depending on
whether it is located in TSC1 or TSC2, given that the
phenotype may be different.
Only one patient was excluded before 12 months due to
reactivation of an erythema nodosum. No changes were found
in renal function, as rapamycin plasma levels were maintained
constant. Despite the adverse effects cited in the medical
literature,25 the authors found a higher incidence of oral aphtae
and dyslipidemia.20 Furthermore, facial angiofibromas in these
patients are smaller and not as relevant.
253
editorial comments
There are very few data in the literature on this matter, and
those found are isolated and based on some clinical cases26
and a trial published in the New England Journal of
Medicine with 25 patients, of which only 20 completed the
12-month follow-up period.25 None of these references
presented genetic studies. Nevertheless, as the authors cited
in their article,20 there are several studies being developed in
the United States and Europe.
Rapamycin, through mTOR inhibition, is an alternative therapy
for this disease. More studies are needed to define the risks and
benefits of long-term rapamycin treatment for this type of
genetic disorder, its use as a monotherapy or in combination,
and considering location and size of the angiomyolipomas.
REFERENCES
1. Pérez Machín R, Rodríguez Díaz Y, Vega Hernández MC. La ruta
mTOR como diana terapéutica. BioCancer 2006;3.
2. Masoumi A, Reed Gitomer B, Kelleher C, Schrier RW. Potential
pharmacological interventions in polycystic kidney disease. Drugs
2007;67:2495-510.
3. Lieberthal W, Levine JS. The role of the mammalian target of
rapamycin (mTOR) in renal disease. J Am Soc Nephrol
2009;20:2493-502.
4. Bonventre JV. Dedifferentiation and proliferation of surviving epithelial
cells in acute renal failure. J Am Soc Nephrol 2003;14(Suppl 1):S55-S61.
5. Lieberthal W, Fuhro R, Andry CC, Rennke H, Abernathy VE, Koh JS,
et al. Rapamycin impairs recovery from acute renal failure: role of
cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal
Physiol 2001;281:F693-F706.
6. Lee CH, Inoki K, Guan KL. mTOR pathway as a target in tissue
hypertrophy. Annu Rev Pharmacol Toxicol 2007;47:443-67.
7. Hostetter TH. Hyperfiltration and glomerulosclerosis. Semin Nephrol
2003;23:194-9.
8. Kasinath BS, Mariappan MM, Sataranatarajan K, Lee MJ, Feliers
D. mRNA translation: Unexplored territory in renal science. J
Am Soc Nephrol 2006;17:3281-92.
9. Lloberas N, Cruzado JM, Franquesa M, Herrero-Fresneda I,
Torras J, Alperovich G, et al. Mammalian target of rapamycin
pathway blockade slows progression of diabetic kidney disease
in rats. J Am Soc Nephrol 2006;17:1395-404.
10. Eddy AA, Neilson EG. Chronic kidney disease progression. J Am
Soc Nephrol 2006;17:2964-6.
11. Bonegio RG, Fuhro R, Wang Z, Valeri CR, Andry C, Salant DJ, et al.
Rapamycin ameliorates proteinuria-associated tubulointerstitial
inflammation and fibrosis in experimental membranous
nephropathy. J Am Soc Nephrol 2005;16:2063-72.
12. Aguiari G, Trimi V, Bogo M, Mangolini A, Szabadkai G, Pinton P, et
al. Novel role for polycystin-1 in modulating cell proliferation
through calcium oscillations in kidney cells. Cell Prolif 2008;
41:554-73.
13. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R,
Brown N, et al. The mTOR pathway is regulated by polycystin1, and its inhibition reverses renal cystogenesis in polycystic
kidney disease. Proc Natl Acad Sci USA 2006;103:5466-71.
14. Baker H, Sidorowicz A, Sehgal SN, Vezina C. Rapamycin (AY22,989), a new antifungal antibiotic. III. In vitro and in vivo
evaluation. J Antibiot (Tokyo) 1978;31:539-45.
15. Davies CB, Madden RL, Alexander JW. Effect of a short course
of rapamycin, cyclosporin A, and donor-specific transfusion on
rat cardiac allograft survival. Transplantation 1993;55:1107-12.
16. Trepanier DJ, Gallant H, Legatt DF, Yatscoff RW. Rapamycin:
distribution, pharmacokinetics and therapeutic range
investigations: an update. Clin Biochem 1998;31:345-51.
17. DiJoseph JF, Mihatsch MJ, Sehgal SN. Renal effects of
rapamycin in the spontaneously hypertensive rat. Transpl Int
1994;7:83-8.
18. Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett
WM. Comparison of acute rapamycin nephrotoxicity with
cyclosporine and FK506. Kidney Int 1996;50:1110-7.
KEY CONCEPTS
1. mTOR is an important modulator of several
types of kidney diseases.
in chronic kidney diseases, reducing their
progression.
2. mTOR is activated following acute kidney damage and contributes to renal regeneration and
repair. Rapamycin can delay renal recovery and
repair.
5. When used as a monotherapy, rapamycin can be an
alternative therapy for preventing the growth of
kidney angiomyolipomas in tuberous sclerosis and
delay/prevent renal failure. Possible adverse effects
of rapamycin must be taken into consideration.
3. mTOR plays an important role in the formation
and growth of cysts in ADPKD.
4. Rapamycin may, through different mechanisms,
delay the reduction of glomerular filtration
254
6. Although intervention on the mTOR complex
in progression of chronic kidney diseases may
seem straightforward, more studies must be
performed to establish this interconnection.
Nefrologia 2011;31(3):251-5
19. Sousa JE, Sousa AG, Costa MA, Abizaid AC, Feres F. Use of
rapamycin-impregnated stents in coronary arteries. Transplant Proc
2003;35:165S-170S.
20. Cabrera López C, Martí T, Catalá V, Torres F, Mateu S, Ballarín
Castán J, et al. Efectos de la rapamicina en los angiomiolipomas de
pacientes con esclerosis tuberosa. Nefrologia 2011;31(3):292-8.
21. Krueger DA, Franz DN. Current Management of tuberous sclerosis
complex. Paediatr Drugs 2008;10:299-313.
22. Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int
2004;66:924-34.
23. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis
editorial comments
complex. N Engl J Med 2006;355:1345-56.
24. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular
switchboard controlling cell growth. Biochem J 2008;412:179-90.
25. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard
JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis
complex or lymphangioleiomyomatosis. N Engl J Med 2008;
358:140-51.
26. Wienecke R, Facler I, Linsenmaier U, Mayer K, Licht T, Kretzler M.
Antitumoral activity of rapamycin in renal angiomyolipoma
associated with tuberous sclerosis complex. Am J Kidney Dis
2006;48:E27-E29.
Sent for review: 26 Apr. 2011 | Accepted: 26 Apr. 2011
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editorial comments
Establishing and controlling chronic renal failure
treatment costs. A pressing need
R. Martín Hernández
Nephrology Department. San Carlos Clinical Hospital. Madrid, Spain
Nefrologia 2011;31(3):256-9
doi:10.3265/Nefrologia.pre2011.May.10959
INTRODUCTION
Chronic renal failure (CRF) is currently one of the main problems of public heath in Western countries due to its high
prevalence and high social and economic costs. From the data
published in the last report of the Registro Español de Enfermos Renales (Spanish Registry of Renal Patients) for 2009,1
we can see that around 48600 CRF patients (0.1%) are currently alive in Spain thanks to different methods of renal replacement therapy. This represents a prevalence of 1039 cases per million population (pmp), with a growth of 1.6% in the
last year. Around 6000 patients start renal replacement therapy every year, with an incidence of 129 new patients pmp.
Both of these figures are at the middle-upper end of the countries surrounding Spain. In Spain, incidence has remained stable for the last five years and prevalence has increased by
1.6% in the last year and a little higher in previous years;
however, there are significant differences between the different Autonomous Communities of Spain. The Registry shows
that 47% of CRF patients (23000 patients) are undergoing
haemodialysis (HD), 6% (2350) peritoneal dialysis (PD) and
47% (23000) have a functioning kidney transplant (KT).
There are also large differences in these figures between the
different Autonomous Communities.
END-STAGE RENAL FAILURE TREATMENT COSTS IN
SPAIN
Although the actual cost of CRF replacement therapy is unknown in Spain (there are large differences in the articles
published),2,3 it is estimated that it makes up between 1.6%
and 2.5% of total healthcare costs. Villa estimated the total
Correspondencia: Roberto Martín Hernández
Hospital Clínico San Carlos. Madrid. Spain.
[email protected]
256
cost to be 1400 million Euros in a recent publication in
Nephrol Dial Traspant: 73% of this cost was for HD, 6% for
PD and 31% for KT.4 The annual increase in costs is also unknown, although the introduction of highly expensive new
drugs in dialysis and transplantation, new solutions in PD,
new HD and PD techniques and the tendency in recent years
to increase the frequency of dialysis sessions in certain patients or to implement HD sessions daily, must have led to a
large increase recently.
Public or reference hospitals (PH) provide approximately
40% of HD services in Spain and private hospitals that provide services for patients referred from the Spanish National
Health System (PCNHS) provide 60% of HD. The hospitals
also take on the care costs of all patient complications, hospitalisation, the execution and maintenance of the vascular
access, and the administration of erythropoietin (EPO) and
other drugs for all the patients being treated.
Some articles have been published in Spain with interesting
data and conclusions with regard to CRF treatment costs, although not with the frequency that one would expect for such
a costly issue. These articles are becoming more frequent at
the present time: a period of crisis and cuts in the healthcare
system. In this way, 16 articles on costs have been published
in NEFROLOGÍA since 1994, three of them in the last few
months.5-13
However, it does not seem as if this analysis has sparked
much interest amongst nephrologists, as the subject of CRF
treatment costs is notable for its absence in the Masters programmes, postgraduate certificate courses, general or monographic congresses or conferences, or in training for the speciality itself. Also, as Rodríguez Carmona already stated in
2007, it has hardly had any impact on our clinical practice.5
Healthcare planners, managers and administrators do not
seem to prioritise improving efficiency in CRF treatment
when planning and providing resources for treating CRF.
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R. Martín Hernández. CRF treatment costs
We have two examples of this in the Autonomous Community of Madrid, where they chose to increase hospital
haemodialysis (HHD), which is the least efficient method,
creating macro-units in new hospitals. Another example is
the differences in the rates for the same service in the
agreements with private hospitals in the different Autonomous Communities. These differences can exceed 45%
between some communities.
Analysis carried out on cost articles published and reports
prepared by the Evaluation Agencies in Spain14,15 highlights
how difficult it is to draw conclusions from studies based on
theoretical models with different cost allocation regimes and
methodologies. Furthermore, many of them are estimates,
and/or studies that base their data and calculations on those
provided in previous publications, some of which are old
and/or are based on consultancy databases or the rates of the
Autonomous Communities, which are not actual costs.
Meanwhile, although these are not actual costs, the studies
comparing different techniques, especially in PD and HD
outsourced to private hospitals, which have known rates justifying a large part of their costs, do seem to be more valuable. HHD is the hardest method to analyse given that each
department and unit is managed separately, the number and
type of techniques used and the different structural costs.
Considering the above mentioned limitations, the following
deductions can be made from analysing articles and reports
published in Spain, especially in the last few years, and the
data of some publications from other countries16,17:
KT is the most efficient therapeutic option and the cheapest
from the second year. Furthermore, it offers the patients a
higher quality of life. It is necessary to update the costs of
some very old studies in Spain18-20 due to the use of new immunosuppressive drugs with very high costs, the results with
the current type of donations and the need to use other drugs
in many patients, such as EPO and antiviral drugs. It is crucial that the actual costs of KT are known in the country
where the transplants are performed so that the results and
efficiency of the different transplant teams can be compared
and resources optimised, among other reasons.
PD, in any of its forms, is a more economical therapeutic option than HHD.3,4 PD costs less than HD outsourced to a private hospital, according to current rates; however, it may
have a higher cost in automatic peritoneal dialysis (APD)
and when special, more expensive liquids are used for the
exchanges. Moreover, these regimes are becoming increasingly more wide-spread in daily medical practice.
With regard to the costs of HD, HHD is the most expensive
treatment method. It costs between 25% and 48% more than
the rate for HD outsourced to private centres, according to
different studies.2-4
Nefrologia 2011;31(3):256-9
editorial comments
COMPARING AND ANALYSING THE COSTS OF
HAEMODIALYSIS
The publication of the study by Parra Moncasi and other
members of the Quality Management Group of the Spanish
Society of Nephrology (S.E.N.) in this issue of the Journal,21
which is the reason for this Editorial comment, provides new
interesting data on the costs of HD. It is a pioneering,
prospective and descriptive study that was financed by public funds. It analysed for the first time in Spain the actual
costs allocated using analytical accounting in six hospitals
(two PH and four PCNHS).
The article shows, in contrast to what had been previously
thought in other publications,5 that there were no significant
differences in age, time on dialysis, Charlson comorbidity index or dialysis techniques between the PH and the PCNHS.
Clinical results and quality indicators were not analysed,
which according to the authors will be looked at in a later
study, although we can assume that they will be analysed in
a similar way. It is worth remembering that a lot more PCNHS have external quality accreditation than PH do in Spain.
With the limitations that the authors themselves recognise,
the study reported that the cost per session in PH was 30%
higher than in PCNHS (€257 compared to €198). As the authors state, these differences are due to the higher staffing
(67%) and consumables (83%) costs in PH. There are smaller differences in other items, such as drug consumption,
maintenance management, etc., and others which are difficult
to explain, such as the higher costs of outpatient pharmacy
and transport in two of the PCNHS.
With regard to staffing costs, the differences are not due to
higher wages in PH as shown in Table 4 of the article, which
are equal or lower in overall wages as well as price per hour
compared to PCNHS. They, therefore, must be explained by
a less efficient organisation of the PH units and lower staff
productivity rate (no. of patients seen to or sessions by each
member of staff during their working day).
The productivity rate highlighted in the article using number of sessions/12 hours was 46% lower for doctors, 46%
for nurses and 49% for nursing auxiliaries in PH. If we calculate the staff/session cost, productivity would also be lower in PH: 34% for doctors, 100% for nurses and 99% for
nurse assistants.
These differences in productivity can be explained by the differences in the ratios of staff per patient or station between
PH and PCNHS. The S.E.N., in the Guidelines for dialysis
centres,22 recommends ratios of 40-50 patients per nephrologist, 4-5 stations in operation per nurse and 8-10 per nurse assistant. Some Autonomous Communities, such as the Autonomous Community of Madrid,23 have established 4
stations per nurse or 8 per nurse assistant under their legisla257
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editorial comments
tion. This means that, in the best case scenario, we can
achieve an actual ratio of 3-3.5 sessions per nurse and 6-7
sessions per nurse assistant, and 4-4.5 actual sessions per
nurse and 8-9 per nurse assistant if 5 and 10 sessions are
scheduled for the nurse and nurse assistant. It is impossible
to improve these ratios, especially in small units, as a result
of deaths, transplants, admissions and the fact that patients
start on dialysis when they need it and not when there is a station free.
has been made for a set length of time, and the introduction
of new products in several protocols. Also, as De Francisco24
stated in 2004, the financing of continuous training of
nephrologists by the pharmaceutical and dialysis industry
must be another factor that increases the costs of consumables
for PH. This financing, without a doubt, must have grown
over the last few years with the rise in congresses, conferences, general, local and monographic courses of all types.
The PCNHS do this on a much lower scale.
The other factor that, in our opinion, has an effect on the difference in staffing costs between the two types of hospitals is
the organisation of the unit. In general, PCNHS schedule
three HD sessions in a 14-15 hour day, while many PH schedule one HD session of 5 hours for a 7-hour day. Therefore,
28% of nursing staff’s day is unproductive.
Lastly, the study also highlights that other costs such as
equipment maintenance, management, food, waste products,
etc., which make up between 12% and 14% of the total, are
also 19% lower in PCNHS. This may be due to the fact that
it is easier to manage simpler units and that PCNHS are more
concerned with costs and controlling any type of cost.
Furthermore, with regard to staff management, the greater
working flexibility in PCNHS to adapt staffing to the healthcare needs at each moment in time is, without doubt, another
factor that contributed to reducing these costs in PCNHS.
We agree with Arrieta and with the authors of this study when
they reported that the understanding of the costs must be used
to allocate resources. However, we cannot agree with them
that making savings is not the objective of cost studies. When
the sustainability of CRF treatment as we know it may be
compromised, establishing, controlling and reducing costs
becomes a priority.
Improving the patient or session ratios per doctor, nurse
and nurse assistant, adapting the organisation of staff working hours to the needs of the unit and scheduling higher activity with short, daily or other types of dialysis between
work shifts are all essential measures to improve the units’
productivity.
The second piece of information that is highlighted in the
article is the 83% difference in the costs of consumables
between the PH and PCNHS, when, as the authors stated,
better prices would be expected according to the use of
economies of scale. We think that this difference is even
greater between the prices awarded in public tenders and
the prices that can be achieved in direct negotiations.
These differences may be explained by the delay in payments in government bodies and the need to finance monitors, ultrasound scanners or other equipment for the units,
which results in high financing costs and makes it impossible to manage future purchases better as a commitment
REFERENCES
1. Registro Español de Enfermos Renales. Informe de Diálisis y
Trasplante, 2009. Página Web de la Sociedad Española de
Nefrología. www.senefro.org.
2. Lorenzo V, Perestelo I, Barroso M, Torres A, Nazco J. Evaluación
económica de la hemodiálisis. Análisis de los componentes del
coste basado en datos individuales. Nefrologia 2010;30(4):40312.
3. Arrieta J. Evaluación económica del tratamiento sustitutivo renal
(hemodiálisis, diálisis peritoneal y trasplante) en España. Nefrologia
2010;1(Supl Ext 1):37-47.
4. Villa G, Rodríguez Carmona A, Fernández Ortiz L, Cuervo J, Rebollo
P, Otero A, et al. Cost analysis of the Spanish renal replacement
therapy programme. Nephrol Dial Tansplant 2011;0:1-6.
KEY CONCEPTS
1. Awareness of costs should always be present
in the nephrologist’s clinical decisions.
a pressing need in order to maintain the
healthcare model.
2. Establishing costs and their economic impact
should be an essential aspect when making
planning decisions and allocating resources.
4. The increase in staff productivity in public
hospitals and an improved economic
management of purchases are essential to be
able to improve the costs of these units.
3. Establishing and limiting costs in all CRF
treatment methods in Spain (HD, PD and KT) is
258
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5. Rodríguez Carmona A, Pérez Fontan M. Estudio de costes en
diálisis. Un instrumento esencial para optimizar recursos. Nefrologia
2007;27(3):237-40.
6. Rodríguez Carmona A, Pérez Fontan M, Valdés Cañedo F. Estudio
comparativo de costes de las diferente modalidades de diálisis.
Nefrologia 1996;16(6):539-48.
7. Hernández-Jaras H, García A, Bernat V. Aproximación al análisis de
costes de diferentes tipos de hemodiálisis mediante unidades
relativas de valor (URV). Nefrologia 2000;20(3):284-90.
8. Rodríguez Carmona A, Castro A, Pérez Fontan M. Estudio
económico de diálisis por el método de costes por procedimiento
ajustado a protocolo clínico. Nefrologia 2007;27(3):359-69.
9. Lamas J, Alonso M, Saavedra J, García-Trío G, Rionda M, Ameijeiras
M. Costes de la diálisis en un hospital público: mitos y realidades.
Nefrologia 2001;21(3):283-94.
10. Martín Hernández M. Análisis de los costes en nefrología. Situación
actual y futuro. Nefrologia 1998;18(Supl 6):40-51.
11. Conde J. Aspectos económicos y organizativos del tratamiento de
la insuficiencia renal crónica. Nefrologia 1994;14(Supl 1):3-9.
12. Temes JL. Coste y calidad en el tratamiento de la insuficiencia renal
crónica. Nefrologia 1994;14(Supl 1):9-13.
13. Burgos R, Martín Martín J, Pérez del Amo MP, Arellano J, Pérez
Romero C, Pozo F. Importancia del método de estimación de costes
en diálisis y trasplante renal. Nefrologia 2001;21(4):86-90.
14. Estrada MD. Diálisis peritoneal en comparación con hemodiálisis en
centros de diálisis: beneficios riesgo, coste y preferencia. Barcelona:
Agencia de Información, Evaluación y Calidad en Salud, Servicio
Catalán de la Salud; 2010.
editorial comments
15. Varela Lema L, Ruano Raviña A. Efectividad y seguridad de las
diferentes variantes de hemodiálisis y hemodiafiltración. Santiago
de Compostela: Servicio Galego de Saude. Axencia de Evaliacion de
Tecnoloxias Sanitarias de Galicia, INF 2005/03.
16. Haller M, Gutjahr G, Kramar R, Harnoncourt F, Oberbauer R. Costeffectiveness analysis of renal replacement therapy in Austria.
Nephrol Dial Tansplant 2011;0:1-8.
17. Benain JP, Faller B, Jaquelinet C, Barmi M, Dubois JP, Rieu P, et al.
Cost of dialysis in France. Nephrol Ther 2007;3:96-106.
18. Aranzábal J, Perdigo L. Renal transplantation costs: an economic analysis
and comparison with dialysis costs. Transplant Proc 1991;23:2574.
19. Felipe C, Naya M, Rivilla R, Matesanz R. Impacto económico de la
incorporación de nuevos avances biotecnológicos en el tratamiento
de la insuficiencia renal crónica en España (1992). Nefrologia
1994;14(Supl 1):111-7.
20. Ortega Montoliu T, Ortega Suárez F. Diversos aspectos del análisis
de costes en el trasplante renal. Nefrologia 2005;25(3):213-6.
21. Parra E, Arenas MD, Alonso M, Martínez MF, Gámen A, Rebollo P,
et al., Grupo de Gestión de la calidad de la Sociedad Española de
Nefrología. Estudio multicéntrico de costes en hemodiálisis.
Nefrologia 2011;31(3):299-307.
22. Alcalde G, Martín de Francisco AL, Fernández A, Conde JL.
Dotación de personal para centros de hemodiálisis ambulatoria.
Guías de Centros de Hemodiálisis. Nefrologia 2006;26(Supl 8):11-4.
23. Orden 101/2008 del 14 de febrero de la Consejería de Sanidad de
la CAM. B.C.O.M n.º 50:13-28.
24. Martín de Francisco AL. El futuro del tratamiento de la enfermedad
renal crónica. Nefrologia 2010;30(1):1-9.
Sent for review: 3 May 2011 | Accepted: 3 May 2011
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short reviews
Management of HCV infection
in chronic kidney disease
S. Aoufi Rabih1, R. García Agudo2
1
2
Digestive System Department. La Mancha-Centro Hospital Complex. Alcázar de San Juan, Ciudad Real, Spain
Nephrology Department. La Mancha-Centro Hospital Complex. Alcázar de San Juan, Ciudad Real, Spain
Nefrologia 2011;31(3):260-7
doi:10.3265/Nefrologia.pre2011.Jan.10768
ABSTRACT
The prevalence of chronic infection with the hepatitis C
virus (HCV) in patients with chronic kidney disease is higher
than in the general population. The estimated prevalence
is 13% in haemodialysis, with wide variations
geographically and between units in the same country. A
liver biopsy is a useful tool for deciding whether to start
antiviral therapy and to exclude concomitant causes of liver
dysfunction. Examples of this include nonalcoholic fatty
liver disease, whose incidence is on the rise, and
haemosiderosis, which may affect the progression of the
disease and condition the response to antiviral therapy. In
addition, the transjugular route can be used to measure
the hepatic venous pressure gradient and confirm the
existence of portal hypertension. Chronic hepatitis due to
HCV has been shown to reduce survival in haemodialysis,
renal transplantation and graft survival. It is the fourth
leading cause of death and the leading cause of post-renal
transplantation liver dysfunction. HCV behaves as an
independent risk factor for the occurrence of proteinuria; it
increases the risk of developing diabetes, de novo
glomerulonephritis and chronic allograft nephropathy; it
leads to a deterioration in liver disease and causes a greater
number of infections. An increased frequency of fibrosing
cholestatic hepatitis has also been described which,
together with the rapid evolution to cirrhosis, can
significantly increase morbidity and mortality and lead to
the need for liver transplantation. In addition,
immunosuppression in renal transplantation predisposes a
reactivation of HCV. However, as the pharmacokinetics of
interferon and ribavirin is impaired in kidney failure and
their use has adverse effects on function and graft survival,
Correspondence: Rebeca García Agudo
Servicio de Nefrología. Complejo Hospitalario La Mancha-Centro. Avda.
de la Constitución, s/n. 13600 Alcázar de San Juan.
Ciudad Real. Spain.
[email protected]
[email protected]
260
a combination therapy is limited to non-transplanted
individuals with an estimated glomerular filtration rate
greater than 50 ml/min, and with the interferon being used
as monotherapy in dialysis. The fact that a quarter of HCVpositive patients evaluated for a renal transplant have
bridging fibrosis or cirrhosis in the liver biopsy may renew
renal pre-transplant treatment planning.
la biopsia
Keywords: Hepatitis C virus. Chronic kidney disease.
Hemodialysis. Liver biopsy. Renal transplantation.
Interferon. Ribavirin.
Manejo de la infección por el VHC en la enfermedad renal
crónica
RESUMEN
La prevalencia de la infección crónica por el virus de la
hepatitis C (VHC) en pacientes con enfermedad renal
crónica es mayor que en la población general. En
hemodiálisis, se estima una prevalencia del 13%, con una
amplia variabilidad geográfica y entre las unidades de un
mismo país. La biopsia hepática es una herramienta útil
para decidir el inicio de la terapia antiviral y excluir causas
concomitantes de disfunción hepática, como la hepatopatía
grasa no alcohólica, cuya incidencia está en auge, y la
hemosiderosis, que pueden afectar a la progresión de la
enfermedad y condicionar la respuesta al tratamiento
antiviral; además, la vía transyugular se puede utilizar para
medir el gradiente de presión venoso hepático y confirmar
la existencia de hipertensión portal. La hepatitis crónica
por el VHC ha demostrado reducir la supervivencia en
hemodiálisis y en el trasplante renal, así como la
supervivencia del injerto. Constituye la cuarta causa de
mortalidad y la principal causa de disfunción hepática
postrasplante renal. El VHC se comporta como un factor de
riesgo independiente para la aparición de proteinuria,
R. García Agudo. Management of HCV infection in CKD
aumenta el riesgo de desarrollar diabetes, una
glomerulonefritis de novo o una nefropatía crónica del
injerto, de empeorar la enfermedad hepática y de provocar
un mayor número de infecciones. También se ha descrito
un incremento de la frecuencia de hepatitis colestásica
fibrosante que, junto a la evolución acelerada a cirrosis,
puede elevar significativamente la morbimortalidad y
conllevar la necesidad de un trasplante hepático. Además,
la inmunosupresión en el trasplante renal predispone a
la reactivación del VHC. Sin embargo, como la
farmacocinética del interferón y la ribavirina está alterada
en la insuficiencia renal y su uso tiene efectos adversos
sobre la función y la supervivencia del injerto, la terapia
combinada se limita a los individuos no trasplantados con
un filtrado glomerular estimado mayor de 50 ml/min y en
diálisis suele emplearse el interferón en monoterapia. El
hecho de que una cuarta parte de los pacientes VHCpositivos evaluados para trasplante renal tenga fibrosis en
puente o cirrosis en la biopsia hepática puede renovar el
planteamiento del tratamiento pretrasplante renal.
Palabras clave: Virus de la hepatitis C. Enfermedad renal
crónica. Hemodiálisis. Biopsia hepática. Trasplante renal.
Interferón. Ribavirina.
INTRODUCTION
The World Health Organisation estimates the global
prevalence of chronic infection with the hepatitis C virus
(HCV) to be 3%, with wide geographic variation: less
than 5% in most Northern European countries, about 10%
in southern Europe and the United States, and between
10%-50% and up to 70% in many developing countries,
including parts of Asia, Latin America and North Africa.
The incidence of HCV infection has been reduced to less
than 1%-2% in developed countries.1-3
HCV infection in patients with stage 5 chronic kidney
disease (CKD) is higher than in the general population. In
haemodialysis patients, there is a prevalence of 13%, with
a range of 1%-70% 4 (Table 1). Furthermore, the
prevalence of HCV is highly variable among
haemodialysis units within the same country. 5 In Spain,
the prevalence of HCV infection in haemodialysis in
1997-2001 was estimated at 22%.4
In renal transplant patients, the prevalence of HCV
infection ranges between 7% and 40%, also with a wide
geographic and demographic variation.4,17-19
Up to 55%-85% of those infected with HCV progress to
the chronic stage, 20-23 and 5%-25% of these develop
cirrhosis at 25-30 years.20,24 Individuals with cirrhosis have
Nefrologia 2011;31(3):260-7
short reviews
a higher risk of hepatocellular carcinoma than the noncirrhotic population. In Spain, HCV is currently the main
risk factor associated with hepatocellular carcinoma, 25
although the risk varies with the extent to which the liver
is affected. It is less than 1% annually in patients with
chronic hepatitis without significant fibrosis, and reaches
3%-7% annually for cirrosis. 26 Once liver cirrhosis is
found, there is a risk of liver hepatocellular carcinoma
continuing to develop, despite having a sustained viral
response to treatment.27 Several factors for progression to
cirrhosis have been identified: advanced age, obesity,
immunosuppression, alcohol consumption greater than
50g/day, 28-31 and a more rapid evolution to cirrhosis has
been described in renal transplant patients.32-34
LIVER HISTOLOGY: ROLE OF BIOPSY
A liver biopsy is of substantial value in assessing the
severity of liver disease in chronic HCV infection, in
relation to the degree of fibrosis and necroinflammatory
activity, as well as for excluding other concomitant causes
of liver dysfunction. These include non-alcoholic fatty
liver disease, whose incidence is on the rise, and
haemosiderosis, which may affect the progression of the
disease and determine the response to treatment. 35-38 The
KDIGO guides (Kidney Disease Improving Global
Outcomes)39 recommend a liver biopsy in the liver disease
study of patients eligible for renal transplantation. The
AASLD guide (American Association for the Study of
Liver Diseases) limits it to HCV-positive patients with
genotypes 1 and 4, but considers it unnecessary in
genotypes 2 and 3,40 given that over 80% of patients (with
normal renal function) achieve a sustained viral response.
The METAVIR score evaluates necroinflammatory
activity (grade) and fibrosis (stage). It consists of a
coding system of two letters and two numbers: A=
histological activity (A0= no activity, A1= mild activity,
A2= moderate activity, A3= severe activity); and F=
fibrosis (F0= no fibrosis, F1= portal fibrosis without
septa, F2= portal fibrosis with few septa, F3= numerous
septa without fibrosis, F4= fibrosis). 41 It requires a high
quality liver biopsy of at least 2cm in length, with more
than 5 portal tracts, to calculate an appropriate METAVIR
score.42,43
According to the KDIGO guidelines, patients on the
waiting list for a kidney transplant who do not respond to
or refuse antiviral treatment must undergo a liver biopsy
every 3-5 years, depending on the initial METAVIR score
(every 3 years for a METAVIR score of 3, and every 5
years for a METAVIR score of 1-2). 39 There is no
evidence to support this recommendation, although it has
been shown that liver disease progresses in patients on
dialysis. 17,34 Liver damage markers like GPT do not
261
short reviews
Table 1. Prevalence of HCV infection in haemodialysis
Country
HCV Prevalence
Year of Study
Reference
Germany
7%
1996-1997
Hinrichsen et al.6
Saudi Arabia
68%
1994
Huraib et al.7
Belgium
7%
2000
Jadoul et al.3
Brazil
17%
2002-2005
Santos y Souto8
Spain
22%
1997-2001
Fissell et al.4
United States
14%
1997-2001
Fisell et al.4
France
15%
1997-2001
Fisell et al.4
Japan
20%
1997-2001
Fisell et al4
India
12-42%
2001
Saha y Agarwal9
Iran
9%
2004
Shamshirsaz et al.10
Italy
22%
1997-2001
Fisell et al.4
New Zealand
5%
1992
Blackmore et al.11
Netherlands
3%
1997
Schneeberger et al.12
Poland
42%
1992
Hruby et al.13
United Kingdom
3%
1997-2001
Fisell et al.4
South Africa
21%
1994
Cassidy et al.14
Thailand
20%
1994
Luengrojanakul et al.15
Tunisia
20%
2001-2003
Hmaied et al.16
accurately reflect the histological severity of liver disease
of CKD patients, and up to 25% of patients with HCV
infection evaluated for renal transplantation have bridging
fibrosis or cirrhosis in the liver biopsy (METAVIR>3).44-49
No definitive studies have investigated whether the
histological stage of the pre-transplant biopsy predicts
post-transplant liver disease and its outcomes. However,
the presence of cirrhosis in the pre-transplant liver biopsy
has been associated with a 26% survival at 10 years. 50
Several studies have shown that 19%-64% of renal
transplant patients infected with HCV have posttransplant liver disease, compared with only 1%-30% of
patients not infected. 18,50-56 Most studies are retrospective,
with patients without a pre-transplant liver biopsy. This
could result in an underestimation of advanced liver
disease, given the increase in the rate of decompensated
liver disease. Studies without a pre-transplant liver
biopsy, but with a post-transplant sequential liver biopsy,
have shown that liver histology may progress in 20% of
patients. 57,58 Since there is a 6%-8% annual mortality risk
in patients on a transplant waiting list, 59 it seems
reasonable to monitor their liver disease to check if a
renal transplant is still appropriate for their condition.
Liver damage before renal transplantation is an
independent predictor of poor long-term survival.50
dysfunction associated with uraemia, haemodialysis
anticoagulation and antiplatelet therapy, a liver biopsy via
the transjugular or transfemoral route is often
recommended. This can provide additional diagnostic
information, such as the hepatic venous pressure gradient,
to confirm the existence of portal hypertension.39,40
Desmopressin (DDAVP, 0.3mg/kg) has been used more
often immediately before liver biopsy in CKD patients.
However, we were not able to find defined serum
creatinine level or glomerular filtration rates which
should be used for desmopressin indication.61
The utility of non-invasive markers (Index of Forns,
APRI or FIB-4) in the study of liver damage in patients
with CKD and HCV infection is not known at present. 62
There were hopes for transient elastography (FibroScan),
which has failed to replace the biopsy: it has not been
approved by the FDA (Food and Drug Administration),
the error rate is higher in obese patients and may be
overestimated in acute hepatitis, which is associated with
high necroinflammatory activity and low or nil
fibrosis.63,64
TREATMENT
Coagulopathy secondary to hepatocellular dysfunction
and thrombocytopaenia due to portal hypertension and
hypersplenism poses an increased risk of bleeding. 60 Due
to the presence of ascites in CKD patients, and because of
the added risk of increased bleeding from platelet
262
The treatment of choice for chronic HCV hepatitis is
conventional or pegylated interferon, alone or in
combination with ribavirin. The antiviral treatment
should be individualised, depending on the severity of
Nefrologia 2011;31(3):260-7
the liver disease, the possibility of serious adverse
effects, variability in the response to treatment, the
presence of comorbidity (particularly renal failure) and
the patient’s decision.40 Individuals with CKD have lower
to normal levels of transaminases 45,65-67 compared to those
without CKD. Traditionally, it was considered that
subjects with genotype 1 and persistently normal
transaminases had minimal hepatic fibrosis and were thus
not appropriate for treatment. Today, it has been shown
that up to 25% of these patients have significant fibrosis,
and that their response to treatment is similar to patients
with elevated transaminases. 68-74 Patients with
extrahepatic manifestations have to be treated, regardless
of the severity of the liver disease.75
In individuals with normal renal function, antiviral
therapy is aimed at eradicating HCV infection to
improve liver histology, which in the long term results
in lower morbidity and improved survival. In patients
with CKD, the treatment of HCV is even more relevant,
because chronic hepatitis has been shown to reduce
survival in haemodialysis, renal transplantation and
renal graft survival, 18,50-56,76-78 compared with non-infected
patients. This is partly due to the progression of liver
disease, the rapid evolution to cirrhosis and/or
appearance of hepatocellular carcinoma. 18,32-34,50,56,79 HCV
infection is the leading cause of renal post-transplant
liver dysfunction and the fourth cause of mortality in
this group. 33 HCV behaves as an independent risk factor
for the occurrence of proteinuria, 53,80 it increases the risk
of developing diabetes after transplantation, 81-83 de novo
glomerulonephritis, 84-87
and
chronic
allograft
nephropathy, and worsens liver disease and causes more
infections. 39 In addition, immunosuppression in renal
transplantation enhances HCV reactivation. In
particular, steroids have been associated with a 10 to
100 fold increase in the viral load. 88 They should
therefore be avoided or minimised in HCV-positive
patients. 89 In addition, an increased frequency of
fibrosing cholestatic hepatitis has been described which,
together with the rapid evolution to cirrhosis, may
significantly increase morbidity and mortality, leading to
the need for a liver transplant.90,91
However, antiviral therapy in CKD remains controversial.
There are no comparative studies to support the decision
of an appropriate antiviral treatment. Most haemodialysis
studies have investigated the use of conventional alpha
interferon (3MIU 3 times a week) or pegylated alpha
interferon (alpha 2a, 135µg/week; or alpha 2b,
50µg/week, or 0.5-1µg/kg/week) in monotherapy. The
results are different but, generally, there is a low
sustained viral response (19%-75%) and significant drug
intolerance (30%-50% of dialysis patients interrupt the
therapy). 92-95
The
American
Gastroenterological
Association (AGA) and the AASLD recommend the use
Nefrologia 2011;31(3):260-7
short reviews
of reduced doses of pegylated alpha interferon in
monotherapy, and consider the association of ribavirin
as a contraindication in patients with an estimated
glomerular filtration rate less than 50ml/min. 40,96,97-104
There is little experience with the ribavirin combination
therapy (200mg, 3 times a week or 200mg/24h) in
dialysis. Better results have been suggested, although
the studies were for few case series with a very limited
number of patients. 105-110 A recent meta-analysis of
existing clinical trials on combination therapy in dialysis
showed that about half of the patients obtained a
sustained viral response. 111 The risk of severe anaemia
due to secondary haemolysis makes it difficult to use,
although some researchers have used it based on serum
drug levels, obtaining uneven results. 106-110,112 Available
data, however, are encouraging and its use may be
indicated in centres where patient are treated by
hepatologists and nephrologists. Antiviral treatment in
renal transplant recipients is rare except in cases with
limited therapeutic alternatives or severe cholestatic
hepatitis. 90,91 The main drawback of antiviral treatment
before transplantation is the delayed inclusion of the
patient on the waiting list, without being able to ensure
HCV eradication due to the low response figures.
Therefore, all haemodialysis patients with detectable HCV
RNA and an F0-F2 METAVIR score should be considered
as candidates for treatment with alpha interferon. The
bridging fibrosis patients with compensated cirrhosis
should also receive antiviral therapy, and be eventual
candidates for renal transplantation if they achieve a
sustained viral response. Patients with decompensated
cirrhosis should be evaluated for a combined kidney and
liver transplant.40
In light of the impact of chronic HCV infection in renal
transplantation, it is recommended that patients with
CKD are treated prior to undergoing the transplant. 113,114
However, despite the evidence on the benefits of antiviral
treatment in patients with chronic HCV infection and
CKD prior to renal transplantation, only a few kidney
transplant protocols recommend treatment against HCV,
and it is not usually listed as a pre-transplant criterion.115117
In fact, the evaluation before a kidney transplant for
HCV-positive patients on renal replacement therapy
shows that, as well as not considering treatment for HCV
before transplantation, hepatology monitoring of these
patients on dialysis is virtually nonexistent in many cases.
This may be due to the inherent complexity of CKD
treatment, leading the nephrologist to assume all the
patient pathology in haemodialysis.
Further studies are needed to assess the clinical situation and
monitoring of HCV hepatitis in patients on haemodialysis, to
identify improvements and involve both nephrologists and
hepatologists in its management.
263
short reviews
REFERENCES
1. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysisassociated diseases in the United States, 2002. Semin Dial 2005;18(1):52-61.
2. Espinosa M, Martín-Malo A, Ojeda R, Santamara R, Soriano S, Aguera M, et al. Marked reduction in the prevalence of hepatitis C virus
infection in hemodialysis patients: causes and consequences. Am J
Kidney Dis 2004;43(4):685-9.
3. Jadoul M, Poignet JL, Geddes C, Locatelli F, Medin C, Krajewska M,
et al. The changing epidemiology of hepatitis C virus (HCV) infection in haemodialysis: European multicentre study. Nephrol Dial
Transplant 2004;19(4):904-9.
4. Fissell RB, Bragg-Gresaham JL, Woods JD, Jadoul M, Gillespie B,
Hedderwick SA, et al. Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.
Kidney Int 2004;65(6):2335-42.
5. Sivapalasingam S, Malak SF, Sullivan JF, Lorch J, Sepkowitz KA. High
prevalence of hepatitis C infection among patients receiving hemodialysis at an urban dialysis center. Infect Control Hosp Epidemiol
2002;23(6):319-24.
6. Hinrichsen H, Leimenstoll G, Stegen G, Schrader H, Fölsch UR,
Schmidt WE; PHV Study Group. Prevalence and risk factors of hepatitis C virus infection in haemodialysis patients: a multicentre
study in 2796 patients. Gut 2002;51(3):429-33.
7. Huraib S, Al-Rashed R, Aldrees A, Aljefry M, Arif M, Al-Faleh FA.
High prevalence of and risk factors for hepatitis C in haemodialysis
patients in Saudi Arabia: a need for new dialysis strategies. Nephrol
Dial Transplant 1995;10(4):470-4.
8. Santos MA, Souto FJ. Infection by the hepatitis C virus in chronic renal failure patients undergoing hemodialysis in Mato Grosso state, central Brazil: a cohort study. BMC Public Health
2007;7:32.
9. Saha D, Agarwal SK. Hepatitis and HIV infection during haemodialysis. J Indian Med Assoc 2001;99(4):194-9.
10. Shamshirsaz AA, Kamgar M, Bekheirnia MR, Ayazi F, Hashemi SR,
Bouzari N, et al. The role of hemodialysis machines dedication in reducing Hepatitis C transmission in the dialysis setting in Iran: a multicenter prospective interventional study. BMC Nephrol 2004;5(1):13.
11. Blackmore TK, Stace NH, Maddocks P, Hatfield P. Prevalence of antibodies to hepatitis C virus in patients receiving renal replacement
therapy, and in the staff caring for them. Aust N Z J Med
1992;22(4):353-7.
12. Schneeberger PM, Keur I, Van Loon AM, Mortier D, De Coul KO,
Van Haperen AV, et al. The prevalence and incidence of hepatitis C
virus infections among dialysis patients in the Netherlands: a nationwide prospective study. J Infect Dis 2000;182(5):1291-9.
13. Hruby Z, Sliwinski J, Molin I, Zalewska M, Knysz B, Czyz W, et al.
High prevalence of antibodies to hepatitis C virus in three haemodialysis centres in south-western Poland. Nephrol Dial Transplant
1993;8(8):740-3.
14. Cassidy MJ, Jankelson D, Becker M, Dunne T, Walzl G, Moosa MR.
The prevalence of antibodies to hepatitis C virus at two haemodialysis units in South Africa. S Afr Med J 1995;85(10):996-8.
15. Luengrojanakul P, Vareesangthip K, Chainuvati T, Murata K, Tsuda F,
Tokita H, et al. Hepatitis C virus infection in patients with chronic li264
ver disease or chronic renal failure and blood donors in Thailand. J
Med Virol 1994;44(3):287-92.
16. Hmaied F, Ben Mamou M, Saune-Sandres K, Rostaing L, Slim A,
Arrouji Z, et al. Hepatitis C virus infection among dialysis patients in
Tunisia: incidence and molecular evidence for nosocomial transmission. J Med Virol 2006;78(2):185-91.
17. Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R, Schmid
CH, et al. Effects of hepatitis C infection and renal transplantation
on survival in end-stage renal disease. The New England Organ Bank
Hepatitis C Study Group. Kidney Int 1998;53(5):1374-81.
18. Hanafusa T, Ichikawa Y, Kishikawa H, Kyo M, Fukunishi T, Kokado
Y, et al. Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation
1998;66(4):471-6.
19. Vosnides GG. Hepatitis C in renal transplantation. Kidney Int
1997;52(3):843-61.
20. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med
2000;132(4):296-305.
21. Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis
2005;9(3):383-98.
22. Strader DB, Seeff LB. The natural history of chronic hepatitis C infection. Eur J Gastroenterol Hepatol 1996;8(4):324-8.
23. Seeff LB, Hoofnagle JH. National Institutes of Health Consensus Development Conference: management of hepatitis C: 2002. Hepatology 2002;36(5 Suppl 1):S1-2.
24. Seeff LB. Natural history of chronic hepatitis C. Hepatology
2002;36(5 Suppl 1):S35-S46.
25. Forner A, Ayuso C, Real MI, Sastre J, Robles R, Sangro B, et al. Diagnóstico y tratamiento del carcinoma hepatocelular. Med Clin (Barc)
2009;132(7):272-87.
26. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: Incidente and risk factors. Gastroenterology
2004;127(5 Suppl 1):S35-50.
27. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella
G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: A retrospective study. Hepatology 2007;45(3):579-87.
28. Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency
virus and hepatitis C virus coinfected patients. The Multivirc Group.
Hepatology 1999;30(4):1054-8.
29. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR,
CLINIVIR, and DOSVIRC groups. Lancet 1997;349(9055):825-32.
30. Harris DR, Gonin R, Alter HJ, Wright EC, Buskell ZJ, Hollinger FB, et
al. The relationship of acute transfusion-associated hepatitis to the
development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001;134(2):120-4.
31. Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005;42(1):5-13.
32. Marcelli D, Stannard D, Conte F, Held PJ, Locatelli F, Port FK. ESRD patient mortality with adjustment for comorbid conditions in Lombardy
(Italy) versus the United States. Kidney Int 1996;50(3):1013-8.
Nefrologia 2011;31(3):260-7
33. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999;354(9173):939.
34. Nakayama E, Akiba T, Marumo F, Sato C. Prognosis of anti-hepatitis
C virus antibody-positive patients on regular hemodialysis therapy. J
Am Soc Nephrol 2000;11(10):1896-902.
35. Kleiner DE. The liver biopsy in chronic hepatitis C: a view from the
other side of the microscope. Semin Liver Dis 2005;25(1):52-64.
36. Rubbia-Brandt L, Fabris P, Paganin S, Leandro G, Male PJ, Giostra E,
et al. Steatosis affects chronic hepatitis C progression in a genotype
specific way. Gut 2004;53(3):406-12.
37. Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem
S, et al. Effect of treatment with peginterferon or interferon alfa-2b
and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003;38(1):75-85.
38. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick
JL, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology
1995;108(4):1104-9.
39. Kidney Disease Improving Global Outcomes. Clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int 2008;73(Suppl
109):S53-S68.
40. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association
for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49(4):1335-74.
41. Knodell RG, Ishak KG, Black WC, et al. Formulation and application
of a numeral scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1(5):431-5.
42. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med
2001;344(7):495-500.
43. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos
NT, et al. Sampling error and intraobserver variation in liver biopsy
in patients with chronic HCV infection. Am J Gastroenterol
2002;97(10):2614-8.
44. Martin P, Carter D, Fabrizi F, Dixit V, Conrad AJ, Artinian L, et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000;69(7):1479-84.
45. Caramelo C, Ortiz A, Aguilera B, Porres JC, Navas S, Marriott E, et
al. Liver disease patterns in hemodialysis patients with antibodies to
hepatitis C virus. Am J Kidney Dis 1993;22(6):822-8.
46. Cotler SJ, Diaz G, Gundlapalli S, Jakate S, Chawla A, Mital D, et al.
Characteristics of hepatitis C in renal transplant candidates. J Clin
Gastroenterol 2002;35(2):191-5.
47. Glicklich D, Thung SN, Kapoian T, Tellis V, Reinus JF. Comparison of clinical features and liver histology in hepatitis C-positive dialysis patients
and renal transplant recipients. Am J Gastroenterol 1999;94(1):15963.
48. Pol S, Romeo R, Zins B, Driss F, Lebkiri B, Carnot F, et al. Hepatitis C
virus RNA in anti-HCV positive hemodialyzed patients: significance
and therapeutic implications. Kidney Int 1993;44(5):1097-100.
49. Sterling RK, Sanyal AJ, Luketic VA, Stravitz RT, King AL, Post AB, et al.
Chronic hepatitis C infection in patients with end stage renal disease:
characterization of liver histology and viral load in patients awaiting
renal transplantation. Am J Gastroenterol 1999;94(12):3576-82.
Nefrologia 2011;31(3):260-7
short reviews
50. Mathurin P, Mouquet C, Poynard T, Sylla C, Benalia H, Fretz C, et al.
Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29(1):257-63.
51. Breitenfeldt MK, Rasenack J, Berthold H, Olschewski M, Schroff J,
Strey C, et al. Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation. Clin Transplant
2002;16(2):130-6.
52. Bruchfeld A, Wilczek H, Elinder CG. Hepatitis C infection, time in
renal replacement therapy, and outcome after kidney transplantation. Transplantation 2004;78(5):745-50.
53. Morales JM, Domínguez-Gil B, Sanz-Guajardo D, Fernández J, Escuin F. The influence of hepatitis B and hepatitis C virus infection in
the recipient on late renal allograft failure. Nephrol Dial Transplant
2004;19(Suppl 3):iii72-6.
54. Gentil MA, Rocha JL, Rodríguez-Algarra G, Pereira P, López R, Bernal
G, et al. Impaired kidney transplant survival in patients with antibodies
to hepatitis C virus. Nephrol Dial Transplant 1999;14(10):2455-60.
55. Legendre C, Garrigue V, Le Bihan C, Mamzer-Bruneel MF, Chaix ML,
Landais P, et al. Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998;65(5):66770.
56. Murthy BV, Muerhoff AS, Desai SM, Yamaguchi J, Mushahwar IK,
Schmid CH, et al. Impact of pretransplantation GB virus C infection
on the outcome of renal transplantation. J Am Soc Nephrol
1997;8(7):1164-73.
57. Kamar N, Rostaing L, Selves J, Sandres-Saune K, Alric L, Durand D.
Natural history of hepatitis C virus-related liver fibrosis after renal
transplantation. Am J Transplant 2005;5(7):1704-12.
58. Zylberberg H, Nalpas B, Carnot F, Skhiri H, Fontaine H, Legendre C,
et al. Severe evolution of chronic hepatitis C in renal transplantation:
a case control study. Nephrol Dial Transplant 2002;17(1):129-33.
59. U.S. Renal Data System, USRDS 2002 Annual Data Report: Atlas of
End-Stage Renal Disease in the United States, in, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2002.
60. Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy
KR, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assesment of current management. Hepatology 2006;44(4):1039-46.
61. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990;33(1):39-45.
62. Campbell MS, Reddy KR. Review article: the evolving role of liver
biopsy. Aliment Pharmacol Ther 2004;20(3):249-59.
63. Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute
viral hepatitis increases liver stiffness values measured by transient
elastography. Hepatology 2008;47(2):380-4.
64. Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography
is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008;47(2):592-5.
65. Espinosa M, Martín-Malo A, Álvarez de Lara MA, Soriano S, Aljama
P. High ALT levels predict viremia in anti-HCV-positive HD patients if
a modified normal range of ALT is applied. Clin Nephrol
2000;54(2):151-6.
66. Guh JY, Lai YH, Yang CY, Chen SC, Chuang WL, Hsu TC, et al. Impact of decreased serum transaminase levels on the evaluation of
viral hepatitis in hemodialysis patients. Nephron 1995;69(4):459-65.
265
short reviews
67. Fabrizi F, Lunghi G, Finazzi S, Colucci P, Pagano A, Ponticelli C, et al.
Decreased serum aminotransferase activity in patients with chronic
renal failure: impact on the detection of viral hepatitis. Am J Kidney
Dis 2001;38(5):1009-15.
68. Martinot-Peignoux M, Boyer N, Cazals-Hatem D, Pham BN, Gervais
A, Le Breton V, et al. Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase
with or without detectable serum hepatitis C virus RNA. Hepatology
2001;34(5):1000-5.
69. Shiffman ML, Diago M, Tran A, Pockros P, Reindollar R, Prati D, et
al. Chronic hepatitis C in patients with persistently normal alanine
transaminase levels. Clin Gastroenterol Hepatol 2006;4(5):645-52.
70. Boccato S, Pistis R, Noventa F, Guido M, Benvegnù L, Alberti A. Fibrosis progression in initially mild chronic hepatitis C. J Viral Hepat
2006;13(5):297-302.
71. Persico M, Persico E, Suozzo R, Conte S, De Seta M, Coppola L, et
al. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000;118(4):760-4.
72. Yu ML, Dai CY, Lee LP, Hou NJ, Hsieh MY, Huang JF, et al. A 24week course of high-dose interferon-alpha plus ribavirin for Taiwanese chronic hepatitis C patients with persistently normal or
near-normal alanine aminotransferase levels. Liver Int
2006;26(10):1187-95.
73. Jacobson IM, Ahmed F, Russo MW, Lebovics E, Dieterich DT, Esposito SP, et al. Interferon alfa-2b [correction of alpha-2b] and ribavirin
for patients with chronic hepatitis C and normal ALT. Am J Gastroenterol 2004;99(9):1700-5.
74. Zeuzem S, Diago M, Gane E, Reddy KR, Pockros P, Prati D, et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with
chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004;127(6):1724-32.
75. Yee HS, Curie SL, Darling JM, Wright TL. Management and treatment of hepatitis C viral infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program
and the National Hepatitis C Program Office. Am J Gastroenterol
2006;101(10):2360-78.
76. Lee WC, Shu KH, Cheng CH, Wu MJ, Chen CH, Lian JC. Long-term
impact of hepatitis B, C virus infection on renal transplantation. Am
J Nephrol 2001;21 (4):300-6.
77. Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M, Campise
MR, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation 2005;79(9):1132-6.
78. Morales JM, Marcén R, Andrés A, Domínguez-Gil B, Campistol JM,
Gallego R, et al. Renal transplantation in patients with hepatitis C
virus antibody. A long national experience. NDT Plus 2010;3(Suppl
2):ii41-ii46.
79. Gheith OA, Saad MA, Hassan AA, A-Eldeeb S, Agroudy AE, Esaza
H, et al. Hepatic dysfunction in kidney transplant recipients: prevalence and impact on graft and patient survival. Clin Exp Nephrol
2007;11(4):309-15.
80. Hestin D, Guillermin F, Castin N, Le Faou A, Champigneulles J, Kessler M. Pretransplant hepatitis C virus infection: a predictor of proteinuria after renal transplantation. Transplantation 1998;65(5):741-4.
81. Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC. Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 2002;13(5):1374-80.
266
82. Kamar N, Mariat C, Delahousse M, Dantal J, Al Najjar A, Cassuto E,
et al. Diabetes mellitus after kidney transplantation: a French multicentre
observational
study.
Nephrol
Dial
Transplant
2007;22(7):1986-93.
83. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G. Posttransplant diabetes mellitus and HCV seropositive status after renal
transplantation: meta-analysis of clinical studies. Am J Transplant
2005;5(10):2433-40.
84. Roth D, Cirocco R, Zucker K, Ruiz P, Viciana A, Burke G, et al. De
novo membranoproliferative glomerulonephritis in hepatitis C virus-infected
renal
allograft
recipients.
Transplantation
1995;59(12):1676-82.
85. Floege J. Recurrent glomerulonephritis following renal transplantation: an update. Nephrol Dial Transplant 2003;18(7):1260-5.
86. Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after kidney transplantation. Am J Transplant 2006;6(11):2535-42.
87. Kamar N, Izopet J, Alric L, Guilbeaud-Frugier C, Rostaing L. Hepatitis C virus-related kidney disease: an overview. Clin Nephrol
2008;69(3):149-60.
88. Humar A, Crotteau S, Cruessner A, Kandaswamy R, Gruessner R,
Payne W, et al. Steroid minimization in liver transplant recipients:
impact on hepatitis C recurrente and post-transplant diabetes. Clin
Transplant 2007;21(4):526-31.
89. Pascual J, Crespo M, Mateos ML, Marcén R, Orofino L, Burgos FJ, et
al. Reduced severity of acute rejection in hepatitis C virus positive
renal allograft recipients: are milder immunosuppressive regimens
advisable? Transplant Proc 1998;30(4):1329-30.
90. Kamar N, Ribes D, Izopet J, Rostaing L. Treatment of hepatitis C virus infection (HCV) after renal transplantation: implications for HCVpositive dialysis patients awaiting a kidney transplant. Transplantation 2006;82(7):853-6.
91. Toth CM, Pascual M, Chung RT, Graeme-Cook F, Dienstag JL, Bhan
AK, et al. Hepatitis C virus-associated fibrosing cholestatic hepatitis
after renal transplantation: response to interferon-alpha therapy.
Transplantation 1998;66(9):1254-8.
92. Covic A, Maftei I-D, Mardare NGI, Ionita-Radu F, Totolici C, Tuta L,
et al. Analysis of safety and efficacy of pegylated-interferon alpha2a in hepatitis C virus positive hemodialysis patients: results from a
large, multicenter audit. J Nephrol 2006;19(6):794-801.
93. Tan SS, Abu Hassan MR, Abdullah A, Ooi BP, Korompis T, Merican
MI. Safety and efficacy of an escalating dose regimen of pegylated
interferon alpha-2b in the treatment of haemodialysis patients with
chronic hepatitis C. J Viral Hepat 2010;17(6):410-8.
94. Kokoglu OF, Ucmak H, Hosoglu S, Cetinkaya A, Kantarceken B, Buyukbese MA, et al. Efficacy and tolerability of pegylated-interferon
alpha-2a in hemodialysis patients with chronic hepatitis C. J Gastroenterol Hepatol 2006;21(3):575-80.
95. Russo MW, Ghalib R, Sigal J, Joshi V. Randomized trial of pegylated
interferon ?-2b monotherapy in haemodialysis patients with chronic
hepatitis C. Nephrol Dial Transplant 2006;21(2):437-43.
96. Dienstag JL, McHutchinson JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006;130(1):231-64.
97. Bocci V, Pacini A, Muscettola M, Paulesu L, Pessina GP, Santiano M
et al. Renal filtration, absorption and catabolism of human alpha interferon. J Interferon Res 1981;1(3):347-52.
Nefrologia 2011;31(3):260-7
98. Bino T, Madar Z, Gertler A, Rosenberg H. The kidney is the main site
of interferon degradation. J Interferon Res 1982;2(2):301-8.
99. Kramer TH, Gaar GG, Ray CG, Minnich L, Copeland JG, Connor JD.
Hemodialysis clearance of intravenously administered ribavirin. Antimicrob Agents Chemother 1990;34(3):489-90.
100. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis
1999;19(Suppl 1):17-24.
101. Uchihara M, Izumi N, Sakai Y, Yauchi T, Miyake S, Sakai T, et al. Interferon therapy for chronic hepatitis C in hemodialysis patients: increased serum levels of interferon. Nephron 1998;80(1):51-6.
102. Rostaing L, Chatelut E, Payen JL, Izopet J, Thalamas C, Ton-That H,
et al. Pharmacokinetics of alpha IFN-2b in chronic hepatitis C virus
patients undergoing chronic hemodialysis or with normal renal function: clinical implications. J Am Soc Nephrol 1998;9(12):2344-8.
103. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, et
al. Pegylated interferon-alpha 2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68(5):556-67.
104. Gupta SK, Pittenger AL, Swan SK, Marbury TC, Tobillo E, Batra V, et
al. Single-dose pharmacokinetics and safety of pegylated interferon
alpha 2b in patients with chronic renal dysfunction. J Clin Pharmacol 2002;42(10):1109-15.
105. Luzon BA, Muir AJ, Heneghan MA. Safety and tolerability of pegylated interferon with or without low dose ribavirin for treatment of
hepatitis C in hemodialysis. Hepatology 2005;42(Suppl):703A-704A.
106. Hakim W, Sheik S, Inayat I, Bia M, Caldwell C, Jain D, et al. Inicial
HCV response in patients with end stage renal disease treated with
combination pegylated interferon alfa-2a and ribavirin. Presented
at: Digestive Disease Week; May 20-25, 2006; Los Angeles, CA.
107. Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Herat 2006;13(5):316-21.
short reviews
108. Mousa DH, Abadía AH, Al-Shoail G, Al-Sulaiman MH, Al-Hawas
FA, Al-Khader AA. Alpha-interferon with ribavirin in haemodialyzed patients with chronic hepatitis C: a prospective study.
Presented at: 57th Annual Meeting of the American Association for the Study of Liver Diseases; October 27-31, 2006; Boston, MA.
109. Van Leusen R, Adang RP, De Vries RA, Cnossen TT, Konings CJ,
Schalm SW, et al. Pegylated interferon alfa-2a (40 kD) and ribavirin
in haemodialysis patients with chronic hepatitis C. Nephrol Dial
Transplant 2008;23(2):721-5.
110. Carriero D, Fabrizi F, Uriel AJ, Park J, Martin P, Dieterich DT. Treatment of dialysis patients with chronic hepatitis C using pegylated
interferon and low-dose ribavirin. Int J Artif Organs 2008;31(4):295302.
111. Fabrizi F, Dixit V, Martin P, Messa P. Combined antiviral therapy of
hepatitis C virus in dialysis patients: meta-analysis of clinical trials.
J Viral Hepat 2010. doi: 10.1111/j.1365-2893.2010.01405.x. [Epub
ahead of print]
112. Tan AC, Brouwer JT, Glue P, Van Leusen R, Kauffmann RH, Schalm
SW, et al. Safety of interferon and ribavirin therapy in haemodialysis
patients with chronic hepatitis C: results of a pilot study. Nephrol
Dial Transplant 2001;16(1):193-5.
113. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med
2003;139(2):137-47.
114. Barril G, González Parra E, Alcázar R, Arenas D, Campistol JM, Caramelo C, et al. Guía sobre enfermedades víricas en hemodiálisis.
Nefrologia 2004;24(Suppl 2):43-66.
115. García García M, Oppenheimer F, Valencia J. Valoración y seguimiento de inclusión en lista de espera para trasplante renal. Nefrologia
2006;26(Suppl 8):60-9.
Sent for review: 7 Dec. 2010 | Accepted: 17 Jan. 2011
Nefrologia 2011;31(3):260-7
267
short reviews
Vascular and metabolic properties of manidipine
N. Buset Ríos1, F. Rodríguez Esparragón1, C. Fernández-Andrade Rodríguez2,
J.C. Rodríguez Pérez3
Research Unit. Dr. Negrín Gran Canaria University Hospital, University of Las Palmas de Gran Canaria. Las Palmas de Gran Canarias, Spain
Nephrology Department. Virgen del Rocío University Hospitals. Seville, Spain
3
Nephrology Service and Research Unit. Dr. Negrín Gran Canaria University Hospital, University of Las Palmas de Gran Canaria. Las Palmas
de Gran Canarias, Spain
1
2
Nefrologia 2011;31(3):268-74
doi:10.3265/Nefrologia.pre2010.Nov.10643
ABSTRACT
The combination of renin-angiotensin system blockers
with calcium channel blockers appears to be one of the
most effective options for treating hypertension and diabetes. Nevertheless, not all calcium blockers behave in the
same manner. Manidipine, unlike other third-generation
dihydropyridine derived drugs, blocks T-type calcium channels present in the efferent glomerular arterioles, reducing
intraglomerular pressure and microalbuminuria. In addition, T-type channels are related to proliferation, inflammation, fibrosis, vasoconstriction and activation of the renin-angiotensin system. The inhibition of these factors
could explain the non-haemodynamic effects of manidipine as compared to other blockers.
Keywords: Calcium channel blockers, Manidipine, T-type
calcium channels.
Aspectos vasculares y metabólicos de manidipino
RESUMEN
En el tratamiento de la hipertensión y la diabetes, la combinación de bloqueantes del sistema renina-angiotensina
y de los canales de calcio se presenta como una de las opciones más eficaces. Sin embargo, no todos los bloqueantes de calcio se comportan del mismo modo. Manidipino, a diferencia de otros derivados dihidropiridínicos
de tercera generación, bloquea los canales de calcio T presentes en las arteriolas glomerulares eferentes, disminuyendo la presión intraglomerular y la microalbuminuria.
Además, los canales T están relacionados con proliferación,
inflamación, fibrosis, vasoconstricción y activación del sistema renina-angiotensina. La inhibición de estos factores
podría explicar la acción no hemodinámica del manidipino
frente a otros bloqueantes.
Palabras clave: Bloqueantes de
Manidipino. Canales de calcio tipo T.
canales
de
calcio.
CALCIUM CHANNELS
Voltage-dependent calcium channels mediate the flow of
calcium in response to the depolarisation of the cell
membrane and regulate intracellular processes such as
contraction, secretion, neurotransmission, and gene
expression, in which calcium acts as a second messenger.
The channels are composed of multiple heteromeric
subunits: α, β, γ and δ , which are coded for by several
Correspondence: José Carlos Rodríguez Pérez
Servicio de Nefrología y Unidad de Investigación.
Hospital Universitario de Gran Canaria Dr. Negrín.
Universidad de Las Palmas de Gran Canaria.
Bco. La Ballena, s/n.
35010 Las Palmas de Gran Canaria. Spain.
[email protected]
268
different genes. They are named using the chemical symbol
of the principal ion they regulate the passage of (Ca) and the
primary physiological regulator, voltage (v). The numerical
identifier corresponds to the gene subfamily to which the
channel corresponds (1-3), and the letter (A-I) indicates the
order in which it was identified, except subunit a1S, which
was assigned the letter S due to its presence in skeletal
muscle.
Subunit α1, which is coded for by CACNA1, appears to be
responsible for the main characteristics of these channels,
since it is involved in ion selectivity and conductivity and
sensitivity to voltage.1-3
The calcium currents registered in different cell types have
multiple pharmacological and physiological properties, so it
N. Buset Ríos et al. Vascular and metabolic properties of manidipine
is possible to group calcium channels into L, P/Q, N, R, and
T types.1
L-type (long-lasting) calcium channels are activated by
strong depolarisations, mediated by the prolonged flow of
calcium into a wide variety of cell types. In this manner,
these channels play a central role in the contraction and
excitation of skeletal, cardiac, and smooth muscle4 (Cav 1.2
[α1C]). They are responsible for muscle tone in arterial
smooth muscles, and have become a target for drugs to treat
hypertension and angina. In the kidney (Cav1.2 [α1C] and
Cav1.3 [α1D]), these channels promote the dilation of
preglomerular (afferent) arterioles, ostensibly increasing
intraglomerular pressure. Additionally, other L-type channels
are found in the skeletal muscle (Cav1.1 [α1S]), brain and
kidney (Cav1.2 [α1C], Cav1.3 [α1D]), pancreas (Cav1.3 [α1D]),
and retina (Cav1.4 [α1F]).1
Other lesser-known channel types are P/Q, N, and R, and
these also require strong depolarisation in order to be
activated.1
Contrary to the previously mentioned channel types, T-type
(transient) channels are activated by weak depolarisations,
and provoke a transitory flow of calcium.5 T-type channels
are present in the nervous system (Cav3.1 [α1G]), brain
(Cav3.1 [α1G,] Cav3.2 [α1H] and (Cav3.3 [α1D]), heart (Cav3.2
[(α1H]), kidneys (Cav3.1 [α1G], Cav3.2 [α1H]) and liver
(Cav3.2 [α1H]).1 These are involved in heart rate, vascular
smooth muscle contraction, and cell growth.4 T-type
channels have been implicated on several occasions in the
secretion of hormones such as renin, aldosterone, atrial
natriuretic peptide, and insulin. Only T-type channels (not Ltype) are found in postglomerular (efferent) arterioles, and so
the tone of these vascular muscles must be controlled by Ttype channels and angiotensin II AT1 receptors.
short reviews
In principle, L-type channel blocking is considered to be
the most important type in the regulation of vascular
functioning, since Cav1.2 is the major route of calcium
entry into skeletal muscle, heart, and kidney cells. 1,6
However, the non-haemodynamic action of T-type channel
blockers could have multiple beneficial effects by
inhibiting inflammatory processes (inhibition of Rho
kinases, NF-kB, leukocyte adhesion), blocking the reninangiotensin system, and blocking the sympathetic nervous
system (Table 1).7
TYPES OF CALCIUM CHANNEL BLOCKERS
Calcium channel blockers (CCB) are highly heterogeneous
molecules that can be grouped into: derived from
phenylalkylamine, such as verapamil; derived from
benzodiazepines, whose prototype is diltiazem; and derived
from 1,4-dihydropyridines, such as manidipine.8 These
molecules mainly block L-type channels.
The first generation of dihydropyridine calcium channel
blockers, such as nifedipine, are characterised by
instantaneous release, a short lifetime, and quick absorption.
In spite of a favourable metabolic profile, these drugs cause
some adverse effects such as sharp drops in blood pressure,
tachycardia, and sympathetic activation. In the second
generation of drugs, including nimodipine, the release of the
molecule is slower.9
The latest-generation CCB have a long lifetime and
prolonged action that significantly reduces blood pressure,
thus notably diminishing the secondary side effects of the
drug (Table 2). In contrast with traditional blockers, this new
group of molecules, including manidipine, blocks both Ltype and T-type channels.10
Table 1. Calcium channels
Type
Protein (subunit α)
Gene
Location
L
Cav1.1(α1S)
CACNA1S
Skeletal muscle
L
Cav1.2(α1C)
CACNA1C
Heart, brain, smooth muscle, adrenal gland, kidney
L
Cav1.3(α1D)
CACNA1D
Brain, kidney, pancreas
L
Cav1.4(α1F)
CACNA1F
Retina
T
Cav3.1(α1G)
CACNA1G
Brain, kidney, nervous system
T
Cav3.2(α1H)
CACNA1H
Brain, kidney, heart, liver
T
Cav3.3(α1I)
CACNA1I
Brain
P/Q
Cav2.1(α1A)
CACNA1A
Brain, hypophysis, kidney
N
Cav2.2(α1B)
CACNA1B
Brain, nervous system
R
Cav2.3(α1E)
CACNA1E
Brain, heart, hypophysis
Source: Hayashi K, et al. Circ Res 2007;100:342-53..
Nefrologia 2011;31(3):268-74
269
short reviews
Table 2. Calcium channel blockers
Molecule
Chemical structure
Mibefradil
Phenylalkylamine
Nifedipine
1.4- dihydropyridine
Nimodipine
Generation
Channel
Reference
L/T
Moosmang et al. 200646
1st
L
Hayashi et al. 20071
2nd
L/T
Peltz et al. 200947
Manidipine
3rd
L/T
Martínez-Martín 200748
Lercanidipine
3rd
L/T
Patel et al. 200949
Amlodipine
3rd
L/T
Nivaldipine
3rd
L/T
Nakano et al. 201050
Efonidipine
3rd
L/T
Cilnidipine
3rd
L/N
THE EFFECTS OF CCB ON CARDIOVASCULAR
MORBIDITY
Cardiovascular disease is clearly and consistently
related to blood pressure. The main objective of
antihypertensive therapy is to reduce both
cardiovascular and renal morbidity and mortality. In
order to achieve this, a target blood pressure level was
established at below 140/90mm Hg, although in patients
with diabetes or kidney disease, it appears that this limit
should be less than 130/80mm Hg. 11
According to the guidelines for the management of
arterial hypertension, 12 thiazide diuretics should be the
treatment of choice, although certain high-risk cases
could be treated with angiotensin II receptor antagonists
(ARA-II), CCB, or angiotensin-converting enzyme
(ACE) inhibitors as a first choice. 11 Precise indications
exist for the use of antihypertensive agents such as
CCB, ACE inhibitors, and ARA-II in order to prevent
the development of diabetes in hypertensive patients. 11
The CAMELOT study concluded that, as a monotherapy,
CCB are more efficient at diminishing cardiovascular events
and slowing the progression of atherosclerosis than ACE
inhibitors.13 With regard to CCB combined with other drugs,
Fogari et al. demonstrated that manidipine (CCB) and
delapril (ACE inhibitor) provide increased benefit over
olmesartan (ARA II) and hydrochlorothiazide, as this
combination reduces orthostatic blood pressure and does not
cause adverse metabolic effects.14
Other studies, such as the one carried out by the Japanese
Hypertension Society, affirm that CCB possess greater
antihypertensive efficacy than all other preferred
antihypertensive drugs available, without affecting blood
flow to the body’s organs. This characteristic makes this
group of drugs particularly indicated in elderly patients and
those with complications such as left ventricular
hypertrophy, tachycardia, angina pectoris, and chronic
cerebrovascular disease.15
270
In this respect, one trial treated 30 obese hypertensive
patients with amlodipine, manidipine, and cilnidipine,
revealing that these long-acting CCB reduce blood pressure
and also diminish resistance to insulin, suggesting valuable
cardio-metabolic properties.16
However, other studies have not observed significant
differences in the efficacy of reducing blood pressure
between different latest generation calcium channel
blockers.17,18
CCB AND INSULIN RESISTANCE. MANIDIPINE AND
THE EXPRESSION OF AP2
In terms of cardiovascular morbidity and mortality, arterial
hypertension and diabetes are key risk factors. These are
interrelated in a complex and multifactorial manner.
Hypertensive patients with metabolic syndromes (MS) have
an elevated risk of diabetes mellitus (DM). The incidence of
DM appears to increase in patients with AHT, partly due to
the high percentage of obese patients in both groups. The
UKPDS study demonstrated that high blood pressure and
glycaemia independently and additively increase the risk of
cardiovascular disease.19,20
In this respect, the MARIMBA study compared the effects of
administering manidipine and amlodipine21 in non-diabetic
MS patients, and found that blood pressure and C-reactive
protein (CRP) levels decreased with both types of treatment,
although manidipine also significantly reduced albuminuria
and insulin resistance, associated with an increase in serum
adiponectin levels. Manidipine also caused fewer adverse
effects.
By comparing manidipine with another CCB with similar
kinetic and lipophilic characteristics, such as lercanidipine,
manidipine is more effective in reducing insulin resistance in
obese and hypertensive patients.22 In other studies,
manidipine proves itself to be just as effective as
pioglitazone in reducing the expression of RAGE and the
Nefrologia 2011;31(3):268-74
The “lipotoxicity hypothesis” correlates type 2 diabetes with
a loss in capacity of adipose tissue to accommodate excess
calories. The loss in adipocyte differentiation makes the
excess calories accumulate primarily in the liver, pancreas,
and muscles, contributing to the development of insulin
resistance.24 We know that small adipocytes are sensitive to
insulin, as opposed to mature cells, which undergo
hypertrophy and become resistant to the hormone. For this
reason, favouring adipogenesis would contribute to reducing
insulin resistance in type 2 diabetes patients.
The improvement produced in insulin sensitivity by
dihydropyrimidine CCB is almost imperceptible. In the case
of nifedipine, which blocks only L-type channels, the body
becomes even more desensitised to insulin, and glucose
release is inhibited.16 However, studies with manidipine have
reported surprising results in this respect. Although some of
these studies were already taken into account, a clinical trial
performed with 64 hypertensive MS patients. The patients
were evaluated using NCEP/ATPIII criteria and randomly
assigned to manidipine or amlodipine treatments for 12
weeks. Similar reductions in blood pressure were observed
with both treatments, and the patients treated with
manidipine also experienced significant reductions in insulin
resistance.25 In this same manner, a more recent analysis on
insulin sensitivity and plasma fibrinogen in obese and
hypertensive patients compared the combination of
manidipine and delapril versus olmesartan and
hydrochlorothiazide. It demonstrated that the first
combination significantly reduced insulin resistance and
plasma fibrinogen levels, in spite of the fact that the
reduction in blood pressure values would indicate similar
efficacy between both combinations.26 A later study
compared the combination of manidipine and delapril with
losartan and hydrochlorothiazide in patients with diabetes
and microalbuminuria, and concluded that the first
combination was the more useful therapeutic option for
these patients.27
Experiments have shown that manidipine, but not
amlodipine or lercanidipine, activates PPAR-γ in 3T3-L1 rat
adipocytes.23,28 In our studies, we have observed that NIH3T3
cells treated with manidipine29 experience increased PPAR-γ
(Peroxisome Proliferator-activated Receptor gamma)
expression and adipocyte differentiation 2 (aP2) gene
expression, which can be considered as evidence of the
expression of the first (Figure 1). These results indicate
mechanisms that link manidipine to the increase observed in
insulin sensitivity in hypertensive, diabetic patients and with
de novo adipocyte formation. In this sense, the increase in
Nefrologia 2011;31(3):268-74
intracellular calcium levels has been observed to inhibit
preadipocyte differentiation.30 This contrasts with the normal
role of calcium in faster processes, such as neurosecretion,
excitation, and contraction.
Adipogenesis, as other differentiation processes, depends on
stimulating transcription factors, such as PPAR-γ, and
inhibitors such as the GATA family, which in turn is
activated by extracellular signals. Calcium homeostasis has
been studied with special emphasis on calreticulin, which is
one of the main calcium binding proteins in the lumen of the
endoplasmic reticulum, and is largely responsible for a rapid
calcium exchange. One study performed with stem cells and
3T3-L1 preadipocytes demonstrated how calreticulin can
modulate adipogenesis through a negative feedback
mechanism. PPAR-γ is a potent transcription activator for
calreticulin, as it binds to its promoter. In this manner, it
increases the expression of calreticulin, but once this protein
is over-expressed, calreticulin inhibits the cis-bond of the
PPAR-γ-RxR heterodimer to PPAR-γ response elements
(PPRE), thus cancelling the transcriptional activation of
PPAR-γ by fatty acids. Through this mechanism, calreticulin
negatively regulates both the expression of PPAR-γ and
other critical proadipogenic transcription factors such as
C/EBPa.31
Manidipine’s calcium channel blocking activity could
impede the entrance of calcium into the cells, thus reducing
calcium concentrations in the endoplasmic reticulum, and in
turn, that of calreticulin, favouring the differentiation of
adipocytes.
EFFECTS OF CCB ON MICROALBUMINURIA
The renal protection is associated with cardiovascular
protection as well, and the evolution of albuminuria is an
a
200
150
aP2 (%)
production of ROS, as well as reducing CRP levels. These
experiments with specific inhibitors have concluded that the
mechanism depends on PPAR-γ. This mechanism could
explain the reduced inflammatory effect of hyperglycaemia
and vascular damage.23
short reviews
100
50
0
a
Control
Differ.
6h
12 h
24 h
P <.05. Differ: differentation cocktail.
Figure 1. Exposure of NIH-3T3 preadipocyte cells to manidipine
activates the expression of the aP2 gene in a time-dependent
manner.
271
short reviews
excellent predictor of both the evolution of renal function
and the development of cardiovascular complications.32 The
presence of microalbuminuria makes the use of ACE
inhibitors or ARA-II necessary, even as CCB are still
considered for combined therapy. In the absence of
albuminuria, and with maintained or diminished glomerular
filtration rate, CCB could be the first pharmacological
option. However, a high percentage of patients do require
ACE inhibitors and/or ARA-II.33
anti-inflammatory effects of manidipine and other CCB such
as amlodipine, mediated by the increased expression of
endothelial nitric oxide synthase (eNOS) and the inhibition
of angiotensin converting enzyme (ACE) expression, but not
their possible activity in reducing blood pressure. In this
study, the authors observed how manidipine normalises the
reduction in the expression of both the eNOS gene and
protein, and reduces the over-expression of NADPH oxidase,
VCAM, and MCP-1 in hypertensive rat aortas.41
Furthermore, manidipine has another beneficial effect on
atherogenesis, as it inhibits the expression of LOX-1, a lowdensity lipoprotein receptor induced into action by
angiotensin II.43
Contrary to other dihydropyridines, manidipine blocks Ttype channels of efferent arterioles, which diminishes
glomerular pressure and, consequently, albumin excretion,
but at the same time it blocks L-type channels, thus
favouring the dilation of the afferent arteriole. In this
manner, T-type calcium channel blockers (CCB)1,7,34
influence haemodynamics through their antihypertensive
effect. Thus, we could consider their effect as protective
against kidney damage, since the kidney is one of the target
organs in hypertensive and diabetic patients. The
AMANDHA study (Efficacy and Safety Assessment of
Manidipine in Type 2 Diabetic Patients with Hypertension
and Microalbuminuria Uncontrolled with Renin-Angiotensin
System Blockers)35 compared manidipine and amlodipine in
diabetic patients with uncontrolled hypertension and
microalbuminuria. Although both CCB are equally effective
in reducing CRP and blood pressure, the first implies fewer
adverse effects. Also, the reduction in albuminuria and
insulin resistance was significantly higher in patients treated
with manidipine. A recent study demonstrated yet again that
manidipine is capable of significantly reducing albumin
urine excretion in patients with essential hypertension
without causing adverse effects, and so the combination of
manidipine with renin-angiotensin antagonists could be
beneficial in these cases.36
Sun X et al.44 recently demonstrated that both in mature
differentiated adipocytes and 3T3-L1 cells, and in cocultures of both cell types, calcitrol increases the expression
of inflammatory molecules such as MCP-1, MIF, M-CSF,
MIP, IL-645, TNF and CD14. Treatment with nifedipine or
dinitrophenol inhibits the activity of calcitrol, which could
reveal a calcium-dependent mechanism that requires
mitochondrial uncoupling. As such, we could expect the
blockage of calcium channels with manidipine to also show
anti-oxidative and α anti-inflammatory effect by reducing
intracellular calcium levels.
Our preliminary studies on smooth muscle cells
revealed an increase in endothelial nitric oxide
synthase (eNOS) gene after being treated with
manidipine. In response to many types of aggression,
the expression of eNOS in cells treated with
manidipine is essentially stable, compared to the
control culture. This data may reveal a beneficial effect
of CCB against endothelial dysfunction (Figure 2).
MANIDIPINE AND OXIDATIVE STRESS
The beneficial effects of calcium blockers in macrovascular
endothelial cells must be demonstrated and justified through
mechanisms that do not include calcium channels, since
these are not expressed in endothelial cells.39,40 To this end,
some authors have postulated that the action of DHP in this
type of tissue are related to their lipophilicity.41
Oxidative stress plays a fundamental role in the development
of atherosclerosis. Toba et al. pointed out the antioxidant and
272
200
a
150
eNOS (%)
Endothelial structure and function could improve considerably
with the use of CCB. Research such as the INSIGHT study
(International Nifedipine Intervention as a Goal in
Hypertension Treatment) and MIDAS study (Myocardial
Infarction Data Acquisition System) demonstrates the
superiority of these drugs as compared to thiazide diuretics in
terms of lower increases in intimal thickness.33,37,38
100
50
0
Control Manidipine
a
AngII Manidipine/AngII
P <.05.
Figure 2. The Expression of eNOS in cells treated with
angiotensin II and manidipine is significantly greater than in
cells treated with just angiotensin II
Nefrologia 2011;31(3):268-74
short reviews
CONCLUSIONS
T-type calcium channel blockers provide protection to the
kidneys, as they improve glomerular microcirculation due
to their vasodilatory effect both on afferent and efferent
arterioles. Manidipine stands out from among these types
of calcium channel blockers due to its anti-inflammatory
activity, which does not rely on the renin-angiotensin
system, and because of its possible beneficial effects
against endothelial dysfunction.
12.
13.
14.
Acknowledgements
15.
This manuscript was developed with the aid of authors from the Fundación Mapfre-Guanarteme (Mapfre-Guanarteme Foundation) and Laboratorios Chiesi (Chiesi Laboratories), who we thank for their support and
collaboration. The authors declare a Research Agreement between Chiesi Farmaceutica S.p.A. and the Research Unit of the Dr. Negrín Gran Canaria University Hospital.
16.
17.
REFERENCES
1. Hayashi K, Wakino S, Sugano N, et al. Ca2 channel subtypes and
pharmacology in the kidney. Circ Res 2007;100:342-53.
2. Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM. Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel
alpha1C subunit. Proc Natl Acad Sci USA 2006;103:17024-9.
3. Bergh JJ, Shao Y, Puente E, Duncan RL, Farach-Carson MC. Osteoblast Ca(2 ) permeability and voltage-sensitive Ca(2 ) channel expression is temporally regulated by 1,25-dihydroxyvitamin D(3). Am
J Physiol Cell Physiol 2006;290:C822-C31.
4. Tanaka H, Shigenobu K. Pathophysiological significance of T-type
Ca2 channels: T-type Ca2 channels and drug development. J Pharmacol Sci 2005;99:214-20.
5. Catterall WA, Striessing J, Terrance P, Snutch P, Perez-Reyes E. International Union of pharmacology. XL. Compedium of Voltage-Gated
Ion Channels: Calcium channels. Pharmacol Rev 2003;55:579-81.
6. Cheng X, Liu J, Asuncion-Chin M, et al. A novel Ca(V)1.2 N terminus
expressed in smooth muscle cells of resistance size arteries modifies
channel regulation by auxiliary subunits. J Biol Chem 2007;282:2921121.
7. Hayashi K, Wakino S, Homma K, Sugano N, Saruta T. Pathophysiological significance of T-type Ca2 channels: role of T-type Ca2 channels in renal microcirculation. J Pharmacol Sci 2005;99:221-7.
8. Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J
Med 1999;341:1447-57.
9. Gojanovic B, Feihl F, Liaudet L, Waeber B. Concomitant calcium
entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension. J Renin Angiotensin Aldosterone Syst 2008;9:1-9.
10. Hayashi K, Nagahama T, Oka K, Epstein M, Saruta T. Disparate effects of calcium antagonists on renal microcirculation. Hypertens
Res 1996;19:31-6.
11. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint
Nefrologia 2011;31(3):268-74
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
Bonny A, Lacombe F, Yitemben M, et al. The 2007 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens
2008;26:825-6.
Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents
on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled
trial. JAMA 2004;292:2217-25.
Fogari R, Derosa G, Zoppi A, et al. Effects of manidipine/delapril versus olmesartan/hydrochlorothiazide combination therapy in elderly
hypertensive patients with type 2 diabetes mellitus. Hypertens Res
2008;31:43-50.
Ebina T, Kimura K, Umemura S. Calcium antagonists: current and
future applications based on new evidence. Calcium channel blockers and JSH 2009. Clin Calcium 2010;20:16-22.
Ueshiba H, Miyachi Y. Effects of the long-acting calcium channel
blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients. Intern Med
2004;43:561-5.
Payeras AC, Sladek K, Lembo G, Alberici M. Antihypertensive efficacy and safety of manidipine versus amlodipine in elderly subjects
with isolated systolic hypertension: MAISH study. Clin Drug Invest
2007;27:623-32.
Zanchetti A, Omboni S, La Commare P, De Cesaris R, Palatini P. Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential
hypertension. J Cardiovasc Pharmacol 2001;38:642-50.
Scheen AJ, Paquot N, Lefebvre PJ. United Kingdom Prospective Diabetes Study (UKPDS): 10 years later. Rev Med Liege 2008;63:624-9.
Gore MO, McGuire DK. The 10-year post-trial follow-up of the United Kingdom Prospective Diabetes Study (UKPDS): cardiovascular
observations in context. Diab Vasc Dis Res 2009;6:53-5.
Martínez Martín FJ. Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study. Expert Review of Cardiovascular Therapy 2009;7:863-9.
Li CJ, Shi ZD. Calcium channel blockers. Clin Ther 2009;31:1652-63.
Nakami T, Martinez MFJ. Manidipine prevents hepatic C-reactive
protein production and reactive oxygen species generation by
down-regulation of the age receptor expression, dependent on
PPAR-gamma activation. J Hypertens 2007;25:S119-S20.
Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin
blockade prevents type 2 diabetes by formation of fat cells. Hypertens 2002;40:609-11.
Martínez Martín FJ. Manidipine (but not amlodipine), increases insulin sensitivity and rises plasma adiponectin cocentrations in hypertensive non-diabetic patients with metabolic syndrome and impaired fasting glucose. Diabetologia 2005;48(Suppl 1):A374.
Fogari R, Derosa G, Zoppi A, et al. Effect of delapril/manidipine vs
olmesartan/ hydrochlorothiazide combination on insulin sensitivity
and fibrinogen in obese hypertensive patients. Intern Med
2008;47:361-6.
Kohlmann O, Jr., Roca-Cusachs A, Laurent S, et al. Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive
patients with type 2 diabetes and microalbuminuria. Adv Ther
2009;26:313-24.
273
short reviews
28. Oshimura H, Nakami T, Javier MF. Manidipine has a marked nonhaemodynamic nephroprotective action; Partly dependent on PPARgamma activation, and synergistic with angiotensin receptor blockade. J Hypertens 2007;25(Suppl):S8.
29. Buset Ríos N, Rodríguez Esparragón F, Rodríguez Pérez J. Cardiometabolic properties of manidipine: beyond lowering arterial
pressure?. Nefrologia 2009;29(3):203-7.
30. Meldolesi J. Inhibition of adipogenesis: a new job for the ER Ca2
pool. J Cell Biol 2008;182:11-3.
31. Szabo E, Qiu Y, Baksh S, Michalak M, Opas M. Calreticulin inhibits commitment to adipocyte differentiation. J Cell Biol 2008;182:103-16.
32. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in
adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive
Committees Working Group. Am J Kidney Dis 2000;36:646-61.
33. Segura J, García-Donaire JA, Ruilope LM. Calcium channel blockers
and renal protection: insights from the latest clinical trials. J Am Soc
Nephrol 2005;16 (Suppl 1):S64-S6.
34. Sabbatini M, Leonardi A, Testa R, Vitaioli L, Amenta F. Effect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats. Hypertension 2000;35:775-9.
35. Martínez-Martín FJ, Saiz-Satjes M. Add-on manidipine versus amlodipine
in diabetic patients with hypertension and microalbuminuria: the AMANDHA study. Expert Review Cardiovascular Therapy 2008;6:1347-55.
36. Galceran J, Plana J, Felip A, et al. Manidipine treatment in patients with
albuminuria not sufficiently reduced with renin-angiotensin system
blockers. Expert Review Cardiovascular Therapy 2010;8:751-7.
37. Rosenthal T. Role of calcium channel blockers in the future, in view
of the INSIGHT Study. Kidney Int 2002;82(Suppl):S32-S5.
38. Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of
the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A
randomized controlled trial. JAMA 1996;276:785-91.
39. Simon A, Levenson J. Effects of calcium channel blockers on atherosclerosis: new insights. Acta Cardiol 2002;57:249-55.
40. Adams DJ, Barakeh J, Laskey R, Van Breemen C. Ion channels and
regulation of intracellular calcium in vascular endothelial cells. FASEB J 1989;3:2389-400.
41. Berkels R, Breitenbach T, Bartels H, et al. Different antioxidative po-
tencies of dihydropyridine calcium channel modulators in various
models. Vasc Pharmacol 2005;42:145-52.
42. Toba H, Nakagawa Y, Miki S, et al. Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of
endothelial nitric oxide synthase and the inhibition of angiotensin
converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood
pressure-lowering effects of amlodipine and manidipine. Hypertens
Res 2005;28:689-700.
43. Toba H, Shimizu T, Miki S, et al. Calcium [corrected] channel
blockers reduce angiotensin II-induced superoxide generation
and inhibit lectin-like oxidized low-density lipoprotein receptor1 expression in endothelial cells. Hypertens Res 2006;29:10516.
44. Sun X, Zemel MB. Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk. J Nutr Biochem
2008;19:392-9.
45. Costa S, Zimetti F, Pedrelli M, Cremonesi G, Bernini F. Manidipine
reduces pro-inflammatory cytokines secretion in human endothelial
cells and macrophages. Pharmacol Res 2010;62:265-70.
46. Moosmang S, Haider N, Bruderl B, Welling A, Hofmann F. Antihypertensive effects of the putative T-type calcium channel antagonist
mibefradil are mediated by the L-type calcium channel Cav1.2. Circ
Res 2006;98:105-10.
47. Peltz A, Sherwani SI, Kotha SR, et al. Calcium and calmodulin regulate mercury-induced phospholipase D activation in vascular endothelial cells. Int J Toxicol 2009;28:190-206.
48. Martínez Martín FJ. Calcium channel-blockers for managing metabolic syndrome-associated hypertension. Trials with manidipine. Nefrologia 2007;27(Suppl 6):26-35.
49. Patel RJ, Patel PD, Patel MM, Patel NJ, Thyagarajan B. Mechanisms
of potentiation of Angiotensin II-induced contractile response of isolated rat aorta by hydrogen peroxide and tert-butyryl hydroperoxide. Indian J Pharmacol 2009;41:140-3.
50. Nakano N, Ishimitsu T, Takahashi T, et al. Effects of efonidipine, an
L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients. Int Heart J
2010;51:188-92.
Sent to review: 22 Sep. 2010 | Accepted: 30 Nov. 2010
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special article
Ethical challenges in transplant practice in
Latin America: the Aguascalientes Document
A. Baquero1, J. Alberú2, Documento de Aguascalientes*
General Coordinator. President of STALYC. Transplant Institute, Dr Baquero Foundation. Santo Domingo. Dominican Republic.
General Coordinator. Head of the Transplant Department. Salvador Zubirán National Institute of Medical Sciences and Nutrition.
Mexico city, Mexico.
1
2
Nefrologia 2011;31(3):275-85
doi:10.3265/Nefrologia.pre2011.Feb.10820
ABSTRACT
Organ transplants are currently an alternative
treatment for a growing number of diseases, which
were previously considered terminal. Bioethics has
played an important role since the advent of this
surgical technique, mainly in defining death criteria
and the optimum transplantation conditions. This issue
continues being a universal focal point, mainly
concerning the equity of access to transplantation,
criteria for assigning deceased-donor organs, livingdonor safety, risk of commercial trade, fair access to
high-quality immunosuppressant drugs and organ
transplant legislation. These problems are characteristic
of Latin America and the Caribbean, and were the
driving force behind the First Latin American Bioethics
and Transplant Forum, sponsored by the Latin
American and Caribbean Transplant Society (STALYC),
and all the transplant societies from subsidiary
countries. The “Document of Aguascalientes” is a
collection of all the ideas and opinions that were
proposed during round tables and analyses. The
document is divided into four sections: 1) living donor;
2) organ trading and transplant tourism; 3) the state
role in legislation, transplant distribution and
coverage; and 4) access to and quality of
immunosuppression. The Bioethics and Transplant
Forum was created to analyse and find solutions for
this complex issue. The “Document of Aguascalientes”
aims to serve as an instrument of expression and a
vehicle for the ideas put forward during the Forum, so
that they can act as transplant practice guidelines in
Latin America.
Correspondence: Ashley Baquero
General Coordinator. President of STALYC. Transplant Institute,
Dr Baquero Foundation. Santo Domingo. Dominican Republic
Ortega y Gasset 46. Santo Domingo. Dominican Republic.
[email protected]
RESUMEN
Keywords: Transplantation. Bioethics. Latin America.
Organ trafficking.
Desafíos éticos en la práctica de trasplantes en América
Latina: Documento de Aguascalientes
Los trasplantes de órganos son actualmente alternativas de
tratamiento para un creciente número de enfermedades,
* Group members:
Ashley Baquero. Dominican Transplant Institute, Dr Baquero Foundation. President of STALYC. Santo Domingo, Dominican Republic. General Coordinator.
Josefina Alberú. Head of the Transplant Department. Salvador Zubirán National Institute of Medical Sciences and Nutrition. Mexico city, Mexico. General
Coordinator. Eduardo Santiago Delpin. Director of the Transplant Programme, Auxilio Mutuo Hospital. San Juan, Puerto Rico. Round table Coordinator.
Eduardo Tanús. Professor of the Medical Humanities Department, National University of Buenos Aires. Bioethics Committee of the Argentinean Transplant
Society. Round table Coordinator. Rafael Reyes Acevedo. Head of the Transplant Department. Miguel Hidalgo Hospital, Aguascalientes, Mexico. Round table
Coordinator. María Amalia Matamoros. Hepatobilliary and Transplant Surgeon. Director of the Centre of Liver Transplant and Hepatobilliary Surgery. Costa
Rican Social Security Funding. San José, Costa Rica. Round table Coordinator. Roberto Tanús. Professor of the Organ and Tissue Transplant Programme of the
Medicine Faculty in the La Planta National University, Buenos Aires, Argentina. Round table Coordinator. Mariela Salomé Bacile. Legal advisor from the
Argentinean Transplant Society. Full Member of the Bioethics Committee of the Argentinean Nephrology Society. Argentina. Round table Coordinator.
Sergio Orihuela. Clinic Hospital of Republic University and Italian Hospital. Uruguay. Round table Coordinator. Mario Abbud Fihlo. Head of the Organ and
Tissue Transplant Centre, Urology and Nephrology Institute, S.J. University Hospital. Rio Preto, Brazil. Round table Coordinator. María del Carmen Bacque.
Transplant Programmes Coordinator. Health Minister of the Autonomous City of Buenos Aires. Argentina. Round table Coordinator. Domingo Casadei.
Director of Kidney and Pancreas Transplant Programme, Institute of Nephrology. Buenos Aires, Argentina. Round table Coordinator.
275
special article
A. Baquero et al. Aguascalientes Document
otrora consideradas terminales. Los aspectos de orden bioético han tenido una relevancia particular desde los inicios,
principalmente en la definición de criterios de muerte y en
las condiciones óptimas para la realización de los trasplantes. Esta problemática sigue siendo un foco de atención
universal, principalmente en lo referente a equidad en el
acceso a trasplante, criterios de asignación de órganos de
donante fallecido, seguridad en el donante vivo, riesgo de
prácticas de comercialización, acceso equitativo a fármacos
inmunosupresores de alta calidad y legislación sobre trasplantes de órganos. Esta problemática tiene rasgos particulares en la región de América Latina y el Caribe; ello motivó la realización del Primer Foro Latinoamericano de
Bioética en Trasplante, con el auspicio de la Sociedad de
Trasplantes de América Latina y el Caribe (STALYC), así
como de todas las Sociedades de trasplantes de los países
subsidiarios. El «Documento de Aguascalientes» es una recopilación de las ideas y opiniones vertidas durante las mesas de discusión y análisis. Se presentan en cuatro apartados: 1) donante vivo; 2) turismo y comercio de trasplante;
3) papel del Estado en legislación, distribución y cobertura
para trasplante, y 4) acceso y calidad de la inmunosupresión. El Foro de Bioética en Trasplante se debe a la irrenunciable necesidad de analizar y buscar soluciones a una compleja problemática; el «Documento de Aguascalientes»
pretende servir como instrumento de expresión y difusión
de las ideas vertidas en el Foro para que sirvan como guías
en la práctica de trasplantes en América Latina.
been clearly defined,12-18 and have been accepted almost
universally for more than 4 decades.19-22 Likewise, transplant
regulations and optimal conditions have also been defined.
Palabras clave: Trasplante. Bioética. América Latina.
Tráfico de órganos.
4. Countries need legislative systems that ensure
optimum conditions for donation and human organ
transplantation.
PREAMBLE
Transplant medicine is practiced with great dignity and
professionalism throughout the world. It is an exemplary
field of contemporary science and its scientific contribution
has been vast and generous, with thousands of human
beings having benefited from it. Nevertheless, it is
important to recognise that there are key issues concerning
transplant practice.
The important technical and scientific advances over the past
six decades have allowed organ transplant to become an
optimum alternative for an ever-increasing number of
patients with irreversible organ failure. Offering these
procedures to patients has required great generosity and
altruism from donors and their families.
Since the 1950s, when the first human transplants were
performed,1-3 the bioethical complexity involved in
transplantation has become apparent.4-6 It was initially due to
the need to establish death criteria, and of course, because
transplant practice incorporated an unprecedented and
extremely complex variable: the organ donor.
Many organ transplant-related bioethical issues arose during
the second half of the 20th century, encouraging intense debate
and constituting a real challenge for scientific, legal, moral
and religious dimensions throughout these years.4-11
International standardisation of transplant practice has been
the gradual fruition of these debates. Brain-death criteria have
276
Various arguments explain why the bioethical debate on
transplantation is still open. Some of the most important
(listed below) inspired the First Latin American Bioethics
and Transplant Forum:
1. Organ transplantation has become an ever-increasingly
important part of the therapeutic armament for a large
number of diseases, which were previously considered
terminal. This creates the need to ensure that patients have
correct and fair access to medical assistance and to
medical treatments which entail highly elevated costs.
2. Until now, deceased-donor transplants have always been
a scarce resource. Given the growing number of patients
that require a transplant, it is absolutely essential to ensure
equity in access to this resource.
3. Living donors are not an exception. Given the growing
demand for transplant services, there is always the
possibility that transplant programmes become more
permissive in accepting potential living donors, even
when the donor’s safety may be put at risk. Furthermore,
the pressure that this demand represents may promote
organ trading.
Recently, the sixty-third World Health Assembly
unanimously endorsed the WHO’s Guiding Principles on
Human Cell, Tissue and Organ Transplantation, and
approved various measures for optimising transplant safety
and efficacy. The document states: “to oppose […] organ
trafficking and transplant tourism and encourage healthcare
professionals to notify relevant authorities when they
become aware of such practices […] and to improve the
safety and efficacy of donation and transplantation by
promoting international best practices.”23
However, there is global disparity between the growing
demand and limited supply of transplant organs, meaning
that undesirable practices have been revealed, such as:
“...trafficking in human beings who are used as sources
Nefrologia 2011;31(3):275-85
of organs and of patient-tourists from rich countries who
travel abroad to purchase organs from poor people…,”
as was recently expressed in the Declaration of Istanbul.24
The meeting that brought about this Declaration was
based on the principles of the Universal Declaration of
Human Rights. 25 This document presents the pressing
need for international collaboration to seek a global
consensus for optimising donation and transplantation
practices. It was the fruit of the meeting between more
than 150 representatives of international medical and
scientific organisations, government members, social
scientists and ethics specialists. The meeting emphasised
the fact that “the legacy of transplantation must not be
the impoverished victim of organ trafficking and
transplant tourism but rather a celebration of the gift of
health by one individual to another.” 24 Furthermore,
debate on the matter has a long history and tradition, and
the central objective has always been to protect the donor
and to perform the transplantation under the best
conditions, with certified programmes and duly educated
and qualified staff.26-32
The efforts made by healthcare authorities and other
organisations involved in transplantation throughout
the world to promote the Declaration of Istanbul has
been commendable. Its aim is an unprecedented attempt
to organise and standardise the best possible donation
and transplantation practices. Many countries have
endorsed the guidelines stated in the Declaration, and
they have even positively influenced the adoption of
its regulations.
Latin America and the Caribbean is a multicultural region
with great diversity and contrasts. It also possess common
grounds concerning transplants, since, despite its uneven
education and health development, studies from the past
decade reveal that transplants are increasingly being used
in all countries in this region. The results from the Latin
American Transplant Registry, a feature of the Latin
American and Caribbean Transplant Society (STALYC),33
show that deceased donations increased by 3.8 per million
population (pmp) in 6 years, with a perspective to reach an
average of 20pmp in 10 years, with a growth rate of 11.5pmp per year.
The same trend is observed for different types of organ
transplants during the same analysis period (10 years). The
annual growth rate for kidney transplant was 7%,
(15.7pmp). Liver transplant was somewhat higher, 11%
(3.4pmp), and the increase in heart transplant was 5.8%.33
The region’s potential places it in a particularly interesting
positioning, which allows us to further the progress already
achieved, improving the system’s weaknesses, which is
especially caused by the socioeconomic reality and health
policies present in each country.
Nefrologia 2011;31(3):275-85
special article
Progress must be made in creating plans that guarantee
accessibility, transparency, and quality in transplantation
in Latin America and the Caribbean.
The idea behind the first Bioethics and Transplant Forum
was conceived at the core of the Latin American and
Caribbean Transplant Society. The Forum originated
because a platform for analysing the region’s situation was
lacking. We saw that reflection was needed and that
solutions would be necessary in some cases and consensus
in others. However, we would only be able to make
proposals for solutions in some instances. The Latin
American transplant community decided that it could in no
way continue being indifferent to such problems.
The Forum has not only focused on issues concerning
transplant bioethics (although a priority), it has also
proposed to evaluate the fundamentals with regard to which
transplant and deceased-donor organ distribution
legislation applies to these countries, acknowledging its
qualities and proposing solutions for its shortcomings,
which are very much associated with the correct
application of fundamental ethical principles. It is also
essential to analyse the way in which health authorities
from these countries attend to the permanent and universal
care coverage required by transplant recipients, including
immunosuppressive therapy and its quality, as well as the
commitment implied in the short- and long-term
monitoring of living donors.
With the aim of producing a sufficiently detailed and useful
document, transplant doctors and bioethics specialists in
Latin America and the Caribbean were convened to
participate in developing the Forum and were assigned
different tasks. They examined in depth the practices that
currently prevail in our countries, detecting the weaknesses
and proposing solutions which were later assessed and
discussed in work groups throughout the first Bioethics and
Transplant Forum held in Aguascalientes, Mexico, from 24 September 2010. During the event, the coordinators
analysed opinions and agreed upon proposals at each of the
four round tables. Once each group had concluded their
discussions, all of the Forum participants attended a
plenary session in which the results and proposals for each
matter were presented and consensus reached. A draft
document, including points of reflection, analysis criteria
and action guidelines, was then produced and was sent to
all of the participants so that they could evaluate it and
provide their final comments.
Four topics were chosen for discussion during the First
Bioethics and Transplant Forum:
1. Living donor.
2. Organ trading and transplant tourism.
277
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3. The state role in legislation, transplant distribution and
coverage.
experienced. As such, resources, taxes, and opportunities are
shared fairly.
4. Access to and quality of immunosuppression.
The justice principle in bioethics refers to access to health
resources and health promotion, offering a response to the
community’s needs and protecting the State.
GENERAL PRINCIPLES RECOMMENDED
The main bioethics fundamentals that must be considered are
dignity and beneficence, integrity and nonmaleficence,
precaution and/or vulnerability, autonomy and responsibility,
distributive and local justice.
Bioethics, as a science and an art, is continuously
evolving. Therefore, new principles have been
formulated to clarify the conflicts that imply progress in
life sciences, as well as reintroducing others. These first
principles of good will, nonmaleficence, autonomy and
justice were formulated in an English-speaking context,
but new contributions in the field of human know-how
are therefore necessary in our environment, given that
bioethics have globalised.
The term Human Dignity means that the person has worth
but not a price, i.e. he or she is not on object of gain Principle
of beneficence: in this context it is understood as acting on
the best interest of the donor and recipient.
We understand integrity and nonmaleficence as being the
patient’s right to preserving his or her functional unit, and
precaution and/or vulnerability represent the threat to the
fragility of a given person due to biological, psychological
and cultural risk.
The terms equity, worth and ownership, or the expression “to
which one has right” have been used in health services to
explain distributive justice. A situation is considered fair
when a person receives the care to which he or she has right.
Injustice emerges when an individual is deprived of the care
that he or she should receive due to his or her need or social
conditioning.
Distributive justice seeks to supervise the methods employed
to successfully assign a replacement therapy, such as
transplantation, with the aim of avoiding discriminatory
effects.37-39
The Aguascalientes Document also considers important the
definitions of solidarity and subsidiary:
Solidarity
If every human being has the right to find what was needed
for his/her growth and development, solidarity means that
we take on the needs of other people who do not have these
resources, so that they are able to obtain the means of survival
and the instruments of personal progression.
Subsidiary
Autonomy
The word autonomy comes from the Greek autos (self) and
nomos (law). Being autonomous involves taking on the right
to have one’s own opinions, making choices and performing
actions based on values and personal beliefs. We must always
respect people’s points of view and rights, provided that their
ideas and actions are not detrimental to other or to
themselves.34,35
The principle responsibility is defined as the obligation that
everyone who has access to science and technology is aware
of one’s own actions, which should respect human life and
preservation.36
In a social reality where there is inequality of opportunities,
this principle’s aims is that those who know more, are more
capable and have more may see and attend to those who are
lacking. This does not limit the initiative or the responsibility
of people and social groups, but makes them be more valued,
promoting and encouraging them.
Furthermore, we believe that it is of utmost importance that a
joint-responsibility is established between the medical team
and the donor-recipient pair and their social environment.
This joint-responsibility does not exempt state responsibility.
It is therefore necessary to highlight the following:
Informed consent
Distributive and local justice
The expression distributive justice refers to the suitable
distribution of the goods and/or burdens belonging to a given
society so as to compensate for the inequalities that are
278
In the Aguascalientes Document we reiterated that the
informed consent must be used with regard all components
in order to safeguard the donor’s and the patient’s autonomy
throughout the transplant procedure. We can summarise these
components as:
Nefrologia 2011;31(3):275-85
Voluntary action
It must be guaranteed that donors have freely chosen to
subject themselves to a procedure, medical treatment or
clinical study without having being coerced, persuaded or
manipulated.
Right to information
Information must be easily understandable and must explain
the object of the study, treatment or medical procedure. It
must clearly explain the benefits, short-, medium-, and longterm risks of the procedure or the medical treatment, as well
as the alternative therapies.
special article
to live with a single kidney. In fact, many people considered
as good candidates for kidney donation are found to be at
the limit of current criteria, concerning age, weight, blood
pressure, and could be at risk in the short- or long-term.
Similar situations can arise for living donors of other organs
(e.g. liver).
It is therefore considered to be the responsibility of each
transplant programme to establish a system ensuring that the
donor undergoes detailed assessment to guarantee minimal
additional risks. This task would ideally be performed by an
independent group of transplant experts who assess the
donor at every stage of the procedure: pre-surgical
assessment, surgery; immediate post-operative care; and
long-term treatment to monitor this person’s overall health.
It is essential for there to be an interdisciplinary transplant
committee which helps in decision making.
Understanding
The patient’s level of understanding should be assessed
by different people, as well as the informing doctor. This
information may be provided by a psychologist, social
worker or a nurse who fully understands the procedure
that is being offered to the patient or the organ donor.
The patient must be given the information in their mother
tongue or the regional dialect, providing the patient with
translation or interpreting services if necessary. The
written document granting authorisation shall be signed
by the potential donor, and if it is not provided in his or
her mother tongue, it shall be signed by the translator and
at least two civil servants from the institution, testifying
that information that has been consented to in writing is
the same as that which appears in the document. It is
necessary to take into consideration the person’s
education and social background with the aim of
understanding whether he or she has completely
understood the information given both verbally and in
writing.
The Societies and law-makers in each country should use
strategies that produce national laws based on
international law models, so as to achieve and maintain
optimum results and protect recipients’ and donors’
rights.
Nonmaleficence should be a priority over other bioethical
principles, so as to protect donors with additional risks,
even when the donor wishes to practice his or her autonomy,
insisting on donating.
DEFINITIONS
1. Blood-related living donor. Genetically-related donor
with first, second, third or fourth degree of consanguinity
with the recipient (father, mother, grandparents, aunties
and uncles, and cousins).
2. Non-blood related living donor.
A. Emotionally-related living donor. Donors that are not
blood- or genetically-related, but which have a strong
emotional link which is perceived and evident, and can
be determined and evidenced. Spouses, common-law
partners, step-parents, and, step-children are included in
this category.
B. Non-related living donor. Donors which are neither bloodor emotionally-related, such as:
-
Altruistic donor. Any person that offers an organ to
any other person that is ill, even if a stranger, for the
good and benefit of someone else and for purely
humanitarian reasons.
The evaluation of a potential donor should only be limited to
certain bio-psychological aspects. However, it is difficult to
be able to ensure that the individual is not part of other
underlying environmental circumstances, which may be
capable of influencing his or her final decision.
-
Crossover donation. Crossing over donor and
recipient pairs, whether genetically- or emotionallyrelated, with ABO incompatibility, sensitisation,
hereditary kidney disease or because no other donor
is available.
The kidney donor may be subject to risks, both during and
after the surgical procedure, given that he or she will have
-
Paid donors. The person is subject to “regulated” or
illegal sale of organs.
LIVING DONOR
Nefrologia 2011;31(3):275-85
279
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RECOMMENDATIONS FOR ACCEPTING A LIVING
DONOR
The Aguascalientes Document endorses the following
definitions from the Declaration of Istanbul24:
-
Organ trafficking is the recruitment, transport, transfer,
harboring or receipt of living or deceased persons or their
organs by means of the threat or use of force or other
forms of coercion, of abduction, of fraud, of deception, of
the abuse of power or of a position of vulnerability, or of
the giving to, or the receiving by, a third party of payments
or benefits to achieve the transfer of control over the potential donor for the purpose of exploitation by the removal of organs for transplantation.
-
Transplant commercialism is a policy or practice in
which an organ is treated as a commodity, including by
being bought or sold or used for material gain.
-
Travel for transplantation is the movement of organs, donors, recipients or transplant professionals across jurisdictional borders for transplantation purposes. Travel for
transplantation becomes transplant tourism if it involves
organ trafficking and/or transplant commercialism or if
the resources (organs, professionals and transplant centers) devoted to providing transplants to patients from
outside a country undermine the country’s ability to provide transplants for its own population.
Blood-related living donor. Donors with first, second, third
and fourth degree of consanguinity are accepted.
Emotionally-related living donor. Spouses, common-law
partners, step-parents and step-children which have been
legally checked and approved by the relevant judicial
department are accepted.
Crossover donation. Only blood- and emotionally-related
pairs are accepted. All pairs must be assessed by specialised
committees in the hospital and obtain authorisation from the
relevant health and legal authorities.
Non-blood or emotionally-related living donor. They are
not accepted, except in the following cases:
1. Altruistic donor. Only accepted if not directed donation.
We recommend that all cases are assessed carefully by
expert committees authorised by the relevant health and
legal authorities.
2. Paid donors. They should not be accepted under any
circumstance whatsoever.
ORGAN TRADING AND TRANSPLANT TOURISM
Recent events concerning organ transplantation, the laxity in
the resource of non-related living donors and using
prisoners condemned to death in China has aroused
international criticism. The Latin American and
Caribbean Transplant Society, concerned with this
situation, considers it necessary to emphatically declare
its opinion with regard to organ trading and transplant
tourism. Unethical transplant practices have been
recognised which promote inequality and human
explotation. 40 These unethical practices are based upon
false premises such as “profit” and “opportunity” that a
person can obtain to “improve” his or her financial
situation. In the same manner, “autonomy” is used to
justify the right that these people have to sell their organs.
However, this is nothing more than a way of hiding an
“illegal trade” in which poor people in need of money are
not those that benefit from organ trading: it is the
intermediates that make the profit. It is clear that the poor
people are those who are at risk from participating in this
type of procedure, given their vulnerability. Latin
America has had to take necessary measures to protect
the vulnerable population from new forms of human
exploitation, such organ trading and trafficking, given the
social gap between rich and poor in our region, the high
poverty rates, and low level of education.
280
The Aguascalientes Document categorically refuses any
idea or mechanism which tends towards organ and
tissue trading by individuals or by States. It opposes
any mechanism that disguises organ trading and the
functioning of any type of organisation that ascertains
that organs are tradable articles. For example, this
includes the regulated market, free sale of organs, or
payment to donors beyond the costs for assessments,
surgical procedure, follow-up and complications after
donating.
THE STATE ROLE IN LEGISLATION, TRANSPLANT
DISTRIBUTION AND COVERAGE
On the understanding that our States are responsible for
the welfare of the citizens and aim to promote common
good, their role must be mentioned with regard to
authority, funding, safeguarding, availability, control and
surveillance of any activity carried out in their own
country associated with human organ, tissue and cell
transplantation.
The growing demand for donated human biological
materials to tackle the situation of thousands of our
citizens, requires organised development of donation and
transplant systems, and specific policies set within an
ethical and legal context which considers the common
good and universal access.
Nefrologia 2011;31(3):275-85
To a lesser or greater extent, there is a strong and
growing unbalance between supply and demand of
organs for transplantation in each of our countries.
Furthermore, there is a fragmentation in health care and
partial or restricted access to transplantation as an
alternative therapy in wide groups of the Latin American
and the Caribbean population.
Even though the rate of deceased donors in many of our
countries has grown extensively, at present other
internationally-used alternatives are analysed which need
strict ethical, legal, and citizen control if they are to be
considered appropriate.
The only way to face this situation is for the different
components of our society to take responsibility and a
committed attitude, especially those that hold greater
political, ethical-legal, health and economic power.
In this context, the public society holds a very special
role, having a more active and organised attitude towards
defending its rights.
The political decision giving impetus to these systems
has clear objectives, such as guaranteeing the right to
transplantation, increasing the number of transplants,
reducing waiting lists and improving transplant results.
This should be developed by means of donation and
transplant policies, considering the problems associated
with access and equity, coverage, and the integrity in
health care.41,42 For these measures to be applied correctly,
the States must guarantee universal coverage of health
services to all individuals in need of transplantation.
Each State’s organisational characteristics must meet
“correct” ethical guidelines.
In those countries in which donation or transplantation
do not exist, the authorities should make every effort to
develop systems that attend to the needs of the population
with the objective of achieving self-sufficiency.
In all cases, all information related to access to current
transplant programmes, patient and graft survival rates,
availability, coverage levels and allocation criteria,
should be made available.
Access to information by the different actors, including
patients, ensures transparency in allocation and forces
results to be accounted for.
ACCESS TO AND QUALITY OF
IMMUNOSUPPRESSION
The objective is to guarantee the health of the patients by
using drugs that have proven quality and efficacy by
Nefrologia 2011;31(3):275-85
special article
means of a process defined and approved by a scientific
and academic institution.43 This process does not however
approve or disapprove the use of generic drugs, but does
require that they meet the conditions established.
Transplant coverage should be understood as the need to
implement health care strategies to ensure access, quality,
transparency, equity and efficacy in patient care, ensuring
that patients are quickly registered onto waiting lists,
being on them for as short as possible, and the possibility
of receiving a transplant with the aim of the patient being
fully reincorporated into society.
Health care professionals must be ethically committed to
the transplantation, not only with the patient, but also with
the community enabling donation to be a common, yet
scarce good, further implying their responsibility for the
patient that continues on the waiting list.
The State must ensure that the doctor-patient relationship
remains within the ethical framework which assumes the
dignity and autonomy of the individual. Any change or
regulation that may modify this balance may affect the
patient’s psycho-physical welfare.
Problems associated with incorporating generic
immunosuppressive drugs on the market are a current
issue. It is a universal debate, and to date, there is not
enough information in the literature concerning the
therapeutic safety of generic immunosuppressive drugs,
and there is even less on the results of their
interchangeability.
The transplant doctor must supervise the quality of the
immunosuppressive drug that the patient receives, being
an ethical obligation. As a result, adherence to the
prescription should also be achieved, and the patient must
be provided with all information to ensure that he or she
is able to exercise his or her autonomy and freely make a
decision. Any change in immunosuppressive treatment
should be authorised by the patient by means of signing a
legally accepted informed consent. Furthermore, the
person who shall be legally responsible for the
consequences due to the change in medication must also
be acknowledged.
Immunosuppressive drugs constitute a special category
of drugs which have special characteristics, making them
different from other therapeutic groups.44 These drugs are
associated with a high health risk, given that they have a
narrow therapeutic window and a high inter-population
and intra-individual variability. As such, dosage errors,
no matter how small, may cause the following results: 1)
lack of efficacy and transplant loss; 2) an excessive
immunosuppression accompanied by infections; or 3)
severe undesired effects due to the drug’s toxicity. As
281
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such, it is believed that the variability in bioavailability
of immunosuppressive drugs in transplanted patients is
significantly greater than in healthy volunteers. As a
result, the results from pharmacokinetic bioequivalence
studies performed on health volunteers can not be directly
extrapolated to the highly heterogeneous population of
patients subjected to transplantation. It is therefore
necessary to carry out studies on the efficacy and safety
of the generic immunosuppressive drugs to provide
evidence of equivalence, or at least non-inferiority,
compared with patented immunosuppressants.45
We believe that health authorities, by means of
specialist drug control entities, must test generic
immunosuppressive drugs to monitor serum, plasma or
blood concentration in transplant patients, assessing
the intra-individual and inter-individual variability of
the different formulas available. Intensive drug
monitoring studies should also be conducted to
recognise the variables that may interfere in the
availability of new formulas. 45
A data capture tool must also be made available, so that all
doctors can provide information on adverse effects and so
that it can be made available on scientific Societies’ public
websites in conjunction with the regulating documentation,
to ensure drug monitoring. It is recommended that each
countries’ scientific Societies generate an information flow
about drug monitoring which is circulated in transplant
hospitals and in health centres which follow-up patients
with low immunological risk.
Interchangeability between innovative and generic
immunosuppressive drugs is not recommended if the
clinical verification process has not been completed.
Children, elderly patients and those at high
immunological risk are vulnerable groups and should not
be incorporated in any interchangeability programme.45
Purchasing generic immunosuppressants at a lower cost
is not a valid argument within the bioethical principles
framework, which must ensure that the principles of
beneficence
and
nonmaleficence
are
met.
Pharmacoeconomics does not just consider the
purchasing cost of the drugs, but also includes those costs
associated with lack of effectiveness and safety of a drug.
If using generic immunosuppressants results in a greater
graft rejection rate, savings generated from the drug price
shall be exceeded by therapeutic failure costs. Therefore,
using a poor quality generic immunosuppressant results
in additional costs. In contrast, a generic
immunosuppressant that is as effective and safe as a lowcost innovative immunosuppressant provides significant
savings. This type of generic immunosuppressive drug
should therefore be promoted by the regulatory
authorities.45
282
Lastly, we consider that health authorities have the
opportunity to define policies that guarantee the best
universal coverage for immunosuppressant treatment and that
in conjunction with regulatory authorities, commercialisation
of new generic drugs may be authorised once their quality
standard is assured.46-48
RECOMMENDATIONS AT A COUNTRY AND
PROGRAMME LEVEL
Below are the conditions for developing a salutary donation
and transplant system in each country of this region:
1. It must have a specific legislation, based on bioethical
considerations that contemplate regulating donation,
allocation, transplant and follow-up.
2. It must guarantee universal access to the health services,
including transplant access, in all region countries.
3. It must establish a state national organisation responsible
for donation, procurement and allocation of organs, as
well as promoting and creating national transplant
policies.
4. It must promote deceased-donor programmes and ensure
maximum use of each countries’ resources, as well as
international cooperation, including the exchange of
medical-clinic, educational, bioethical and scientific
research resources on donation, immunology and
transplantation.
5. It must create a national waiting list for each organ or
tissue and allocation systems with defined criteria with
regards the order, certainty, transparency, credibility, and
traceability of the system.
6. It must promote the creation of necessary controls in
health institutions to protect the vulnerable population.
7. It must unite the principles of distributive justice
(equality, usefulness and community).
8. It must rely on systems for monitoring and accounting
allocation processes.
9. It must promote the need to report when a living-donor
transplant has been performed to the national donation
and transplant system in each country and the relevant
ministries of public health. Data related to traceability and
follow-up must also be reported.
10. It must create assessment committees for non-related
donors in hospitals that perform transplants.
Nefrologia 2011;31(3):275-85
11. It must create national donation and transplant registers
which assure adequate analysis of the short- and longterm results.
12. It must establish criteria for certifying hospitals where
transplant procedures are to take place.
special article
and Transplant Forum and its publication complies with
the proposal to circulate the content to all health care
professionals who give every effort on a daily basis to
caring for transplant patients, as well as to the medical
Societies involved in transplant activities and the health
authorities from all countries in the Latin American and
Caribbean region.
13. It must register and authorise transplant programmes.
14. It must establish national criteria and protocols for
selecting deceased donors and procurement.
15. It must define criteria for certifying staff dedicated to
procurement and transplant activities.
16. It must prepare competent and qualified clinical transplant
teams for different organs, with transplantation
programmes which include different pre-transplant,
transplant and post-transplant activities.
17. It must train staff for donation and procurement activities.
18. It must establish mechanisms that support and encourage
deceased-donor and procurement programmes in all
region countries.
19. Companies initiating negotiations for generic
immunosuppressive drug formula approval before the
relevant health ministries must fulfil the following:
a. Present references on the origin of the drug and its use
in other countries.
b. Submit the generic formula to clinical transplant trials
which guarantee therapeutic safety and efficacy, with
the supervision of authorised third parties. These trials
should obtain adequate statistical power.
c. Guarantee the provision of the drug for a period of no
less than one year to prevent the risk of drug interruption
and interchangeability. It is likely that the generic
marketer may have production and/or distribution
problems that restrict adequate drug supply.
20. It must announce and circulate the Aguascalientes
Document in all transplant forums and conferences that
take place in Latin America and the Caribbean.
21. It must make this Document reach all State institutions
that participate in health management in the region.
CONCLUSIONS
This Document contains the results from the work sessions
and round tables from the First Latin American Bioethics
Nefrologia 2011;31(3):275-85
The Aguascalientes Document does not attempt to be a
dogma which censures transplant practices or defining
what is correct and what is not.
The Aguascalientes Document reaffirms its identity
with the highest values which define medical practice,
strengthens its commitment to dignity, respect to life
and duty to helping those that are suffering.
Although the Aguascalientes Document accepts that
each country and each transplant centre has the
prerogative to defining their own practices, it does aim
to serve as an instrument of expression for transplant
groups in Latin America and the Caribbean. It is
therefore determined to influence the transplant
activities that are carried out within the context of
justice and equity.
The greatest challenge, and consequently the task which
all groups involved in transplants will probably have in
the coming years, will be granting the necessary control
of the commendable measures suggested in this
Document, in an effort to optimise (under the strictest
ethical principles) the donation and transplantation
results obtained from the joint effort of the region’s
countries.
REFERENCES
1. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantations of human kidney between identical twins.
JAMA 1956;160:277-82.
2. Küss R, Bourget P. An illustrated history of organ transplantation.
Special Commemorative Edition by Laboratoires Sandoz; 1992, p.
18-77.
3. Barnard CN. A human cardiac transplant: an interim report of
a successful operation performed at Groote Schuur Hospital,
Cape Town. S Afr Med J 1967;41:1271-4.
4. Veatch RM. Transplantation Ethics. Washington, D.C.: Georgetown University Press; p. 46.
5. Lucas Lucas R. Antropología y Problemas Bioéticos. Capítulo
VI. En: Muerte encefálica y muerte humana. Madrid: Estudios
y Ensayos; 2001, p. 111.
6. Lucas Lucas R. Antropología y Problemas Bioéticos. Capítulo II. El
valor del cuerpo humano. Madrid: Estudios y Ensayos; 2001, p. 15.
7. Pérez-Tamayo R. Ética Médica Laica. México: Fondo de Cultura Económica; El Colegio Nacional, 2002;17-63;250-74.
283
special article
8. Pius XII. To the delegates of the Italian Association of Cornea
Donors and the Italian Union for the Blind (May 14, 1956). In:
Acta Apostolicae Sedis. Vatican City 1956;48:462-5.
9. John Paul II. To the participants at the First International Congress on the Transplant of Organs (June 20, 1991). In: Teachings of Jean Paul II. Vatican City 1991;XIV/1:1710-12.
10. Pontifical Council for Pastoral Assistance to Health Care Workers. Charter for Health Care Workers. Vatican City 1995; ns
83-91.
11. John Paul II. Enciclical setter «Evangelium Vitae». Vatican City
1995;ns. 15-86.
12. Mollaret P, Goulon M. Le coma dépasse. Revue Neurologiche
1959;101:3-15.
13. Harvard Medical School. A definition of irreversible coma. Report
of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337-40.
14. Diagnosis of brain death: statement issued by the honorary
secretary of the Conference of Medical Royal Colleges and
their Faculties in the United Kingdom on 11 October 1976. Br
Med J 1976;2:1187-8.
15. Guidelines for the determination of death: report of the medical consultants on the diagnosis of death to the President’s commission for the study of ethical problems in medicine and biochemical and behavioral research. JAMA 1981;246:2184-86.
16. Uniform determination of death Act, 12 uniform laws annotated 589 (West 1993 and West suppl 1997).
17. The quality standards subcommittee of the American Academy of Neurology: Practice parameters for determining brain
death
in
aults
(summary
statement).
Neurology
1995;45:1012-4.
18. Wijdicks, EFM, Varelas PN, Gronseth GS, Greer DM. Evidencebased guideline update: Determining brain death in adults.
Neurology 2010;74:1911-1918.
19. Namihira E. Shinto concept concerning the dead human body.
Transplant Proc 1990;22:940-1.
20. Sugunasiri SHJ. The Buddhist view concerning the dead body.
21. Bulka RP. Jewish perspective on organ transplantation. Transplant Proc 1990;22:945-6.
22. Al Bar MA. Islamic view on organ transplantation. In Proceedings of the 2nd International Conference of Middle East Society of Organ Transplantation. Kuwait, 11-15 March 1990.
23. Sixty-Third World Health Assembly. WHA63.22. MAY
2010.apps.who.int/gb/ebwha/pdf_files/WHA63.
24. Declaración de Estambul. Cumbre Internacional sobre turismo de
trasplante y tráfico de órganos convocada por la Sociedad de Trasplantes y la Sociedad Internacional de Nefrología en Estambul, Turquía del 30de abril al 2 mayo de 2008. http://www.slanh.org/img/inicio/Declaracion_Estambul.pdf
25. Declaración Universal de los Derechos Humanos, adoptada
por la Asamblea General de las Naciones Unidas el 10 de diciembre de 1948, http://www.un.org/Overview/rights.html
26. Barr ML, Belghity J, Villamil FG, et al. A report of the Vancouver Forum of the Care of the Live Organ Donor: Lung, Liver,
Pancreas and Intestines-Data and Medical Guidelines. Transplantation 2006;81:1373-87.
284
27. A report of the Amsterdam Forum on the care of the Live Kidney Donor: data and medical guidelines. Transplantation
2005;79(2S):S53-S66.
28. The Ethics Committee of the Transplantation Society: The
consensus of the Amsterdam Forum on the Care of the Live
Kidney Donor. Transplantation 2004;78:491-2.
29. Constitución de la Sociedad de Trasplante de América Latina
y el Caribe, según aprobada, Canela, Brasil 1999.
30. Pan-American Society of Dialysis and Transplantation. Document of Transplant Ethics. Bulletin South Eastern Organ Procurement Foundation, Feb/Mar 1989.
31. Santiago-Delpín EA. Guidelines to Assist Authorities in Each
Country with Regards to Transplantation. Transplantation Society Bulletin 1997;6:9-11.
32. Dossetor JB, Monaco AP, Stiller CR, Guest Editors. First International Congress on Ethics, Justice, and Commerce in Transplantation:
A Global View, Transplantation Proceedings 1990;12(3):891-1056.
33. Sociedad de Trasplantes América Latina y del Caribe. Registro
Latinoamericano de Trasplantes 2009 [17-November-2010].
http://www.stalyc.net/index.php?option=com_flippingbook&v
iew=book&id=4:registros-latinoamericanos-2009&catid=1:registros-register&tmpl=component
34. Kemp P. La mundialización de la ética. México: Fontamara,
2007.
35. Beauchamp T, Childress J. Principios de Etica Biomédica. Barcelona: Editorial Masson S.A., 1999;113-4.
36. Jonas H. El principio de responsabilidad: ensayo de una ética
para la civilización tecnológica. México DF: Editorial Herder,
1995.
37. Cantú G, Medeiros M, et al. En hospitales de México: criterios de asignación de riñón de pacientes fallecidos. Persona y
Bioética 2009;13(32):20-33.
38. Cantú G, Orta Sibu N, et al. Patrones de suficiencia y prioridad de la justicia distributiva en atención de los pacientes pediátricos con enfermedad renal crónica terminal en América
Latina y el Caribe. Arch Latin Nefr Ped 2010;10(1):1-9.
39. Cantú G. Justicia Distributiva y trasplante renal. México,
2009. In press.
40. Firmenich B, Fontana R, Barone ME, Fernández M, Maglio I, Tanús
E, et al. Turismo de trasplantes: Una mirada desde la bioética. Archivos Latinoamericanos de Nefrología Pediátrica 2008;8(3):205.
41. Rawls J. Teoría de la Justicia. Segunda edición, 1995.
42. Declaración de la Asociación Médica Mundial sobre la donación y trasplante de órganos y tejidos-2000- Sección C Valores inc. 7 y Sección H Justicia en el acceso a los órganos y tejidos.
43. Homedes N. ¿Se puede hablar de políticas de genéricos en
América Latina? Revista de Salud Pública y Nutrición de la
Universidad Autónoma de Nuevo León 2004;5(1).
44. Magos-Guerrero GA, Lorenzana-Jiménez M. Las fases en el desarrollo de nuevos medicamentos. Rev Fac Med UNAM 2009;52(6):2604.
45. Alloway RR, Isaaqcs R, Lake K, Hoyer P, First R, Helderman H, et al.
Report of the American Society of Transplantation conference on
immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant 2003;3(10):1211-5.
Nefrologia 2011;31(3):275-85
46. Homedes N, Ugalde A. Multisource drug policies in Latin America.
Bull WHO 2005;83:64-70.
47. H o m e d e s N , L ó p e z - L i n a re s R , U g a l d e A . H e a l t h , N u t r i t i o n a n d P o p u l a t i o n ( H N P ) D i s c u s s i o n P a p e r. G e n e r i c
D r u g P o l i c i e s i n L a t i n A m e r i c a . H N P, T h e Wo r l d B a n k ,
special article
March 2005.
48. Documento de Consenso en la Utilización de Nuevas Formas Farmacéuticas en Drogas Inmunosupresoras en Pacientes Trasplantados. Ministerio de Salud de la Ciudad Autónoma de Buenos Aires
y Sociedad Argentina de Trasplante. 30 june de 2010.
Collaborators
Alger Aquino Figueroa. Liver and Kidney Transplant Surgeon. VELMAR Hospital. Ensenada, Baja California, Mexico. Roberto Barriga Arroyo.
Chairman of the Bolivian Organ and Tissue Transplant Society. La Paz, Bolivia. Martha Magalis Bello Bello. Dominican Transplant Institute, Dr
Baquero Foundation. Santo Domingo, Dominican Republic. Milka Bengochea. Assistant Director of the Donation and Transplant National Institute.
Ministry of Public Health. Assistant Professor at Republic University. Uruguay. Jorge David Cancino López. Transplant Surgeon. Specialities Hospital,
Transplant Unit. 21st Century National Medical Centre, Mexican Institute for Social Security. Mexico city, Mexico. Guillermo Rafael Cantú
Quintanilla. Researcher of the Bioethics Department. School of Medicine. Pan American University. Mexico city, Mexico. Gilberto Castañeda
Hernández. Pharmacology Department, Research and Advanced Studies Centre of the National Polytechnic Institute. Mexico city, Mexico.
Irene Córdova Jiménez. Coordinator of Legal Matters for the Organ and Tissue Transplant State Board, Jalisco, Mexico. Ramón Espinoza Pérez.
Urologist and Transplant Surgeon. Specialities Hospital, Transplant Unit. 21st Century National Medical Centre, Mexican Institute for Social Security.
Mexico city, Mexico. José Pablo Garbanzo Corrales. Hepatobilliary and Transplant Surgeon. Centre of Liver Transplant and Hepatobilliary Surgery.
Costa Rican Social Security Funding. San José, Costa Rica. Carmen Gracida Juárez. Transplant Surgeon. Head of the Transplant Unit. High Speciality
Medical Unit, Specialities Hospital, 21st Century National Medical Centre, Mexican Institute for Social Security. Mexico city, Mexico. María de Jesús
Gutiérrez Navarro. Paediatric Nephrologist. Transplant Nephrologist. Interinstitutional Programme. Regional General Hospital SSA and Regional
Hospital for High Specialities. León, Guanajuato, México. Mariela Mautone. Ethics Committee of the Transplant National Institute in Uruguay.
Montevideo, Uruguay. José Luis Medina Cerriteño. Urologist Surgeon. Clinic No 80. Mexican Institute for Social Security and Regional General
Hospital No. 1. Morelia, Michoacán. Member of the Transplant State Board. Michoacán, Mexico. Avelino Méndez Rangel. Federal Member of
Parliament. Federal District, Mexico. Arnoldo Mondragón Padilla. Nephrologist. General Hospital of Area No 50 of the Mexican Institute for Social
Security and Pedro Bárcenas Hiriart Specialities Clinic of the Institute for Social Security to the Service of the State Workers. San Luis Potosí, SLP,
Mexico. Cruz Netza Cardoso. Head of the Nephrology Department, Puebla Hospital, Mexico. Vice-chair woman of the Bioethics Committee in the
Puebla General Hospital. Mexico. María del Carmen Rial. Co-director of the Kidney Transplantation Specialist degree at the University of Buenos
Aires. Argentina. Ana Rodríguez Allen. Director of the Interuniversity Master’s Degree in Bioethics in Costa Rica, National University of Costa Rica,
C.A. María de la Cruz Ruiz Jaramillo. Regional General Hospital of Leon, Guanajuato Health Secretary, Mexico. Luciano Zylberberg Panebianco.
Political Scientist. Mexico city, Mexico.
Sent to review: 26 Ene. 2011 | Accepted: 26 Feb. 2011 | Epub: 15 Mar. 2011
Nefrologia 2011;31(3):275-85
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See editorial comment on page 247
Efficacy and safety of combined cyclosporin A and
mycophenolate mofetil therapy in patients with
cyclosporin-resistant focal segmental
glomerulosclerosis
A. Segarra Medrano1, J. Vila Presas1, L. Pou Clavé2, J. Majó Masferrer3, J. Camps Domenech1
Nephrology Department. Vall d’Hebron Hospital. Barcelona, Spain
Biochemistry Department. Vall d’Hebron Hospital. Barcelona, Spain
3
Anatomical Pathology Department. Vall d’Hebron Hospital. Barcelona, Spain
1
2
Nefrologia 2011;31(3):286-91
ABSTRACT
Introduction: The combination of cyclosporin A (CsA) and
mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission
of nephrotic syndrome in patients with steroid- and CsAresistant focal segmental glomerulosclerosis (FSGS). Objective: To analyse the efficacy and safety of the combined
CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. Patients and methods: Twenty-seven patients
with CsA-resistant FSGS were treated for 12 months with
CsA (4mg/kg/day) combined with MMF (2g/day). The overall follow-up lasted for 5 years. The proportion of patients
with remission of proteinuria and the evolution of kidney
function after 5 years were used to measure the outcome.
Results: At the end of the treatment period, no patients
were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had
significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, P=.042), significantly lower GFR
(-0.08 compared to -0.69±0.38; P=.003) and higher baseline kidney function (99.6±12.9 compared to
85.05±15.5ml/min; P=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease
at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients
and acute transitory nephrotoxicity in 14.8%. The
dosage and/or number of anti-hypertensive drugs had to
be increased in 22.2% of patients during the 12 months
of treatment. Conclusions: Twelve months of combined
CsA and MMF therapy does not significantly alter the
Correspondence: Alfonso Segarra Medrano
Hospital Vall d'Hebron.
Vall d'Hebron, 119-129. 08036 Barcelona. Spain.
[email protected]
[email protected]
286
evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial
reductions in proteinuria. : vamente el curso evolutivo de
Keywords: Cyclosporin A. Mycophenolate mofetil.
Focal and segmental glomeruloesclerosis. Cyclosporine
resistance.
Eficacia y seguridad del tratamiento combinado
con ciclosporina A y micofenolato de mofetilo en
enfermos con glomeruloesclerosis segmentaria y focal
ciclosporina-resistente
RESUMEN
Introducción: La asociación de ciclosporina A (CsA) y micofenolato mofetil (MMF) tiene un efecto inmunosupresor sinérgico y, en consecuencia, podría inducir una remisión del síndrome nefrótico en enfermos con
glomeruloesclerosis segmentaria y focal resistente a esteroides y a CsA. Objetivo: Analizar la eficacia y el perfil de
seguridad de la asociación CsA y MMF en enfermos con
GSF resistente a ciclosporina A. Pacientes y método: 27
enfermos con GSF resistente a CsA recibieron tratamiento con CsA (4 mg/kg/día) asociada a MMF (2 g/día) durante 12 meses. El seguimiento total fue de 5 años. Como
medida de resultado, se consideró la proporción de enfermos con remisión de la proteinuria y la evolución de
la función renal a los 5 años. Resultados: Al finalizar el
período de tratamiento, ningún paciente presentó remisión completa; 4 pacientes (14,8%) presentaron reducción de proteinuria a valores <3,5 g/día. Estos enfermos
presentaban proteinuria basal (5,62 ± 2,19 frente a 8,1 ±
A. Segarra Medrano et al. cyclosporin A and mycophenolate on FSGS
2,96 g/día; p = 0,042) y pendientes de FG (–0,08 ± 0,12
frente a –0,69 ± 0,38; p = 0,003) significativamente inferiores y mayor función renal basal (99,6 ± 12,9 frente a
85,05 ± 15,5 ml/min; p = 0,003). Dieciséis de los 27 enfermos (59,2%) presentaron una enfermedad renal progresiva o estadio V al final del período de seguimiento. Se
apreciaron efectos adversos gastrointestinales en el
33,3% de los enfermos y nefrotoxicidad aguda transitoria en el 14,8%. El 22,2% de los enfermos precisó un incremento en la dosis y/o número de hipotensores durante los 12 meses de tratamiento. Conclusiones: En
enfermos con GSF resistente a ciclosporina, el tratamiento con asociación de CsA y MMF durante 12 meses, aunque puede inducir reducciones parciales de la proteinuria, no modifica significativamente el curso evolutivo de
la función renal.
Palabras clave: Ciclosporina. Micofenolato de mofetil.
Glomeruloesclerosis focal y segmentaria. Resistencia a
ciclosporina.
INTRODUCTION
Current available evidence shows that for patients with
focal segmental glomerulosclerosis (FSGS) who have
steroid-resistant nephrotic syndrome, treatment with
cyclosporine A (CsA) can improve the long-term
prognosis for renal function. However, despite initial
reports that up to 75% of patients may have full or
partial remission of proteinuria, more than 50% of
steroid-resistant cases also develop resistance to
treatment with cyclosporine and, in the long term, suffer
progressive kidney disease. For these cases, apart from
hypertension control and angiotensin II blockers, there is
no treatment with proven efficacy that would modify the
clinical course of the disease.1-4
In recent years, there have been various observational
studies analysing the efficacy and safety of
mycophenolate mofetil (MMF), in monotherapy and in
combination with steroids, in the treatment of idiopathic
FSGS, with conflicting response rates that are generally
low. 5-13 Studies carried out in organ transplantation show
that the combination of MMF and CsA has an additive or
synergistic immunosuppressive effect. 14,15 This effect
could be useful in treating patients with FSGS who show
resistance to steroids and/or CsA. However, the efficacy
of this combination in FSGS has only been described in
a single observational study in steroid-resistant patients
who also received other immunosuppressants. 16
The aim of this pilot study was to analyse the potential
efficacy and safety of CsA and MMF therapy in a group
of patients with primary CsA-resistant FSGS.
Nefrologia 2011;31(3):286-91
originals
PATIENTS AND METHODS
Design
Observational study with prospective follow-up.
Patients
Between 1996 and 2004, 27 patients who met the following
criteria were included in the study:
1. Histological diagnosis of FSGS (all biopsies were
analysed by the same pathologists).
2. Exclusion of secondary aetiologies including: renal mass
reduction, morbid obesity, HIV-related nephropathy,
heroin or cocaine use, analgesic treatment, vesicoureteral
reflux and obstructive sleep apnoea.
3. Previous resistance to a treatment cycle of six months
with steroids and a treatment cycle of six months with
CsA, defined as persistent proteinuria >3.5g/day.
4. Glomerular filtration rate >60ml/min/1.73m2.
5. No other therapy with immunosuppressive or nonsteroidal anti-inflammatory drugs in the six months prior
to inclusion.
6. No family history of chronic kidney disease or renal
replacement therapy.
7. Absence of contraindications for treatment with MMF.
8. Provided written informed consent.
Studies prior to inclusion
After verifying resistance to steroids and CsA, all patients
were followed for at least six months before being
included in the study. During this period, they were only
prescribed a low-sodium diet (5g/day) and treatment with
angiotensin-converting enzyme inhibitors (ACEi) or
angiotensin II receptor blockers (ARB). The dosage of
these drugs was adjusted to achieve blood pressure
readings under 140/80. If necessary, amlodipine and/or
furosemide treatment was included. None of the patients
were treated with combined ACEi/ARB or with
aldosterone antagonists. In case of hypercholesterolaemia,
statins were prescribed to achieve LDL cholesterol levels
under 120 mg/dl.
Treatment protocol
After inclusion in the study and throughout the
follow-up, ACEi and ARB doses were kept constant.
All patients received treatment with CsA at an initial
dose of 4mg/kg/day, which was later adjusted to
maintain trough levels between 150 and 200ng/ml
(12h post-dose in total blood). The MMF dose was
2000mg/day in all cases.
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originals
After 12 months of treatment, patients with persistent
proteinuria >3.5g/day were considered resistant. The study
proceeded with the withdrawal of both drugs. If there was
evidence of full or partial remission of proteinuria, the
treatment could be continued for another 12 months. At the
end of this period, the dose was reduced by 25% each month
until full withdrawal had been achieved.
renal function check was performed seven days later. For
those cases where gastrointestinal symptoms appeared after
initiating MMF therapy, the total dose was reduced by 50%
for one week. The dose was subsequently increased
progressively until the maximum tolerated dose was
reached. MMF therapy was suspended for cases of
persistent gastrointestinal symptoms, onset of leukopaenia or
fever.
Anatomopathological analysis of renal biopsies
Outcome variables
All biopsies were stained with haematoxylin-eosin, PAS and
Masson’s trichrome for morphological analysis.
Immunofluorescence studies were performed with antibodies
against IgA, IgG, IgM, C3, fibrinogen and light chains. In
each biopsy, the percentage of glomeruli with total or
segmental sclerosis was calculated. The extent of interstitial
fibrosis was measured using quantitative morphometry, in
5µm sections stained with Masson’s trichrome, using an
Olympus WCUE-2 autoanalyser.
The primary outcome variable was the number of patients
with total or partial remission of proteinuria after 12 months
of treatment. The secondary variables were the number of
patients with proteinuria reduced to non-nephrotic levels, the
presence of progressive kidney disease or the need for renal
replacement therapy during follow-up and the identification
of independent predictors of the evolution of the glomerular
filtration slope.
Operational definitions
Statistical analysis
Proteinuria was considered to be in the nephrotic range for
readings >3.5g/day. Nephrotic syndrome was defined as
proteinuria >3.5g/day combined with hypoalbuminaemia
<3.5g/dl. Complete remission: proteinuria <0.3g/day in two
consecutive tests. Partial remission: proteinuria <3.5g/day
and >0.3g/day. Arterial hypertension: Systolic blood pressure
(SBP) >140mm Hg or diastolic blood pressure (DBP)
>90mm Hg. Chronic renal failure: GFR<60ml/min
calculated by endogenous creatinine clearance. Chronic renal
failure (Stage 5): GFR<15ml/min. Acute cyclosporine renal
toxicity: >30% increase in serum creatinine reversible after
25% reduction in CsA dose.
The results are expressed as the mean±1 SD. Changes in
urinary protein excretion and GFR throughout treatment
were analysed using an analysis of variance for repeated
measures after a logarithmic transformation of both
variables. The GFR slope was used as a criterion for loss
of renal function. It was estimated by including at least 10
GFR measurements, and a linear progression model was
assumed. A simple linear regression analysis was
performed using the logarithm of the glomerular filtration
slope up to the end of follow-up or the start of the renal
replacement therapy as the dependent variable. To analyse
independent predictors of the glomerular filtration
evolution, with the variables that had a significant
association in the univariate analysis, a stepwise multiple
regression model was created. All values with P<.05 were
considered significant.
Clinical follow-up and monitoring
After inclusion in the study, patients were monitored on
an outpatient basis each month for the first six months,
every two months until the end of the first year and every
four months during the remaining follow-up period until
60 months had been completed or renal replacement
therapy was initiated. At each follow-up visit, SBP and
DBP were measured. A general biochemical examination
was performed that included serum creatinine, liver
function, electrolytes, endogenous creatinine clearance,
glycaemia, CsA level and 24-hour proteinuria. Glomerular
filtration was calculated using endogenous creatinine
clearance. Urinary protein excretion was quantified in 24hour urine samples.
If there was evidence of a greater than 30% increase in
creatinine, the CsA dose was reduced by 25% and another
288
The study met the provisions set forth in the Declaration of
Helsinki and was approved by the hospital ethics committee.
The treatment was authorised by the Spanish ministry of
health with the provision for compassionate use in all
patients.
RESULTS
Baseline characteristics
Clinical and biochemical variables
Table 1 shows the main characteristics of the sample of 27
patients studied.
Nefrologia 2011;31(3):286-91
Table 1. Baseline clinical, biochemical and histological
characteristics
No.=27
Mean (SD)
Age
Sex (% men)
45.8 ± 9.9
63
Time
32.9 ± 8.5
GFR
87.6 ± 16.5
GF slope
–0.63 ± 0.9
Albumin
2.4 ± 1.1
Proteinuria
7.7 ± 3.9
SBP
120.8 ± 4.6
DBP
70.9 ± 9.6
Total no. glomeruli per biopsy
Interstitial fibrosis (%)
14 ± 6
28.4 ± 19.2
Overall glomerular sclerosis (%)
16 ± 9.5
Segmental glomerular sclerosis (%)
45 ± 12
Immunofluorescence
- IgM
16 (49)
- C3
4 (15)
- IgM + C3
4 (15)
- Negative
3 (7.5)
Time since renal biopsy (months); GFR: glomerular filtration rate
(ml/mn/1.73m2); GF slope: prior to inclusion in (ml/min/month); albumin
(g/dl); proteinuria (g/24h); SBP: systolic blood pressure (mm Hg); DBP:
diastolic blood pressure (mm Hg).
Anatomopathological data
According to the morphological pattern, all patients had
predominantly peripheral FSGS lesions (classic form, NOS).
None of the patients had collapsing glomerulonephritis.
Immunofluorescence showed focal IgM deposits in 16
patients, C3 in four cases, IgM and C3 in four, and a lack of
deposits in three patients. A significant correlation was
observed between GFR and the number of glomeruli with
total sclerosis (r=0.48; P<.01) and the extent of interstitial
fibrotic lesions (r=0.52; P<.01).
Response to treatment
After the treatment period was over, none of the patients had
full remission. There were no significant changes in
proteinuria in 23 patients. Four patients (14.8%) had a
decrease in proteinuria to below 3.5g/day (partial remission).
These four patients had baseline proteinuria (5.62±2.19
versus 8.1±2.96g/day; P=.042) and significantly lower GFR
slopes prior to inclusion in the study (–0.08±0.12 versus
–0.69±0.38; P=.003) and greater baseline renal function
Nefrologia 2011;31(3):286-91
originals
(99.6±12.9 versus 85.05±15.5ml/min/1.73 m2; P=.003) than
patients without changes in urinary protein excretion.
Treatment with CsA and MMF in these four patients was
maintained for an average of 17.6 months (maximum: 24
months, minimum: 17 months). After drug withdrawal,
proteinuria was kept at levels lower than 3.5g/day in three
patients throughout the follow-up. In the fourth patient, it
increased to levels of 5.5g/day, but a new pattern of
immunosuppressive treatment was not indicated.
During the five years of follow-up, patient GFR suffered a
significant
decline
(mean
absolute
decline:
–32.5±13.77ml/min/1.73 m2; P=.0001; average slope:
–0.54±0.19ml/min/month; P=.001). Sixteen out of the 27
patients (59.2%) met the criteria for progressive renal failure
or stage 5 CKD at the end of follow-up. Regarding patients
with no evidence of significant loss of renal function, these
16 patients had significantly lower baseline levels of GFR
(70.3±7.39 versus 97±10.3ml/min/1.73 m2; P=.001), greater
baseline proteinuria (10.56±3.2 versus 6.1±2.42g/day;
P=.006), evidence of a faster drop in renal function during
the follow-up prior to inclusion in the study (–1.3±0.8 versus
–0.19±0.41ml/min/month; P=.002) and greater proteinuria
during the follow-up after treatment with CsA and MMF
(7.2±3.1 versus 4.1±1.93g/day; P=.033). The slope of
glomerular filtration loss in the four patients with partial
remission was significantly lower than in the patients who
did not respond (–0.073±0.19 versus –0.71±0.29; P=.002).
However, none of the four patients showed a significant
difference between the slopes prior to and after the treatment
period. In the entire sample, there were no significant
differences between the slope of GFR loss prior to inclusion
and that observed during the five years of follow-up after
treatment with CsA and MMF (–0.63±0.9ml/min/month
versus –0.54±0.19ml/min/month; P=NS). The only variables
associated with the glomerular filtration slope throughout the
follow-up period in the multivariate analysis were initial
glomerular filtration (P=.041) and mean proteinuria during
the follow-up (P=.037).
Side effects
All patients completed the 12-month treatment period.
Gastrointestinal side effects appeared in 33.3% of the
patients. In all cases, the symptoms were mild and
disappeared when the MMF dose was reduced. In none of
the cases was it necessary to withdraw treatment. Transient
acute renal toxicity was observed in 14.8% of the patients.
Three patients (11.1%) had gingival hyperplasia. Some
22.2% of the patients required an increase in the dose and/or
number of anti-hypertensive drugs during the 12 months of
treatment with CsA and MMF (Table 3 shows the antihypertensive treatment used throughout the follow-up
period). None of the patients had episodes of fever or
leukopaenia.
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originals
DISCUSSION
This study was established with the aim of analysing the
potential efficacy and safety of the CsA and MMF treatment
in patients with steroid- and CsA-resistant FSGS. When it
was designed, the clinical usefulness of CsA in the treatment
of FSGS had been adequately shown in randomised clinical
trials,1-3 but there was no data on the potential efficacy of
MMF. The decision to combine both drugs was based
exclusively on the possible additive immunosuppressive
effect described in organ transplantation.14,15
The observed results indicate that for patients with resistance
to glucocorticoids and CsA, treatment with CsA and MMF
for 12 months does not induce total remission of proteinuria.
Throughout the follow-up period, however, a moderate but
significant reduction in proteinuria was observed in four
patients. Considering the relationship observed between
Table 2. Evolution of proteinuria and renal function
throughout follow-up
Baseline GFR
GFR 12 months
GFR 60 months
88.6 ± 16.5
87 ± 14
56.4 ± 13.9c
Baseline proteinuria
Proteinuria 12 months
Proteinuria 60 months
7.74 ± 3.9
6.03 ± 4.1
4.26 ± 2.02b
Baseline albumin
Albumin 12 months
Albumin 60 months
2.4 ± 0.8
2.5 ± 0.7
3.6 ± 0.46a
Baseline SBP
SBP 12 months
SBP 60 months
120.8 ± 4.6
128 ± 5.2
129.7 ± 7.3
Baseline DBP
DBP 12 months
DBP 60 months
70.9 ± 9.6
74.3 ± 7.32
71.56 ± 7.04
Baseline UNa
UNa 12 months
UNa 60 months
134 ± 79
176 ± 101
128 ± 93
Renal function at 60 months (%)
- Non-RRT progressive kidney failure RRT
- RRT
- Total patients with CRF progression
10 (37)
6 (22.2)
16 (59.2)
GFR glomerular filtration (ml/min/1.73m2); albumin: serum albumin
(g/dl); proteinuria: g/24H; SBP: systolic blood pressure (mm Hg); diastolic blood pressure (mm Hg); UNa: urine sodium excretion (mEq/24h);
RRT: renal replacement therapy.
a
P<.05; bP < .01; cP<.0001.
290
mean proteinuria and the glomerular filtration slope during
the follow-up, treatment with CsA and MMF would be
expected to have a beneficial effect in the preservation of
renal function in patients who had a greater reduction in
proteinuria. However, none of the four cases showed
significant differences between the pre- and post-treatment
slopes of glomerular filtration loss. The improved evolution
of this small subgroup of patients is associated with the
course of the disease prior to inclusion in the study, but not
with the effect of the treatment. A reasonable explanation for
this would be that since patients with greater reductions in
baseline proteinuria also showed significantly lower levels of
proteinuria, better renal function and lower slope of
glomerular filtration loss, they may have suffered from a
histologically indistinguishable form of FSGS with slower
more benign evolution. Both the percentage and the type of
response observed in our patients was lower than those
reported in the only study published to date that examines
the effect of combining MMF with calcineurin inhibitors in
patients with FSGS.16 This is probably because that study
included patients with resistance to glucocorticoids, while
our study included patients with resistance to glucocorticoids
and CsA. Moreover, the data observed in our cohort of
patients in terms of proteinuria reduction are at the lower
limit of the interval described in observational studies that
analyse the potential efficacy of MMF in FSGS adults (in
monotherapy or combined with steroids).5-13 Overall, the
available information does not suggest that the combination
of CsA and MMF has a relevant role in inducing remission
in patients with multiple resistance.
Although this is not a controlled study, the likelihood of
progression to chronic renal failure and renal replacement
therapy observed in the whole sample of patients after five
years of follow-up does not differ from that described in
most series of symptomatically treated patients with
resistance to CsA.3,4,17-19 This would also be an argument
against a possible beneficial effect of the combination of
CsA and MMF for long-term preservation of renal function.
All patients included had proteinuria in the nephrotic range
and hypoalbuminaemia and were carefully studied to rule
out secondary aetiologies. However, we are not able to
definitively reject that some of them present with forms of
FSGS that can not be modified using immunosuppressive
treatment. In this regard, it should be noted that a genetic
study was not performed in any of the cases, and therefore it
is possible that some of the patients who were classified as
having idiopathic forms actually suffered sporadic mutations
of the podocyte proteins. This limitation is common to all
studies performed to date that analyse the effectiveness of
various immunosuppressants in FSGS patients. However,
given the low reported prevalence of these types of
mutations in FSGS adults with no family history of the
disease, it is unlikely that this is the main reason for the
observed lack of response to immunosuppressive treatment.
Nefrologia 2011;31(3):286-91
The treatment was well tolerated but was not without side
effects. The most significant was the high incidence of
gastrointestinal symptoms, which were mild and did not
require withdrawal of either of the two drugs.
In conclusion, the data from this pilot study show that for
CsA-resistant FSGS patients, treatment combination of CsA
and MMF for 12 months does not significantly modify the
evolution of renal function, although it may induce partial
reductions in proteinuria in some patients.
REFERENCES
1. Ponticelli C, Rizzoni G, Edefonti A, Altieri P, et al. A randomized trial
of cyclosporine in steroid-resistant idiopathic nephrotic syndrome.
Kidney Int 1993;43:1377-84.
2. Lee HY, Kim HS, Kang CM, Kim SG, Kim MJ. The efficacy of
cyclosporine A in adult nephrotic syndrome with minimal change
disease and focal-segmental glomerulosclerosis: A multicenter
study in Korea. Clin Nephrol 1995;43:375-81.
3. Meyrier A, Noel LH, Auriche P, Callard P, and the Collaborative
Group of the Société de Néphrologie. Long-term term renal
tolerance of cyclosporine A treatment in adult idiopathic nephrotic
syndrome. Kidney Int 1994;45:1446-56.
4. Cattran DC, Appel GB, Herbert LA, Hunsicker LG, et al, for the
North America Nephrotic Syndrome Study Group. A randomized
trial of cyclosporine in patients with steroid-resistant focal
glomerulosclerosis. Kidney Int 1999;56:2220-6.
5. Briggs WA, Choi MJ, Scheel PJ. Follow-up on mycophenolate
treatment of glomerular disease. Am J Kidney Dis 1998;31:898-9.
6. Radhakrishnan J, Wang MM, Matalon A, Cattran DC, Appel GB.
Mycophenolate mofetil treatment of idiopathic focal segmental
glomerulosclerosis [Abstract]. J Am Soc Nephrol 1999;114A:A584.
7. Segarra A, Amoedo ML, Martínez García JM, Pons S, Praga M, et
al. Efficacy and safety of «rescue therapy» with mycophenolate
mofetil in resistant primary glomerulonephritis-a multicenter study.
Nephrol Dial Transplant 2007;22(5):1351-60.
8. Choi, MJ, Eustace, JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan
R, et al. Mycophenolate mofetil treatment for primary glomerular
diseases. Kidney Int 2002;61:1098-114.
originals
9. Day CJ, Cockwell P, Lipkin GW, Savage CO, Howie AJ, Adu D.
Mycophenolate mofetil in the treatment of resistant
idiopathic nephrotic syndrome. Nephrol Dial Transplant
2002;17:2011-3.
10. Levin ML. Mycophenolate mofetil treatment for primary glomerular
diseases. Kidney Int 2002;62:1475.
11. Bullo B, Zdrojewski Z, Rutkowski B. Mycophenolate mofetil (MMF)
therapeutic approach in patients with chronic glomerulonephritis
(GN). Kidney Int 2003;64:1139.
12. Dimitrakov DJ, Nikolov DG, Dimitrakov JD, Despotov TB, et
al. Effect of mycophenolate mofetil (Cell Cept) in the
treatment of immune glomerulopathies. Folia Med (Plovdiv)
2004;46:15-8.
13. Cattran DC, Wang MM, Appel G, Matalon A, Briggs W.
Mycophenolate mofetil in the treatment of focal segmental
glomerulosclerosis. Clin Nephrol 2004;62(6):405-11.
14. Ostraat O, Qi Z, Olausson M, Gannedahl G, Tufveson G, Ekberg H.
Additive immunosuppressive effect of combined mycophenolate
mofetil and cyclosporine A in experimental rat cardiac
transplantation. Transplant Proc 1995;27(6):3540.
15. Ostraat O, Qi Z, Olausson M, Tufveson G, Ekberg H.
Mycophenolate mofetil, azathioprine and cyclophosphamide
enhanced efficacy combined with cyclosporine in rat cardiac
transplantation. Scand J Immunol 1997;45(4):343-8.
16. El-Reshaid K, El-Reshaid W, Madda J. Combination of
immunosuppressive agents in treatment of steroid-resistant minimal
change disease and primary focal segmental glomerulosclerosis.
Ren Fail 2005;27(5):523-30.
17. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental
glomerular sclerosis in adults: presentation, course, and response to
treatment. Am J Kidney Dis 1995;25(4):534-42.
18. Ponticelli C, Villa M, Banfi G, et al. Can prolonged treatment
improve the prognosis in adults with focal segmental
glomerulosclerosis? Am J Kidney Dis 1999;34:618-25.
19. Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal Segmental
Glomerulosclerosis in Nephrotic Adults: Presentation, Prognosis,
and Response to Therapy of the Histological Variants. J Am Soc
Nephrol 2004;15:2169-77.
20. Troyanov S, Wall CA, Miller JA, et al. Focal and segmental
glomerulosclerosis: Definition and relevance of a partial remission. J
Am Soc Nephrol 2005;16(4):1061-8.
Sent for review: 6 Mar. 2010 | Accepted: 26 Feb. 2011 | Epub: 15 Mar. 2011
Nefrologia 2011;31(3):286-91
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Effects of rapamycin on angiomyolipomas in patients
with tuberous sclerosis
C. Cabrera López1, T. Martí2, V. Catalá2, F. Torres3, S. Mateu4, J. Ballarín Castán1,
R. Torra Balcells1
Hereditary Kidney Diseases. Nephrology Department. Puigvert Foundation. Autonomous University of Barcelona FP/UAB. Barcelona, Spain
Radiology Department. Puigvert Foundation. Autonomous University of Barcelona FP/UAB. Barcelona, Spain
3
Clínic Hospital. Statistics and Methodology Support Unit. IDIBAPS. Biostatistics Unit. Autonomous University of Barcelona. Barcelona, Spain
4
Biomedical Research Unit. Puigvert Foundation. Autonomous University of Barcelona FP/UAB. Barcelona, Spain
5
Hereditary Kidney Diseases. Nephrology Department. Puigvert Foundation. Autonomous University of Barcelona FP/UAB. Barcelona, Spain
1
2
Nefrologia 2011;31(3):292-8
10.3265/Nefrologia.pre2011.Apr.10812
ABSTRACT
Background: Tuberous sclerosis (TS) is a systemic disease,
with an autosomal dominant pattern of inheritance
caused by mutations in two genes (TSC1 and TSC2) that
cause tumours (angiomyolipomas [AML], angiofibromas,
astrocytomas). Constant and inadequate proliferation
occurring in TS may be blocked by mTOR inhibitors
(mammalian target of rapamycin), such as rapamycin.
Material and methods: At present, our study includes
17 patients with TS. All had at least one AML greater
than 2cm in diameter diagnosed by MRI. They received
rapamycin during 12 months. Plasma levels remained
stable between 4-8ng/dl. The AML size was monitored
every six months by abdominal MRI. Results: At 12
months of inclusion, MRI indicated a decrease in the
size of AML in all patients showing at least a 50%
reduction in 82.4% (14/17, 95% CI [56.57%, 96.20%]).
The mean percent reduction was 66.3% (95% CI
[56.9%, 75.6%], P<.0001). The major side effects
observed were: oral aphthous ulcers (5/17);
hypertriglyceridemia
(3/17);
microcytosis
and
hypochromia (3/17); diarrhea (2/17); acne (1/17); acute
pyelonephritis
(1/17);
and
proteinuria
(1/17).
Conclusions: These preliminary clinical data suggest
that rapamycin can play a beneficial role in the
treatment of TS. Our experience in 17 patients treated
for 12 months demonstrates safety and efficacy in
reducing AML volume.
mente el curso evolutivo de
Keywords: Tuberous sclerosis. Angiomyolipoms. Rapamycin.
Correspondence: Cristina Cabrera López
Enfermedades Renales Hereditarias. Servicio de Nefrología.
Fundación Puigvert. Universidad Autónoma de Barcelona FP/UAB.
Cartagena, 340-350. 08025 Barcelona. Spain.
[email protected]
292
Efectos de la rapamicina en los angiomiolipomas de
pacientes con esclerosis tuberosa
RESUMEN
Introducción: La esclerosis tuberosa (ET) es una enfermedad sistémica, de herencia autosómica dominante, ocasionada por
mutaciones en dos genes (TSC1 y TSC2), que causan la aparición
de tumores (angiolipomas [AML], angiofibromas, astrocitomas,
etc.). La proliferación inadecuada y constante que existe en la
ET puede ser bloqueada por inhibidores de la kinasa mTOR
(mammalian target of rapamycin), como la rapamicina. Material y métodos: Se han incluido 17 pacientes afectados de ET y,
al menos, un AML mayor de 2 cm de diámetro diagnosticado
por resonancia magnética (RM). Han recibido tratamiento con
rapamicina durante 12 meses. Los niveles plásmáticos se han
mantenido entre 4 y 8 ng/dl. El tamaño del AML se ha monitorizado semestralmente mediante RM abdominal. Resultados: A
los 12 meses de la inclusión, con la RM se ha objetivado una disminución del tamaño del AML en todos los pacientes incluidos,
mostrando una reducción de, al menos, un 50% en el 82,4%
(14/17; intervalo de confianza [IC] 95% [56,57%, 96,20%]). El
porcentaje medio de reducción fue del 66,3% (IC 95 [56,9%,
75,6%]; p <0,0001). Los principales efectos secundarios observados han sido: aftas orales (5/17); hipertrigliceridemia (3/17); microcitosis e hipocromía (3/17); diarrea (2/17); acné (1/17); pielonefritis aguda (1/17), y proteinuria (1/17). Conclusiones: Los
datos clínicos preliminares sugieren que la rapamicina puede
desempeñar un papel beneficioso en el tratamiento de la ET.
Nuestra experiencia en 17 pacientes tratados durante 12 meses
demuestra seguridad y eficacia en la reducción de AML.
Palabras clave: Esclerosis tuberosa. Angiomiolipomas.
Rapamicina.
INTRODUCTION
Tuberous sclerosis (TS), otherwise known as BournevillePringle disease, is a systemic disease with an autosomal
C. Cabrera López et al. Rapamycin in tuberous sclerosis
dominant pattern of inheritance. It is a rare disease, with
an estimated prevalence of 1/6000 people.1
This disease can cause dermatological (facial
angiofibromas, hypomelanotic macules, ungual fibromas),
renal (angiomyolipomas, cysts) neurological (epilepsy,
mental retardation, subependymal astrocytomas, cortical
tubers) pulmonary (lymphangioleiomyomatosis), and
cardiac (rhabdomyomas) symptoms. These clinical
manifestations and their severity vary greatly. The clinical
presentation of the disease varies from adults with very
few signs of the disease to children with severe
neurological involvement.
originals
Rapamycin
(Sirolimus,
Rapamune ®)
is
an
immunosuppressive agent that inhibits the capacity of
mTOR to phosphorylate S6K and 4EBP1, which controls
cell growth and the uninhibited proliferation produced in
TS patients.
The objective of this clinical trial is to demonstrate that
the uninhibited proliferation that exists in TS patients –
AML – can be blocked by inhibitors of the Akt signalling
cascade, such as rapamycin, which is a safe and effective
therapeutic alternative in the treatment of TS patients.
MATERIAL AND METHOD
Renal angiomyolipomas (AML) are benign tumours
composed of anomalous vessels, immature smooth muscle
tissue, and adipocytes. They can be detected using
ultrasound, computerised tomography (CT), and magnetic
resonance (MRI). In the majority of patients, they occur as
bilateral and multiple tumours. The approximate incidence
ranges between 55% and 75%. 2 and morbidity rates are
high. They can produce spontaneous haemorrhage and, in
some cases of abundant AML, arterial hypertension (AHT)
and kidney failure. This is the most serious nonneurological complication of the disease.
Ours is a phase IV non-blinded, non-controlled clinical trial,
lasting 24 months. It is being held at a single institution,
using a commercialised drug under a new therapeutic
indication.
Our primary objective is to evaluate the effect of rapamycin
on the size of AML in patients with TS. The main variable is
the estimated proportion of patients in which a 50%
reduction was observed in the largest diameter of the AML
with respect to its initial size.
The risk of rupture and spontaneous haemorrhage is
generally related to the size of the AML3 and is especially
high when the tumour is larger than 3-4cm. The growth
rate of AML varies among patients and tumours. In
general, resection is avoided in order to prevent the loss of
renal parenchyma, and thus renal function. Until now, the
primary therapeutic options have been AML embolisation,
elective surgery, and emergency nephrectomy in the case
of uncontrollable haemorrhage.4
Our secondary objectives are to evaluate the treatment effect
on tumour volume, cutaneous lesions, the percentage of
patients with surgical complications (haemorrhage, need for
embolisation and/or surgery), and the safety of the drug in
this cohort of patients.
In addition to renal AML, patients with TS may have cysts,
polycystic kidney disease, and renal cell carcinomas.
This clinical trial has been approved by the clinical research
ethics committee of the Puigvert Foundation and the Agencia
Española del Medicamento (Spanish agency of drugs).
TS is caused by mutations in two different genes: TSC1
and TSC2. TSC1 causes the disease in a small percentage
of cases and produces its most benign forms. 2 This gene
is located on chromosome 9q34, is made up of 23 exons,
and codes for the protein hamartin. 5 TSC2 is located on
chromosome 16p13, is made up of 41 exons, and codes
for the protein tuberin.6
Tuberin and hamartin join in a regulatory complex of
mTOR (mammalian target of rapamycin) through the
ribosomal protein S6 kinase (S6K) and the repressors of
the protein synthesis initiation factor eIF4EEl, the 4E
binding protein (4EBP1). Mutations that result in the
absence or dysfunction of tuberin or hamartin cause a
constitutive inactivation of S6K and 4E-BP1, and a loss
of control of cell proliferation 7 caused by permanent
activation of mTOR.
Nefrologia 2011;31(3):292-8
The majority of patients included in our study belong to the
TS association, which referred possible candidates to the
Puigvert Foundation, which is responsible for this study.
We included 17 patients older than 10 years of age,
diagnosed with TS and with at least one renal AML greater
than 2cm in diameter (independently of the central nervous
system [CNS], heart, lungs, and/or skin involvement), and
baseline creatinine levels below 2mg/dl. All patients were
also required to sign an informed consent if they were older
than 18 years, or this was signed by parents or guardians if
the patient was underage. We established the following
exclusion criteria: recent haemorrhage of the AML, altered
liver function or haemogram results, proteinuria (estimated
using the protein/creatinine ratio) greater than 22.6mg/mmol,
active infection, a background of surgery within 8 weeks
before to the start of treatment, history of neoplasia within
the past 2 years, a fasting cholesterol level greater than
7.8mmol/L, LDL greater than 5.1mmol/L, triglycerides
(TG) greater than 4.6mmol/L, and a background of
293
originals
allergies to macrolides. We also performed a pregnancy
test on all female patients before including them in the
study, and continued to test for pregnancy during each
follow-up visit.
Each patient received a dose of rapamycin at 1mg/day in
the first visit. Dosage was adjusted every two weeks, with
1mg increases until reaching stable plasma levels of 48ng/dl. Once these levels were reached, we monitored
plasma levels at 3, 6, 9, and 12 months of treatment,
coinciding with the follow-up visits. During each visit the
patients underwent a physical examination, adverse effects
and compliance with the therapeutic protocol were
evaluated, and lesions were photographed. They also
underwent a complete blood analysis (glucose,
haemogram,
urea,
creatinine,
MDRD
formula
[Modification of Diet in Renal Disease], electrolytes, liver
profile, bilirubin, lipids, and urine analysis for proteinuria
using the protein/creatinine ratio). We performed an
abdominal MRI on each patient upon inclusion in the
study and at 6 and 12 months.
Apart from the follow-up visits, each patient was also
contacted on a monthly basis by telephone. Patients also
had direct telephone access to the research team for any
incidents during the research period.
We registered adverse effects by evaluating the description,
duration, and treatment of each incident, and the researcher
also determined what caused the patient’s condition. Severe
and unexpected adverse reactions were reported to health
care authorities and the clinical research ethics committee
in accordance with the stipulations of the Royal
Decree/2004.
We predetermined a sample size of 17 patients to obtain at
least a statistical power of 80% in order to detect
differences between the study group and the expected
efficacy in the general population with no treatment, which
is 0%, with a two-tailed 5% type I error.8,9
Given that our study design did not include a control group,
we were not able to test additional hypotheses, although we
did estimate 95% confidence intervals (CI) for the primary
variable using exact methods, and we have discussed our
results in the context of previously observed values for this
pathology in the general population.
The tumour volume was analysed using a restricted
maximum likelihood model for repeated measures with an
unstructured covariance matrix. We introduced the baseline
value as a covariable for the models designed for testing
difference and percent differences with regard to initial
values. We established 5% as the two-tailed significance
level, and all data were analysed using SAS software,
version 9.1.3 (SAS Institute Inc., Cary, NC, USA).
294
Study limitations
Design limitations
We have undertaken a study with no controls and a reduced
number of patients, which implies limitations in
methodology and interpretation of results. This study design
was due to the low prevalence of the disease and the limited
availability of patients in Spain; however, we do consider it
to be of great interest to be able to perform a clinical trial for
such a rare disease in which no drug treatment exists, and
which is associated with a high rate of morbidity. Our study
has been carried out in a single institution in order to
maximise the consistency of criteria for assessing the patient
response.
RESULTS
Sixteen out of the 17 patients included in the study (8 men
and 9 women) completed the treatment for the full 12
months. One had to be withdrawn from the study after 11
months due to reactivation of an erythema nodosum which
was already present at the start of the trial, and another
patient was removed from the study after 13 months of
treatment due to the appearance of nephrotic proteinuria
which disappeared after treatment suspension.
The sizes of the AML at the start of the study and after 6 and
12 months of treatment are shown in Table 1, along with the
mean percent decrease in AML volume at 6 and 12 months.
After 6 months, 35.3% (6/17, 95% CI [14.21%, 61.67%]) of
tumours had decreased in size by 50%, and 82.4% (14/17,
95% CI [56.57%, 96.20%]) after 12 months. The mean
percent decrease in volume after 6 months was 55.1% (95%
CI [44.4%, 65.7%]; P<.0001), and was 66.3% after 12
months (95% CI [56.9%, 75.6%]; P<.0001). Figures 1 and 2
show the evolution of the lesion volume, which was
analysed in terms of absolute decrease in volume and mean
percent volume decrease.
With treatment, facial angiofibromas decreased in size, and
became lighter and smoother.
We observed no significant differences in creatinine levels
between initial values and values after 12 months of
treatment, although microalbuminuria did appear, but did not
exceed 300mg/24 hours, except for one patient that
developed nephrotic proteinuria which was resolved by
halting treatment.
The most frequently observed adverse effects (Table 2) were
the appearance of oral aphthous ulcers at the start of
treatment (resolved using topical corticosteroids),
hypertriglyceridemia (controlled using medical treatment),
self-limited episodes of diarrhoea, acne and microcytosis,
Nefrologia 2011;31(3):292-8
originals
Table 1. Evolution in size of angiomyolipomas
Volume
Decrease of at least 50% (%)
Absolute values (cm3)
Adjusted differences (cm3)
N=17
Values per visit
a
Values per visitb
6 months
12 months
0
6
14
0.0% (0.0%,18.4%)
35.3% [14.21%, 61.67%]
82.4% [56.57%, 96.20%]
62.6 (18.3) [23.9, 101.4]
28.6 (7.4) [12.8; 44.4]
34 (11.4) [9.8; 58.3]
P = .0089
23.1 (7.0) [8.2; 37.9]
0 vs 6 months
Ref.
0 vs 12 months
Ref
–
6 vs 12 months
–
Ref.
Ref.
–34.0 (2.4) [-39.0; -29.0]
P <.0001
–
Ref.
5.5 (1.6) [2.1; 9.0]
P = .0035
Ref.
–55.1 (5.0) [-65.7; -44.4]
P <.0001
–
Ref.
–66.3 (4.4) [–75.6; -56.9]
P <.0001
11.2 (2.6) [5.6; 16.8]
P = .0007
Values per visitb
6 vs 12 months
Mean percent decrease (%)
Initial
Values per visitb
6 vs 12 months
–
39.6 (11.8) [14.6; 64.5]
P = .0040
5.5 (1.6) [2.1; 9.0]
P = .0032
–39.6 (2.1) [–44.1; –35.1]
P <.0001
Ref.: reference for comparison.
Means (mean standard error, MSE), [95% confidence interval].
b
Number, percentage [95% confidence interval].
a
DISCUSSION
tuberin by Akt inactivates the GAP activity of the
tuberin/hamartin complex and provokes its dissociation,
which leads to elevated levels of Rheb-GTP and allows for
the activation of specific targets in the later steps of the
mTOR-S6 cascade and the initiation of the 4E-BP1
inhibition factor.
Currently, given the absence of treatment options for this
rare disease, we must expand our knowledge of the
biological, cellular, and molecular aspects of TS, and
research effective therapeutic alternatives.
Mutations that cause the absence or dysfunction of tuberin or
hamartin, such as those that occur in TS patients, produce a
constitutive inactivation of S6K and 4E-BP1 as well as a loss
of control of cell proliferation.7
In this vein, studies performed with Drosophila have
demonstrated that the loss of tuberin produces a defect in the
cell cycle that causes the cell to repeat S phase without
entering M phase.10 In this study, as in others, tuberin and
hamartin were found to be key components of the
PI3K/PKB(Akt)/mTOR/S6K signalling cascade, which
regulates nutrient uptake, cell size, and cell proliferation
(Figure 3).11-13
AML volume
Tuberin and hamartin join in a complex that functions as the
most important regulator of the mTOR kinase in the Akt
cascade through an intermediate protein called Rheb.13,14 It
appears that mTOR mediates the majority of its effects on
cell growth through phosphorylation by way of the
ribosomal protein S6 kinase (S6K) and the repressors of the
protein synthesis initiation factor eIF4EEl, the 4EBP1. S6K
increases cell growth and protein synthesis, whereas 4EBP1
inhibits these processes. mTOR interacts with S6K and
4EBP1 through an associated protein: Raptor. The intact
tuberin/hamartin complex keeps Rheb in an inactive,
dephosphorylated state (Rheb DGP). The phosphorylation of
Nefrologia 2011;31(3):292-8
100
80
60
cm3
and hypochromia related to the antiproliferative effect of
rapamycin. One patient required hospitalisation due to acute
pyelonephritis.
40
20
0
0
2
4
6
8
10
12
Months
Figure 1. Reduced volume of angiomyolipomas.
295
originals
astrocytomas could be blocked by inhibitors of the Akt
signalling cascade, such as rapamycin. This drug has been
demonstrated to reverse the cell size defect in flies with TS
and reduces neoplastic growth in rats and mice with TS.15
This drug also reduces vascular endothelial growth factor
(VEGF) levels, and taking into consideration the high
vascularisation of TS tumours caused by upregulation of
VEGF, its antiangiogenic activity could be very beneficial.
Percent decrease in AML volume
100
80
%
60
40
20
0
0
2
4
6
8
10
12
Months
Figure 2. Percent reduction of angiomyolipoma volume.
Rapamycin (Sirolimus, Rapamune®) is an immunosuppressive
agent that forms an inhibitory complex with the immunophilin
(FKBP12), which joins to the FK-506 binding protein 12
(FKBP-12) and inhibits the capacity of mTOR to
phosphorylate S6K and 4EBP, which, in turn, inhibits the
proliferation of T-cells. This drug is on the market, with
indications for prophylaxis of acute kidney graft rejection in
adults with low immunological risk. This drug is administered
orally, and is absorbed poorly but quickly, with an oral
bioavailability of 15%. Maximum plasma concentrations are
reached within 0.5-2.3 hours. Roughly 95% of the medication
is taken up by red blood cells and is distributed throughout the
organism, even passing through the blood–brain barrier. It is
metabolised by the liver CYP3A4, with a mean lifetime of 5762 hours.
The hypothesis of this trial is that the uninhibited
proliferation observed in TS in the form of AML and
Preliminary clinical data suggest that rapamycin could play a
beneficial role in the treatment of TS. The currently available
medical literature on the subject is limited to publications on
isolated cases of reduced size of astrocytomas and AML in
patients with TS with good tolerance,16-19 and the results from
one clinical trial.20 Several different clinical trials are
currently underway. One phase II trial with no controls
demonstrated a decrease in renal AML size
(49.92%±15.62%) and improved functional respiratory test
results (forced expiratory volume in one second [FEV1],
forced vital capacity, and residual volume) in 20 patients
treated for 1 year.20,21
These positive results have led to the planning of two new US
studies that are currently underway: the TSC Multicenter
Clinical Trial, designed to evaluate the efficacy of rapamycin in
the treatment of AML through the control of the evolution of
other manifestations, and the MILES study, which will evaluate
the effects of the drug on sporadic lymphangioleiomyomatosis
and those cases associated with TS in 240 patients. In Europe,
the TESTAL study will measure the effects of rapamycin on the
size of AML in TS patients. So far, this study, which is being
performed in Great Britain, has included 12 patients.
In this study, we have shown that the treatment of patients
with TS using sirolimus produces a >50% decrease in AML
volume after 12 months of treatment.
We believe that this decrease in volume is due to a double
effect of rapamycin: growth inhibition due to the direct
Table 2. Adverse effects
Adverse effects
Number of patients
Number of events
Aphthous or mucositis
5
7
Hypertriglyceridemia
3
3
Proteinuria
1
1
Diarrhoea
2
4
Acne
1
1
Microcytosis and hypochromia
3
3
Acute pyelonephritis
1
1
Reactivation of erythema nodosum
1
2
296
Nefrologia 2011;31(3):292-8
antiproliferative effect of the drug, and indirectly through the
inhibition of angiogenesis.
originals
Tyrosine kinase receptor
We have observed that the greatest decrease in AML
volume is produced during the first 6 months of treatment,
and is probably due to the initial inhibition of mTOR and
the greater initial volume of the AML at the start of
treatment. Later, with the maintained inhibition of mTOR,
we observed a lower rate of decrease in volume and a
stabilisation in AML size, which leads to the inference
that, on a long-term basis, perhaps it is not necessary to
maintain high doses of the drug in order to sustain the
inhibition of mTOR.
The most frequent adverse reactions that we observed
were the appearance of stomatitis (5/17), observed at the
start of treatment, which was dosage-dependent and easily
controlled using topical corticosteroids and adjusted
treatment doses, followed by hypertriglyceridemia (3/17),
observed in patients that already had levels in the upper
limit before inclusion in the study, which required
medical treatment. We also observed microcytosis and
hypochromia (3/17) due to the antiproliferative effect of
rapamycin, although results from the iron metabolism
analysis were within normal values and haemoglobin
levels were stable. Lastly, we observed one case of
diarrhoea (1/17) and one of acne (1/17), which were
caused by the rapamycin.
No patients developed deteriorated kidney function.
Two patients were removed from the study, one due to
reactivation of an erythema nodosum (1/17) that was
already present before treatment, and another due to the
appearance of nephrotic proteinuria (1/17), which was
resolved after treatment suspension.
The results from our study show that mTOR inhibitors
are a safe and effective alternative for the treatment of
AML in patients with TS. This is a less aggressive
medical treatment than the currently available options,
and reduces the size of AML and thus the risk of
haemorrhage.20
Given the efficacy and acceptable safety profile of
mTOR inhibition in patients with TS, we expect the
studies currently underway to confirm these findings and
support the use of these drugs as a useful therapeutic
option in the treatment of TS.
CONCLUSIONS
1. The mTOR hamartin-tuberin signalling pathway is a
valid and effective treatment target in patients with
TS.
Nefrologia 2011;31(3):292-8
Cell growth
The phosphorylated growth factor receptor activates P13K, followed by Akt. Activated pAkt phosphorylates TSC2, which, in turn,
blocks its GAP activity. When the TSC2/TSC1 complex is not phosphorylated, it acts as a GAP for Rheb, and keeps it inactive in the
form of Rheb-guanosine diphosphate. Activated Rheb (Rheb-GTP)
is thus abundant when TSC1 or TSC2 is lacking, or when TSC is
phosphorylated. Rheb-GTP activates mTOR, and is powered by the
presence of amino acids (AA), phosphatidic acid (PA), and adenosine triphosphate (ATP), and blocked by the absence of AA or the
presence of rapamycin (Rapa). Phosphorylated mTOR targets S6K
and 4E-BP1. pS6K phosphorylates S6, and 4E-BP1 releases e1F4E.
Both activate the translational machinery that promotes cell growth.
Figure 3. Mammalian target of rapamycin cascade (mTOR).
2. Treatment with sirolimus during one year reduces AML
size by over 50% in patients with TS.
3. Given the presence of adverse effects and the
methodological limitations presented by our study, since
this is a study with no controls and a limited number of
patients due to the low prevalence of the disease, we
believe that multicentre studies are needed that evaluate
the long-term efficacy and safety of using rapamycin to
treat patients with TS.
4. However, since this is a rare disease with no other
pharmacological alternative currently available, our
promising short-term results appear to offer an effective
and less aggressive therapeutic alternative in the
treatment of AML in patients with TS.
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originals
REFERENCES
1. Crino PB, Nathason KL, Petri Henske E. The tuberous sclerosis complex. N Engl J Med 2006;355:1345-56.
2. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et
al. Mutational analysis in a cohort of 224 tuberous sclerosis patients
indicates increased severity of TSC2, compared with TSC1, disease
in multiple organs. Am J Hum Genet 2001;68:64-80.
3. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K. Renal angiomyolipoma: relationships between tumor size,
aneurysm formation, and rupture. Radiology 2002;225:78-82.
4. Ewalt DH, Diamond N, Rees C, Sparagana SP, Delgado M, Batchelor
L, et al. Long-term outcome of transcatheter embolization of renal
angiomiolipomas due to tuberous sclerosis complex. J Urol 2005;
174:1764-6.
5. Van Slegtenhorst M, De Hoogt R, Hermans C, Nellist M, Janssen B,
Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1
on chromosome 9q34. Science 1997;277(5327):805-8.
6. Consortium ECTS, 1993. Identification and characterization of the
tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 1993;75(7):1305-15.
7. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg
MK, Yeung RS, et al. Tuberin regulates p70 S6 kinase activation and
ribosomal protein S6 phosphorylation. A role for the TSC2 tumor
suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J
Biol Chem 2002;277(34):30958-67.
8. Dixon WJ, Massey FJ. Introduction to statistical analysis (4th ed.).
New York: McGraw-Hill, 1983;281-4.
9. Chernick MR, Liu CY. The saw-toothed behavior of power versus
sample size and software solutions: single binomial proportion
using exact methods. The American Statistician 2002;56:149-55.
10. Ito N, Rubin GM. Gigas, a Drosophila homolog of tuberous sclerosis
gene product-2, regulates the cell cycle. Cell 1999;96(4):529-39.
11. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with
Tsc2 to antagonize insulin signaling in regulating cell
growth, cell proliferation, and organ size. Cell
2001;105(3):357-68.
12. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The Drosophila tuberous sclerosis complex gene homologs restrict cell
growth and cell proliferation. Cell 2001;105(3):345-55.
13. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P,
Daram P, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003;5(6):559-65.
14. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a
direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003;5(6):578-81.
15. Kenerson HL, Aicher LD, True LD, Yeung RS. Activated mammalian
target of sirolimus pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 2002;62(20):5645-50.
16. Wienecke R, Fackler I, Linsemaier U, Mayer K, Licht T, Kretzler
M. Antitumoral activity of rapamycin in renal angiomyolipomas associated with tuberous sclerosis complex. Am J Kidney
Dis 2006;48:E27-29.
17. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G,
et al. Rapamycin causes regression of astrocytomas in tuberosus
sclerosis complex. Ann Neurol 2006;59:490-8.
18. Leonard J, Tudor C et al. Rapamycin causes regression of astrocytomas in tuberosus sclerosis complex. Ann Neurol
2006;59:490-8.
19. Herry I, Neukirsh C, Debray MP et al. Dramatic effect of sirolimus
on renal angiomyolipomas in a patient with tuberosu sclerosis
complex. Eur J Internal Med 2007;18:76-77.
20. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard
JM, et al. Sirolimus for angiomyolipoma in tuberousclerosis complex
or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51.
21. Bissler JJ, McCormack FX, Young LR. Efficacy and safety of sirolimus
for angiomyolipoma in patients with tuberous sclerosis complex and
linfagioleiomyomatosis. San Diego: ASN, Nov 2006.
Sent for review: 24 January 2011 | Accepted: 3 April 2011
298
Nefrologia 2011;31(3):292-8
originals
Multicentre study of haemodialysis costs
E. Parra Moncasi1, M.D. Arenas Jiménez2, M. Alonso3, M.F. Martínez4, A. Gámen Pardo1,
P. Rebollo5, T. Ortega Montoliú6, T. Martínez Terrer7, F. Álvarez-Ude8,
Grupo de Gestión de la Calidad de la Sociedad Española de Nefrología
Nephrology Department. Reina Sofía University Hospital. Tudela, Navarra, Spain
Nephrology Department. Perpetuo Socorro Hospital. Alicante, Spain
3
Nephrology Department. Valle del Nalón Hospital. Langreo, Asturias, Spain
4
Nephrology Department. Casa de la Salud Hospital. Valencia, Spain
5
BAP Health Outcomes Research. Oviedo, Asturias, Spain
6
Biohealth Research Office Oviedo, Asturias, Spain
7
Biostatistics Unit. University of Zaragoza, Spain
8
Nephrology Department. General Hospital of Segovia, Spain
1
2
Nefrologia 2011;31(3):299-307
ABSTRACT
Background: Previous studies to determine the cost of haemodialysis (HD) in Spain have significant limitations: they
are outdated or used indirect methods. There is also a lack
of analysis performed simultaneously on Public centres
(PC), with direct HD services, and partially state-subsidised
centres (SC). This is an important issue since the two
systems coexist in Spain. Objectives: To estimate the cost of
HD replacement therapy for chronic renal failure in several centres. Methods: This is a prospective and publicly-funded study, which estimates the costs for 2008 using a cost
accounting system with specific allocation criteria. We collected demographic and comorbidity data for each centre. Results: Six centres participated, two PC and four SC.
There were no significant differences between centres in
terms of patient demographics, time on haemodialysis and
the Charlson comorbidity index. The total cost per patient
per year ranged between €46 254 and €33 130. The cost
per patient per year (excluding vascular access and hospital admission) for PC was €42 547 and €39 289 and for SC
€32 872, €29 786, €35 461 and €35 294 (23% more in PC
than SC). Costs related to staff/patient/year and consumables/patient/year were 67% and 83% respectively, higher
for PC than SC. The highest percentage cost was for staff
Correspondence: E. Parra Moncasi
Hospital Reina Sofía.
Ctra. de Tarazona, km 3. 31500 Tudela. Navarra. Spain.
[email protected]
(average 30.9%), which showed significant variability between centres, both in absolute numbers (staff cost per patient per year between €18 151 and €8504) and as a percentage (between 42.6 % and 25.4%). Conclusions: Cost
variability exists among different HD centres, and this can
be attributed primarily to staff and consumables costs,
which is higher for PC than SC.
Keywords: Cost. Hemodialysis. Dialysis. Renal failure.
Estudio multicéntrico de costes en hemodiálisis
RESUMEN
Antecedentes: Los estudios realizados en España para determinar el coste de la hemodiálisis (HD) presentan importantes limitaciones; son antiguos o utilizan metodologías
indirectas. Además, carecemos de análisis realizados simultáneamente en centros públicos (CP), con prestación directa del servicio de HD, y centros concertados (CC) con la Administración. Objetivos: Estimar el coste efectivo del
tratamiento sustitutivo de la función renal con HD en la
enfermedad renal crónica terminal en diversos centros.
Métodos: Estudio prospectivo, financiado con fondos públicos, que estima el coste de 2008 mediante un sistema de
contabilidad analítica que explicita los criterios de imputación. Se recoge información demográfica y de comorbilidad de cada centro. Resultados: Participaron seis centros,
dos CP y cuatro CC. No hubo diferencias significativas en299
originals
tre los diferentes centros en cuanto a los datos demográficos de los pacientes, el tiempo en HD y el índice de comorbilidad de Charlson. El coste/paciente/año osciló entre los
46.254 y los 33.130 €. El coste/paciente/año (excluyendo
hospitalización y acceso vascular) de los CP fue de 42.547
€ y 39.289 € y los de los CC de 32.872 €, 29.786 €, 35.461
€ y 35.294 € (23% superior en CP respecto a los CC). Los
costes de personal/paciente/año y fungible/paciente/año
fueron un 67% y un 83%, respectivamente, superiores en
los CP respecto a los CC. El porcentaje de costes más elevado fue el de personal (media de 30,9%), que mostró una
importante variabilidad entre centros, tanto en cifras absolutas (coste personal/paciente/año entre 18.151 y 8.504 €)
como porcentuales (entre 42,6 y 25,4%). Conclusiones:
Existe una importante variabilidad de coste entre diferentes centros de HD, y ésta puede atribuirse fundamentalmente al coste de personal y fungible, que es superior en
los CP respecto a los CC.
Palabras clave: Coste. Hemodiálisis. Diálisis. Insuficiencia
renal.
INTRODUCTION
The clinical and economic consequences of chronic
renal failure with haemodialysis (HD) certainly
represent a social repercussion. In Spain, there are more
than 19 000 patients undergoing HD, 1 and its cost
represents approximately 1% of the health system’s
expenditure. However, the volume of patients only
represents 0.043% of the population. 2 More information
is therefore needed so that we can improve our
knowledge of the costs associated with this treatment as
a premise to ensure its sustainability.
The studies that have been conducted to determine the
actual cost of HD (even though they only provide an
estimate) have several limitations. The first is that some
are very outdated (before 1999 3-5), which is a
considerable limitation, given that different factors
suggest that costs have risen in recent years. 1.
Technologic factors: costs may increase as procedures
needing more costly material and consumables are used,
such as haemodiafiltration, acetate-free biofiltration
(AFB) and online HD. 2. Human factors: staff demand is
increased because the comorbidity of the patients is
greater or techniques are used more often than usual. 3.
Pharmacological factors: erythropoietin, darbepoetin,
intravenous iron, binders, paricalcitol, calcimimetics and
others.
E. Parra Moncasi et al. Multicentre study of haemodialysis costs
from Spanish official gazettes, which do not necessarily
correspond with actual treatment costs.7,8 Furthermore, in
Spain, public centres (PC) and partially-state subsided
centres (SC) both exist, meaning that “centre ownership”
is very relevant. As far as we are aware, this variable has
yet to be studied. Furthermore, we have not found any
cost studies on renal replacement therapy with HD,
analysing actual costs.
This study aims to estimate the effective costs of renal
replacement therapy with HD for end-stage renal
disease, using a single methodology in several PC and
SC centres.
METHOD
We conducted a prospective and descriptive study, in the
context of the Estudio de Evaluación Global de Centros de
Diálisis (study on the overall evaluation of dialysis
centres) by the Quality Management Group from the
Spanish Society of Nephrology. This study is aimed to
evaluate HD centres, assessing clinical outcomes, patient
satisfaction, health-related quality of life, and costs. In this
article, we shall only present the cost assessment results.
During the first half of 2007, we created an Excel accounting
database which recorded the most HD-relevant financial
items and specific allocation criteria for all the centres.
In October 2007, we sent an email to all centres that
usually collaborate with the Quality Management Group
formally inviting them to participate in the study. We
included all centres that voluntarily and explicitly
accepted the invitation. The accounting department from
each centre participated in the study, choosing an
individual to analyse the financial data (hereinafter
financial researcher). This person was then given the
accounting database to collect the financial data, filling it
out prospectively during the financial year of 2008.
The centres’ costs were calculated using a cost accounting
system, which included the same items and allocation criteria
for all centres, so that we could compare several centres. If a
given centre was not able to provide cost data for an item
according to the pre-defined allocation criterion, an alternative,
second one was created so that the data could be recorded.
We used the following items and allocation criteria for the
financial analysis:
Staff
Another limitation of some of the previous costs studies
is that they use indirect methodologies, calculating costs
using clinical protocols, 6 or “price” assessments taken
300
Effective cost for staff was collected with respect to the
time dedicated to HD. Time for non-HD-related activities
Nefrologia 2011;31(3):299-307
carried out by staff was not considered (hospital
admission, check-ups, night shift, emergency department,
peritoneal dialysis, acute patients). All staff costs were
included (pay, social security contributions, personal
income tax, replacement staff, among others). Each
centre’s financial researcher calculated the time assigned
to HD, and the financial value was provided by the
accounting or human resources department.
Consumables
Cost was measured in accordance with the monthly
computer record for the actual store outputs to the HD unit
throughout 2008. Consumables included dialysers, arterial
and venous lines, needles, syringes, gloves, dressings,
among others.
originals
available, the tariff published on the Spanish official
gazette was used.
Management
Included the head doctor or nurse, supervisors, admission
and reception staff, and other intermediary positions, in
proportion to time dedicated to the HD unit. It also
included indirect costs that have an impact on the HD
unit management, i.e. the building structure, (considering
a 30-year depreciation period) and equipment (10-year
depreciation period), calculated using the cost
accounting system.
Maintenance
Inpatient pharmacy
Analysis was performed using the monthly computer record
of actual pharmacy outputs to the HD unit throughout 2008.
Inpatient pharmacy included: erythropoiesis-stimulating
agents, heparins, HD dialysate, saline, cinacalcet, antibiotics,
fibrinolytic agents, among others.
Outpatient pharmacy
Using each centre’s electronic clinical records, the total
number of outpatient drugs consumed (number of pills)
during a whole week in 2008 was recorded. The public
retail price (PRP) for that year was considered using a
table with reference price per pill. The figure was then
extrapolated to the whole year.
When equipment maintenance was performed by the HD
monitor or consumables supplier, the company provided
data, separating the percentage that corresponded to each
item, and each partial cost was allocated to the relevant
section (consumables, health care equipment or
maintenance). If there was an additional external
maintenance service, the invoice was accounted for
(including the material). If in any of the cases above there
was also an internal service, the proportional period of
time and material used in the unit were taken into
account, as well as the costs outlined in the cost
accounting system.
Health care equipment
Laboratory expenses were calculated by considering the
annual number of tests requested by the dialysis unit
multiplied by the average test cost for 2008, taken from
the centre’s cost accounting system.
When financed by the consumables supplier, each
item was separated in the same way as in the
maintenance section. When owned by the centre, a
depreciation period of 30 000 hours for monitors and
10 years for a water treatment system were
considered. If the health care equipment was leased,
its annual cost was considered. Costs associated with
dialysis monitors and water treatment systems are
also considered.
Diagnostic imaging
Cleaning
Included average cost per test, calculated using the centre’s
cost accounting system. Fistulography was not included.
This is in accordance with the invoice issued to the HD unit,
or the proportion of surface area that the HD unit covers
with regard to the rest of the centre.
Laboratory
Transport
Food
Price of transport was in accordance with the contracted
company’s tariff. When the company’s tariff was not
Nefrologia 2011;31(3):299-307
Calculated according to the invoice issued to the HD unit.
301
originals
Laundry
Depending on the number of kilograms sent to the laundry
during a week, extrapolated to the whole year, and applying
price per kilo for the external service.
To verify the homogeneity of the patient sample from each
centre, its distribution was checked. The Kruskal-Wallis test
was applied for quantitative variables, and the chi-square test
used for qualitative variables.
RESULTS
Other centre costs
Including electricity, water, telephone (in proportion to
the unit’s surface) and waste (in proportion to the number
of containers used in one week, considering the price that
the waste company charges, extrapolating the cost to the
whole year). Other costs included: computing, stationary,
water sample transport and other transport, services,
quality, safety, anatomical pathology, library, preventative
medicine, risk prevention, communication, security,
common areas, legal consultancy, and medicinal gases.
All were considered and allocated using the centre’s cost
accounting system.
Costs for admissions and performing vascular access
were calculated using an estimation based on the authors’
previous cost studies, and weighted by each centre’s
activity.9
The number of patients in each centre was calculated on a
monthly basis: a patient who was in the unit for four weeks
was recorded as 1, three weeks as 0.75, two weeks as 0.5 and
one week as 0.25. Then, the results for each centre were
extrapolated to calculate the annual figure. The demographic
and comorbidity characteristics were also prospectively
collected for each patient.
Alternate-day HD, daily HD, AFB, biofiltration and online
HD were considered as special techniques.
Six centres participated in the study: two were public (PC)
and provided direct HD services, and the other four were
partially state-subsidised (SC). The two PC (1-2) were
dialysis units integrated within regional hospitals, two of the
SC (3-4) were also integrated within hospitals and the other
two SC (5-6) dialysis units were separate from the main
centre building.
Table 1 shows the demographic and comorbidity
characteristics for each centre. There were no statistically
significant differences between the centres with regards
patient age, time on HD, and Charlson comorbidity index.
There were more men than women in all centres, which is
usual in the HD population, as we have found in the regional
and national records.
The cost results per centre and the distribution of
percentage costs per item are included in Table 2. The
highest percentage cost was staff in all centres (30.9%),
but there was significant variability between the centres
(42.6% in centre 1 and 25.4% in centre 5). Other
important costs were: pharmacy at 27.3% (inpatient
13.3%; outpatient 14.0%), consumables (17.5%),
transport (8.1%) and management (4.5%). The rest of the
percentage costs were less than 2.5%.
The average daily cost for hospital stay was estimated at
€498, vascular access at €2649 (autologous or prosthetic
fistula), and placing a catheter at €1380. This was then
Table 1. Demographic and comorbidity characteristics of the centres
Demographics, morbidity/centres
1
2
3
4
5
6
P
67.73 (13.88)
68.38 (13.09)
68.0 (14.20)
66.87 (15.03)
64.31 (14.64)
67.8 (15.28)
0.632a
Men (%)
25 (61.0%)
22 (59.5%)
37 (69.8%)
89 (65.4%)
34 (63.0%)
27 (65.9%)
Women (%)
16 (39.0%)
15 (40.5%)
16 (30.2%)
47 (34.6%)
20 (37.0%)
14 (34.1%)
0.952b
Months on HD (SD)
47.59 (41.23)
43.70 (40.43)
43.37 (39.81)
50.93 (63.11)
50.00 (52.34)
57.32 (59.39)
0.91a
Charlson Index (SD)
7.78 (3.25)
7.68 (2.4)
7.11 (2.06)
7.84 (2.86)
7.55 (3.09)
7.21 (3.02)
0.694a
Age in years (SD)
Sex
a
Kruskal-Wallis test; bChi-square
SD: Standard deviation; HD: haemodialysis.
302
Nefrologia 2011;31(3):299-307
originals
Table 2. Type of centres and their costs. Items listed with percentages of the total
CENTRE
1
2
3
4
5
6
Mean
Mean
1-2
Mean
3 to 6
- Typea
P
P
S
S
S
S
P
S
P and S
1587 993
1202 251
1544 967
4986 131
%
%
%
%
%
%
%
%
%
- Staff
42.6
32.1
28.9
28.5
25.4
28.1
37.3
27.7
30.9
- Doctor
7.8
5.2
7.8
4.9
7.2
14.0
6.5
8.5
7.8
- Nursing
24.5
18.9
17.4
15.4
14.5
9.3
21.7
14.1
16.7
- N. auxiliary
9.4
7.3
2.7
7.9
3.2
4.0
8.4
4.5
5.8
- Other health care staff (porters and others)
1.0
0.7
-
-
-
-
0.8
-
0.3
- Total annual cost (€)
- Item (percentage)
- Administrative staff (if necessary)
1414 910
984 705
-
-
0.9
0.3
0.6
0.9
-
0.7
0.5
- Consumables and pharmacy
37.1
49.5
43.0
47.5
46.9
44.5
43.3
45.5
44.7
- Consumables
16.7
28.2
21.8
13.5
11.4
13.2
22.4
15.0
17.5
- Inpatient Pharmacy
12.1
11.6
10.3
17.7
16.0
12.4
11.8
14.1
13.3
- Outpatient pharmacy
8.4
9.7
10.9
16.2
19.5
19.0
9.0
16.4
14.0
- Diagnostic tests
3.1
1.3
0.6
3.4
2.8
2.8
2.2
2.4
2.3
- Laboratory
3.0
0.9
0.4
3.2
2.6
2.7
2.0
2.2
2.1
- Diagnostic imaging
0.1
0.4
0.2
0.2
0.2
0.1
0.2
0.2
0.2
- Other costs
17.1
17.1
27.5
20.6
24.9
24.6
17.1
24.4
22.0
- Transport
4.8
5.2
14.1
7.7
8.2
8.6
5.0
9.7
8.1
- Management
4.8
1.6
3.7
6.3
5.2
5.3
3.2
5.1
4.5
- Maintenance
1.4
3.1
1.3
0.8
1.8
2.1
2.3
1.5
1.7
- Health care equipment
1.1
1.4
0.5
1.0
1.8
2.2
1.3
1.4
1.3
- Waste
0.1
1.7
0.7
0.5
0.4
0.5
0.9
0.5
0.6
- Cleaning
1.1
1.4
3.3
1.0
0.9
1.4
1.2
1.7
1.5
- Food
1.8
0.2
-
0.9
2.4
2.0
1.0
1.3
1.2
- Laundry
1.3
1.5
0.8
0.5
0.4
0.4
1.4
0.6
0.8
- Others
0.7
1.0
3.1
2.0
3.7
2.0
0.9
2.7
2.1
P: public centre with direct services; S: partially state-subsidised centre; %: percentage of the total cost.
weighted by the number of stays and accesses performed by
the unit.
1. Consumable cost/patient/year: between €11 065 and
€4029.
The cost per patient, per HD session and other items are
shown in Table 3. The six centres’ average cost for a HD
session was €201 and the average cost per patient/year was
€33 479, not including hospital admission or vascular
access. The total average cost per patient/year (including
hospital admission and vascular access) was €40 136,
ranging between €46 254 and €33 130. The
cost/patient/year for PC was €42 547 and €39 289 and it
was €32 872, €29 786, €35 461 and €35 294 for the SC.
2. Inpatient pharmacy/patient/year: between €5665 and
€3376.
Cost/patient/year (without considering hospital admission or
vascular access) ranged between €42 574 (centre 1) and
€29 786 (centre 4). The greatest difference was found for
the staff cost/patient/year in the same centres, being €18 151
and €8504, respectively. Cost variability for other items
was:
Nefrologia 2011;31(3):299-307
3. Outpatient pharmacy/patient/year: between €6923 and
€3564.
4. Diagnostic tests cost/patient/year: between €195 and
€1332.
5. Other costs/patient/year (transport, management,
maintenance, equipment, waste, cleaning, food and
laundry): between €6734 and €9055.
Several parameters were retrospectively analysed in order to
explain why there were differences in staff costs: number of
sessions/staff member/12 hours (nephrologist, nurse and
303
originals
Table 3. Cost of the centres for haemodialysis, hospital admission and vascular access
Centre
- Type
1
2
3
4
5
6
Mean P
Mean
Variation
Total/
(1-2)
S (3-6)
PS (%)
Average
P
S
P
P
S
S
S
S
37.3
30.6
47.0
167.4
39.9
27.9
2
2
1
29.7
0.6
0.4
- No. sessions
5890
4932
7495
28 170
6925
4847
- Cost/HD session
270
244
206
177
204
203
257
198
30
201
- Total cost/patient/yeara
42 574
39 289
32 872
29 786
35 461
35 294
40 931
33 353
23
33 479
- Staff cost/patient/year
18 151
12 594
9 490
8 504
9 009
9 922
15 373
9 231
67
11 278
7112
11 065
7179
4029
4037
4645
9089
4972
83
15 975
5131
4554
3376
5267
5665
4367
4843
4669
4
4727
4904
- Average no. of patients
- No. of patients with special HD
350.1
Haemodialysis
- Consumable cost/patient/year
58 259
- Inpatient pharmacy
cost/patient/year
- Outpatient pharmacy
3564
3811
3576
4840
6923
6709
3688
5512
-33
- Diagnostic test cost/patient/year
cost/patient/year
1332
530
195
1000
1001
973
931
792
18
838
- Other costs/patient/yeara
7284
6734
9055
6146
8826
8678
7009
8176
-14
7787
- No. of hospital stays
235
268
292
888
295
259
252
434
- Stays/patient/year
6.3
8.8
6.2
5.3
7.4
9.3
7.5
7.0
117 030
133 464
3138
4362
3094
2642
3682
4623
3750
3510
4
6
7
34
8
6
5
14
Hospital admissions
- Hospital admissions cost
145 416 442 224 146 910 128 982 125 247
2237
7
215 883
7.2
185 671
- Cost/hospital
admission/patient/year
7
3590
Vascular access
- No. of fistulas
(autologous or prosthetic)
- No. of catheters
(temporary or permanent)
- Vascular access cost
- Access cost/patient/year
7
7
8
20
4
1
7
8
20 256
25 554
29 583
117 666
26 712
17 274
22 905
47 809
543
835
629
703
669
619
689
655
5
667
46 254
44 486
36 595
33 130
39 813
40 536
45 370
37 519
21
40 136
Total cost
- Total cost/patient/yearb
P: public centre with direct services; S: partially state-subsidised centre; adoes not include hospital admission or vascular access; bincludes
haemodialysis, hospital admission and vascular access.
nursing auxiliary), the staff cost in accordance to
professional level, and the hours worked per year in each
centre (Table 4 ).
DISCUSSION
Our study revealed that the cost associated with renal
replacement therapy with HD ranged between €4630 per
patient per year. We understand that this is the first study
conducted this decade, which estimates the actual costs of
this therapy in different centres, simultaneously and using
similar methodology. We therefore believe that the data
provided here is more precise and up-to-date than that of
previous studies.
304
To compare the results from this study with those
conducted in the 1990s, we would have to update the
prices in accordance with the Spanish consumer price
index (CPI). 10 Using the prices given in 1994 and
converting them to the 2008 equivalent, they ranged
between €64 935/patient/year in the Juan Canalejo
Hospital and €34 339 /patient/year in the Consorcio
Hospitalario de Sabadell in the same year. 3 As can be
observed, the costs in our study are almost the same as the
costs found in the previous studies, having updated the
CPI. The data show that costs do not seem to have
increased above the CPI during the past decade, despite
technological and pharmacological sophistication and
more intensive use of human resources. This statement
should however be interpreted with caution, as the
Nefrologia 2011;31(3):299-307
originals
Table 4. Theoretical and effective patient ratios per staff member, staff costs, working hours per centre
Centre
1
2
3
4
5
6
Mean P (1-2)
Mean S (3-6)
Theoretical ratio
No. of patients/doctor
NR
32
NR
40
40
40
No. of patients/nurse
3
4
4
5
5
5
3.5
4.75
No. of patients/n. auxiliary
5
8
12
10
10
10
6.5
10.5
Sessions/doctor/12 h
22.5
20.0
29.7
36.4
30.9
26.7
21.3
30.9
Sessions/nurse/12 h
5.1
8.0
7.4
10.4
10.3
10.7
6.6
9.7
Sessions/n. auxiliary/12 h
8.2
16.0
24.8
14.6
15.4
17.8
12.1
18.1
Effective ratio
Staff cost (€ )
Doctor
57 486
62 073
60 492
97 780
78 158
98 154
59 780
83 646
Nursing
38 665
22 776
33 588
40 324
40 937
36 693
30 721
37 885
N. auxiliary
26 179
17 290
21 120
28 289
22 370
24 533
21 735
24 078
1560
1510
1780
1826
1826
1826
1535
1815
Working hours
Hours worked /year
Staff cost/h (€ )
Doctor
36.9
41.1
34.0
53.5
42.8
53.8
39.0
46.0
Nursing
24.8
15.1
18.9
22.1
22.4
20.1
19.9
20.9
N. auxiliary
16.8
11.5
11.9
15.5
12.3
13.4
14.1
13.3
Sessions/doctor/12 h: number of sessions assisted per doctor in 12 hours; Sessions/nurse/12 h: number of sessions assisted per nurse in 12 hours;
Sessions/nursing auxiliary/12 h: number of sessions assisted per nursing auxiliary in 12 hours; NR: not reported
comparison has not been made between the same centres,
which may have had different initial situations.
Furthermore, it seems that special techniques are not
highly used in the centres studied.
Other more recent studies, which have the previously
mentioned limitations, calculate costs using indirect
methodologies, based on clinical protocols 6 or official
gazette tariffs. 7,8 The estimated HD cost was
€43 234/patient/year and €47 000/patient/year
(including hospital admission cost) in two recent
studies that used the second methodology. As such,
these figures are in the higher part of the range that we
obtained.
HD department outsourcing has stereotypically been
considered as a good way of keeping therapy costs minimal,
although no definite proof of such has been presented and it
has even been questioned.3 We did not consider hospital
admission and vascular access costs to be directly related to
the dialysis unit, we therefore excluded them so that we
could compare the costs between the different centres.
Furthermore, as will be explained in the study limitations,
assessing these costs is very complex and the method used
has a low discriminatory power. In our study, all centres
encountered a similar degree of difficulty in performing
Nefrologia 2011;31(3):299-307
analysis, although, even considering the study limitations,
the results seem to indicate that the costs tend to be higher in
PC than SC.
This difference is mainly associated with costs for staff and
consumables, rather than other therapy-related costs.
Therefore, the results from our study can be considered to
support the stereotype mentioned above. However, we
should point out that an overall evaluation of centres must
analyse the clinical outcome variables, patient satisfaction
and health-related quality of life in order to answer difficult
questions such as: What is the optimum price? what is the
best possible result? or how much is too much?
We decided to perform a retrospective analysis in order to
explain why there was a variation in staff costs among the
different types of centres. The difference between PC and
SC staff costs is surprising. However, it does generally
even out when adjusted to the number of hours worked
annually (staff cost per hour), except for PC doctors,
which is still remarkably lower. However, the difference
that we consider most significant between PC and SC
seems to mainly be organisational, and lies in the
theoretical patient/staff ratio, and especially the effective
patient/staff ratio (number of sessions/staff member/12
hours). We believe that the latter item better represents
305
originals
the actual patient/staff ratio in the dialysis centre. We
think that both ratios, due to organisational or structural
reasons, do not necessarily have to coincide with one
another. In general, the annual staff cost was generally
higher for SC but since the number of hours worked
annually was also more, the hourly cost levelled out.
However, considering the number of HD sessions
performed per staff member and per time period,
considerably fewer HD sessions were performed in PC
than in SC. This data suggests that SC more efficiently
optimise their human resources. However, finding the
difficult equilibrium between working conditions and
efficiency should take into account a third variable, which
as we have mentioned above, is the results obtained.
PC have a higher patient/consumable/year cost than SC.
Theoretically, PC would have a competitive advantage
over SC as they are able to buy in larger quantities.
However, the SC overcame this advantage by having the
incentive to prevent financial losses or generate profits.
The overall result was that SC had more efficient
purchasing management. There were differences in food
costs because the content administered to the patients
varied among the centres. Differences for other items
(management, cleaning, transport, etc.) are not as easily
explained and may be due to various causes. In any case,
apart from transport and management, the differences
were quantitatively lower. The fact that centre 4 had the
lowest costs per patient and the highest number of
patients may be explained by an economy of scale
phenomena, favouring a more efficient use of resources
in the centres after a given patient volume is achieved.
However, we are still lacking information on the
optimum centre size with regard to financial and clinical
perspectives.
Our study has had several limitations. Firstly, a small
number of centres participated in the study, which are
not necessarily representative of all centres. Despite this,
as far as we are aware, our study has included the most
centres in Spain. Secondly, the exact same items could
not be used in all cases, given that some centres were
able to easily adapt to certain item criteria, but it was not
feasible in others. However, the items that were not
recorded in the same way, in general, represented
relatively small costs, and affected items such as
electricity, water and others. A third limitation is that
costs for consumables, equipment and maintenance were
not very clear given as they are interrelated and overlap
one another. As such, it is possible to analyse the total of
all three costs, but it is sometimes difficult to separate it
306
into the three items. Lastly, we understand that using
average estimated costs to calculate hospital admission
and vascular accesses is a severe limitation for
identifying differences between centres, although they
are useful for calculating overall HD costs. This is a
limitation because it tends to even out the costs, which is
why we only used them to assess overall costs, but not to
estimate each centre’s costs. Furthermore, implementing
an ad hoc hospital cost system for each centre exceeds
our study’s capabilities.
An outstanding article was recently published in the
Revista de Nefrología 8 which discussed quality and
sustainability of renal replacement treatment. Dr. Arrieta
economically assessed this treatment, and correctly
reported that the object of his study was not to make cost
savings. We can add to this point, conferring that the
main objective of cost studies is to simply find out what
the costs are, and help distinguish which are appropriate
and which are unnecessary. This is essential to guarantee
that the appropriate costs are funded, and secondly,
ensure treatment sustainability.
We understand that we must make an effort to
standardise the manner that results are presented in cost
studies on renal replacement therapy, so that they can be
compared between centres. As such, they should include
the items relevant to the main production factors, and
which are recognised by nephrologists and other dialysis
unit staff, specifying at least the following: staff,
consumables, inpatient and outpatient pharmacy,
laboratory,
radiology,
transport,
maintenance,
equipment, cleaning, food, hospital admission and
management.
To conclude, our study, even considering its limitations,
seems to indicate that there is an important variation in
the costs among different HD centres. This variability is
mainly due to staff and consumables costs, which tend
to be higher in PC offering direct HD services than in
the SC.
Acknowledgements
We would like to thank a number of people associated with the centres’ dialysis units and financial management departments. Without these people, our study would not have been possible: Araceli Vidal, Francisca Hernández Cobo, Carmen Blanco Suárez, Luis Pérez Puyo, José
Ángel González Herranz and Luis Robledo Díaz.
Nefrologia 2011;31(3):299-307
originals
REFERENCES
1. Informe 2006 de diálisis y trasplante renal en España. Registro Español de Enfermos Renales. Nefrologia 2009;29(6):525-33.
2. Organisation for Economic Co-operation and Development. Consultado Sept 2010.Available at: http://www.oecd.org/home/
3. Lamas J, Alonso M, Saavedra J, García-Trío G, Rionda M, Ameijeiras M.
Costes de la diálisis crónica en un hospital público: mitos y realidades. Nefrologia 2001;3:283-94.
4. Burgos R, Martín Martín J, López del Amo MP, Arellano J, Pérez C,
Pozo F. Importancia del método de estimación de costes en diálisis y
trasplante renal. Nefrologia 2001;Supl 4:86-90.
5. Martín Hernández R. Análisis de los costes en nefrología: situación
actual y perspectivas de futuro. Nefrologia 1998;18(6):40-51.
6. Rodríguez-Carmona A, Castro A, Pérez Fontán M, Mojón M. Estudio económico de diálisis por el método de coste por procedi-
miento ajustado a protocolo clínico. Nefrologia 2007;27(3):35969.
7. Lorenzo V, Perestelo L, Barroso M, Torres A, Nazco J. Economic evaluation of haemodialysis. Analysis of cost components based on patient-specific data. Nefrologia 2010;30(4):403-12.
8. Arrieta J. Evaluación económica del tratamiento sustitutivo renal (hemodiálisis, diálisis peritoneal y trasplante renal) en España. Nefrologia Suplemento Extraordinario 2010;1(1):56-62.
9. Ortega T, Ortega F, Díaz-Corte C, Rebollo P, Baltar JM, ÁlvarezGrande J. The timely construction of arteriovenous fistulae: a
key to reducing morbidity and mortality and to improving cost
management. Nephrol Dial Transplant 2005;20:598-603.
10. Instituto Nacional de Estadística. Consultado Sept 2010.
Available at: http://www.ine.es/
Sent for review: 24 Jan. 2011 | Accepted: 7 Apr. 2011
Nefrologia 2011;31(3):299-307
307
originals
Prophylaxis with gentamicin locking of chronic
tunnelled central venous catheters does not cause
bacterial resistance
J. Fernández-Gallego, M. Martín, E. Gutiérrez , C. Cobelo, P. Frías, C. Jironda,
P. Hidalgo, T. Jiménez
Nephrology Department. Carlos Haya Hospital. Málaga, Spain
Nefrologia 2011;31(3):308-12
ABSTRACT
Introduction: Prophylaxis with gentamicin locking of chronic
tunnelled central venous catheter branches in chronic
haemodialysis patients reduces bacterial infections and morbidity and mortality associated with catheter bacteraemia. Aim: We
undertook a 7-year, prospective, observational study involving
101 patients on chronic haemodialysis with catheters treated
with prophylaxis to evaluate the appearance of bacterial resistance to the antibiotic in pathogens usually sensitive to its action.
Material and Methods: A protocol of universal asepsis in
catheter management. Postdialysis intraluminal locking of the
branches with gentamicin at 5mg/branch + 1% heparin sodium, monitoring trough levels in the blood and modifying the
dose according to the established protocol. The diagnosis of
bacteraemia was based on usual criteria. The main study variables were: Diagnosis by the bacteriology department of bacterial resistance in pathogens sensitive to gentamicin. Diagnosis of
clinical ototoxicity. Secondary variables were: Patients hospitalised/bacteraemia; number of bacteraemia/catheter/1000
days; infectious mortality; and catheter withdrawal/bacteraemia.
Pathogens found in blood culture. Results: Main variables: We
found no resistance of pathogens usually sensitive to the antibiotic or clinical ototoxicity. The mean number of months each patient remained in the study was 23 (1-84). Secondary variables:
Three patients (3%) were hospitalised due to bacteraemia; number of bacteraemias: 8; number of bacteraemia/catheter/1000
days: 0.11; infectious mortality per bacteraemia: 1 patient (1%);
catheter withdrawal due to bacteraemia: 2 (2%). No patients
were diagnosed with endocarditis or spondylodiscitis. The mean
trough level of gentamicin in each patient during the study was
0.17µg/ml (0.05-0.31); the mean intraluminal gentamicin locking dose per branch was 3mg (2-5), equivalent to 1.1-
Correspondence: Juan Fernández-Gallego
Hospital Carlos Haya. Málaga. Spain.
[email protected]
308
1.7mg/ml/branch. Conclusions: This 7-year, prospective observational study of 101 patients on chronic haemodialysis with
tunnelled central venous catheters showed: 1) Prophylaxis with
intraluminal gentamicin locking of the catheter branches does
not cause bacterial resistance in pathogens sensitive to its action. 2) No clinical ototoxicity was seen. 3) The lack of resistance
and ototoxicity may be influenced by the gentamicin prophylaxis dose used, which was much lower than in other studies.
Keywords:
Hemodialysis.
Catheter.
Bacteremia.
Prophylaxis. Gentamicin. Gentamicin bacterial resistance.
La profilaxis con sellado de gentamicina de las ramas del
catéter venoso central crónico tunelizado no causa
resistencia bacteriana
RESUMEN
Introducción: La profilaxis con sellado de gentamicina de las
ramas del catéter venoso central tunelizado en hemodiálisis crónica disminuye la morbimortalidad infecciosa bacteriana asociada a la bacteriemia del catéter. Objetivo: Valorar en un estudio
prospectivo observacional de 7 años de duración de 101 pacientes en hemodiálisis crónica con catéter tratados con profilaxis la
aparición de resistencia bacteriana al antibiótico en gérmenes
habitualmente sensibles a su acción. Material y métodos: Protocolo de asepsia universal en el manejo del catéter. Sellado intraluminal de las ramas posdiálisis con gentamicina 5 mg/rama
+ heparina sódica al 1%, monitorizando su nivel valle en sangre
y modificando la dosis por un protocolo establecido. El diagnóstico de bacteriemia se basa en criterios habituales. Variables
principales estudiadas: Diagnóstico por el servicio de bacteriología de resistencia bacteriana en gérmenes habitualmente sensibles a gentamicina. Diagnóstico de ototoxicidad clínica. Variables secundarias: Pacientes hospitalizados/bacteriemia; número
de bacteriemias/catéter/1.000 días; mortalidad infecciosa y reti-
J. Fernández-Gallego et al. Prophylaxis with gentamicin. Bacterial resistance
rada del catéter/bacteriemia. Gérmenes causantes de bacteriemia. Resultados: Variables principales: No observamos resistencia de gérmenes sensibles al antibiótico, tampoco ototoxicidad
clínica. La media en meses en que cada paciente está incluido
en el estudio es de 23 (1-84). Variables secundarias: Hospitalizados por bacteriemia, 3 casos (3%); número de pacientes con
bacteriemias, 8; número de bacteriemias/catéter/1.000 días,
0,11; mortalidad infecciosa/bacteriemia, un paciente (1%); retirada del catéter/bacteriemia, 2 casos (2%). Diagnosticado de endocarditis o espondilodiscitis, ningún paciente. La media del nivel valle de gentamicina/paciente durante el estudio es de 0,17
µg/ml (0,05-0,31); la dosis media de sellado de gentamicina intraluminal/rama/paciente es de 3 mg (2-5), equivalente a 1,11,7 mg/ml según el volumen de la rama del catéter. Conclusiones: Este estudio prospectivo observacional de 7 años de
duración de 101 pacientes en hemodiálisis crónica con catéter
venoso central tunelizado objetiva: 1) la profilaxis con sellado intraluminal de gentamicina de las ramas del catéter no causa resistencia bacteriana en gérmenes sensibles a su acción; 2) no se
observa ototoxicidad clínica; 3) la profilaxis con dosis bajas de
gentamicina administrada comparada con la mayor dosis empleada en otras investigaciones puede influir en que no aparezcan resistencia y ototoxicidad.
Palabras clave: Hemodiálisis. Catéter. Bacteriemia. Profilaxis.
Gentamicina. Resistencia bacteriana a gentamicina.
INTRODUCTION AND OBJECTIVES
A greater rate of mortality has been shown to be associated
with patients on chronic haemodialysis (HD) being treated
with chronic tunnelled central venous catheters in comparison
to other types of vascular accesses.1-3 Central venous catheterrelated bacteraemia (BCVC) has an important influence on
bacterial infectious morbidity and mortality.1-4 In patients on
HD with a catheter, BCVC develops from a bacterial biofilm
that forms on the internal surface of the catheter branches. It
arises from the bacterial flora that naturally occurs on the skin
around the catheter exit.5 Previous studies and recently
performed meta-analyses have demonstrated the efficacy of
prophylaxis with post-HD intraluminal locking of the catheter
branches with antibiotics, especially with cefotaxime and
gentamicin (G) in reducing the morbidity and mortality
associated with this condition.6-16
European guidelines for BCVC prevention, diagnosis, and
treatment17 recommend this prophylaxis, but also highlight
the importance of strict universal aseptic protocols when
manipulating the catheter. In our unit, G prophylaxis has
been administered since July 2003, along with universal
asepsis in all procedures involving the catheter.
originals
evaluated whether prophylaxis with post-HD intraluminal G
locking of the catheter branches causes bacterial resistance
in pathogens that are normally sensitive to this antibiotic, as
well as the appearance of clinical ototoxicity.
MATERIAL AND METHODS
Patients
In the seven-year period of the study, our unit administered
dialysis to 298 patients. One hundred and forty-two of them had
arteriovenous fistulas, and 156 chronic tunnelled central venous
catheters. We excluded 55 catheterised patients that were in the
unit for less than one month (37 were transferred to other
institution and 16 died due to high comorbidity), and two
because of simultaneous chronic treatment with
immunosuppressants and steroids. We followed 101 patients
treated with prophylaxis for more than one month. The catheter
was implanted in the right internal jugular vein in the vascular
radiology unit, except for 4 cases in which the catheter was
implanted in the right femoral vein due to exhaustion of venous
access sites. HD lasted from 3.5-5 hours, each patient received
3-5 sessions per week, with ultrafiltration control monitor and
bicarbonate dialysate. Some patients left the study before it was
concluded: 7 for developing a fistula, 10 were transferred to
another institution, 3 for receiving kidney transplants and 50
died. At the end of the study we had 31 active patients.
Universal asepsis
All procedures involving a catheter were performed by
nursing staff with the greatest level of asepsis following
standard protocols similar to those previously published.17,18
Prophylaxis
Post-HD intraluminal locking with 5mg of G + sodium
heparin at 1%/branch/patient. In the total volume present in
each branch (e.g., 2ml), one part is the amount of G to be
administered from a 20mg G vial, and the other part is the
1% heparin dose, a protocol that the nursing staff carried out
aseptically. In order to avoid otic iatrogenic incidents, we
designed a control protocol. Trough levels of blood G
content were measured weekly (normal value: 0.2-2µg/ml).
If this value exceeded 0.3-0.5µg/ml, we reduced the G
locking to 3mg/branch/patient; >0.5-2mg/branch.
BCVC diagnosis
Objective
In a 7-year (July 2003-June 2010) prospective, observational
study involving 101 HD patients with a catheter, we
Nefrologia 2011;31(3):308-12
We defined BCVC as clinical improvement following treatment
with antibiotics in patients that had a fever, with or without
catheter removal, with positive blood cultures from peripheral
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originals
blood taken from the HD circuit,18 excluding other infection
sites. According to the NKF 2006 guidelines for vascular access
in HD,19 we also established a possible BCVC diagnosis:
clinical improvement in a patient treated with antibiotics with or
without catheter removal, with negative blood cultures and
excluding other infection sites.
BCVC treatment
Gram-positive pathogens are normally treated with 1g
vancomycin in the first session of HD and with 500mg in
consecutive HD sessions for up to 4 weeks (other antibiotic is
used if the antibiogram indicates it). For gram-negative bacteria,
the antibiotic indicated in the antibiogram is used for 3-4 weeks.
Before the blood culture results came back, we treated all patients
with vancomycin at the established dosage +G (1mg/kg weight
for 3 consecutive HD sessions). Patients diagnosed with BCVC
had positive peripheral blood culture results, except for one,
whose symptoms disappeared with removal of the catheter.
Main variables studied
Ototoxicity
Hypoacusis and/or vertigo.
Bacterial resistance to G20
Pathogens that are normally sensitive to G: gram-positive:
Staphylococcus aureus and coagulase-negative, methicillinsensitive Staphylococcus. Gram-negative: Escherichia coli,
Proteus spp., Serratia spp., Klebsiella spp., Enterobacter
spp., Providencia spp., Shigella spp., Salmonella spp.,
Pseudomonas aeruginosa, etc. The G minimum inhibitory
concentration (MIC) for these pathogens is <4µg/ml, which
is the reference value used by the bacteriology department.
We detected antibiotic resistance in the blood cultures and
antibiograms, where the numerical value of MIC is
expressed for each pathogen, along with the label of S
(sensitive) or R (resistant).
Secondary variables
We also measured blood trough levels of G and
intraluminal locking dosage in G/patient/branch. These
two variables were expressed as the sum of the relevant
means for each patient. We also documented patients
diagnosed with BCVC, hospitalisation due to BCVC, the
number of cases of BCVC and the causal pathogen, the
number of BCVC/catheter/1000 days, mortality from
BCVC, and catheter removal due to BCVC. We estimated
the mean, standard deviation, and range for these variables
using SPSS 11.0 software for Windows.
310
RESULTS
Primary variables
We detected no bacterial resistance in the antibiogram for
pathogens normally sensitive to G. MIC was <4µg/ml except
for two cases of BCVC caused by methicillin-resistant S.
aureus. The blood culture was negative in one patient, and
BCVC symptoms disappeared in this case when the catheter
was removed. Blood cultures taken one week after the
antibiotic treatment ended were negative in all patients
initially diagnosed with BCVC. No patients had clinically
detected ototoxicity. The mean number of months that each
patient stayed in the study was 23 (range: 1-84). We treated
29 patients with prophylaxis for >30 months (29% of the
total number), and they stayed in the study for a mean of 46
months (range: 31-84).
Secondary variables
Mean age: 68±22 years (range: 21-85); 48 patients were
women (47%); 33 patients were diabetic (33%). The mean
trough level of G was 0.17µg/ml (range: 0.05-0.31), and was
obtained by adding all values for each one. The mean
intraluminal locking administered in G/branch/patient was
3mg (range: 2-5), which is equivalent to 1.11.7mg/ml/branch/patient, depending on the branch volume
and the type of catheter used, and it represents the sum of all
G locking values for each one. Seven patients were
diagnosed with BCVC (7%), and 3 (3%) were hospitalised
for BCVC. We observed 0.11 BCVC/catheter/1000 days, one
patient died from BCVC (1%), and the catheter was removed
due to BCVC in 2 patients (2%).
We did not observe BCVC in the 4 cases treated with
femoral catheters. The catheter was removed due to
recurrence of BCVC in one case, and due to a negative
blood culture in other patient, effectively neutralising the
BCVC in this patient. We observed no other BCVC
complications (endocarditis, spondylodiscitis, etc.), except
for one patient who died from sepsis. We observed 8 cases
of BCVC; 5 of them were due to S. aureus, one due to E.
coli, one due to S. bovis, and one case with a negative
blood culture. During the first year, we diagnosed 2 cases
of BCVC, two in the second year, one in the third year, one
in the fourth year, one in the fifth year, one in the sixth
year, and none in the seventh year.
DISCUSSION
In previous studies and recent meta-analyses on post-HD,
prophylaxis with intraluminal locking of chronic tunnelled
central venous catheter branches using antibiotics (among
them, G) has been shown to reduce bacterial BCVC-related
Nefrologia 2011;31(3):308-12
morbidity and mortality (BCVC cases/catheter/1000 days,
mortality, and hospitalisations due to BCVC),6-16 compared to
patients with intraluminal locking using only heparin. Some
meta-analyses have shown that G locking is the best option,14,15
although doubts remain regarding bacterial resistance in
pathogens that are normally sensitive to this antibiotic. When
assessing our results, one must keep in mind a study published
by Bearthar18 with regards to health care quality in HD units,
based on the number of BCVC/catheter/1000 days that is
obtained considering only universal asepsis. It is excellent
when this value is <1. In our case, universal aseptic
procedures in addition to G prophylaxis achieved a value of
0.11 cases of BCVC/catheter/1000 days.
Although we cannot compare them with results from other
studies, our rates of mortality, catheter removal, and
hospitalisations due to BCVC over the course of the 7 years of
the study are all positive results (1%, 2%, and 3%,
respectively). They were achieved using G prophylaxis in
addition to universal aseptic protocols. Furthermore, the
absence of endocarditis, spondylodiscitis, etc. also stands out,
with the exception of the patient that passed away due to sepsis.
The most frequently observed pathogen was S. aureus, which
concurs with previously published studies.17,18 One patient had 2
different cases of BCVC due to a methicillin-resistant strain of
S. aureus. We must also point out that 29 patients were treated
with prophylaxis for more than 30 months (29% of the total),
staying in the study for a mean of 46 months (range: 31-84).
Ototoxicity is a pathology that must be evaluated when
treating patients with intraluminal G locking.7,10 We
measured this by testing for hypoacusis and/or vertigo. One
could argue that audiometric tests would be needed, but the
benefit provided by performing regular audiometric tests is
questionable. The early detection of otic damage using this
technique and consequent suspension of G treatment does
not prevent this pathology from progressing, since G
remains within the cochlea for several months. Its use is
therefore impractical in clinical practice.21 We observed no
clinical ototoxicity in any of our patients and it could be
attributed to the protocol we used, which ensures low
trough blood levels of G, with a mean value of 0.17µg/ml
(range: 0.05-0.31). As a consequence, a low dose of G
locking per branch was administered, with a mean of
3mg/branch/patient (range: 2-5), equivalent to 1.11.7mg/ml/branch/patient, which is lower than the doses
administered in previous studies7,9,22 (Dogra7 administered
40mg/ml/branch, McIntyre9 5mg/ml/branch, and Landry22
4mg/ml/branch). This should influence the level of toxicity
due to the possibility of reduced dribbling of the antibiotic
into the bloodstream from the catheter branches.
Bacterial resistance to prophylaxis with intraluminal G
locking remains a point of debate. Resistance must be
defined by the appearance of antibiotic resistance in
pathogens that are normally sensitive to its activity. The
Nefrologia 2011;31(3):308-12
originals
value of MIC is an important reference value that appears in
the antibiogram provided by the bacteriology department,
diagnosing the sensitivity or resistance of a bacterium to an
antibiotic. In our case, the MIC must be <4µg/ml, as referred
by the bacteriology department (accompanied by the letter S
or R); except for the patient with 2 different cases of BCVC
due to methicillin-resistant S. aureus and the patient with a
negative blood culture. All other cases of BCVC were
sensitive to G.
Recently, in a retrospective 4-year study (October 2002 to
September 2006), with 1410 patients with catheters in 8 HD
different units and prophylaxis with G at a greater dose than
used in our study, Landry22 observed that the rate of
BCVC/catheter/1000 days was reduced from 17 to 0.83
during the first year. From the sixth month onwards, 13
cases of BCVC due to G-resistant coagulase-negative
Staphylococcus were diagnosed. In the following 4 years, 11
cases of BCVC were observed in 10 different patients that
had G-resistant strains (7 due to E. faecalis), with 4 deaths, 2
cases of sepsis and admission to intensive care units, and 4
cases of endocarditis in which prophylaxis with G was
stopped and prophylactic locking of the branches of the
CVC with non-antibiotic medication was recommended.
In recent years, the prevalence of patients on HD with a
catheter has increased,23 which results in an increase in the
number of cases of BCVC and the complications it causes to
patient health in terms of infectious morbidity and mortality
and economic costs (mortality, hospitalisation for
endocarditis, spondylodiscitis, sepsis, catheter removal,
antibiotics, etc.) The appearance of bacterial resistance to
prophylaxis with G is a worrying issue when it occurs in
dialysis units,22 but the nephrologist must remember that we
still do not have access to efficient non-antibiotic
medications or substances that could reduce the rate of
BCVC without creating resistance or causing iatrogenic
incidents. It is evident that if we can reduce the number of
HD patients with catheters, we will improve this issue.
In addition to G, we can lock with other antibiotics,
preferably cefotaxime, or use topical prophylaxis with
antibiotics such as mupirocin, which have proven
effective at reducing BCVC and its complications.10-16 We
must remember the use of strict universal asepsis when
using a catheter,17,18,24 which is an essential accompaniment
to prophylaxis for reducing the bacterial infectious
morbidity and mortality associated with BCVC. Our
experience since July 2003 administering prophylaxis
from the moment the patient is admitted to our unit with
post-HD intraluminal G locking using lower doses (the
dosage that we recommend using) than those used in
other units, such as in the Landry study, 22 does not cause
bacterial resistance in pathogens that are normally
sensitive to its activity. However, we must not forget the
use of traditional aseptic protocols.
311
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CONCLUSIONS
This 7-year observational, prospective study with 101 patients
on chronic HD with tunnelled central venous catheters showed
that: 1) prophylaxis with post-HD intraluminal gentamicin
locking of catheter branches does not cause bacterial resistance
in pathogens that are normally sensitive to this antibiotic; 2) our
treatment does not cause clinical ototoxicity, and 3) prophylaxis
with low doses of gentamicin (when compared to the higher
doses cited by other studies) could have caused the absence of
bacterial resistance and ototoxicity.
11.
12.
13.
14.
IN MEMORIAM
This research is dedicated to the loving memory of my wife, Pepa Anaya,
who was the light of my life for many years. Her light was put out and
the happiness was taken from our beloved home. Rest in peace.
Juan Fernández-Gallego
REFERENCES
1. Dhingra RK, Young EW, Hulbert-Shearon TE, Leavey SF, Port FK.
Type of vascular access and mortality in U.S. hemodialysis patients.
Kidney Int 2001;60:1443-51.
2. Pastan S, Michael Sousie J, Mc Clellan WM. Vascular access and
increased risk of death among hemodialysis patients. Kidney Int
2002;62:620-6.
3. Fernández-Gallego J, López V, Martín MA, Toledo R. El catéter
venoso central crónico tunelizado aumenta la mortalidad en
hemodiálisis. Nefrologia 2005;25:720-1.
4. Nassar GM, Ayus JC. Infectious complications of the hemodialysis
access. Kidney Int 2001;60:1-13.
5. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a
common cause of persistent infections. Science 1999;284:1318-22.
6. Fernández-Gallego J, Alonso A, Sujan S, Gutiérrez E. La profilaxis
con gentamicina disminuye la morbi-mortalidad infecciosa
bacteriana causada por el catéter venoso central permanente
tunelizado. Nefrologia 2007;27:228-30.
7. Dogra GK, Herson H, Hutchison B, Irisk AB, Heath CH, Golled HC, et
al. Prevention of tunneled hemodialysis catheter-related infections
using catheter-restricted filling with of gentamicin and citrate: a
randomized control study. J Am Soc Nephrol 2002;3:2133-9.
8. Hernández-Jaras J, García-Pérez E, Torregrosa E, Pons R, Calvo C,
Serra M, et al. Seguimiento a largo plazo de catéteres permanentes
en pacientes con dificultad en la obtención de un acceso vascular
definitivo. Nefrologia 2004;24:446-52.
9. McIntyre CW, Hulme LJ, Taal M, Fluch RJ. Locking of tunneled
hemodialysis catheters with gentamicin and heparin. Kidney Int
2004;66:801-5.
10. Saxena AK, Panhotra BR. Locking hemodialysis catheters with
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
cefotaxime instead of gentamicin to avoid potential ototoxicity.
Kidney Int 2005;67:2505-6.
Saxena AK, Panthotra BR, Sundaram DS, Al-Hafiz A, Naguib M,
Venkateshappa CK, et al. Tunneled catheters outcome optimization
among diabetics on dialysis through antibiotic-lock placement.
Kidney Int 2006;70:1629-36.
Labriola L, Crott R, Jadoul M. Preventing haemodialysis catheterrelated bacteraemia with an antimicrobian lock solution: A metaanalysis of prospective randomized trials. Nephrol Dial Transplant
2008;23:1666-72.
Jaffer Y, Selby NM, Taal MW, Fluck RJ, McIntyre CW. A metaanalysis of hemodialysis catheter locking solutions in the prevention
of catheter-related infection. Am J Kidney Dis 2008;51:233-41.
Jamey MT, Cooley J, Tonelli M, Manus BJ, MacRae J, Hemmelgarn
BR, Alberta Kidney Disease Network. Meta-analysis: Antibiotics for
prophylaxis against hemodialysis catheter-related infections. Ann
Intern Med 2008;148:596-605.
Yahav D, Rosen-Zvi B, Gafter-Gvili A, Leibovici L, Gafter U, Paul M.
Antimicrobial lock solutions for the prevention of infections
associated with intravascular catheters in patients undergoing
hemodialysis: Sistematic review and meta-analysis of randomized,
controlled trials. Clin Infect Dis 2008;47:83-93.
Kannaiyan SR, Tarun B, Ruma D, Ranjit SH, MacLeod AM, Moore C,
et al. Systematic review of antimicrobials for the prevention of
haemodialysis catheter-related infections. Nephrol Dial Transplant
2009;24:3763-74.
Vanholder R, Canaud B, Fluck R, Jadoul M, Labriola L, Marti-Monros J,
et al. Diagnosis, prevention and treatment of haemodialysis catheterrelated bloodstream infections (CRBSI): a position statement of
European Renal Best Practice (ERBP). NDT Plus 2010;3:234-46.
Beathard GA, Urbanes A. Infection associated with tunneled
hemodialysis catheter. Semin Dial 2008;21:528-38.
NKF K/DOQI Guidelines. Clinical practice guidelines for vascular
access: Guidelines 7: Prevention and treatment of catheter and port
complications. Am J Kidney Dis 2006;48(Suppl 1):S176-S247.
Gilbert DN. Aminoglycosides. En: Mandel GL, Bennet JE, Dolin R
(eds.). Principles and practice of infectious diseases. Philadelphia:
Churchill Livingstone, 1995;279-306.
Negishi K, Efrati S, Eviatar E, Abramsohn R, Yarovoy I, Gersch E, et
al. Gentamicin-induced ototoxicyty in hemodialysis patients is
ameliorated by N-acetylcysteine. Kidney Int 2007;72:359-64.
Landry DL, Braden GL, Gobeille SL, Haessler SD, Vaidya ChK, Sweet
SJ. Emergence of gentamicin-resistant bacteremia in hemodialysis
patients receiving gentamicin lock catheter prophylaxis. Clin J Am
Soc Nephrol 2010;5:1799-804.
Gruss E, Portolés J, Caro P, Merino JL, López-Sánchez P, Tato A, et
al. Los modelos de atención al acceso vascular condicionan
resultados heterogéneos en los centros de una misma comunidad.
Nefrologia 2010;30:310-6.
Albalate M, Pérez García R, De Sequera P, Alcázar R, Puerta M,
Ortega M, Mossé A, et al. ¿Hemos olvidado lo más importante para
prevenir las bacteriemias en pacientes portadores de catéteres para
hemodiálisis? Nefrologia 2010;30:573-7.
Sent for review: 6 Mar. 2010 | Accepted: 26 Feb. 2011 | Epub: 15 Mar. 2011
312
Nefrologia 2011;31(3):308-12
originals
Factors associated with blood pressure control
in diabetic patients treated in nephrology units.
PRESDIAB Study
N. Serra1, A. Oliveras2, S. Bergoñon3, L. Sans2, A. Cobos4, P. Martínez5, R. Artigas5, E. Poch1
Nephrology Department. Clínic Hospital. Barcelona, Spain
Nephrology Department. del Mar Hospital. Barcelona, Spain
3
Pharmacology Department. University of Barcelona, Spain
4
Public Health Department. University of Barcelona, Spain
5
Medical Department. Laboratorios Menarini SA. Barcelona, Spain
1
2
Nefrologia 2011;31(3):313-21
ABSTRACT
Background and objective: Most hypertensive patients do
not reach target blood pressure (BP), especially if they are
diabetic. The objective of the study is to assess the
percentage of tight BP control, defined as BP<130/80mm
Hg and identify factors associated with it in diabetic type 2
(DM2) patients treated in nephrology units. Patients and
methods: Observational and cross-sectional study; we
included 526 patients with DM2 and arterial hypertension
(AHT). We collected data on: demographics, anthropometrics,
harmful habits, history of cardiovascular disease (CVD), blood
pressure, kidney function, glycaemic control, lipid profile,
and drug treatment, among others. Results: The mean age
(SD) was 66 (10.6) years, 61% were male, 12.8% were smokers,
39.4% had a history of CVD, 72% had hypercholesterolemia,
and 44% were obese. Seventeen point five percent of
patients had tight BP control (<130/80mm Hg) (95%
confidence interval [CI]:14.3-21.0), while 36.9% had BP
below 140/85mm Hg. Seventy-one percent of patients were
prescribed two or more anti-hypertensive treatments.
Several factors are associated with tight BP control not being
achieved, and the logistic regression analysis revealed that
LDL cholesterol levels were significantly associated (odds
ratio [OR] 0.55; 95% CI:0.41-0.75 for one standard deviation
increase). Conclusions: Of the DM2 patients that attended the
nephrology units, less than 20% achieved a tight BP control.
Cholesterol levels seem to be the main factor associated with
unsatisfactory BP control within our study population.
Keywords: Arterial hypertension. Type 2 diabetes mellitus.
Blood pressure. Treatment. Blood pressure control.
Correspondence: Esteban Poch
Hospital Clínic de Barcelona.
Villarroel, 170. 08036 Barcelona. Spain.
[email protected]
Factores asociados al control de la presión arterial
en pacientes con diabetes tratados en unidades de
nefrología. Estudio PRESDIAB
RESUMEN
Fundamento y objetivo: La mayoría de pacientes hipertensos
no alcanza los objetivos de control de la presión arterial (PA),
especialmente si son diabéticos. El objetivo del estudio fue evaluar el porcentaje de control estricto de la PA definida como
PA <130/80 mmHg e identificar factores asociados al mismo en
pacientes diabéticos tipo 2 (DM2) tratados en unidades de nefrología. Pacientes y método: Estudio observacional y transversal, en el que se incluyeron 526 pacientes con DM2 e hipertensión arterial (HTA). Se recogieron datos demográficos,
antropométricos, hábitos tóxicos, antecedentes de enfermedad cardiovascular (ECV), medidas de PA, función renal, control glicémico, perfil lipídico y tratamiento farmacológico, entre otros. Resultados: La edad media (DE) fue de 66 (10,6) años,
con un 61% de hombres, un 12,8% de fumadores, un 39,4%
con antecedentes de ECV, un 72% con hipercolesterolemia, y
un 44% con obesidad. El porcentaje de control estricto de la
PA (<130/80 mmHg) fue del 17,5% (intervalo de confianza [IC]
95%: 14,3-21,0), mientras que un 36,9% tenían la PA por debajo de 140/85 mmHg. Un 71,1% de pacientes recibía dos o
más tratamientos antihipertensivos. Diversos factores se asociaron con falta de control estricto de la PA, de los cuales, tras análisis de regresión logística, destacaban los valores de colesterol
LDL (odds ratio [OR] 0,55; IC 95%: 0,41-0,75 para un aumento
de 1 DE). Conclusiones: En pacientes con DM2 atendidos en
unidades de nefrología, el porcentaje del control estricto de la
PA es inferior al 20% en la clínica. Los niveles de colesterol parecen ser el principal factor independiente asociado con el control insuficiente de PA en la población estudiada.
Palabras clave: Hipertensión arterial. Diabetes mellitus
tipo 2. Presión arterial. Tratamiento. Control de la
hipertensión arterial.
INTRODUCTION
The relationship between arterial hypertension (AHT) and
diabetes mellitus type 2 (DM2) is well known. Although the
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N. Serra et al. Blood pressure control in diabetes
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prevalence of AHT in the general population is around 30%,
it is between 51% and 93% in DM2 subjects, depending on
whether the patient suffers from a related kidney disease.1 In
contrast, it is also known that patients with AHT are 2.4
times more likely to develop DM2 than normotensive
subjects.2 The cardiovascular risk associated with AHT or
DM2 is widely recognised, and it is estimated that in
general, 68% of coronary events are due to one of the
conditions being present.3 In a classic study, Haffner et al
showed that DM2 patients that had not suffered any vascular
event had a similar risk to presenting one within 7 years as
non-diabetic patients that had already suffered one, be it a
coronary, cerebral or peripheral vascular event.4 As such, in
practice, DM2 is considered as a coronary equivalent for
assessing the risk of future events, as confirmed by longerterm follow-up studies.5 Furthermore, it is understood that
AHT + DM2 involves an additional increased risk of
vascular complications, as shown in a 28-year follow-up
study which reported that men with AHT and DM2 have a
66% higher risk of suffering a stroke or heart attack than
men who only have AHT.6
There are several studies that have compared the benefits
associated with reducing blood pressure (BP) to prevent
cardiovascular events in DM2 patients and non-diabetic
patients.7 One of the first studies was the UKPDS38,
published in 1998, which revealed that tight BP control in
diabetic patients significantly reduced the risk of
microvascular complications and stroke during an 8.4-year
follow-up.8 More importance has been given to controlling
AHT in DM2 patients since the need to maintain BP control
throughout patient follow-up was documented by Holman et
al.9 These authors conducted a 10-year follow-up of the
patients that underwent the UKPDS38 study, observing that
the differences in BP between the two groups disappeared 2
years after the study was completed, showing that the benefit
of lower risk was lost over time.
Despite these observations, optimal BP control is achieved in
less than 30% of AHT patients, even when more than 60% of
these patients are prescribed anti-hypertensive treatment.7,10
These optimal control percentages are even lower when
examining several risk populations. BP control for DM2
patients (130/85mm Hg in studies) is around 13%, both in
primary care11 and hypertension unit.12 Observational studies
and clinical trials have proven that poor systolic BP control
(SBP) is the main reason for low AHT control percentages.7,13
This is especially relevant for the diabetic population, which
usually have a high pulse pressure.14 We are yet to fully
understand what causes poor BP control in the hypertensive
population. There may in fact be several causes which
almost certainly involve patient- (compliance, comorbidities)
doctor- (attitude), blood pressure-, and environment(primary care, hospital) related factors, among others.
Furthermore, most studies do not examine all possible
aspects that can affect BP control, but only specific aspects.
314
The main objective of this study is to estimate the prevalence
of tight BP control (BP<130/80mm Hg) for patients with
AHT and DM2, who attended nephrology units in Spanish
hospitals. Secondary objectives are to describe the frequency
in which tight control is not achieved due to poor systolic or
diastolic blood pressure (DBP) control, or a poor control of
both. We also aim to investigate the factors associated with
good BP control.
PATIENTS AND METHOD
Study design
We invited 60 nephrologists throughout Spain to participate
in our multi-centre, observational, cross-sectional study. We
informed them of the objectives and the study justification,
and how they could register and participate in the study (via
the especially designed web site). We asked doctors to
choose the first 10 patients that met the selection criteria (see
“Participants”) and visited their unit consecutively, and who
agreed to participate in the study. Being a cross-sectional
study, the most recent patient data were collected, and we
did not perform any type of prospective follow-up. The
study was monitored online to ensure that the correct data
was included.
Participants
We included patients with AHT 15 and DM2 16 clinically
diagnosed in accordance with the current guidelines, at
least 18 years old and who had consented to inclusion in
writing. We did not include patients who were not
physically or mentally capable of giving consent or those
who were already participating in other clinical
investigations that could interfere with our study. The
study was approved by the research ethics committee in
the Clínic Hospital, Barcelona.
Recorded variables
We recorded the following data for each of the patients:
demographic data were age, sex, body mass index (BMI),
waist circumference, mid-upper arm circumference, smoking
habit, alcohol use, history of cardiovascular disease (CVD),
serum creatinine level, estimated glomerular filtration rate
(eGFR), urinary albumin:creatinine ratio (ACRor), total
cholesterol, HDL cholesterol and LDL cholesterol,
triglycerides, baseline glycaemia, glycated haemoglobin
(HbA1c), ambulatory blood pressure monitoring (ABPM)
over the past year, self-monitoring of blood pressure at home
during the past 6 months, time since diagnosed with AHT,
DM and hypercholesterolemia, number of drugs
administered for AHT treatment, use of angiotensinNefrologia 2011;31(3):313-21
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converting enzyme inhibitors (ACEi) and/or angiotensin II
receptor blockers (ARB), AHT treatment compliance,
adherence to dietary advice for AHT, DM2 or
hypercholesterolemia, usual physical exercise, concomitant
treatment with psychoactive drugs, non-steroidal antiinflammatory drugs (NSAID), sympathomimetic drugs,
antiplatelet drugs, number of BP measurements, and number
of hours since AHT treatment was last taken. Clinical
parameters
were:
hypercholesterolemia,
diabetes,
cardiovascular disease or clinical BP, and were defined in
accordance with guidelines from the European Society of
Hypertension and the American Diabetes Association.15,16 BP
was measured in accordance with the standard techniques
described in the medical literature.15,17 Tight BP control was
defined as SBP<130mm Hg and DBP<80mm Hg, in
accordance with the AHT guidelines that were valid when
the study was being conducted.18 Furthermore, given the
recent critical review on the recommendations established,19
we calculated the percentage for a less tight BP control
(<140/85mm Hg). Using the serum creatinine level, we
estimated the GFR using the MDRD equation, and defined
kidney failure as GFR<60ml/min/1.73m2.
We initially considered the following factors: age, sex, BMI,
waist circumference, mid-upper arm circumference,
smoking habit, alcohol use, history of CVD, serum
creatinine level, eGFR, urinary albumin-creatinine ratio
(ACRor), total cholesterol, HDL-cholesterol and LDLcholesterol, triglycerides, baseline glycaemia, glycated
haemoglobin (HbA1c), time since diagnosed with AHT, DM
and hypercholesterolemia, number of drugs administered for
AHT treatment, use of ACEi and/or ARB, AHT treatment
compliance, adherence to dietary advice for AHT, DM2 or
hypercholesterolemia, usual physical exercise, concomitant
treatment
with
psychoactive
drugs,
NSAID,
sympathomimetic drugs, antiplatelet drugs, number of BP
measurements, and number of hours since AHT treatment
was last taken. The overall adjustment of the models was
considered based on the Hosmer-Lemeshow test, and the
(bilateral) significance of the terms using the Wald statistic.
All statistical analyses were performed using the SAS®
statistical package for Windows (version 9.1).
We also asked all doctors to complete a detailed
questionnaire on their usual medical practice, with special
reference to measuring BP, evaluating lifestyle and
hygienic/dietary measures, recommendations given to
patients and their adherence to them.
Patient characteristics
Table 1 summarises the clinical characteristics of patients
included in the study. The mean age was over 65 years old
and there were more males than females. Mean time
between DM2 and AHT diagnosis and inclusion in the study
was more than 10 years. Three-hundred and thirty patients
(63.4%) had been advised to follow a low-salt diet, 55
(10.5%) a low-fat diet due to dyslipidemia (DLP), and 455
(87.5%) had been given dietary advice for DM2.
We used a sample size of 600 patients to ensure that the
estimation of the prevalence for good BP control was accurate
by ±3.5% (95% confidence interval [CI] of 7% amplitude)
supposing that this prevalence were 25%. The study was
finished after the three month inclusion period was complete. We
had 526 patients and considered that the number was adequate to
enable us to make precise estimations. All analyses were
performed on eligible patients i.e. those that complied with
selection criteria and were able to provide the data needed for
examining the main objective. We used the data available, and
did not need to use replacement techniques for missing data. The
prevalence for good BP control was estimated by calculating the
95% CI, using the normal calculations. Prevalence for successful
tight BP control (SBP<130mm Hg and DBP<80mm Hg), for
good SBP control and good DBP control was estimated in
accordance with the clinical BP measurements.
We performed a logistic regression analysis to identify the
factors associated with BP control. Firstly, we analysed the
relationship using univariate models. Secondly, we adjusted
a multivariate model which included all statistically
significant variables (P<.25) in the corresponding univariate
model. Then, using this model, we performed a stepwise
selection, with entry and exit levels set at 0.05.
Nefrologia 2011;31(3):313-21
RESULTS
Fifty-five doctors included a total of 526 patients from April
until July 2008. Six patients were not considered as eligible
as they did not comply with some of the selection criteria.
As such, 520 (98.9%) were included in the analysis.
Prevalence of good BP control
Tight clinical BP control (<130/80mm Hg) was observed in
91/520 cases (17.5% of the sample; 95% CI:14.3-21.0).
Tight clinical SBP control was observed in 110/520 cases
(21.2% of the sample; 95% CI:17.7-24.9), and tight DBP
control was observed in 281/520 cases (54.0% of the
sample; 95% CI: 49.6-58.4).
Table 2 compares the clinical characteristics of the patients with
tight BP control and those that did not reach tight BP control.
Experts have recently started to question whether tight BP
control is beneficial for DM2 patients, given the lack of
clear evidence.19 Although the study objective was to analyse
the variables related to lack of tight BP control, we also
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DISCUSSION
BP control (<130/80mm Hg) was 17.5%. In the univariate
analysis, various factors are associated with unsuccessful BP
control, such as presence of CVD, GFR, treatment with
renin-angiotensin-inhibitors, hypercholesterolemia, and
concomitant treatment with NSAID. However, in the
multivariate analysis, only LDL-cholesterol and GFR were
related to poor BP control. The prevalence of good BP
control in this study is somewhat higher than that found in
previous Spanish studies: in primary care11 and hypertension
units,12 (12.2% and 13%, respectively). This is even more
important considering that the BP criteria was <130/85mm
Hg in these cases. In contrast, a recent study examining
compliance of overall DM2 treatment guidelines in
nephrology units in Catalonia20 observed a BP control rate of
21.8%. However, their criterion for BP control was
≤30/80mm Hg. When observing the control rate in other
countries, we have noted that some observational
epidemiological studies found higher BP control rates in
diabetic patients. A study conducted in the United States
showed that 31.4% had a BP control of <130/80mm Hg.21 In
prospective intervention studies on diabetic patients, the SBP
control (target <130mm Hg) was not achieved by any of the
patients, while the DBP objective (<80mm Hg) was achieved
by half of them. Therefore, the percentage of diabetic
patients with DBP control <80mm Hg in our study (54%) is
similar to those clinical trials. There is little evidence
showing that reducing SBP to below 130mm Hg represents a
clear benefit for the DM2 patient group. Furthermore, in no
clinical trial hypertensive patients with DM2 have reached
this SBP level.22 These facts have encouraged the European
hypertension guidelines to be reviewed, questioning this
target until there is evidence in its favour.19 Until more
evidence is made available, general BP control <140/85mm
Hg is recommended for all hypertensive patients. The
ACCORD study,23 examining more than 4000 patients,
showed that a target SBP control <120mm Hg as compared
with <140mm Hg did not reduce the rate of fatal and nonfatal cardiovascular events. This outcome has confirmed that
the tight BP control levels recommended to date (which are
difficult to achieve) are probably unnecessary. More studies
are certainly needed to clarify this important clinical matter.
The objective of our study was to analyse the factors
associated with a tight BP control, in accordance with a
recommendation that was in practice at the time the study was
designed and performed. However, given that the experts
changed their opinion on the matter, we also analysed the lesstight control rate in our sample. As such, 36.9% of patients
had a <140/85mm Hg control, while 40% had SBP control
and 70% DBP control. These control rates are very close to
those of the general hypertensive population,12 suggesting that
the poor historic control attributed to DM2 is partly due to
therapeutic objectives being too tight and probably unjustified.
In this study we have checked a sample of patients suffering
from AHT and DM2 who were cared for in nephrology units
of Spanish hospitals. We found that the percentage of tight
The UKPDS38 study established a target BP control of
<150/85mm Hg, and observed that 29% of the patients were
being treated with three or more anti-hypertensive drugs.8
examined less-tight BP control. Less-tight clinical BP control
(<140/85mm Hg) was therefore observed in 180/520 cases,
(36.92% of the sample; 95% CI:32.76-41.23). SBP control
was observed in 211/520 cases (40.58% of the sample; 95%
CI:36.32-44.94), and DBP control was observed in 365/520
cases (70.19% of the sample; 95% CI:66.06-74.1).
Relationship between tight BP control and
predictive factors
Table 3 shows the main results from the logistic regression
analysis. This table only includes the variables that had a
significance of P<.25 in the univariate models. The following
variables showed a statistically significant relationship
(P<.05) with BP control (Table 3, univariate models): history
of CVD (P<.001), GFR (P=.019), LDL-cholesterol (P<.001),
treatment with ACEi and/or ARB (P=.003), and total
cholesterol (not shown on the table). Given that the
dependent variable was successful tight BP control, OR>1
showed that BP control was more frequent and OR<1 showed
that BP control was less frequent. As a result, the OR of the
variables mentioned above indicate that history of CVD
(OR=2.19) is associated with a more frequent good BP
control. On the other hand, GFR values (OR=.74 for one
standard deviation increase) or LDL-cholesterol (OR=.52 for
one standard deviation increase) and ACEi and/or ARB
(OR=.39) are associated with less frequent BP control.
We included all of these variables in a multivariate logistic
regression model and achieved a good overall adjustment
(Hosmer-Lemeshow c2=9.81; degrees of freedom [df]=8;
P=.279). According to the results of this adjustment (Table
3, multivariate model), the GFR and LDL-cholesterol have a
statistically significant relationship (P<.05). Using a
stepwise selection, LDL-cholesterol and GFR remained
statistically significant (P<.001). OR for one standard
deviation increase in LDL-cholesterol is 0.55 (0.41-0.75).
This implies that when the LDL-cholesterol or GFR are
higher, the patient is less likely to control BP. Mean SBP and
DBP are higher in patients with LDL>100mg/dl than in
patients with LDL<100mg/dl (Student’s t-test, P<.001) (data
not shown). Furthermore, no statistically significant
differences were found in the SBP and DBP averages for
patients with LDL>100mg/dl, considering whether statins
were used or not (data not shown). Lastly, 84.8% of patients
with history of CVD had GFR values less than
60ml/min/1.73m2, while this occurred for 68.1% of patients
that did not have CVD (OR=.38; 95% CI:0.24-0.60).
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Nefrologia 2011;31(3):313-21
originals
Table 1. Clinical characteristics of patients studied
Characteristics
Anthropometric data
Condition
Other clinical history
Blood pressure measurements
Item
Values
Eligible cases (n=520 or less)
Age (years)
Mean (SD)
66.2 (10.6)
Sex (males)
N (%)
319 (61.3)
BMI (kg/m2)
Mean (SD)
29.7 (5.0)
Waist circumference (cm)
Mean (SD)
104.1 (13.7)
Mid-upper arm circumference (cm)
Mean (SD)
32.6 (5.2)
Hypercholesterolemia (DLP)
N (%)
375 (72.1)
Years since AHT diagnosis
Mean (SD)
12.9 (9.6)
Years since DM2 diagnosis
Mean (SD)
12.5 (9.9)
Years since DLP diagnosis
Mean (SD)
8.6 (6.4)
Smoking habit
N (%)
67 (12.8)
Usual alcohol use
N (%)
17 (3.2)
History of cardiovascular disease
N (%)
205 (39.4)
SBP (mm Hg)
Mean (SD)
144.4 (21.1)
DBP (mm Hg)
Mean (SD)
76.7 (12.3)
Heart rate (bpm)
Mean (SD)
74.6 (11.4)
No. of measurements per visit
Mean (SD)
2.2 (1.1)
DM2 measurements
Baseline glycaemia (mg/dl)
Mean (SD)
147.5 (47.1)
HbA1c (%)
Mean (SD)
7.0 (1.3)
Lipid measurements
Total cholesterol (mg/dl)
Mean (SD)
186.1 (43.8)
Triglycerides (mg/dl)
Mean (SD)
167.3 (107.8)
LDLc (mg/dl)
Mean (SD)
110.1 (37.7)
Kidney function measurements
HDLc (mg/dl)
Mean (SD)
47.1 (14.9)
Serum creatinine (mg/dl)
Mean (SD)
2.2 (7.0)
eGFR (ml/min/1.73 m )
Mean (SD)
44.9 (24.7)
Urinary albumin:creatinine ratio (mg/g)
Median (IQR)
35.8 (173)
2
Anti-AHT treatment
ACEI and/or ARB
N (%)
468 (90.0)
Three or more anti-AHT drugs
N (%)
186 (35.5)
Anti-DM2 treatment
Insulin
N (%)
236 (45.3)
Anti-DLP treatment (for patients with DLP)
Statins
N (%)
312 (60.0)
Other chronic treatments
NSAID
N (%)
36 (6.9)
Sympathomimetic drugs
N (%)
2 (0.3)
Antiplatelet drugs
N (%)
352 (67.6)
DM2: diabetes mellitus type 2; AHT: arterial hypertension; DLP: dyslipidemia;BMI: body mass index; BP: blood pressure; SBP: systolic blood pressure;
DBP: diastolic blood pressure; HbA1c: glycated haemoglobin;LDLc: LDL-cholesterol; HDLc: HDL-cholesterol; eGFR: estimated glomerular filtration rate;
ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blockers; NSAID: non-steroidal anti-inflammatory drugs; SD: standard
deviation;IQR: interquartile range; N: number; bpm: beats per minute.
Our study’s target was <130/80mm Hg and only 35% of
patients were treated with three or more drugs, which to
some extent suggests that this poor control may be due to
undertreatment. Even though in most clinical trials diabetic
patients use three or more drugs to reach the BP target, (3.2
drugs according to Bakris et al24) the implementation of
Nefrologia 2011;31(3):313-21
intense treatment in clinical practice does not seem to be
achieved, according to the results that we present here.
Although the univariate analysis showed a worse control
rate for patients treated with ACEi or ARB, we believe
that this finding should be interpreted with caution.
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Table 2. Clinical characteristics of the patients in accordance with degree of blood pressure control
Characteristics
Condition
Other clinical history
Blood pressure
Item
Values
With
controlled BP
(n=91)
Without
controlled BP
(n=429)
Hypercholesterolemia (DLP)
N (%)
61 (67.0)
314 (73.2)
Smoking habit
N (%)
9 (9.9)
58 (13.5)
Usual alcohol use
N (%)
4 (4.5)
13 (3.0)
Previous cardiovascular disease
N (%)
50 (55.5)
155 (36.3)
SBP/DBP (mm Hg)
Mean (SD)
117.8 (8.8)
150.1 (18.4)
DBP (mm Hg)
Mean (SD)
64.8 (7.9)
80.0 (18.1)
Heart rate (bpm)
Mean (SD)
75.3 (11.5)
74.5 (11.4)
No. of measurements per visit
Mean (SD)
2.2 (1.0)
2.2 (1.0)
DM2 measurements
Baseline glycaemia (mg/dl)
Mean (SD)
142.6 (52.3)
148.5 (45.9)
HbA1c (%)
Mean (SD)
6.8 (1.4)
7.0 (1.3)
DLP measurements
Total cholesterol (mg/dl)
Mean (SD)
163.8 (44.3)
190.7 (42.2)
Triglycerides (mg/dl)
Mean (SD)
146.6 (69.0)
171.6 (113.7)
LDLc (mg/dl)
Mean (SD)
92.5 (35.1)
113.6 (37.3)
HDLc (mg/dl)
Mean (SD)
44.6 (15.9)
47.6 (14.7)
Serum creatinine (mg/dl)
Mean (SD)
2.3 (2.1)
2.2 (7.6)
Kidney function measurements
eGFR (ml/min/1.73m )
Mean (SD)
39.1 (26.3)
46.0 (24.3)
Urinary albumin:creatinine ratio (mg/g)
Median (IQR)
35.7 (214.0)
37.1 (162.7)
2
Anti-hypertensive treatment
ACEI and/or ARB
N (%)
74 (81.3)
394 (91.8)
Polymedicated
N (%)
62 (68.1)
307 (71.6)
Anti-diabetic treatment
Insulin
N (%)
50 (55.0)
186 (43.3)
Hypolipaemic treatment (for DLP patients)
Statins
N (%)
50 (55.0)
262 (61.1)
Other chronic treatments
NSAID
N (%)
1 (1.1)
35 (8.2)
Sympathomimetic drugs
N (%)
1 (1.1)
1 (0.2)
Antiplatelet drugs
N (%)
62 (68.1)
290 (67.9)
DM2: diabetes mellitus type 2; AHT: arterial hypertension; DLP: dyslipidemia;BMI: body mass index; BP: blood pressure; SBP: systolic blood pressure;
DBP: diastolic blood pressure; HbA1c glycated haemoglobin;LDLc: LDL-cholesterol; HDLc: HDL-cholesterol; eGFR: estimated glomerular filtration rate;
ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blockers; NSAID: non-steroidal anti-inflammatory drugs; SD: standard
deviation; IQR: interquartile range;N: number;bpm: beats per minute.
Firstly, this is because more than 90% of the patients
were treated with these drugs. Secondly, we do not know
the dosage that was taken, making interpretation difficult.
Furthermore, this correlation was not observed in the
multivariate model.
The correlation that we have observed between the GFR
and BP control is in the opposite direction than was
expected. Although this was analysed in a different way,
the CLUE study reported a lower BP control (12%) in
patients with kidney failure (defined as creatinine >1.41.5mg/dl, depending on sex), compared with the general
sample (42%). 12 In this respect, we must take into
consideration that the control limits were tight
(<130/80mm Hg) when considering kidney failure. The
318
COPARENAL study, 25 which is the most important study
that has been conducted in Spain on BP control of kidney
failure patients, showed a (<130/80mm Hg) BP control
rate of only 17%. However, no difference was shown
between serum creatinine and creatinine clearance
between groups with and without optimal BP control. In
our study, although we observed a statistically significant
correlation with GFR, we believe that the difference of
7ml/min has little clinical importance to be able to
consider it the cause of good or bad control. In our
sample, there was a correlation between the GFR
<60ml/min and cardiovascular disease. However, the
correlation between GFR and BP control was no longer
significant when we examined each CVD category. We
could also believe that patients with lower GFR (as well
Nefrologia 2011;31(3):313-21
originals
Table 3. Variables that affect good control of blood pressure according to the logistic regression analysis
Univariate models
Variable
Multivariate modela
Final modelb
P
OR (CI 95%)c
P
OR (CI 95%)c
P
OR (CI 95%)c
0.091
1.23 (0.97 to 1.56)
0.979
1.00 (0.68 to1.47)
-
-
circumference (cm)
0.073
0.80 (0.62 to 1.02)
0.511
0.89 (0.62 to 1.26)
-
-
Smoking habit
0.122
(2 g/dl)
0.273
(2 gdl)
-
-
0.001d
2.19 (1.38 to 3.47)
0.965
1.02 (0.46 to 2.23)
-
-
GFR (ml/min/1.73 m )
0.019d
0.74 (0.58 to 0.95)
0.023d
0.63 (0.42 to 0.94)
0.023d
0.72 (0.54 to 0.96)
LDL (mg/dl)
<0.001d
0.52 (0.39 to 0.70)
0.005d
0.55 (0.36 to 0.84)
<0.001d
0.55 (0.41 to 0.75)
Age (years)
Mid-upper arm
CV disease
2
HbA1c (%)
0.192
0.85 (0.66 to 1.09)
0.436
1.15 (0.81 to 1.64)
-
-
DM evolution (years)
0.212
1.15 (0.92 to 1.43)
0.508
0.88 (0.61 to 1.32)
-
-
ACEI and/or ARB
0.003d
0.39 (0.21 to 0.73)
0.549
0.72 (0.24 to 2.11)
-
-
DM dietary advice
0.138
2.49 (0.75 to 8.31)
0.304
3.21 (0.34 to 29.85)
-
-
DLP dietary advice
0.123
2.14 (0.81 to 5.61)
0.579
0.71 (0.21 to 2.40)
-
-
Regular physical exercise
0.156
1.58 (0.84 to 2.97)
0.159
2.29 (0.72 to 7.30)
-
-
Dependent variable: good tight BP control (SBP<130mm Hg and DBP<80mm Hg)
P: degree of significance from the Wald statistic for the effect. OR (95% CI): odds ratio (95% confidence interval).
a
Forcing the inclusion of all variables with P<.25 in the corresponding univariate model (except NSAID) to achieve an appropriate adjustment
Goodness-of-fit (Hosmer-Lemeshow): c2=12.135; df=8; P=.145.
b
Stepwise selection, with entry and exit probabilities of 0.05. Goodness-of-fit (Hosmer-Lemeshow): c2=4.875; df=8; P=.771.
c
For continuous variables, OR corresponds to one standard deviation increase.
d
Statistically significant (P<.05). DM: diabetes mellitus; DLP: dyslipidemia;DM: diabetes mellitus; DM: diabetes mellitus; DLP: dyslipidemia; CV: cardiovascular; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: glycated haemoglobin; LDLc: LDL-cholesterol;
HDLc: HDL-cholesterol; GFR: glomerular filtration rate; ACEi: angiotensin-converting enzyme inhibitors.
as those that have more serious cardiovascular disease)
could cause the doctor to pay more attention to
improving BP control, although this is merely
speculative. Meanwhile, a correlation between poor BP
control and the proteinuria level was found in the
COPARENAL study. We did not find this correlation in
our study, partly because the proteinuria level in our
patients was low (ACR median: 36mg/g, mean:
200mg/g). This was probably because were more patients
with nephrosclerosis than with diabetic nephropathy, and
they were undergoing anti-hypertensive treatment.
Furthermore, results from the multivariate logistic
regression analysis show and that independent BP control
was lower when LDL-cholesterol values were higher.
This correlation matches with that observed in other
studies on BP control in Spain: such as the one conducted
in a primary care setting (PRESCAP) 26 or in the
COPARENAL study, mentioned above. 25 The correlation
between dyslipidemia and AHT is well known.
Hypercholesterolemia is related to endothelial
dysfunction, both in human and animal models 27 and it
seems that a deficiency of the nitric oxide vasodilator, 28
which is involved in its mechanism, is partly produced by
the oxidative effect of atherogenic lipoproteins. 29 The
mean LDL-cholesterol values for patients in our study
were above 110mg/dl (Table 1), being higher than the
Nefrologia 2011;31(3):313-21
figure recommended in current dyslipidemia guidelines
for DM2 patients. 16 However, it matches the figure found
by other authors in a recent analysis of overall DM2
treatment guide compliance, 20 in which only 39% of
patients
achieved
the
LDL-cholesterol
target
(<100mg/dl).
One limitation of our study was that we were not able to
assess the doctor’s attitude when their patient did not
achieve BP control, given that it was a single crosssectional study. Another limitation found in observational
and cross-sectional studies is that convenience samples
are used, although this is not greatly relevant to our study
as our results are similar to those found in other studies
on BP control.
In summary, tight AHT control for patients with DM2
who attended nephrology units is low, while the less-tight
control is similar to the general hypertensive population.
Among the factors analysed, the LDL-cholesterol and
GFR have an impact on the degree of BP control.
Likewise, despite the vast range of drugs available, data
suggest that they are underused in these patients, given
that the percentage of patients treated with three or more
drugs was relatively low despite poor BP control. This
warns us that we need to emphasise on the number of
drug used to improve BP control in diabetic patients.
319
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Similarly, the percentage of patients treated with statins
may seem inappropriate, which would indicate that
doctors are placing less emphasis on controlling lipids, as
well as the BP. We therefore believe that understanding
the factors that influence BP control could help when
implementing strategies for fulfilling tight therapeutic
targets in this risk population.
12.
13.
Acknowledgements
14.
This study has been financed by an unconditional grant from Laboratorios Menarini, S.A.
15.
REFERENCES
1. Tarnow L, Rossing P, Gall MA, Nielsen FS, Parving HH. Prevalence of
arterial hypertension in diabetic patients before and after the JNCV. Diabetes Care 1994;17:1247-51.
2. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL.
Hypertension and antihypertensive therapy as risk factors for type 2
diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl
J Med 2000;342:905-12.
3. Danaei G, Lawes CM, Vander Hoorn S, Murray CJ, Ezzati M. Global
and regional mortality from ischaemic heart disease and stroke
attributable to higher-than-optimum blood glucose concentration:
comparative risk assessment. Lancet 2006;368:1651-9.
4. Haffner SM, Lehto S, Ronnemaa T, Pyörälä K, Laakso M. Mortality
from coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med 1998;339:229-34.
5. Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be
considered a coronary heart disease risk equivalent?: results from
25 years of follow-up in the Renfrew and Paisley survey. Diabetes
Care 2005;28:1588-93.
6. Almgren T, Wilhelmsen L, Samuelsson O, Himmelmann A,
Rosengren A, Andersson OK. Diabetes in treated hypertension is
common and carries a high cardiovascular risk: results from a 28year follow-up. J Hypertens 2007;25:1311-7.
7. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL, Jr., et al. Seventh report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. Hypertension 2003;42:1206-52.
8. UK Prospective Diabetes Study Group. Tight blood pressure control
and risk of macrovascular and microvascular complications in type 2
diabetes: UKPDS 38. BMJ 1998;317:703-13.
9. Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term
follow-up after tight control of blood pressure in type 2 diabetes. N
Engl J Med 2008;359:1565-76.
10. Banegas JR, Rodríguez-Artalejo F, De la Cruz Troca JJ, GuallarCastillón P, Del Rey Calero J. Blood pressure in Spain: distribution,
awareness, control, and benefits of a reduction in average pressure.
Hypertension 1998;32:998-1002.
11. García Vallejo O, Vicente Lozano J, Vegazo O, Jiménez Jiménez FJ,
Llisterri Caro JL, Redón J, et al. Control of blood pressure in diabetic
320
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
patients in primary care setting. DIAPA study. Med Clin (Barc)
2003;120:529-34.
Banegas JR, Segura J, Ruilope LM, Luque M, García-Robles R,
Campo C, et al. Blood pressure control and physician management
of hypertension in hospital hypertension units in Spain.
Hypertension 2004;43:1338-44.
Lloyd-Jones DM, Evans JC, Larson MG, O’Donnell CJ, Roccella EJ,
Levy D. Differential control of systolic and diastolic blood pressure:
factors associated with lack of blood pressure control in the
community. Hypertension 2000;36:594-9.
Rodríguez Roca GC, Alonso Moreno FJ, García Jiménez A, Llisterri
Caro JL. Factors conditioning pulse pressure in type-2 diabetics in a
primary care population suffering from hypertension. Aten Primaria
2003;31:486-92.
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R,
Germano G, et al. 2007 ESH-ESC Practice Guidelines for the
Management of Arterial Hypertension: ESH-ESC Task Force on the
Management of Arterial Hypertension. J Hypertens 2007;25:175162.
American Diabetes Association. Standards of medical care in
diabetes-2007. Diabetes Care 2007;30(Suppl 1):S4-S41.
O’Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, et al.
European Society of Hypertension recommendations for
conventional, ambulatory and home blood pressure measurement.
J Hypertens 2003;21:821-48.
2003 European Society of Hypertension-European Society of
Cardiology guidelines for the management of arterial hypertension.
J Hypertens 2003;21:1011-53.
Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M,
Caulfield MJ, et al. Reappraisal of European guidelines on
hypertension management: a European Society of Hypertension
Task Force document. J Hypertens 2009;27:2121-58.
Fontsere N, Bonal J, Torres F, De las Cuevas X, Fort J. Compliance
with the 2002 consensus document of the Spanish Society of
Nephrology for the control of diabetic nephropathy in Catalonia
(ECCODIAB). Nefrologia 2006;26:679-87.
Andros V, Egger A, Dua U. Blood pressure goal attainment
according to JNC 7 guidelines and utilization of antihypertensive
drug therapy in MCO patients with type 1 or type 2 diabetes. J
Manag Care Pharm 2006;12:303-9.
Zanchetti A, Grassi G, Mancia G. When should antihypertensive
drug treatment be initiated and to what levels should systolic blood
pressure be lowered? A critical reappraisal. J Hypertens
2009;27:923-34.
Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr,
Cutler JA, et al. Effects of intensive blood-pressure control in type 2
diabetes mellitus. N Engl J Med 2010;362:1575-85.
Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, et
al. Preserving renal function in adults with hypertension and
diabetes: a consensus approach. National Kidney Foundation
Hypertension and Diabetes Executive Committees Working Group.
Am J Kidney Dis 2000;36:646-61.
Marín R, Fernández-Vega F, Gorostidi M, Ruilope LM, Díez J, Praga
M, et al. Blood pressure control in patients with chronic renal
insufficiency in Spain: a cross-sectional study. J Hypertens
2006;24:395-402.
Nefrologia 2011;31(3):313-21
26. Alonso-Moreno FJ, Llisterri Caro JL, Rodríguez-Roca GC, Ferreiro
Madueño M, González-Segura Alsina D, Divisón Garrote JA, et al.
Primary care physicians behaviour on hypertensive patients with
poor blood pressure control. The PRESCAP 2006 study. Rev Clin Esp
2008;208:393-9.
27. Stokes KY. Microvascular responses to hypercholesterolemia: the
interactions between innate and adaptive immune responses.
Antioxid Redox Signal 2006;8:1141-51.
originals
28. Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke
JP. L-arginine improves endothelium-dependent vasodilation in
hypercholesterolemic humans. J Clin Invest 1992;90:1248-53.
29. Engler MM, Engler MB, Malloy MJ, Chiu EY, Schloetter MC, Paul
SM, et al. Antioxidant vitamins C and E improve endothelial
function in children with hyperlipidemia: Endothelial Assessment of
Risk from Lipids in Youth (EARLY) Trial. Circulation 2003;108:105963.
Sent for review: 23 Feb. 2011 | Accepted: 26 Feb. 2011 | Epub: 15 Mar. 2011
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Impact of an interdisciplinary training course
on Counselling and decision making support
for nephrology department professionals
H. García-Llana1, J. Barbero2, E. Remor3, L. Díaz-Sayas2, R. Rodríguez-Rey3, G. del Peso1, R. Selgas1
Nephrology Department. La Paz University Hospital-IdiPAZ (REDinREN, Kidney Research Theme Network from the Carlos III Health
Institute, FEDER Funds). Madrid, Spain
2
Haematology Department. La Paz University Hospital. Madrid, Spain
3
Health and Biological Psychology Department. Psychology Faculty. Autónoma University of Madrid. Madrid, Spain
1
Nefrologia 2011;31(3):322-30
ABSTRACT
A 12-hour training program was delivered to the professionals
of a nephrology department. Contents of the course were
about difficult communication skills in health care interactions.
Counselling was the relational methodology instructed. The
objective was to assess changes in attitudes in relation with
bioethics principles and knowledge. Variables were measured
before and after the training program. Sample was composed
by 76 professionals (57% nurses, 26% auxiliary nurses y 17%
nephrologists) for knowledge and 27 professionals for variable
attitudes. Considering the total sample, results show changes in
implication with bioethics principles (P <.05) and knowledge (P
<.001). There are differences related to the kind of profession.
Nurses benefit more from the training program attending in
the variable knowledge (P <.001).
Impacto de un curso interdisciplinar de formación en
Counselling y apoyo en la toma de decisiones a
profesionales de un servicio de nefrología
RESUMEN
Los profesionales sanitarios del servicio de nefrología de un hospital de tercer nivel recibieron entrenamiento en comunicación
terapéutica mediante un curso de 12 horas centrado en el instrumento terapéutico conocido como Counselling. El objetivo fue
evaluar cambios en actitudes en relación con los principios bioéticos y en conocimientos sobre comunicación y gestión emocional.
Las variables evaluadas se midieron antes y después de la implantación del curso. La muestra estaba formada por 76 profesionales
(un 57% profesionales de enfermería, un 26% auxiliares y un
17% médicos especialistas en nefrología) para la variable conocimientos y por 27 profesionales para la variable de actitudes. Considerando la muestra total, en los resultados se observan cambios
en implicación con los principios bioéticos (p <0,05) y conocimientos (p <0,001). Se observan diferencias en función de la profesión
y son los profesionales de enfermería quienes más se benefician
del curso en el área de conocimientos (p <0,001).
Keywords: Counselling.
Nephrology. Bioethics.
Palabras clave: Counselling. Formación interdisciplinar.
Nefrología. Bioética.
Interdisciplinary
training.
INTRODUCTION
Health professionals who attend to patients with renal
diseases frequently find themselves in situations of very
high stress derived from the uncertainty associated with
caring for patients with progressive chronic diseases. 1
Correspondence: Helena García-Llana
Hospital Universitario La Paz.
P.º de la Castellana, 261. 28046 Madrid. Spain.
[email protected]
322
Several different studies have shown that patients on
haemodialysis suffer from very high rates of depression,2-6
which can influence the level of compliance with
treatment plans and relationships with health
professionals. 7-9 Authors such as Cukor, Cohen, Peterson,
and Kimmel 10 consider the renal patient as a paradigm of
chronic patients from a psychological perspective. These
are complex patients, with multiple associated
comorbidities and, as such, the psychological need for
adaptation both to the disease itself and to the treatment
methods that imply a high impact on quality of life.11,12 To
H. García-Llana et al. Training on Counselling for nephrology professionals
suffer from a renal disease usually implies a serious
challenge to a person’s emotional balance, since the
patient must deal with multiple issues and threats
throughout the diagnosis and treatment periods. A poor
state of health creates a personal crisis in which the patient
suffers from very intense emotional reactions and requires
specific resources in order to recover overall balance.
Inevitably, all this affects the interactions between patients
and health professionals.
Although proper use of medical and biological technology
and procedures is of great importance, they are
insufficient if we are to offer an effective and efficient
response to the personal crisis this causes the patient and
his/her family. 13 As Chochinov stated, 14 health care
focused on maintaining patient dignity, improving
communication and developing an emotional approach,
has a significant influence on the patient’s experience.
This framework can be applied in clinical practice as well
as in the training of multidisciplinary teams, paramedics,
and medical students of all specialties.
Difficult communication in situations of high emotional
intensity and a lack of professional resources have a major
impact on the quality of health care provided.15,16 The
medical literature indicates that the communicative
relationship between a nephrologist and the patient should
promote a shared-decission making process.17-19 In many
occasions, these patients must make very difficult decisions,
such as starting a chronic dialysis programme, halting a
treatment plan, or composing an advance health care
directive.20-22 In all of these cases, the attending doctor and
nursing staff can aid in resolving conflicts, offering
information tailored to the patient’s needs, and establishing
the patient’s general expectations and expected quality of life
so that all decisions are made voluntarily and using all
available information. For this communication process to be
effective, health care staff must have, in addition to good
communication skills, training in the attitudes and value
systems necessary to create an environment of trust and
understanding that facilitates decision-making.23
The training of health professionals in communication skills is
necessary for both directly and indirectly improving the quality
of life of renal patients and facilitating compliance with
treatment plans and the process of adapting to the disease.24-27 It
also provides a fundamental source of support to doctors and
nurses, as improving the level of care given to the patients and
their families usually aids in preventing work-related stress.28-30
Within the nephrology department at an acute care hospital,
in which the workload can be high and hectic, patients
may experience even more intense levels of suffering
caused by their conditions and may react to health care
professionals with aggressiveness or be excessively
demanding. 31-33 Proper training in communication skills
Nefrologia 2011;31(3):322-30
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and techniques for handling strong emotions aids in
minimising the impacts associated with health care.
Generally, health care professionals have not properly
developed these skills in chronic patient care due to the lack
of training and general ignorance regarding the need for this
type of training.34 Most assume (erroneously) that good
intentions are sufficient to guarantee proper communication.
Hospital infrastructure, workload, and a procedure-focused
health system can all decrease the quality of health care due
to a shortage of good communication skills and emotional
competency.35 Counselling training is not a normal
component of medical education, but studies have shown
that this model of communication, and treatment technique,
facilitates patient adaptation to the disease and reduces the
level of conflict and emotional stress, both in patients and
health care workers.36,37
Clinical work in a specialised hospital implies the need for
continuous interaction, and thus, communication among health
professionals. Obviously, we cannot expect to observe significant
changes in their communication process if training and interaction
processes are not included as an independent variable. Health care
is provided under a chain of command, and this chain is only as
strong as its weakest link. As such, to not take into consideration
the professional development of certain components of this chain,
such as nursing assistants, puts the work of the entire team in
jeopardy. Certain concepts and tools, such as how to manage
patient aggressiveness as an adaptive emotional reaction to
hospitalisation, must be taught universally, since they affect the
objectives and decisions made by all health professionals. A team
that does not receive common training in fundamental areas
(communication and values) will only achieve partial objectives
(such as increasing dialysis doses), but not integrated objectives
regarding the biological and psychosocial well being of the
patients and their families. A lack of a formal environment for
mutual understanding and communication can cause differences in
language, concepts, and perspectives from other disciplines and
co-workers may seem inefficient, ineffective, or even completely
opposed to the common task that brings them together.
Another fundamental aspect that must be considered is that
proper communication regarding treatment does not come
naturally. We all have acquired attitudes and abilities in our
processes of personal and professional growth; even so, we
are not always conscious that some learned behaviours
create a negative atmosphere for communication, especially
because hospital employees find it difficult to give
constructive criticism about their own or other professionals’
style of communication. We need platforms for mutual
understanding in which an environment is created to
facilitate the detection and redirect of the automated
communication patterns that we are not always aware of.
Keeping in mind all of the aforementioned variables, the
administration of the nephrology department at our hospital
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facilitated and promoted the development of a training
course for doctors, nurses, and other hospital staff with the
objective of improving attitudes, abilities, and understanding
within the context of communication among health care
professionals and patients.
The hypothesis of our study is that a formal training
course in communication directed towards the entire
multidisciplinary work team (doctors and nursing staff)
within a single department will produce changes in both
attitudes and knowledge (considered as dependent
variables).
MATERIAL AND METHODS
Study subjects
Our study involved a pretest-posttest design with no control
group. The initial sample was composed of a total of 76
health professionals from the nephrology department at a
tertiary hospital. The study subjects accepted the proposal of
receiving training in difficult communication and decisionmaking within the framework of continued education
established by the hospital. The study sample represented
86% of the department employees, and the reasons for
abstaining from the study of the other 14% were unknown.
Of the participants, 57% were nurses (43), 26% were nursing
assistants (20), and 17% were nephrologists (13). By
professional category, the study subjects represented 93% of
nurses, 95% of nursing assistants, and 61% of specialist
doctors. By age, 38% of study subjects were between 25 and
35 years old, 37% were between 36 and 50 years old, 22%
were older than 50, and 3% were younger than 25. We were
also interested in the amount of experience (how many
years) that each participant had with this type of chronic
patient: 50% had more than 10 years of experience in
working with renal patients, 16% had between 6 and 10
years experience, 26% had between 1 and 5 years
experience, and 8% had less than one year of experience. A
large majority of the study group (89.5%) were women.
Finally, we would like to point out that the directors of the
nursing staff along with the head of department actively
promoted this training course and participated in it.
a) Importance of the bioethical principles in hospital
work (α=.76): made up of four items with a Likert
scale ranging between 1 (unimportant) and 10
(extremely important).
b) Personal compliance with the bioethical principles in
my daily work (α=.89): made up of four items with a
Likert scale ranging between 1 (no compliance) and
10 (total compliance).
2. Knowledge (α=.85): made up of 15 items with four
possible responses each, and no penalty given for
wrong answers. This section was composed of two
categories (difficult communication and managing
emotions).
Construction of the questionnaire:
The creation of the initial version of the questionnaire was
supported by a basic literature review regarding the training
of health professionals in communication skills. Through
this review of previous publications, we identified two
relevant areas of evaluation for the study: attitudes
(importance of bioethical principles and compliance with
them) and knowledge (both in difficult communication and
managing emotions). We developed 23 possible items for
assessing these two areas. In order to evaluate the validity
of the content and face validity of each item,
comprehension by the participant, and the relevance of
each item for Counselling training, we sent the
questionnaire to a group of expert faculty members (n=10)
along with a standardised evaluation form. The
standardised evaluation facilitated the assessment of the
comprehension and relevance of each point. We
established criteria for revising or eliminating each item
based on the percentage of agreement between judges (the
expert faculty) in the evaluation of the comprehension and
relevance of each item. If inter-judge accordance was 80%
or higher, the item was kept in the survey. If the value was
below 50%, it was eliminated from the questionnaire. If
the value was between 50% and 80%, the item was
scrutinised and revised using the observations and
suggestions provided by the reviewers. None of the items
were eliminated from the initial list. We took into
consideration the observations and suggestions provided
by the judges when revising the form and producing the
final document.
Tools
We evaluated the participants using a questionnaire that was
put together ad hoc on the following areas (the number in
parentheses expresses the Cronbach’s alpha coefficient for
the pretest evaluation):
1. Attitudes regarding the four basic bioethical principles
(nonmaleficence, justice, respect for autonomy, and
beneficence):
324
Course content
The course content considered various health care
situations (chronic/acute, exacerbations, terminal-stage
patients, etc.) that present themselves to health
professionals and their patients in a hospital department
that treats a wide range of complex cases. This content is
summarised in Table 1.
Nefrologia 2011;31(3):322-30
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Table 1. Content of the Counselling course for the nephrology department
Difficult communication and decision making
Session 1
1. Detection of problematic situations in daily clinical practice: the participants are asked to write what they perceive to be as the most problematic situations from an emotional point of view in their own personal clinical experience. These are later shared with the group in a personal presentation.
2. Counselling as a tool for therapeutic communication: a Counselling model centred on training for attitudes, communication skills, and managing emotions as tools for decision making in renal patients.
3. Model for acting out against suffering: we describe a balance between the perception of threats to biological and psychosocial integrity and
the perception of the availability of internal and external resources for dealing with these threats.
4. Preventing burnout: skills in self-regulation: development of cognitive, emotional, and personal skills in the detection of stress factors and
how to deal with them.
Session 2
5. Basic communication skills: training in me-messages, validation, active listening, reinforcement, open and focused questions, how to give and
receive criticism, and how to deny requests.
6. Difficult communication: protocol for delivering bad news, difficult questions, and managing intense emotional reactions.
7. Treatment relationship and decision making: development of models for clinical relations as defined by Emanuelle and Emanuelle (1999):
paternalist, informative, interpretive, and deliberative. Focus is placed on deliberative communication in order to arrive at agreements regarding
treatment and to facilitate compliance.
The course was focused on using Counselling as a therapeutic
tool. A good communication model is needed that facilitates
the patient-health care professional relationship and the
decision-making process in order to produce effective clinical
practice in nephrology. This is especially important when
facing scenarios as severe as starting renal replacement
therapy or witholding it. Counselling is a therapeutic tool that
has proven to be very useful in health care.38,39 It consists of an
interactive and relational process that develops between the
patient and his/her caregivers that facilitates psychological
adaptation to the disease, avoids adverse emotional states,
promotes self-regulation by the health care professional, and
motivates to health behaviour changes.40
Procedure
A 12-hour interdisciplinary course was organised on 5
separate occasions during 2007. The course was divided into
two sessions that were held on two consecutive days during
mornings or afternoons. The hospital department for
continued training collaborated directly with the design and
execution of the course. We also procured that all hospital
staff were released for training sessions without having to
make up for missed time. This was done in such a manner as
to include the greatest possible number of participants
without causing notable losses in productivity. At the start of
each course, we asked all participants to list their three most
feared situations, or those that produced the greatest amount
of difficulty from an emotional standpoint. The main
situations that were identified by the study group are listed
in Table 2 (there was no need tobe hierarchical).
The course was taught by a team of four hospital
psychologists with experience in Counselling training for
health professionals. Each course was led by a subgroup of
two psychologists. The maximum number of participants
was 20 per course. We used a methodology of active
Table 2. Difficult situations faced by health professionals in daily practice
Situation
Percentage
Managing aggressive patients
39
Supporting the family of a terminal-stage patient
17
Delivering bad news
15
Resistance to starting dialysis
10
Over-involved in the clinical relationship
9
Patient attempts to limit the amount of treatment given
6
Non-compliance with treatment plan
4
Nefrologia 2011;31(3):322-30
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participation to support interactive learning and to act out most
of the difficult situations identified using role-playing. This
teaching method allows for the students to identify key aspects
of communication, such as attitudes, skills, and value systems.
Using these shared observations, we provided key techniques
for managing personal relationships that were revisited in a
role-playing context in order to observe student assimilation of
the techniques. The different scenarios that were worked
through included all the situations that may occur in
nephrology (hospital/home dialysis, outpatient/hospitalised
patients). All study subjects that participated in the different
courses were evaluated using the ad hoc questionnaire before
and after the training course.
3. Knowledge. All differences between the two surveys
(managing emotions and difficult communication) were
statistically significant (P<.001), with higher scores
obtained after the training course. This indicates that
attending the training course produces significant
positive effects in acquiring knowledge.
The statistical results from comparing means are summarised
in Table 3.
We used SPSS software for Windows (version 17.0) for all
statistical analyses. We produced descriptive statistics of
sample and point scores from the before and after studies.
We tested the reliability of the data using the Cronbach’s
alpha coefficient for analysing the internal consistency of the
questionnaire areas described in the “tools” section. We used
non-parametric tests (Wilcoxon’s test) to compare the before
and after scores in attitudes and knowledge in the overall
study group and by type of profession (doctors, nurses, and
nursing assistants). We used the Spearman’s correlation
coefficient to analyse the differences in scores for
“importance of bioethical principles,” and “compliance with
bioethical principles” between surveys taken before and after
the training course.
2. Compliance with the bioethical principles. We observed
significant differences in the global score (P=.034) and
the nonmaleficence category (P=.046), with higher
values produced in the post-training survey, but no
differences were observed for respect for autonomy,
justice, and beneficence.
Correlations between importance
of and compliance with the bioethical
principles in health care practice
We observed significant direct correlations between all study
variables, indicating that when the four primary bioethical
principles (nonmaleficence, justice, respect for autonomy,
and beneficence) and the values that they imply are given
importance, health professionals also tend to comply with
them. This trend was observed in both the pre- and posttraining surveys.
The results for data correlations are summarised in Table 4.
RESULTS
Programme results by type of health profession
Sample characteristics
Taking into consideration that each profession is based on a
distinct set of abilities and skills that are specialised for the work
activity to be carried out, we set out to compare the effects of the
training programme (pretest-posttest) by type of profession. We
used non-parametric tests (Wilcoxon’s test) for this analysis.
When dividing the study sample into professional categories, we
observed statistically significant differences between the two
surveys in nurses. The variables in which we observed these
differences were acquired knowledge (P<.001) and difficult
communication (P<.001). We observed no significant differences
in attitudes related to the bioethical principles.
As we mentioned in the “study subjects” section, the total
sample size was 76 health professionals from the nephrology
department in a tertiary hospital. All participants filled out
the knowledge questionnaire, but only 27 (18 nurses, five
nursing assistants, and four doctors) did so for the attitudes
questionnaire in both pre- and post-training course surveys.
For this reason, n is greater for knowledge than for the other
variables evaluated.
Training course results
DISCUSSION
Comparison of means from pre- and post-training
surveys
The most important findings of this study were:
1. Importance of bioethical principles. There were no
differences observed in the importance given to
bioethical principles, with very high mean values in
before and after surveys.
1. The majority of health care professionals surveyed had a
high level of familiarity with the importance of bioethical
principles. The more they knew, the more they complied
with them.
326
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Table 3. Comparison of before and after mean values for the variables regarding importance of bioethical principles,
compliance with the bioethical principles, and knowledge
Importance of bioethical principles
Pretest mean (n=27)
Posttest mean (n=27)
Significance of difference
Respect for autonomy
8.38 (SD=1.85)
8.73 (SD=1.51)
NS
Justice
9.04 (SD=1.67)
9.26 (SD=1.48)
NS
Beneficence
9.27(SD=1.00
9.08 (SD=1.23)
NS
Nonmaleficence
9.54 (SD=0.90)
9.62 (SD=0.80)
NS
Overall
9.04 (SD=1.07)
9.13 (SD=1.00)
NS
Pretest mean (n=27)
Respect for autonomy
7.76 (SD=2.77)
8.44 (SD=1.68)
NS
Justice
7.54 (SD=2.98)
8.50 (SD=1.30)
NS
Beneficence
8.44 (SD=2.27)
8.76 (SD=1.66)
NS
Nonmaleficence
8.95 (SD=1.89)
9.31 (SD=1.51)
0.046a
Overall
8.11(SD=2.15)
8.73 (SD=1.29)
0.034a
Pretest mean (n=76)
Managing emotions
3.17 (SD=1.23)
3.62 (SD=1.15)
0.001b
Communication
5.19 (SD=2.03)
6.53 (SD=1.82)
0.000b
Compliance with bioethical principles
Knowledge
SD: standard deviation
a
P<.05; b P<.001
2. Participation in an interdisciplinary training course in
Counselling and emotional support improved the
compliance with the bioethical principles, especially in
the nonmaleficence category.
3. The group of nurses was the only one that significantly
improved in the managing emotions and difficult
communication categories.
Our study group was relatively young (88% of participants
were younger than 50 years), but with extensive experience in
caring for renal patients: 50% of the sample indicated over 10
years of experience. As we have described earlier in greater
detail,41 a high level of quality in nephrology health care requires
the development of an interdisciplinary and experienced team to
properly attend to the physical and emotional needs of their
patients. One way to attend to the multi-dimensional nature of
renal patients is by promoting training courses in communication
skills and managing emotions.
The health care professionals evaluated in our study
indicated that the most difficult situations that they face
in normal clinical practice are those that have to do with
communication with patients (for example, dealing with
an aggressive patient, resistance to dialysis, etc.) and the
family (for example, giving support to the family of a
terminal-stage patient). In previous studies 42 carried out
with similar study subjects, the most feared situations
Nefrologia 2011;31(3):322-30
were communicating with patients (51.7%) and their
families (39.3%).
We observed significant differences in all areas of acquired
knowledge when evaluating all of the professions in the
sample group. This is in line with some teaching
experiences43 involving groups of doctors and nurses or
students which have come to the conclusion that mixed
training in communication dealing with certain emotional
reactions provides the participants with increased knowledge
of daily clinical practice.
With regard to the attitudes of the participants, we did not
observe changes in the importance of bioethical principles
(the rate was very high from the beginning and remained
so after the training course), but survey results did
significantly improve in the section on the compliance
with these principles (both in the global score and in the
nonmaleficence section). This makes sense since one of
the principle components of the course is the development
of moral responsibility in the face of suffering, which is
reflected in the nonmaleficence principle. A conceptual
understanding of these values does not necessarily
conduce to complying with them; however, in this study,
it appears that an initially high conceptual value given to
bioethical principles, which did not change after the
training course, provides a foundation for the
development of personal compliance with them through
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originals
Table 4. Correlation between the importance and compliance with the bioethical principles (n=27)
Pretest
Compliance
Compliance with
Compliance with
Compliance with
Overall
with autonomy
justice
beneficence
nonmaleficence
compliance
Importance autonomy
0.79b
0.68b
0.66b
0.67b
0.79b
Importance justice
0.61b
0.63b
0.47b
0.56ª
0.63b
Importance beneficence
0.71b
0.72b
0.67b
0.70b
0.77b
Importance nonmaleficence
0.53b
0.55b
0.56b
0.62b
0.59b
Overall importance
0.81b
0.74b
0.68b
0.70b
0.81b
Compliance
with autonomy
Compliance with
justice
Compliance with
beneficence
Compliance with
nonmaleficence
Overall
compliance
Importance autonomy
0.56b
0.74b
0.65b
0.34ª
0.70b
Importance justice
0.57b
0.68b
0.56b
0.39ª
0.62b
Importance beneficence
0.45b
0.64b
0.57b
0.41ª
0.59b
Importance nonmaleficence
0.52b
0.52b
0.48b
0.79b
0.61b
Overall importance
0.65b
0.76b
0.66b
0.48b
0.74b
Posttest
a
P<.05; b P<.001
participation in the training course. To this end, the
atmosphere created in the training course was not one of
indifference, but rather of a dynamic, but direct, approach
of how these values are incorporated into everyday
clinical practice. Thus the training was not simply about
giving information, but also upholding values. In other
words, seeing the connection between the common
clinical situations and the basic values previously
mentioned can increase the interest in applying them in
the clinical setting (for example, if as a nephrologist, I am
conscious of the fact that by effectively managing the
visits time I am working towards the principle of justice, I
will put more energy towards this pursuit). The ability to
see everyday situations in terms of personal values can
increase the personal compliance with these values and
improve treatment results.
By breaking up the results of our study into different
professions, we observe that nurses obtained the greatest
benefit from this type of training course in comparison to
doctors and nursing assistants. Probably, one of the most
important factors involved in this disparity is the smaller
sample size in the other two groups, especially in the
attitudes section, in which an important part of the
sample was lost, since not all participants filled out the
questionnaire completely. This is probably due to the fact
that the evaluation form did not consist of one single
document, and several participants believed that they had
finished the survey after completing only the section on
knowledge. However, over 90% of the nursing staff and
61% of doctors participated in the training course. These
328
differences may have been due to the lower level of
interest held by nephrologists in these matters, or simply
due to the higher workload of hospital doctors, making
free time for further training very scarce. Several studies
have analysed the same differences found in our study
variables among the different types of health professions.
One study from Norway that was performed in nursing
homes concluded that, when making health decisions at
the end of a patient’s life, doctors tended to guide
themselves more by the principles of beneficence and
nonmaleficence, whereas nurses did so following the
principle of respect for autonomy, even in patients with
communication problems and dementia. 44 Another study
involving 1910 health professionals from 14 public
hospitals in Hong Kong showed that different sectors of
health services (doctors and nurses) and previous
experience in the clinical setting were independent
variables for predicting the perception of ethical
dilemmas with terminal-stage patients and difficult
communication, among others. 45 In intensive care units
and with trauma patients, nurses and doctors have also
professed different perceptions regarding whether to
apply life support techniques (such as cardiopulmonary
resuscitation). 46-48 Most studies have concluded that nurse
practitioners believe that cardiopulmonary resuscitation
is a procedure that causes ethical dilemmas and anxiety if
there is no consensus in the medical team about the
prognosis of the patient. However, both doctors and
nurses coincide that including the patient’s family in
making decisions with a high emotional impact is very
important.49
Nefrologia 2011;31(3):322-30
Traditionally, this type of training course was designed to
provide nurses with resources and tools for handling
emotional situations.50 Our study results support the validity
of providing training in communication skills and handling
emotions, as other authors have shown51 or sought52 in order
to face the complex situations that arise in clinical practice.
In spite of producing interesting results, this study did have
certain limitations. Methodologically, the lack of some type of
follow-up or control group made it difficult to extract
conclusions regarding the stability of the changes produced by
the training course, or to attribute causality of the results
observed to the programme alone. We also lost an important
section of the sample in some parts of the questionnaire, which
has limited the power of the statistical methods used to analyse
the data. We would also like to incorporate into the next version
of the training course another independent variable: level of
satisfaction with teamwork. We believe that a secondary benefit
derived from this type of interdisciplinary course is improved
personal relations amongst the hospital staff.
This type of continued training is a good stimulus for the
different approaches to providing health care to renal
patients and their families. Studies such as ours are needed in
order to continue revealing to the nephrological community
the importance of a biopsychosocial decision-making
approach to the disease and the possible suffering of the
patient.53-55 To conclude, it is important to point out the
relevance of working on value systems based on modern
bioethical principles within the training given in personal
relations to health care workers that treat renal patients and
share in making complicated life decisions.
REFERENCES
1. Mesa E, Gálvez A, Calvo MA, Vázquez MD, Castilla R, Luque A.
Valoración del riesgo psicosocial en las enfermeras de nefrología
de los hospitales de Sevilla. Revista de la Sociedad Española de
Enfermería Nefrológica 2005;8(4):266-71.
2. Cohen SD, Norris L, Acquaviva K, Peterson R, Kimmel P. Screening
diagnosis, and treatment of depression in patients with end-stage
renal disease. Clin J Am Soc Nephrol 2007;2:1332-42.
3. Cukor D, Coplan J, Brown C, Peterson R, Kimmel P. Course of
depression and anxiety diagnosis in patients treated with hemodialysis: a
16-month follow-up. Clin J Am Soc Nephrol 2008;3:1752-8.
4. Finkelstein FO, Finkelstein SH. Depression in chronic dialysis
patients: assessment and treatment. Nephrol, Dial Transplant
2000;15:1911-3.
5. Watnick S, Kirwin P, Mahnensmith R, Concato J. The prevalence
and treatment of depression among patients starting dialysis. Am J
Kidney Dis 2003;41(1):105-10.
6. Moreno E, Arenas MD, Porta E, Escalant L, Cantó MJ, Castell G, et
al. Estudio de la prevalencia de trastornos ansiosos y depresivos en
pacientes en hemodiálisis. Revista de la Sociedad Española de
Enfermería Nefrológica 2004;7(4):225-33.
Nefrologia 2011;31(3):322-30
originals
7. Cukor D, Rosenthal DS, Jindal RM, Brown CD, Kimmel P.
Depression is an important contributor to low medication
adherence in hemodialyzed patients and transplant recipients.
Kidney Int 2009;75:1223-9.
8. García-Valderrama FW, Fajardo C, Guevara R, González-Pérez V,
Hurtado A. Mala adherencia a la dieta en hemodiálisis: papel de los
síntomas ansiosos y depresivos. Nefrologia 2002;23(3):245-52.
9. Plantinga LC, Fink NE, Sadler JH, Levey AS, Levin NW, Rubin HR, et
al. Frecuency of patient-physician contact and pacient outcomes in
hemodialysis care. J Am Soc Nephrol 2004;15:210-8.
10. Cukor D, Cohen SD, Peterson RA, Kimmel P. Psychosocial aspects of
chronic disease: ESRD as a paradigmatic illness. J Am Soc Nephrol
2007;18:3042-55.
11. Álvarez-Ude F, Rebollo P. Alteraciones psicológicas y de calidad de
vida relacionada con la salud en el paciente con enfermedad renal
crónica estadios 3-5 (no en diálisis). Nefrologia 2008;3:57-62.
12. Finkelstein FO, Wuerth D, Finkelstein SH. Health related quality of
life and the CKD patient: challenges for the nephrology community.
Kidney Int 2009;76:946-52.
13. Larsson LB, Yao X. Clinical empathy as an emotional labor in the
patient-physician relationship. JAMA 2005;293(9):1100-6.
14. Chochinov HM. Dignidad y la esencia de la medicina: el A, B, C y D del
cuidado centrado en la dignidad. Medicina Paliativa 2009;16(2):95-9.
15. Bayés R. Medicina paliativa: psicología y cuidados paliativos.
Medicina Paliativa 2005;12:137-8.
16. Fallowfield L, Jenkins V, Farewell V, Saul J, Daffy A, Eves R. Efficacy
of a cancer research UK communication skills training model for
oncologists: a randomized controlled trial. Lancet 2002;359:650-6.
17. Galla JH. Clinical practice guideline on shared decision-making in
the appropriate initiation of and withdrawal from dialysis. J Am Soc
Nephrol 2000;11:1340-2.
18. Lelie A. Decision-making in nephrology: shared decision making?
Patient, Education and Counselling 2000;39:81-9.
19. Tamura MK, Goldstein MK, Pérez-Stable EJ. Preferences for dialysis
withdrawal and engagement in advanced care planning within a
diverse simple of dialysis patients. Nephrol, Dial, Transplant
2010;25:237-42.
20. Rodríguez-Jornet A, Ibeas J, Real J, Peña S, Martínez JC. Documento
de voluntades anticipadas de pacientes con insuficiencia renal crónica
terminal en tratamiento sustitutivo mediante diálisis. Nefrologia
2007;27(5):581-92.
21. Swartz RD, Perry E. Advanced directives are associated with «good
deaths» in chronic dialysis patients. J Am Soc Nephrol
1993;3:1623-30.
22. Davison S. The creation of an advanced care planning process for
patients with ESRD. Am J Kidney Dis 2007;49:27-36.
23. Arranz P, Cancio C. Una herramienta del psicólogo hospitalario: el
Counselling. En: Remor E, Arranz P, Ulla S (eds.). El psicólogo en el
ámbito hospitalario. Bilbao: Desclée Brouwer, 2003;94-119.
24. Barbero J. El derecho del paciente a la información: El arte de
comunicar. Anales del Sistema Sanitario Navarro 2006;29(3):19-27.
25. Moss AH, Holley JL, Davidson SN, Dart RA, Germain MJ, Cohen L,
et al. Core curriculum in nephrology: palliative care. Am J Kidney
Dis 2004;43(1):172-85.
26. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med
2005;353(5):487-97.
329
originals
27. Sarrías X, Bardón E, Vila ML. El paciente en pre-diálisis: toma de
decisiones y libre elección terapéutica. Nefrologia 2008;3:119-22.
28. Klerssy C, Callegari A, Martinelli V, Vizzardi V, Navino C, Malberti F,
et al., for the working group on burnout and dialysis. Burnout in
health care providers of dialysis services in Northern Italy-a
multicentre study. Nephrol, Dial, Transplant 2007;22:2283-90.
29. Kruijver IP, Kerkstra A, Francke AL, Bensing JM, Van de Wiel HB.
Evaluation of communication training programs in nursing care: a review
of the literature. Patient, Education and Counselling 2000;39:129-45.
30. Wilkinson S, Roberts A, Aldridge N. Nurse-patient communication
in palliative care: an evaluation of a communication skills
programme. Palliative Medicine 1998;12:13-22.
31. Andrades F, Expósito C, García R. El paciente etiquetado de difícil. Revista
de la Sociedad Española de Enfermería Nefrológica 2005;8(3):243-5.
32. Johnson CC, Moss AH, Clarke SAD, Armistead NC. Working with
noncompliant and abusive dialysis patients: practical strategies
based on ethics and the law. Advanced Renal Replacement
Therapies 1996;3:77-86.
33. Lewinsky NG, Friedman EA, Levine DZ. What is our duty to a
«hateful» patient? Differing approaches to a disruptive dialysis
patient. Am J Kidney Dis 1999;34:775-89.
34. Moss AH, Holley JL, Davison SN, Dart RA, Germain MJ, Cohen L,
Swartz RD. The need of end-of-life care training in nephrology:
national survey results of nephrology fellows. Am J Kidney Dis
2003;42:813-20.
35. Bensing J. Bridging the gap. The separate worlds of evidence-based
medicine and patient-centered medicine. Patient, Education and
Counselling 2000;39:17-25.
36. Dowsett SM, Saul JL, Butow PN, Dunn SM, Boyer MJ, Findlow R, et
al. Communication styles in the cancer consultation: preferences
for a patient-centered approach. Psycho-Oncology 2000;9:147-56.
37. Shovholt TM. The cycle of caring: a model for expertise in the
helping professions. Journal of Mental Health Counselling
2000;27(1):82-93.
38. Barreto P, Arranz P, Molero M. Counselling, instrumento fundamental
en la relación de ayuda. In: Martorell MC, González R (eds.). Entrevista
y consejo psicológico. Madrid: Síntesis, 1997;83-104.
39. Bartz R. Beyond the biopsychosocial model: new approaches to
doctor-patient interactions. J Fam Pract 1999;48:601-7.
40. Arranz P, Cancio H. Counselling: habilidades de información y
comunicación con el paciente oncológico. In: Gil F (ed.). Manual de
psico-oncología. Madrid: Nova Sidonia; 2000:39-56.
41. García-Llana H, Barbero J, Olea T, Jiménez C, Del Peso G, Miguel JL,
et al. Incorporación de un psicólogo en un servicio de nefrología:
criterios y proceso. Nefrologia 2010;30(3):297-303.
42. Cabodevilla I, Giacchi A, Martínez L, Jusue L, Garde C. Temores del
profesional de atención primaria en el cuidado a la persona y su
familia en el final de vida. Medicina Paliativa 1999;6(3):104-7.
43. León MX, Flórez SP, Torres M, Trujillo CC, Castilla M. Educación en
el cuidado paliativo para pregrado de medicina: resultados de una
encuesta acerca de la percepción de los conocimientos adquiridos.
Medicina Paliativa 2009;16(1):31-6.
44. Dreyer A, Førde R, Nortvedt P. Life-prolonging treatment in
nursing homes: how do physicians and nurses describe and
justify their own practice? J Med Ethics 2010;36(7):396400.
45. Hui EC. Perceptions of ethical practice in Hong Kong public
hospitals: inter and intra professional similarities and differences.
Journal of Nursing Management 2010;18(6):736-56.
46. Saevareid TJ, Baladin S. Nurses´ perceptions of attempting
cardiopulmonary resuscitation on oldest old patients. Journal of
Advanced Nursing 2011;67:no. doi: 10.1111/j.1365-2648.2011.05622.x
47. Festic E, Wilson ME, Gajic O, Divertie GD, Rabatin JT. Perspectives
of physicians and nurses regarding en-of-life care in the intensive
care unit. J Intens Care Med 2011; Jan 21, 0885066610393465.
48. Jacobs LM, Burns KJ, Jacobs BB. Nurse and physician preference for
end-of-life care for trauma patients. J Trauma 2010;69(6):1567-73.
49. Fumis RR, Deheinzelin D. Respiratory support withdrawal in
intensive care units: families, physicians and nurses views on two
hypothetical scenarios. Critical Care 2010;14(6):R235.
50. Arranz P, Ulla S, Del Rincón C, López-Fando T. Evaluation of a
Counselling training program for nursing staff. Patient, Education
and Counselling 2005;56:233-9.
51. Santiesteban-Etxeburu I, Mier O. Estudio descriptivo de la
ansiedad ante la muerte y factores estresantes en los distintos
profesionales de una unidad de cuidados paliativos. Medicina
Paliativa 2006;13(1):18-24.
52. Vallés-Martínez P. Formación de pregrado en enfermería en
cuidados paliativos. Medicina Paliativa 2005;12(4):187-8.
53. Santacruz PL, Rangel M, Navas N, Bolívar Z. La visión integradora
como estrategia ante el paciente con enfermedad renal crónica
(ERC). Requisito contemporáneo. Nefrologia 2006;5:635-6.
54. Bayés R, Arranz P, Barbero J, Barreto P. Propuesta de un modelo
integral para una intervención terapéutica paliativa. Medicina
Paliativa 1996;3(3):114-21.
55. Emanuel EJ, Emanuel LL. Cuatro modelos de la relación médicopaciente. En: Couceiro A (ed.). Bioética para clínicos. Madrid:
Triacastela, 1999;109-26.
Sent for review: 5 Feb. 2011 | Acceptedl: 25 Apr. 2011
330
Nefrologia 2011;31(3):322-30
consensus
document
Consensus Document. Recommendations
on assessing proteinuria during the diagnosis
and follow-up of chronic kidney disease
R. Montañés Bermúdez1, S. Gràcia García1, D. Pérez Surribas2, A. Martínez Castelao3,
J. Bover Sanjuán3
1
2
3
Kidney Function Commission of the Spanish Society of Clinical Biochemistry and Molecular Pathology (SEQC).
Protein Commission of the Spanish Society of Clinical Biochemistry and Molecular Pathology (SEQC).
Spanish Society of Nephrology (S.E.N.).
Nefrologia 2011;31(3):331-45
doi:10.3265/Nefrologia.pre2011.Jan.10807
ABSTRACT
The presence of persistently elevated urinary concentrations of
protein or albumin is considered a sign of kidney damage. The
diagnosis and staging of chronic kidney disease (CKD) is
nowadays based upon the presence of signs of kidney damage
together with the estimation of the glomerular filtration rate.
The presence of either proteinuria or albuminuria identifies a
group of patients with higher risk of CKD progression and
higher cardiovascular risk. Treatment with angiotensinconverting enzyme inhibitors or angiotensin-receptor blockers,
for instance, decreases both the progression of CKD and the
incidence of cardiovascular events and death in patients with
CKD and proteinuria. Thus, proteinuria is currently considered
a therapeutic target by itself. Despite of the importance of
detecting and monitoring proteinuria in the diagnosis and
follow-up of CKD, there is not a consensus among the clinical
practice guidelines published by different scientific societies on
the diagnostic cut-off levels, on different sampling procedures,
on the units used in laboratory reports or just on whether it
should be defined in terms of albumin or proteinuria. The
goal of this document, created by the consensus of the Spanish
Society of Clinical Biochemistry and Molecular Pathology
(SEQC, representing its spanish acronym) and the Spanish
Society of Nephrology (S.E.N.), is to recommend to medical and
laboratory clinicians appropriate guidelines for the detection
and monitorization of proteinuria as a marker of CKD in adults
and children. These recommendations result from searching,
evaluating and summarizing current scientific evidence
published in the last years.
Keywords: Chronic kidney disease. CKD. Proteinuria.
Albuminuria. Urinary albumin-creatinine ratio. Urinary proteincreatinine ratio.
Correspondence: J. Bover Sanjuán
Sociedad Española de Nefrología (S.E.N.).
Fundació Puigvert.
Cartagena, 340-350. 08025 Barcelona. Sapin.
[email protected]
Documento de Consenso. Recomendaciones sobre la
valoración de la proteinuria en el diagnóstico y
seguimiento de la enfermedad renal crónica
RESUMEN
La presencia de concentraciones elevadas de proteína o albúmina en orina, de modo persistente, es un signo de lesión renal y constituye, junto con la estimación del filtrado glomerular, la base sobre la que se sustenta el diagnóstico de la
enfermedad renal crónica (ERC). Su presencia identifica a un
grupo de pacientes con un riesgo superior de progresión de la
enfermedad renal y con mayor morbilidad cardiovascular. El
tratamiento con inhibidores de la enzima de conversión de la
angiotensina o antagonistas del receptor de la angiotensina,
en individuos con ERC y proteinuria, ha demostrado que disminuye tanto la progresión de la enfermedad renal como la incidencia de eventos cardiovasculares y muerte, por lo que la
disminución del valor de la proteinuria es considerado un objetivo terapéutico. Pese a la importancia de la detección y monitorización de la proteinuria en el diagnóstico y seguimiento
de la ERC, no existe consenso entre las guías de práctica clínica
publicadas por distintas Sociedades científicas sobre cuáles son
los valores que indican su presencia, si ésta debe ser definida
en términos de albúmina o de proteína, el espécimen más adecuado para su medida o el tipo de unidades en que deben ser
expresados los resultados. La finalidad de este documento, elaborado con el consenso de la Sociedad Española de Bioquímica Clínica y Patología Molecular (SEQC) y la Sociedad Española
de Nefrología (S.E.N.), es proporcionar recomendaciones, a los
facultativos clínicos y de laboratorio, para la detección y monitorización de la proteinuria como marcador de la presencia de
ERC en adultos y en niños. Las recomendaciones son el resultado de la búsqueda, evaluación y síntesis de la evidencia científica publicada sobre el tema en los últimos años.
Palabras clave: Enfermedad renal crónica. ERC. Proteinuria.
Albuminuria. Cociente albúmina-creatinina en orina. Cociente
proteína-creatinina en orina.
INTRODUCTION
Different epidemiological studies have shown that chronic
kidney disease (CKD) has a high prevalence.1-4 The number
331
consensus document
R. Montañés Bermúdez et al. Proteinuria during the diagnosis and follow-up of CKD
of patients with advanced CKD requiring renal replacement
therapy has increased in the last few years as a result of an
aging population and the fact that older patients and patients
with associated conditions are now included on dialysis.
Furthermore, the incidence and prevalence of CKD due to
glomerulonephritis or type 1 diabetes mellitus (DM) has
stabilised and today, atherosclerosis, type 2 DM or
hypertension are now the main causes of CKD; these are
conditions that may affect kidney function silently. This is
why CKD is detected at an advanced stage. Diagnosing the
disease early is important to prevent kidney function from
deteriorating as well as cardiovascular complications
responsible for the high morbidity and mortality of these
patients compared to individuals with similar clinical
symptoms but without CKD.5
Different studies promoted by the Spanish Society of
Nephrology (S.E.N.) report that CKD has a prevalence of
around 9.16% in the population of over-18s.6 It also reaches
values of 21% in patients attended by primary care
physicians.7 The data from the registers of CKD stage 5
patients on renal replacement therapy (haemodialysis,
peritoneal dialysis or kidney transplantation) show an
incidence and prevalence of 129 and 1039 patients per
million inhabitants/year, respectively.8
The Spanish registry of children with chronic kidney disease
(REPIR II, abbreviation in Spanish), which includes pre-dialysis
patients diagnosed with CKD stage 2-5, shows an incidence and
prevalence rate of 8.6 and 71.0 cases per million inhabitants/year,
according to the data from 2008.9 The most frequent causes of
CKD in children are obstructive uropathy secondary to congenital
defects, glomerulonephritis and hypertension.10
The presence of persistently high urinary concentrations of
protein or albumin is a sign of kidney damage. Diagnosis of
CKD is based on the presence of signs of kidney damage
together with the estimation of the glomerular filtration rate
(GFR).11 The presence of high urinary concentrations of protein
or albumin shows a higher risk of kidney disease progression12-18
and a higher cardiovascular morbidity19,20; furthermore, this risk
is linear and continuous, even for concentrations within the
reference range.21 Treatment with angiotensin-converting
enzyme inhibitors (ACEI) or angiotensin-receptor blockers
(ARB) in patients with CKD and proteinuria has been shown to
reduce the progression of kidney disease as well as the
incidence of cardiovascular events and death. Reducing the
level of proteinuria is therefore a therapeutic target by itself.22-30
Despite the importance of detecting and monitoring
proteinuria in the diagnosis and follow-up of CKD, there is
no consensus between the clinical practice guidelines
published on the cut-off values, whether it should be defined
in terms of albuminuria or proteinuria, the most appropriate
sampling procedure, or how useful reagent strips are as an
initial screening method.
332
OBJECTIVE AND SCOPE
The objective of this document is to provide
recommendations for detecting and monitoring proteinuria as
a CKD marker in adults and children. The recommendations
are different for each group due to the differences in
prevalence and the type of disease responsible for the CKD in
each group.
METHODOLOGY USED TO PREPARE THE
DOCUMENT
The recommendations in this document are the results of
searching, evaluating and summarising current scientific
evidence on the assessment of proteinuria in the diagnosis
and follow-up of CKD. The information has been collected
principally from clinical practice guidelines published in
recent years.
The level of evidence or strength of the recommendations
has not been included in this document, as it is impossible to
exchange the grading systems used by each scientific
society. The guidelines consulted as well as their evidencegrading systems are described at the end of the document
(Appendix).
CURRENT DIAGNOSIS CRITERIA AND
CLASSIFICATION OF CHRONIC KIDNEY DISEASE
The National Kidney Foundation (NKF)-Kidney Disease
Outcomes Quality Initiative (K/DOQI) defines the following
diagnosis criteria in its guidelines on the evaluation,
classification and staging of CKD11:
1. GFR under 60ml/min/1.73m2 during a time period greater
than or equal to three months.
2. The presence of kidney damage, with or without a
decrease in the GFR, during a time period greater than or
equal to three months. The concept of kidney damage
refers to structural or functional abnormalities of the
kidney manifested directly by histological disorders in
the kidney biopsy, or indirectly, from the presence of
albuminuria, proteinuria, urine sediment abnormalities or
imaging techniques.
The combination of both diagnostic criteria is the basis for
CKD classification in 5 stages (Table 1). In stages 1 and 2,
the presence of kidney damage on its own is used to
diagnose CKD.
This definition and classification into stages has been
accepted by the large majority of scientific societies,
including the S.E.N.31 and the international initiative Kidney
Nefrologia 2011;31(3):331-45
Disease: Improving Global Outcomes.32 In recent years, changes
have been proposed to this classification such as: a) adding the
letter “T”, “D” or “p” to identify patients with kidney transplants,
on dialysis and with proteinuria, respectively33-35; b) the
subdivision of stage 3 CKD into 3A (GFR 45-59ml/min/1.73m2)
and 3B (30-44ml/min/1.73m2)32,34,36.37; c) the elimination of stages
1 and 238 or combining these into one stage,39 given that there is
no optimum measurement of kidney function in this range of
GFR; d) the need for additional evidence of kidney damage for
GFR values over 30 or 45ml/min/1.73m2 as a prerequisite for
diagnosing CKD40,41; e) decreasing the cut-off point from 60 to
45ml/min/1.73m2 for stage 3 CKD42; or f) introducing GFR
reference values depending on age and sex.11,39,40,42 Some of these
considerations have been included in guidelines published after
the KDOQI (Table 2).
DEFINITIONS
Proteinuria
Under normal conditions, a healthy individual eliminates
between 40-80mg of protein/day through urine, about 1015mg of this is albumin and the rest is made up of TammHorsfall protein43 and small amounts of low-molecularweight proteins.
consensus document
In this document, the term proteinuria is used to indicate the
presence of concentrations of urine above the reference
range. However, there is not a universal cut-off point that
defines this range, as this depends on the type of sample
used for the measurement (24-hour or random urine sample),
the way the results are expressed (in terms of concentration
or excretion) or the population being assessed (adults or
children) (Table 3).
When a random urine sample is used, the results must be
expressed as the ratio between the urinary concentration of
protein and creatinine (Pr/Cr).
Albuminuria
In healthy individuals the excretion of albumin in urine is
below 30mg/day.11,34,44,45 In this document the term
albuminuria refers to the presence of an albumin excretion
above this value. When a random urine sample is used, the
results must be expressed as the ratio between the urinary
concentration of albumin and creatinine (ACR) and the cutoff points that have the highest international consensus are
>2.5mg/mmol or >17mg/g (men) and >3.5mg/mmol or
>25mg/g (women). However, some societies recommend
using only one criterion. These values were obtained from
Table 1. Classification of chronic kidney disease stages according to the KDOQI guidelines of the National Kidney
Foundation (2002)
Stage
Description
Glomerular filtration rate (ml/min/1.73m2)
1
Kidney damage with normal or increased glomerular filtration rate
>90
2
Kidney damage with mild decrease in the glomerular filtration rate
60-89
3
Moderate decrease in the glomerular filtration rate
30-59
4
Severe decrease in the glomerular filtration rate
15-29
5
Renal failure or dialysis
<15
Table 2. Classification chronic kidney disease stages according to the UK Renal Association (2007), NICE (2008) and SIGN
(2008) guidelines
Stage
Description
1
Normal or increased glomerular filtration rate with evidence of kidney damage
>90
2
Mild decrease in the glomerular filtration rate with evidence of kidney damage
60-89
3A
Moderate decrease in the glomerular filtration rate with
or without evidence of kidney damage
3B
4
5
Glomerular filtration rate (ml/min/1.73m2)
45-59
30-44
Severe decrease in the glomerular filtration rate with or without evidence
of kidney damage
15-29
Renal failure or dialysis
<15
Include the suffix “p” for any stage if proteinuria is present.
Proteinuria is defined as protein excretion >0.5g/day or protein-creatinine ratio in a urine sample >50mg/mmol or the albumin-creatinine ratio in a
urine sample >30mg/mmol (NICE Guidelines).
Nefrologia 2011;31(3):331-45
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consensus document
Table 3. Values used to define proteinuria according to the different scientific societies
Sample
24 hour urine
Timed urine
Random urine (Pr/Cr)1
Adults
>150mg/day3
>300mg/day4
Children
>100mg/m2/day9
>4mg/m2/hour10
>6 months to 2 years
>0.5mg/mg10
>50mg/mmol4
>200 mg/g
>45 mg/mmol6
>50 mg/mmol7
>100 mg/mmol8
5
>2 years
>0.2mg/mg10
>20-25mg/mmol4
Reactive strip2: «1+»
PR/CR: 1Pr/Cr: urinary protein-creatinine ratio
A value of «1+» generally corresponds to a protein level of 150-300mg/L.
3
KDOQI, NICE, SIGN, CARI and UK Guidelines.
4
CARI Guidelines.
5
KDOQI Guidelines.
6
NICE Guidelines.
7
SIGN Guidelines.
8
Welsh Guidelines.
9
PARADE Guidelines for children and SIGN Guidelines.
10
PARADE Guidelines for children.
1
2
individuals with insulin-dependant diabetes46,47 and have been
applied to the rest of the population.48
The values that define microalbuminuria and macroalbuminuria
vary depending on the clinical guidelines consulted (Table 4).
Both terms, despite being widely used, can give rise to confusion
and should therefore be abandoned.49
Under normal conditions the concentration of albumin
represents only a small part of the concentration of protein in
urine. As the concentration of protein increases so does the
proportion of albumin. This ranges between 5% and 70% for
Pr/Cr values <2.5 and >90mg/mmol, respectively.50,51 Due to
the varying relationship between both measurements, it is
not advisable to use conversion factors from ACR to Pr/Cr
and viceversa.11
type of proteinuria is due to an impaired renal tubular
reabsorption as a result of congenital structural or functional
defects, which are the most frequent causes of CKD in
children.
Another type of proteinuria that must be mentioned is
orthostatic or postural proteinuria, which only appears when
the patient is in the supine position and disappears in the
upright position. This mainly affects children and teenagers
and tends to disappear when they reach adulthood. Its value
is normally below 1g/m2/day and is caused by glomerular
haemodynamic abnormalities.53,54
METHODOLOGICAL CONSIDERATIONS IN THE
ASSESSMENT OF PROTEINURIA
Pre-analytical conditions
TYPES OF PROTEINURIA
Patients
Increased urinary concentrations of protein may be a result
of different aetiopathogenic mechanisms,52 and each of them
is associated with a type of proteinuria with specific
quantitative and qualitative characteristics.
Albumin is the most abundant protein in urine in CKD due to
DM, glomerular disease or ATH, which are the main causes of
CKD in adults. This is due to an abnormal filtration process,
whether structural damage or an alteration in the electrical
charges of the glomerular basement membrane.
The presence of fever, stressful situations or performing
intense physical exercise55 may cause proteinuria to rise
temporarily. This usually reverts back to normal levels after
a few days, once the triggering factor disappears. Urinary
tract infections or menstruation can result in false positives.
For this reason, it is recommended to avoid collecting a urine
sample to assess proteinuria in these circumstances.
Sampling procedure
The presence of low-molecular-weight proteins in urine (β2microglobulin, α1-microglobulin, retinol-binding protein,
etc.) shows the existence of tubulo-interstitial disease. This
334
As proteins are removed at a varying rate throughout the day,
as a result of factors such as level of hydration, physical
Nefrologia 2011;31(3):331-45
consensus document
Table 4. Values used to define albuminuria according to the different scientific societies
Guidelines
Sample
Normal
Microalbuminuriaa
Macroalbuminuriaa
SIGN
Random urine
<20 µg/min
20-200 µg/min
>200 µg/min
24-hour urine
<30 mg/day
30-300 mg/day
>300 mg/day
Random urine
M <2.5 mg/mmol
M 2.5-30 mg/mmol
(ACR)
F <3.5 mg/mmol
F 3.5-30 mg/mmol
Strip
<3 mg/dl
>3 mg/dl
24-hour urine
<30 mg/day
30-300 mg/day
>300 mg/day
M <17 mg/g
M >17 mg/g
M >250 mg/g
<1.9 mg/mmol
>1.9 mg/mmol
>28 mg/mmol
CARI
>30 mg/mmol
>20 mg/dl
Random urine
(ACR)
KDOQI
ADA
F <25 mg/g
F >25 mg/g
F >355 mg/g
<2.8 mg/mmol
>2.8 mg/mmol
>40 mg/mmol
Strip
<3 mg/dl
>3 mg/dl
>30 mg/dl
24-hour urine
<30 mg/day
30-300 mg/day
>300 mg/day
Random urine
M <17 mg/g
M 17-250 mg/g
M >250 mg/g
(ACR)
F <25 mg/g
F 25-355 mg/g
F >355 mg/g
<30 mg/g
30-300 mg/g
>300 mg/g
<30 mg/g
30-299 mg/g
>300 mg/g
Random urine
(ACR)
SEN-semFYC
Random urine
(ACR)
ACR: Urinary albumin-creatinine ratio; M: male; F: female.
Multiply by 8.84 to convert from International System of Units (mg/mmol) to conventional units (mg/g).
Multiply by 0.113 to convert from conventional units (mg/g) to International System of Units (mg/g).
a
Note: although the use of these terms is advised against in this document, they have been used in the table as this is how they appear in the guidelines consulted.
activity or protein intake, the 24-hour urine sample has been
considered as the reference sample for measuring
proteinuria. However, problems associated with collecting a
24-hour urine sample have led researchers to look for
alternatives such as first morning urine or random urine
samples, expressing the results in terms of concentration or
even urinary concentration of creatinine in order to remove
the variations depending on the level of hydration. The
biological variability must be known to be able to decide
which type of sampling procedure is the most appropriate for
screening and monitoring proteinuria and assessing the
clinical significance of a change.
The studies that have assessed the suitability of Pr/Cr in
random urine samples as an alternative to protein excretion
in 24-hour urine samples56-60 agree that there is good
correlation and agreement between both values, even
between samples from individuals with different levels of
kidney function impairment61,62 and for a wide range of
proteinuria values.63,64 However, correlation as well as
agreement worsen when proteinuria is in the nephrotic range
(>3.5g/1.73m2/day).64,65 When Pr/Cr is expressed in mg/mg,
the quantitative value obtained is approximately the same as
that obtained for an excretion of protein expressed in g/day.
If Pr/Cr is expressed in mg/mmol, the excretion in 24-hour
urine is approximately 10 times this value, considering an
average creatinine excretion of 10mmol/day.36
Nefrologia 2011;31(3):331-45
Likewise, the studies that have assessed which is the most
appropriate type of sampling procedure for measuring
albumin in urine (first morning urine or random urine sample
as an alternative to the 24-hour urine sample) and the best way
to express the results (urinary concentration of albumin
compared to ACR) have found greater agreement with first
morning urine compared to second or random urine sample.66,67
They also found a lower intraindividual variability for this
type of sample when expressed as ACR. As a consequence,
first morning urine is considered the most appropriate sample
for screening and monitoring albuminuria. The results should
be expressed as ACR (mg/mmol, mg/g) rather than as a
concentration value (mg/L).
Conservation
The urine sample remains stable for 7 days at 2-8ºC.49,68 If it
has to be frozen, it must be done at a temperature of ≤-70ºC.
Lower values, especially at -20ºC, cause the albumin
concentration to drop. This especially affects urine samples
with albumin values below 300mg/L.69-72 The sample must be
thawed at room temperature and homogenised before
measuring it, to dissolve the precipitates that may have
formed as well as any albumin absorbed by the container. It
is not well understood what effect freezing and thawing has
on different molecular forms.
335
consensus document
Before freezing and analysing the sample, the urine must be
visually inspected to check for the presence of precipitates.
These must be eliminated by centrifugation.
If for some reason a 24-hour urine sample is needed, the
urine must be kept refrigerated. It is not necessary to add any
type of preservative.
Methods for assessing proteinuria
Screening methods
Reagent strips for protein screening
This is a strip of paper impregnated with tetrabromophenol
blue buffered at pH 3.0,68 and its colour changes when it comes
in contact with the proteins of the sample. The intensity of the
colour varies according to the concentration of protein. The
result is interpreted by visually comparing the colour obtained
with a chromatic scale, and it is translated into values that
oscillate from negative to a “+” scale, according to the different
concentration values. The scale varies depending on the
manufacturer of the strips. Using automated readers reduces
the possibility of error and the interpersonal variability when
interpreting the results.73 Proteinuria is considered to exist
when the colour changes by “1+” or higher. For the majority of
manufacturers this corresponds to a concentration of between
150 and 300mg/L.68 The reagent strips are especially sensitive
to proteins with a negative charge, such as albumin, and less
sensitive to globulins and low-molecular-weight proteins. The
most significant limitations of these measuring systems are:
inability to detect concentrations below 300mg/L, false
negatives in diluted urine and false positives in concentrated or
alkaline urine, and in the presence of haematuria and coloured
components such as bilirubin and drugs (ciprofloxacin, quinine
and chloroquine).74
Different studies have compared how precise the diagnosis
with reagent strips is against the protein measurement in a
24-hour urine sample in populations with a high prevalence
of proteinuria.75-77 The results showed a sensibility and
specificity which varied depending on the concentration of
protein used as the cut-off point. For this reason, most of the
clinical practice guidelines advise against using it as a
screening test to detect proteinuria34,35,45 and those that do
include it, recommend that a positive result should be
confirmed with a quantitative measurement.11,78
In recent years, some manufacturers have incorporated an
area in their reagent strips which measures creatinine and
expresses the protein to creatinine ratio semi-quantitatively.
The results can be read visually or by automated devices.
Although the initial results have shown it to be effective in
monitoring patients with CKD,79 more studies are needed to
evaluate its diagnostic value.
336
Reagent strips for albumin screening
The semi-quantitative measurement of albumin by reagent
strips is based on immunological or non-immunological
methods that use a strip of paper coated with a tetrabromosulfonephthalein derivative.68 They are able to detect small
concentrations of albumin (30-40mg/L). There are also test
strips on the market with two reaction areas, one saturated
with a high affinity and specificity dye (tetrabromosulfonephthalein) for albumin and another area to measure
creatinine (based on the peroxidase-like activity of a coppercreatinine complex). These strips provide semi-quantitative
estimates of the albumin-creatinine ratio in three categories:
<3.4mg/mmol, 3.4-33.9mg/mmol and >33.9mg/mmol. These
devices have been recently evaluated with results that show a
good diagnostic accuracy in the general population as well as
in patients with CKD of various origins.80,81
The studies performed to find out the diagnostic accuracy of
the specific strips for detecting albumin at concentrations
above 30mg/g creatinine have found that they have a low
sensibility (from 37% to 83%) and a high specificity (from
93% to 98%). The positive and negative predictive value
varies depending on the concentration used to define
albuminuria.34
Quantitative methods
Quantitative methods for measuring protein
There are some significant difficulties when measuring
protein in urine due to the variability in the make-up and
proportion of the different types of protein, as well as the
high concentrations of non-protein substances that may
interfere with the measurement.
The most used methods are turbidimetric methods (based on
the binding of proteins to substances such as trichloroacetic
acid or benzethonium chloride) and dye binding methods
(Ponceau-S, Coomassie brilliant blue and pyrogallol redmolybdate). Both of the methods have different analytical
sensitivity and specificity for the different types of proteins.
They strongly react with albumin.82-84
There is currently no measurement procedure or reference
material to determine the urinary concentration of protein.
This means that there is a lot of variability between the
results obtained in different laboratories. This variation has
an effect, especially at low concentrations, and decreases at
higher concentrations due in part to the higher relative
concentration of albumin that they have.
The data from the external quality control programme
(FPCQLC) of the Spanish Society of Clinical Biochemistry
and Molecular Pathology (SEQC) for 2009 show that
Nefrologia 2011;31(3):331-45
turbidimetric methods that use benzethonium chloride
(48.5% of laboratories) and pyrogallol red-dye binding
(44.9% of laboratories) are the most used methods for
measuring protein. The coefficients of variation range
between 7.7% and 10.5% (turbidimetric methods) and from
4.5% to 7.7% (pyrogallol red-dye binding) for a
concentration range between 0.31 and 1.07g/l.85
consensus document
measurement in laboratory tests. The data for 2009 from the
FPCQLC of the SEQC shows that 87.8% of registered
laboratories determined albumin in urine using turbidimetric
methods compared to 12.1% that used nephelometric
methods. The coefficients of variation oscillate between
5.4% and 10.0% (turbidimetric methods) and 6.8% and
15.5% (nephelometric methods) for a concentration range
between 260 and 970mg/L.85
Quantitative methods for measuring albumin
FUTURE LINES OF RESEARCH
The most common methods for measuring albumin levels in
urine are the turbidimetric or nephelometric immunoassays
with detection limits between 2 and 10mg/L. The antibodies
used can be monoclonal or polyclonal with different
sensitivities for detecting anomalous albumin or fragments
of albumin present in urine. Methods based on high
performance liquid chromatography (HPLC) have appeared
in recent years. These methods have higher values than
immunoassays as they detect non-immunoreactive albumin.
Several external quality control programmes have shown
that there are differences in the results obtained by different
laboratories and in the units used to express the results.86
This is because there is no reference laboratory test; no
international reference material and due to the presence of
different molecular forms of albumin both in the urine
sample and the calibrators (fragmented molecules,
glycosylated molecules and dimeric forms), the presence of
degraded albumin or non-antibody-reactive albumin; nonspecific binding of albumin to the tubes used to collect the
sample, as well as polymerisation and fragmentation that
occurs during storage and the freeze/thaw process.87
Most of the manufacturers of products for in vitro diagnosis
state that the value assigned to their calibrators is traceable
to the certified reference material ERM®-DA470k/IFCC
(previously called CRM 470), which is distributed by the
Institute for Reference Materials and Measurements of the
European Commission. This material, with an albumin
concentration of 37.2g/l, is the same as the one used for
serum albumin calibration. There are differences between the
manufacturers in the protocols for preparing the calibrators,
the solvent used, the dilution factor, the plasma or urine
matrix, etc. Recently, the Japanese Society of Clinical
Chemistry has developed a candidate for a reference material
devised from monomeric human albumin with over 97.5%
HPLC purity in a buffered and lyophilised aqueous matrix.
The Japanese Committee for Clinical Laboratory Standards
is currently evaluating it.88 Furthermore, researchers from the
Mayo Clinic are working on a method based on liquid
chromatography-isotope dilution mass spectrometry (LCIDMS)89 as a possible reference method candidate.
Specific immunoassays for determining albumin provide a
better albumin measurement compared to the protein
Nefrologia 2011;31(3):331-45
There was a conference in 2007 organised by the Laboratory
Working Group of the National Kidney Disease Education
Program (NKDEP) and the International Federation of
Clinical Chemistry and Laboratory Medicine (IFCC). The
objectives of this conference was to highlight the problems
associated with measuring albuminuria and to organise
working groups in order to formulate recommendations that
could be included in clinical practice guidelines.49 The group
of experts believed that the following aspects had to be
further investigated in order to standardise the measurement
of albumin and how the results are expressed:
1. Pre-analytical requirements regarding the container used
to collect the sample; the need to carry out further
investigation into biological variability in order to decide
when to obtain the sample or the influence of blood,
seminal fluid and other physiological contaminants in
urine.
2. Clarify the definition of the mesurand and research the
molecular forms of albumin in freshly voided urine
sample and the level of degradation of albumin
depending on the storage conditions.
3. Develop a reference measurement procedure as well as
urine albumin and creatinine primary and secondary
reference materials with standardised and certified
commutability by the Joint Committee for Traceability in
Laboratory Medicine (JCTLM).
4. Determine the most appropriate measurement procedure,
considering the variation in urinary composition.
5. Define the total acceptable error clinical requirements for
measurement procedures, as well as the materials to be
used in Quality Control Programmes that allow the
different methods to be compared.
6. Assess whether different decision thresholds are needed
depending on the sampling procedure, anthropometric
characteristics (age, sex or ethnicity) and different
population groups (general population or high-risk
groups such as DM, hypertension or cardiovascular
disease [CVD]).
337
consensus document
7. Research on the usefulness of age- and sex-specific
equations to convert ACR to an albumin excretion/day value
for which a single reference limit may be appropriate.
KEY ASPECTS ON THE EVALUATION OF
PROTEINURIA IN CLINICAL PRACTICE GUIDELINES
Different scientific societies have prepared guidelines that
include recommendations for evaluating proteinuria in CKD
patients. The most important aspects are summarised in Table 5.
They are displayed below according to the year of publication.
Target population
All the guidelines agree on the fact that screening for
proteinuria must be carried out on individuals with high risk of
CKD: DM, hypertension, CVD, GFR below 60ml/min/1.73m2,
multi-systemic diseases with possible kidney impairment,
over 60 years old, past family history of CKD, or specific
ethnic groups with a high prevalence of CKD. There are
guidelines with recommendations for specific population
groups such as those by the American Diabetes Association
(ADA)90 or the Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure.91
Use of reagent strips for proteinuria detection
Only the KDOQI11 and Welsh Renal NSF78 guidelines state that
the use of reagent strips as acceptable for screening for
proteinuria. They propose that any result “>
_1+” should be
confirmed using a quantitative measurement (Pr/Cr or ACR)
within the following 3 months. The other guides advise against
its use due to its low sensibility and specificity even though
there is evidence that a strip test value of “>
_1+” can be used to
identify patients with a high risk of end-stage CKD and CVD.35
Furthermore, all the guidelines agree that analysing protein
in urine is not sufficiently sensitive to identify the presence
of incipient diabetic nephropathy. They suggest determining
albumin expressed as ACR once a year. In other
circumstance, the guidelines vary on recommending using
ACR or Pr/Cr. Thus, KDOQI, KDIGO, ADA, NICE, JNC-7
and SEN-semFYC recommend using ACR while PARADE
(children), CARI, SIGN, UK Guidelines, Welsh Renal NSF
and CSN recommend using Pr/Cr.
Cut-off values
Table 5 shows reference ranges and values considered as
pathological by each of the guidelines.
Units used to express the results
The PARADE (children), KDOQI, JNC-7, CARI, KDIGO,
ADA and SEN-semFYC guidelines recommend using
conventional units (mg/g), the rest of the guidelines suggest
using International System of Units (mg/mmol).
Recommendations for children
Only the KDOQI, Welsh Renal NSF, PARADE (children) and
CARI guidelines include children-specific recommendations.
All the guidelines agree that Pr/Cr must be used to detect and
monitor proteinuria in children, except in children with postpubertal onset of DM with more than 5 years of duration. In
these cases, the use of ACR is recommended in the same way
as in adults.
They recommend this because of the low prevalence of CKD
due to DM or hypertension in children compared to diseases
linked to urinary tract abnormalities or congenital tubular
disorders, which are characterised by the elimination of lowmolecular-weight proteins.
Sampling procedure
RECOMMENDATIONS
All the guidelines agree that the most appropriate sample is
the 24-hour urine specimen; although collection problems
make its use difficult in clinical practice. For that reason, they
recommend using a urine sample, preferably first-morning
urine; although a random urine sample is also acceptable.
Biological measurement that must be determined
(protein or albumin)
There is general consensus between the guidelines that
determining Pr/Cr or ACR in a random urine sample must
replace measuring protein or albumin in 24-hour urine.
338
Assessment of proteinuria and/or albuminuria
1. The presence of high urinary concentrations of protein or
albumin on two or more occasions during a period of 3 or
more months is a sign of kidney damage. The diagnosis
of CKD is based on signs of kidney damage and the
GFR.
2. The estimation of the glomerular filtration rate should
be measured together with urinary concentration of
protein and/or albumin in individuals at risk of
developing CKD.
Nefrologia 2011;31(3):331-45
consensus document
Table 5. Summary of the guidelines
Guideline
Detection
Sample
Random
urine
Monitoring
Units
Reference values
Decision criteria
First
morning
urine
PARADE54
2000
KDOQI11
2002
Reagent strip: a value of >
_1+
needs to be confirmed with Pr/Cr
in first morning urine
Pr/Cr
ACR in DM
Reagent strip: a positive result
Adults:
needs to be confirmed with Pr/Cr
ACR
Specific albumin reagent strip is Pr/Cr is acceptable if
acceptable for albuminuria scree- ACR is high (>500 to
ning. A positive result needs to be
1000mg/g)
confirmed with ACR
Adults: specific reagent strip for
Children:
albumin or ACR
Pr/Cr
Children at a high risk of CKD but
ACR in DM
without diabetes: standard reagent
strip or Pr/Cr
Children with DM of more than 5
years duration or post-pubescent:
ACR. Otherwise, the same recommendations as for children without
diabetes
JNC-791
2003
Measure the level of albumin in
urine as excretion or ACR annually
only in the high-risk population (DM
or confirmed CKD)
CARI45
2004
Adults: Pr/Cr
If it is negative, assess ACR in
another sample
In DM and specific ethnic groups:
ACR
Confirm a positive result with new
samples
P
P
A
A
Pr/Cr: mg/mg
Pr/Cr
ACR: mg/g <0.5mg/mg (6-24 months)
<0.2mg/mg (>2 years)
ACR<30mg/g
Pr/Cr: mg/g
ACR: mg/g
P
A
Pr/Cr<200mg/g
ACR
M<17mg/g
F<25mg/g
ACR
M>250mg/g
F>355mg/g
ACR: mg/g
ACR<30mg/g
Diagnostic of CKD:
ACR>200mg/g
Pr/Cr: mg/g
ACR: mg/g
Adults: ACR
M<17mg/g (1.9mg/mmol)
F<25mg/g (2.8mg/mmol)
ACR
M>250mg/g (28mg/mmol)
F>355mg/g (40mg/mmol)
Children:
Pr/Cr
<2 years: <50mg/mmol
>2 years:
<20-25mg/mmol
Children:
Pr/Cr
<2 years: >50mg/mmol
>2 years: >20-25mg/mmol
ACR (in DM):
<3.5mg/mmol
ACR (in DM): >3.5mg/mmol
Diagnostic of CKD:
ACR>30mg/g
M>20mg/g
F>30mg/g
Children: Pr/Cr
ACR in DM. If DM starts before
puberty, screen 5 years after onset,
at 11 years old, or at puberty. If DM
starts during puberty, screen 2 years
after onset. In both cases, screen
annually thereafter.
KDIGO32
2005
Reagent strip: acceptable if it is
ACR
the only option available
Recommended for screening: ACR Pr/Cr can be used as
If initial ACR is >
_30mg/g, rule out an alternative if ACR
is pathological
infection or contamination by
blood (menstruation) with a
reagent strip that assesses whether
leukocytes and/or red blood cells
are present
Confirm a positive result with new
samples
Monitoring by
Joint Speciality
Committee on
reagent strips A
needs
to
be
confirmed
by
Pr/Cr
or
Renal Medicine
positive results needs
ACR (depending on the local
of the Royal
to be confirmed by
College of
clinical practice)
Pr/Cr or ACR
General
Practitiones.
(depending on the
CKD in adults:
local clinical practice)
UK guidelines
for
Identification,
ACR in DM: check
Management
annually
and Referal44
2006
ACR>30mg/g
Pr/Cr<200mg/g
Not Available
Pr/Cr
ACR in DM
Pr/Cr
>0.5mg/mg (6-24 months)
>0.2mg/mg (>2 years)
P
A
ACR: mg/g
ACR<30mg/g
M<20mg/g
F<30mg/g
P
A
Pr/Cr: mg/mmol
ACR: mg/mmol
Pr/Cr<15mg/mmol
ACR:
M<2.5mg/mmol
F<3.5mg/mmol
Pr/Cr>
_45mg/mmol
ACR>
_30mg/mmol
In DM:
ACR M>
_2.5mg/mmol
ACR F>
_3.5mg/mmol
Criteria for referring patient to
nephrologist:
Pr/Cr>
_100mg/mmol or
Pr/Cr>
_45mg/mmol + haematuria
Criteria for indicating treatment
with ACEI or ARB in DM:
ACR M>
_2.5mg/mmol
ACR F>
_3.5mg/mmol
Continues on next page >
Nefrologia 2011;31(3):331-45
339
consensus document
Table 5. Summary of the guidelines (Continues)
Guideline
Detection
Monitoring
Sample
Units
Reference values
PR/CR:
mg/mmol
Not Available
Not Available.
Standardising
results is
advised to
avoid confusion
Not Available
Decision criteria
First
Random
morning
urine
urine
UK Renal
Association36
2007
needs to be confirmed with
Pr/Cr or ACR
Welsh Renal
NSF78
2007
Pr/Cr
ACR in DM
Children:
High risk for CKD: screening with
reagent strip. A positive result needs to be confirmed with Pr/Cr
SIGN35
2008
NICE34
2008
P
Pr/Cr
ACR in DM
In non-diabetic
Do not use reagent strips on
patients with
their own to assess whether
confirmed CKD, use
proteinuria is present/absent
Pr/Cr to assess the
In groups with a high prevalenrisk of progressing
ce of proteinuria without diabeto ESCKD
tes: Pr/Cr
ACR in DM
ACR in DM
Preferably first
morning urine
Not Available
Pr/Cr: mg/mmol
ACR: mg/mmol
P
Reagent strip: only if it detects
albumin specifically at low
concentrations and express the
results as ACR
ACR
If initial ACR is
>
_mg/mmol and<70mg/mmol, it
must be confirmed in another
first morning urine sample.
>_0mg/mmol or
Pr/Cr>
_100mg/mmol, it is not
necessary to confirm it
A
A
Pr/Cr: mg/mmol
ACR: mg/mmol
Pr/Cr>
_45mg/mmol
ACR?30mg/mmol
Not Available
with ACEI or ARB:
No DM:
Pr/C r >
_50mg/mmol
ACR>
_30mg/mmol
Protein excretion>
_0.5 g/day
DM
ACR M>2.5mg/mmol
ACR F>3.5mg/mmol
nephrologist:
Pr/Cr >
_100mg/mmol
ACR >
_50mg/mmol
Protein excretion>
_1g/day
Pr/Cr: mg/mmol
ACR: mg/mmol
Not Available
with ACEI or ARB in DM:
ACR M>2.0mg/mmol
ACR F>2.8mg/mmol
nephrologist:
Pr/Cr >
_100mg/mmol
ACR >
_60mg/mmol
A
ACR: mg/g
ACR <30 mg/g
with ACEI or ARB:
ACR: >
_300mg/g
nephrologist:
In DM:
ACR>300mg/g
No DM and age<70 years old:
ACR>500mg/g
Random urine
sample
ACR: mg/g
ACR <30 mg/g
>
_300mg/g
Random
urine sample
Pr/Cr or ACR
ACR in DM
P
ACR
ACR
ADA90
2010
ACR in patients with type 1
DM>5 years duration and in
type 2 DM since diagnosis
with ACEI or ARB:
No DM:
Pr/Cr>
_100mg/mmol
In DM:
ACR M>
_2.5mg/mmol
ACR F>
_3.5mg/mmol
PR/CR <15 mg/mmol
ACR
M ≤2.5 mg/mmol
F ≤3.5 mg/mmol
ACR
Pr/Cr can be used
as an alternative.
ACr in DM is recommended
CSN92
2008
SENsemFYC93
2008
with ACEI or ARB:
No DM:
Pr/Cr>
_100mg/mmol
In DM:
ACR M>
_2.5mg/mmol
ACR F>
_3.5mg/mmol
Monitor ACR
annually
Pr/Cr: urinary protein-creatinine ratio; ACR: urinary albumin-creatinine ratio; DM: diabetes mellitus; CKD: chronic kidney disease; M: male; F: female;
P: preferable; A: acceptable; ACEI: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blockers.
340
Nefrologia 2011;31(3):331-45
3. The detection and monitoring of protein and/or albumin
in urine must be based on a quantitative measurement.
4. When detecting, staging and monitoring CKD, the
presence of proteinuria must be assessed:
a. In adults proteinuria must be assessed by measuring
the albumin-creatinine ratio in a urine sample.
Albuminuria is a more sensitive marker than
proteinuria in CKD due to DM, hypertension or
glomerular disease, which are responsible for most of
CKD cases in adults.
If a laboratory decides to use the protein-creatinine
ratio as an initial quantitative test, they should also
measure the albumin-creatinine ratio if the result is
within the reference range.
b. In children without DM, proteinuria must be
assessed using the protein-creatinine ratio in a
urine sample.
There is a much lower prevalence of CKD due to DM
or hypertension in children than in adults; however,
there is a high prevalence of CKD due to urinary tract
defects or congenital tubular disorders that may cause
non-glomerular proteinuria.
c. In children with postpuberal onset of DM with more
than 5 years of duration, the albumin-creatinine ratio
must be measured in a urine sample. In other
circumstances, the same recommendation for children
without DM must be followed.
5. “Clinically significant proteinuria” should be considered:
a. In individuals without DM: protein excretion
>0.5g/day, protein-creatinine ratio in a urine sample
>50mg/mmol or albumin-creatinine ratio in a urine
sample >30mg/mmol.
b. In individuals with DM: albumin-creatinine ratio in a
urine sample >2.5mg/mmol or 17mg/g (men) and
>3.5mg/mmol or 25 mg/g (women).
This recommendation is based on the criteria established
by the NICE guidelines. These criteria are an indication
to start ACEI or ARB treatment.
6. It is possible to monitor individuals with CKD and
clinically significant proteinuria using the proteincreatinine ratio.
consensus document
9. First-morning urine is the most appropriate sample for
detecting and monitoring proteinuria and/or
albuminuria. It is the sample with the lowest biological
variability and has the best correlation with protein
and/or albumin excretion in 24-hour urine. The
presence of orthostatic proteinuria can also be excluded
with this sample. If this is not available, a random
sample is acceptable.
10. The most appropriate sample to assess proteinuria
and/or albuminuria is freshly voided urine. If the
samples are not processed on the same day as they are
taken, they should be stored for up to 7 days at
temperatures between 2 ºC and 8 ºC. If the samples
have to be frozen, this should be done at temperatures
≤-70ºC and they should be thawed at room temperature.
Any cloudiness should be removed by centrifugation.
Clinical laboratory reports
11. The urinary concentration of protein or albumin must
always be compared against the concentration of
creatinine to reduce the effect that hydration may have
on the results.
12. The results can be expressed in mg/g or mg/mmol
depending on the type of units used in each laboratory,
although the use of International System of Units is
recommended (mg/mmol).
13. The terms microalbuminuria and macroalbuminuria
should no longer be used and should be replaced by
albuminuria.
Members of the SEQC Commissions
Kidney function: J. Ballarín Castán*, P. Bermejo LópezMuñiz, J. Bover Sanjuán*, A. Cases Amenós*, M.J. Díez de
los Ríos Carrasco, S. Gràcia García, J.A. Jiménez García, C.
Macías Blanco, R. Martínez López, R. Montañés Bermúdez
(President), G. Ruiz Martín, L.J. Morales García, J. Ruiz
Altarejos, S. Sanz Hernández, S. Ventura Pedret.
*Associate members.
7. Given that the proportion of albumin in urine with
regard to the concentration of protein varies, the use of
conversion factors from creatinine-albumin ratio to proteincreatinine ratio and vice versa is not recommended.
Proteins: C. Bermudo Guitarte, M.C. Cárdenas Fernández,
M. Cortés Rius, M. Fernández García, M. García Montes*,
C. Martínez-Brú (President), D. Pérez Surribas, T. Rodríguez
González, C. Valdecabres Ortiz, J.A. Viedma Contreras, E.
Zapico Muñiz.
Sampling procedure
8. It is not necessary to collect a 24-hour urine sample to
detect and monitor proteinuria and/or albuminuria.
Nefrologia 2011;31(3):331-45
Members of the S.E.N. who collaborated in the revision
of the document: R. Alcázar Arroyo, J.L. Górriz Teruel, F.
Rivera Hernández.
341
consensus document
APPENDIX. Guidelines consulted while preparing this document
Guidelines
Abbreviated name
Name of guidelines
Author
Date of publication
Date of revision
Evaluation and Management of Proteinuria and
American Academy of
Pediatrics
June, 2000
14 November 2005
K/DOQI
KDOQI Clinical Practice Guidelines for Chronic
Kidney Disease: Evaluation, Classification, and
Stratification
National Kidney
Foundation
February, 2002
JNC-7
The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7)
National Heart, Lung, and
Blood Institute
PARADE (children)
Evidence-grading systems
Nephrotic Syndrome in Children:
Recommendations From a Pediatric Nephrology
Panel Established at the National Kidney
Foundation Conference
on Proteinuria, Albuminuria, Risk, Assessment,
Detection, and Elimination (PARADE)
CARI
Urine Protein as Diagnostic Test Guidelines
National Kidney Foundation1
December, 2003
October, 2004
Last JM, et al.2
25 April 2010
Criteria of Jaeschke, et al.3,4
KDIGO
Kidney Disease: Improving Global Outcomes
UK Guidelines
Joint Specialty Committee on Renal Medicine of
the Royal College of Physicians and the Renal
Association, and the Royal College of General
Practitioners. Chronic kidney disease in adults: UK
guidelines for identification, management and
referral
Royal College of
Physicians of London
March, 2006
UK Consensus
Conference
UK Consensus Conference on
Early Chronic Kidney Disease
Royal College of
Physicians of Edinburgh
(RCPE)
February, 2007
UK Renal Association
Guidelines
Clinical Practice Guidelines for the Care of Patients
with Chronic Kidney Disease
UK Renal Association
Clinical Practice Guidelines
March, 2007
Criteria of the National Service
Framework for Renal Services5
Designed to Tackle Renal Disease in Wales:
A National Service Framework
April, 2007
Welsh Renal NSF
The Welsh Assembly
Government
Criteria of the Health Care Evaluation
Unit of the Department of Public Health
Sciences at St George’s
Hospital Medical School6
SIGN
Diagnosis and Management of Chronic Kidney
Scottish Intercollegiate
June, 2008
SIGN7
Disease
Guidelines Network
Chronic Kidney Disease
Royal College of
Physicians
September, 2008
NICE8
NICE
February, 2005
Criteria of the National Service
Framework for Renal Services5
National clinical guideline for early identification
and management in adults in primary and
secondary care
Guidelines for the management of chronic kidney
Disease
Canadian Society of
Nephrology
November 2008
CSN
GRADE9
SEN-semFYC
Documento de Consenso SEN-semFYC sobre la
enfermedad renal crónica
SEN-semFYC
November, 2008
ADA
Standards of Medical Care in Diabetes 2010
American Diabetes
Association
January, 2010
Criteria of the Kidney Disease Improving
Global Outcomes (KDIGO) based on
GRADE modified for CKD10
Criteria of the American Diabetes
Association11
K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266.
Last JM, Abramson JH. A Dictionary of Epidemiology. 3rd ed. New York, NY: Oxford University Press; 1995.
3
Jaeschke R, Guyatt GH, Sackett DL. Users’ guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and
will they help me in caring for my patients? The Evidence-Based Medicine Working Group. JAMA 1994;271:703-7.
4
Jaeschke R, Guyatt G, Sackett DL. Users’ guides to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the study
valid? Evidence-Based Medicine Working Group. JAMA 1994;271:389-91.
5
Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and the Renal Association and tre Royal College of General Practitioners.
Chronic Kidney Disease in Adults: UK Guidelines for Identification, Management and Referral [Internet]. London: Royal College of Physicians, 2006.
Available at: http://www.renal.org/CKDguide/full/CKDprintedfullguide.pdf
6
Cluzeau F, Littlejohns P, Grimshaw J, Feder G. Appraisal instrument for clinical guidelines (version 1). London: St George’s Hospital Medical School, 1997.
7
Scottish Intercollegiate Guidelines Network. A guideline developer’s handbook [Internet]. Edinburgh: Scottish Intercollegiate Guidelines Network; 2008.
Available at: http://www.sign.ac.uk/guidelines/fulltext/50/index.html
8
National Institute for Clinical Excellence (Update 2008) Guideline Development Methods: Information for National Collaborating Centres and Guideline
Developers [Internet]. London: National Institute for Clinical Excellence. Available at: http://www.nice.org.uk/guidelinesmanual
9
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations.
BMJ 2004 ;328:1490.
10
Uhlig K, Macleod A, Craig J, Lau J, Levey AS, Levin A, et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A
position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;70:2058-65.
11
Standards of medical care in diabetes-2010. Diabetes Care 2010;33 Suppl 1:S11-S61.
1
2
342
Nefrologia 2011;31(3):331-45
consensus document
REFERENCES
1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van LF,
Levey AS. Prevalence of chronic kidney disease in the United States.
JAMA 2007;298:2038-47.
2. Singh NP, Ingle GK, Saini VK, Jami A, Beniwal P, Lal M, Meena GS.
Prevalence of low glomerular filtration rate, proteinuria and associated
risk factors in North India using Cockcroft-Gault and Modification of
Diet in Renal Disease equation: an observational, cross-sectional study.
BMC Nephrol 2009;10:4.
3. Iseki K. Chronic kidney disease in Japan. Intern Med 2008;47:681-9.
4. Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, et
al. Chronic kidney disease as a global public health problem:
approaches and initiatives-a position statement from Kidney Disease
Improving Global Outcomes. Kidney Int 2007;72:247-59.
5. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney
disease and the risks of death, cardiovascular events, and
hospitalization. N Engl J Med 2004;351:1296-305.
6. Otero A, De Francisco A, Gayoso P, Garcia F. Prevalence of chronic
renal disease in Spain: results of the EPIRCE study. Nefrologia
2010;30:78-86.
7. De Francisco AL, De la Cruz JJ, Cases A, de la FM, Egocheaga MI,
Gorriz JI, et al. Prevalence of kidney insufficiency in primary care
population in Spain: EROCAP study. Nefrologia 2007;27:300-12.
8. Sociedad Española de Nefrología. Registro de Enfermos Renales: Diálisis y
Trasplante [Internet], 2009; [Accessed 22-11-2010]. Available at:
http://www.senefro.org/modules.php?name=webstructure&idwebstruct
ure=128.
9. Areses TR, Sanahúja Ibáñez MJ, Navarro M. Epidemiology of chronic
kidney disease in Spanish pediatric population. REPIR II Project.
Nefrologia 2010;30: 508-17.
10. Baum M. Overview of chronic kidney disease in children. Curr Opin
Pediatr 2010;22:158-60.
11. K/DOQI clinical practice guidelines for chronic kidney disease:
evaluation, classification, and stratification. Am J Kidney Dis
2002;39:S1-266.
12. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G. Urinary protein
excretion rate is the best independent predictor of ESRF in non-diabetic
proteinuric chronic nephropathies. Gruppo Italiano di Studi
Epidemiologici in Nefrologia (GISEN). Kidney Int 1998;53:1209-16.
13. Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of
developing end-stage renal disease. Kidney Int 2003;63:1468-74.
14. Shani A, Grandits GA, Grimm RH, Svendsen KH, Collins AJ,
Prineas RJ, et al. Association of single measurements of dipstick
proteinuria, estimated glomerular filtration rate, and hematocrit
with 25-year incidence of end-stage renal disease in the
multiple risk factor intervention trial. J Am Soc Nephrol
2006;17:1444-52.
15. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, De Jong
PE, et al. Progression of chronic kidney disease: the role of blood
pressure control, proteinuria, and angiotensin-converting
enzyme inhibition: a patient-level meta-analysis. Ann Intern Med
2003;139:244-52.
16. Taal MW, Brenner BM. Renal risk scores: progress and prospects.
Kidney Int 2008;73:1216-9.
Nefrologia 2011;31(3):331-45
17. Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR.
Combining GFR and albuminuria to classify CKD improves prediction
of ESRD. J Am Soc Nephrol 2009;20:1069-77.
18. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn
RR, et al. Relation between kidney function, proteinuria, and
adverse outcomes. JAMA 2010;303:423-9.
19. Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment,
detection, elimination (PARADE): a position paper of the National
Kidney Foundation. Am J Kidney Dis 1999;33:1004-10.
20. Brantsma AH, Bakker SJ, De ZD, De Jong PE, Gansevoort RT.
Extended prognostic value of urinary albumin excretion for
cardiovascular events. J Am Soc Nephrol 2008;19:1785-91.
21. Bover J, Fernández-Llama P, Montanes R, Calero F. Albuminuria:
beyond the kidney. Med Clin (Barc) 2008;130:20-3.
22. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni
C, et al. Proteinuria as a modifiable risk factor for the progression
of non-diabetic renal disease. Kidney Int 2001;60:1131-40.
23. Ruggenenti P, Perna A, Remuzzi G. Retarding progression of chronic
renal disease: the neglected issue of residual proteinuria. Kidney Int
2003;63:2254-61.
24. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et
al. Renoprotective properties of ACE-inhibition in non-diabetic
nephropathies with non-nephrotic proteinuria. Lancet 1999;354:359-64.
25. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of
angiotensin-converting-enzyme inhibition on diabetic nephropathy.
The Collaborative Study Group. N Engl J Med 1993;329:1456-62.
26. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al.
Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N
Engl J Med 2001;345:851-60.
27. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, et al.
Efficacy and safety of benazepril for advanced chronic renal
insufficiency. N Engl J Med 2006;354:131-40.
28. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T.
Combination treatment of angiotensin-II receptor blocker and
angiotensin-converting-enzyme inhibitor in non-diabetic renal disease
(COOPERATE): a randomised controlled trial. Lancet 2003;361:117-24.
29. Kent DM, Jafar TH, Hayward RA, Tighiouart H, Landa M, De JP, et
al. Progression risk, urinary protein excretion, and treatment effects
of angiotensin-converting enzyme inhibitors in nondiabetic kidney
disease. J Am Soc Nephrol 2007;18:1959-65.
30. Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, et al.
Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a
randomized controlled study of benazepril and losartan in chronic
renal insufficiency. J Am Soc Nephrol 2007;18:1889-98.
31. Gracia S, Montañés R, Bover J, Cases A, Deulofeu R, Martín de
Francisco AL, et al. Recomendaciones sobre la utilización de
ecuaciones para la estimación del filtrado glomerular en adultos.
Nefrologia 2006;26:658-65.
32. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et
al. Definition and classification of chronic kidney disease: a position
statement from Kidney Disease: Improving Global Outcomes
(KDIGO). Kidney Int 2005;67:2089-100.
343
consensus document
33. Eckardt KU, Berns JS, Rocco MV, Kasiske BL. Definition and
classification of CKD: the debate should be about patient
prognosis—a position statement from KDOQI and KDIGO. Am J
Kidney Dis 2009;53:915-20.
34. National Institute for Health and Clinical Excellence. Chronic Kidney
Disease: National Clinical Guideline for Early Identification and
Management in Adults in Primary and Secundary Care.Clinical
Guideline 73 [Internet], 2008; [Accessed 15-6-2010]. Available at:
http://www.nice.org.uk/Guidance/cg73.
35. Scottish Intercollegiate Guidelines Network. Diagnosis and
Management of Chronic Kidney Disease: Guideline 103
[Internet], 2008; [Accessed 15-6-2010]. Available at:
http://www.sign.ac.uk/guidelines/fulltext/103/index.html.
36. Taal M, Tomson C. Clinical Practice Guidelines for the Care of Patiens with
Chronic Kidney Disease. UK Renal Association Clinical Practice Guidelines
[Internet],
2007;
[Accessed
15-6-2010].
Available
at:
http://www.renal.org/pages/media/download_gallery/CKDfinalMar07.pdf.
37. Crowe E, Halpin D, Stevens P. Early identification and management
of chronic kidney disease: summary of NICE guidance. BMJ
2008;337:a1530.
38. Bauer C, Melamed ML, Hostetter TH. Staging of chronic kidney
disease: time for a course correction. J Am Soc Nephrol 2008;19:8446.
39. Glassock RJ, Winearls C. The global burden of chronic kidney
disease: how valid are the estimates? Nephron Clin Pract
2008;110:c39-c46.
40. De Jong PE, Gansevoort RT. Fact or fiction of the epidemic of
chronic kidney disease-let us not squabble about estimated GFR
only, but also focus on albuminuria. Nephrol Dial Transplant
2008;23:1092-5.
41. Glassock RJ, Winearls C. Screening for CKD with eGFR: doubts and
dangers. Clin J Am Soc Nephrol 2008;3:1563-8.
42. Glassock RJ, Winearls C. An epidemic of chronic kidney disease:
fact or fiction? Nephrol Dial Transplant 2008;23:1117-21.
43. Hoyer JR, Seiler MW. Pathophysiology of Tamm-Horsfall protein.
Kidney Int 1979;16:279-89.
44. Joint Specialty Committee on Renal Medicine of the Royal College of
Physicians and the Renal Association, and the Royal College of General
Practitioners. Chronic Kidney Disease in Adults: UK Guidelines for
Identification, Management and Referral. London: Royal College of
Physicians [Internet], 2006; [Accessed 15-6-2010]. Available at:
http://www.renal.org/CKDguide/full/CKDprintedfullguide.pdf.
45. Caring for Australasians with Renal Impairment (CARI). Chronic
Kidney Disease Guidelines: Urine Protein as Diagnostic Test
http://www.cari.org.au/ckd_urineprot_list_pub2004.php.
46. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in
insulin-dependent patients. N Engl J Med 1984;311:89-93.
47. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive
antihypertensive treatment reduces rate of decline in kidney
function in diabetic nephropathy. Lancet 1983;1:1175-9.
48. Halimi JM, Hadjadj S, Aboyans V, Allaert FA, Artigou JY, Beaufils M,
et al. Microalbuminuria and urinary albumin excretion: French
guidelines. Ann Biol Clin (Paris) 2008;66:277-84.
49. Miller WG, Bruns DE, Hortin GL, Sandberg S, Aakre KM, McQueen
MJ, et al. Current issues in measurement and reporting of urinary
344
albumin excretion. Clin Chem 2009;55:24-38.
50. Atkins RC, Briganti EM, Zimmet PZ, Chadban SJ. Association
between albuminuria and proteinuria in the general population: the
AusDiab Study. Nephrol Dial Transplant 2003;18:2170-4.
51. Newman DJ, Thakkar H, Medcalf EA, Gray MR, Price CP. Use of
urine albumin measurement as a replacement for total protein. Clin
Nephrol 1995;43:104-9.
52. Kashif W, Siddiqi N, Dincer AP, Dincer HE, Hirsch S. Proteinuria: how
to evaluate an important finding. Cleve Clin J Med 2003;70:53546.
53. Brandt JR, Jacobs A, Raissy HH, Kelly FM, Staples AO, Kaufman E,
et al. Orthostatic proteinuria and the spectrum of diurnal variability
of urinary protein excretion in healthy children. Pediatr Nephrol
2010;25:1131-7.
54. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J.
Evaluation and management of proteinuria and nephrotic syndrome
in children: recommendations from a pediatric nephrology panel
established at the National Kidney Foundation conference on
proteinuria, albuminuria, risk, assessment, detection, and elimination
(PARADE). Pediatrics 2000;105:1242-9.
55. Heathcote KL, Wilson MP, Quest DW, Wilson TW. Prevalence and
duration of exercise induced albuminuria in healthy people. Clin
Invest Med 2009;32:E261-E265.
56. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single
voided urine samples to estimate quantitative proteinuria. N Engl J
Med 1983;309:1543-6.
57. Christopher-Stine L, Petri M, Astor BC, Fine D. Urine protein-tocreatinine ratio is a reliable measure of proteinuria in lupus nephritis.
J Rheumatol 2004;31:1557-9.
58. Xin G, Wang M, Jiao LL, Xu GB, Wang HY. Protein-to-creatinine
ratio in spot urine samples as a predictor of quantitation of
proteinuria. Clin Chim Acta 2004;350:35-9.
59. Price CP, Newall RG, Boyd JC. Use of protein:creatinine ratio
measurements on random urine samples for prediction of significant
proteinuria: a systematic review. Clin Chem 2005;51:1577-6.
60. Gaspari F, Perico N, Remuzzi G. Timed urine collections are not
needed to measure urine protein excretion in clinical practice. Am J
Kidney Dis 2006;47:1-7.
61. Morales JV, Weber R, Wagner MB, Barros EJ. Is morning urinary
protein/creatinine ratio a reliable estimator of 24-hour proteinuria
in patients with glomerulonephritis and different levels of renal
function? J Nephrol 2004;17:666-72.
62. Kristal B, Shasha SM, Labin L, Cohen A. Estimation of quantitative
proteinuria by using the protein-creatinine ratio in random urine
samples. Am J Nephrol 1988;8:198-203.
63. Rodby RA, Rohde RD, Sharon Z, Pohl MA, Bain RP, Lewis EJ. The
urine protein to creatinine ratio as a predictor of 24-hour urine
protein excretion in type 1 diabetic patients with nephropathy. The
Collaborative Study Group. Am J Kidney Dis 1995;26:904-9.
64. Chitalia VC, Kothari J, Wells EJ, Livesey JH, Robson RA, Searle M, et
al. Cost-benefit analysis and prediction of 24-hour proteinuria from
the spot urine protein-creatinine ratio. Clin Nephrol 2001;55:436-47.
65. Lane C, Brown M, Dunsmuir W, Kelly J, Mangos G. Can spot urine
protein/creatinine ratio replace 24 h urine protein in usual clinical
nephrology? Nephrology (Carlton) 2006;11:245-9.
66. Chaiken RL, Khawaja R, Bard M, Eckert-Norton M, Banerji MA,
Nefrologia 2011;31(3):331-45
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
Lebovitz HE. Utility of untimed urinary albumin measurements in
assessing albuminuria in black NIDDM subjects. Diabetes Care
1997;20:709-13.
Marshall SM. Screening for microalbuminuria: which measurement?
Diabet Med 1991;8:706-11.
Lamb E, Newman D, Price C. Kidney function test. En: Burtis C,
Ashwood E, Bruns D (eds.). Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. Saint Louis: Saunders Elsevier, 2006.
Brinkman JW, De ZD, Duker JJ, Gansevoort RT, Kema IP, Hillege HL,
et al. Falsely low urinary albumin concentrations after prolonged
frozen storage of urine samples. Clin Chem 2005;51:2181-3.
Brinkman JW, Heerspink HL, De ZD, Gansevoort RT, Bakker SJ.
Urinary pH affects albumin concentrations after prolonged frozen
storage. Nephrol Dial Transplant 2007;22:3670.
Brinkman JW, De ZD, Gansevoort RT, Duker JJ, Kema IP, De Jong PE,
et al. Prolonged frozen storage of urine reduces the value of
albuminuria for mortality prediction. Clin Chem 2007;53:153-4.
Brinkman JW, De ZD, Lambers Heerspink HJ, Gansevoort RT, Kema
IP, De Jong PE, et al. Apparent loss of urinary albumin during longterm frozen storage: HPLC vs immunonephelometry. Clin Chem
2007;53:1520-6.
Rumley A. Urine dipstick testing: comparison of results obtained by
visual reading and with the Bayer CLINITEK 50. Ann Clin Biochem
2000;37(Pt 2):220-1.
Scotti A, Falkenberg M. Analytical interferences of drugs in the
chemical examination of urinary protein. Clin Biochem
2007;40:1074-6.
Ralston SH, Caine N, Richards I, O’Reilly D, Sturrock RD, Capell HA.
Screening for proteinuria in a rheumatology clinic: comparison of
dipstick testing, 24 hour urine quantitative protein, and
protein/creatinine ratio in random urine samples. Ann Rheum Dis
1988;47:759-63.
Waugh JJ, Clark TJ, Divakaran TG, Khan KS, Kilby MD. Accuracy of
urinalysis dipstick techniques in predicting significant proteinuria in
pregnancy. Obstet Gynecol 2004;103:769-77.
James GP, Bee DE, Fuller JB. Proteinuria: accuracy and precision of
laboratory diagnosis by dip-stick analysis. Clin Chem 1978;24:1934-9.
Welsh Assembly Government. Designed to Tackle Renal Disease in Wales:A
National Service Framework [Internet], 2007; [Accessed 15-6-2010].
Available at: http://www.wales.nhs.uk/sites3/Documents/434/Designed to
Tackle Renal Disease in Wales - Eng.pdf.
Guy M, Newall R, Borzomato J, Kalra PA, Price C. Use of a first-line
urine protein-to-creatinine ratio strip test on random urines to rule
out proteinuria in patients with chronic kidney disease. Nephrol Dial
Transplant 2009;24:1189-93.
consensus document
80. Graziani MS, Gambaro G, Mantovani L, Sorio A, Yabarek T,
Abaterusso C, et al. Diagnostic accuracy of a reagent strip for
assessing urinary albumin excretion in the general population.
Nephrol Dial Transplant 2009;24:1490-4.
81. Guy M, Newall R, Borzomato J, Kalra PA, Price C. Diagnostic
accuracy of the urinary albumin: creatinine ratio determined by the
CLINITEK Microalbumin and DCA 2000 for the rule-out of
albuminuria in chronic kidney disease. Clin Chim Acta 2009;399:548.
82. Sedmak JJ, Grossberg SE. A rapid, sensitive, and versatile assay for
protein using Coomassie brilliant blue G250. Anal Biochem
1977;79:544-52.
83. McElderry LA, Tarbit IF, Cassells-Smith AJ. Six methods for urinary
protein compared. Clin Chem 1982;28:356-60.
84. Nishi HH, Elin RJ. Three turbidimetric methods for determining total
protein compared. Clin Chem 1985;31:1377-80.
85. Sociedad Española de Bioquímica Clínica y Patología Molecular. XIX
Programa de Garantía Externa de la Calidad de Bioquímica (orina)
http://www.contcal.org/k3/docs/2009/ANUAL/orina.pdf.
86. Aakre KM, Thue G, Subramaniam-Haavik S, Bukve T, Morris H,
Muller M, et al. Postanalytical external quality assessment of urine
albumin in primary health care: an international survey. Clin Chem
2008;54:1630-6.
87. Osicka TM, Comper WD. Characterization of immunochemically
nonreactive urinary albumin. Clin Chem 2004;50:2286-91.
88. Itho Y, Hosogaya S KKHS. Standardization of immunoassays for
urine albumin. Jpn J Clin Chem 2008;5-14.
89. Singh R, Crow FW, Babic N, Lutz WH, Lieske JC, Larson TS,
et al. A liquid chromatography-mass spectrometry method
for the quantification of urinary albumin using a novel 15Nisotopically labeled albumin internal standard. Clin Chem
2007;53:540-2.
90. Standards of medical care in diabetes-2010. Diabetes Care
2010;33(Suppl 1):S11-S61.
91. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL, Jr., et al. Seventh report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. Hypertension 2003;42:1206-52.
92. Levin A, Hemmelgarn B, Culleton B, Tobe S, McFarlane P, Ruzicka
M, et al. Guidelines for the management of chronic kidney disease.
CMAJ 2008;179:1154-62.
93. Alcázar R, Egocheaga MI, Orte L, Lobos JM, González PE, Álvarez
GF, et al. Documento de consenso SEN-semFYC sobre la
Enfermedad Renal Crónica. Nefrologia 2008;28:273-82.
Sent for review: 18 Jan. 2011 | Accepted: 26 Jan. 2011
Nefrologia 2011;31(3):331-45
345
a history of
Nephrology
Fuller Albright and our current understanding
of calcium and phosphorus regulation
and primary hyperparathyroidism
A.J. Felsenfeld, B.S. Levine, C. R. Kleeman
Department of Medicine. VA Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA.
Los Angeles, CA (USA)
Nefrologia 2011;31(3):346-57
doi:10.3265/Nefrologia.pre2011.Mar.10774
ABSTRACT
The major contributions of Fuller Albright to our
understanding of calcium and phosphorus regulation and
primary hyperparathyroidism are highlighted. Albright
was the first investigator to initiate a systematic study of
mineral metabolism. With resources limited to the
measurement of serum calcium and phosphorus and the
infusion of parathyroid extract, Albright used balance
studies to establish a framework for our understanding of
calcium and phosphorus regulation and primary
hyperparathyroidism. Albright was the first to show that
the etiology of primary hyperparathyroidism could be
from either an adenoma or hyperplasia of the parathyroid
glands and stone disease was a separate manifestation of
primary hyperparathyroidism. Albright also showed that:
1) a renal threshold for calcium excretion was present in
hypoparathyroid patients; 2) correction of hypocalcemia in
hypoparathyroid patients with vitamin D had a phosphaturic
action; 3) renal failure reduced the intestinal absorption of
calcium in primary hyperparathyroidism; 4) the “hungry
bone” syndrome developed after parathyroidectomy in
severe primary hyperparathyroidism; and 5) a target organ
can fail to respond to a hormone. He also suggested that a
malignant tumor could be responsible for ectopic hormone
production. Finally, our review integrates the observations of
Albright with our current knowledge of calcium regulation
and disorders.
Fuller Albright y nuestro conocimiento actual
sobre la regulación del calcio y del fósforo
y el hiperparatiroidismo primario
RESUMEN
Se destacan las principales contribuciones de Fuller Albright
sobre el conocimiento de la regulación del calcio y del fósforo
en el hiperparatiroidismo primario. Albright fue el primer investigador que inició un estudio sistemático sobre el metabolismo de los minerales. Con unos recursos que se limitaban a
la medición de la concentración de calcio y fósforo en suero y
la infusión de extracto paratiroideo, Albright, a través de estudios del equilibrio, estableció unas bases para entender la
regulación del calcio y del fósforo y el hiperparatiroidismo primario. Albright fue el primero en afirmar que un adenoma o
una hiperplasia de las glándulas paratiroideas podrían ser las
causantes del hiperparatiroidismo primario. Además indicó
que la litiasis sería una manifestación independiente del hiperparatiroidismo primario. Albright observó también que:
1) los pacientes con hipoparatiroidismo primario presentaban
un valor umbral para la eliminación renal del calcio; 2) en pacientes con hipoparatiroidismo la rectificación de la hipocalcemia con vitamina D tenía un efecto fosfatúrico; 3) en el hiperparatiroidismo primario, la insuficiencia renal reducía la
absorción intestinal del calcio; 4) en el hiperparatiroidismo primario grave, tras una paratiroidectomía se observaba el síndrome del «hueso hambriento» y 5) es posible que un órgano
diana deje de responder a una hormona. Albright también defendió la posibilidad de que un tumor maligno provocara la
producción ectópica de hormona. Por último, nuestra revisión
integra las observaciones de Albright con los conocimientos
actuales sobre la regulación y los trastornos del calcio.
Keywords: Calcium. Hyperparathyroidism. Hypoparathyroidism.
Parathyroid hormone. Phosphorus.
Palabras clave: Calcio. Hiperparatiroidismo. Hipoparatiroidismo.
Hormona paratiroidea. Fósforo.
Correspondence: A.J. Felsenfeld
Department of Medicine. VA Greater Los Angeles Healthcare System
and the David Geffen School of Medicine at UCLA.
Nephrology Section (111L). West Los Angeles VA Medical Center,
11301 Wilshire Boulevard, 900073, Los Angeles, CA, USA.
[email protected]
INTRODUCTION
346
Fuller Albright’s academic career began in the late 1920s and
ended in 1956 after brain surgery for Parkinson’s disease
resulted in a non-functional state until his death in 1969.
A.J. Felsenfeld et al. Fuller Albright and Ca regulation and disorders
Although increasingly disabled by Parkinson’s disease from the
mid 1930s, Albright continued to make important contributions
to our knowledge of calcium and phosphorus disorders.1 His
book, “Parathyroid Glands and Metabolic Bone Disease”,
published in 1948, is a testimony to his many important
observations.2 Our goal is to highlight some of the many
contributions made by Albright on calcium and phosphorus
regulation and primary hyperparathyroidism and to integrate the
findings of Albright with more recent studies. Albright’s
contributions to our understanding of renal phosphate transport
have been discussed elsewhere.3 Virtually all that Albright
observed remains valid today, but as often happens, the
explanations and their complexity continue to evolve.
Our retrospective highlights Albright’s enduring legacy to
the modern study of calcium and phosphorus regulation
and primary hyperparathyroidism. The following topics
are discussed: 1) the resources available to Albright to
study calcium and phosphorus regulation and primary
hyperparathyroidism; 2) Albright’s studies of calcium
balance; 3) phosphaturia resulting from the correction of
hypocalcemia in hypoparathyroid patients; 4) primary
hyperparathyroidism as a surgically curable disorder; and
5) several clinical vignettes which include: a) a prelude to
the trade-off hypothesis of Slatopolsky and Bricker
advanced by Albright to explain the development of
secondary hyperparathyroidism in renal failure; b) the
suggestion that a malignant tumor could be responsible
for ectopic hormone production; c) the realization that
vitamin D deficiency can be associated with the failure to
respond to parathyroid hormone (PTH); and d) the
appreciation that immobilization can be a cause of
hypercalcemia.
TOOLS OF THE TRADE
In the late 1920s when Albright first started his studies of
calcium and phosphorus regulation and primary
hyperparathyroidism, his primary tools were: 1) parathyroid
extract (PTE), which was a bovine preparation from Eli Lilly
and Company; 2) the personnel on the newly organized Ward
4 at Massachusetts General Hospital who were trained to
perform balance studies in which dietary calcium and
phosphorus could be prepared with accuracy and the fecal
and urine excretion of calcium and phosphorus collected
with precision;4 and 3) the measurement of calcium and
phosphorus in the blood, urine and feces. As a result of
balance studies it became possible to determine how
variations in dietary calcium and phosphate content and the
administration of PTE affected: 1) serum calcium and
phosphorus concentration; 2) fecal and urinary excretion of
calcium and phosphorus; and 3) retention or loss of calcium
and phosphorus from the body (figure 1). Because PTH
could not be measured, Albright could not know whether
PTH values were modified by serum calcium.
Nefrologia 2011;31(3):346-57
a history of Nephrology
EFFECT OF PARATHYROID EXTRACT AND DIETARY
CALCIUM AND PHOSPHATE ON CALCIUM BALANCE
IN NORMAL SUBJECTS AND IN PATIENTS
WITH HYPOPARATHYROIDISM
AND HYPERPARATHYROIDISM
In an early study, Albright infused PTE into a patient with
longstanding idiopathic hypoparathyroidism (figure 2).5
Albright observed that: 1) urine phosphorus excretion
immediately increased and peaked within two hours; 2) the
increase in serum calcium and decrease in serum phosphorus
followed the increase in phosphorus excretion; and 3) there
was a critical serum calcium value at about 8.5 mg/dl at
which a negligible urinary calcium excretion suddenly
became appreciable. Albright concluded that the action of
PTE was rapid, its first effect was phosphaturia, and the
increase in serum calcium followed the increase in
phosphorus excretion. Thus, Albright developed the
hypothesis that PTH primarily modified phosphorus rather
than calcium, a view that he still championed when his book
was published almost 20 years later.2 Albright argued that the
PTH-induced increase in phosphorus excretion and the
resulting decrease in serum phosphorus promoted bone
dissolution releasing calcium. While such a conclusion
might sound somewhat fanciful today, it should be
remembered that Albright had participated in studies in
which ammonium chloride-induced acidosis increased the
serum calcium concentration and urinary calcium excretion
without increasing intestinal calcium absorption suggesting
that acidosis induced bone dissolution.6,7 Today it is
recognized that phosphate depletion increases calcium
release from bone resulting in hypercalciuria and even
hypercalcemia despite a marked reduction in PTH values
suggesting that bone dissolution is an important feature.8,9
Finally, Albright was correct in his hypothesis that phosphate
was a major modifier of the calcemic response of bone to
PTH. Many subsequent studies have shown that phosphate
loading and restriction change the calcemic response to
PTH.10-12
As already mentioned, Albright had observed during a PTEinduced increase in serum calcium in a hypoparathyroid
patient that the serum calcium threshold at which urinary
calcium excretion increased from negligible values was
approximately 8.5 mg/dl. However, that threshold value did
not account for the now known effect of PTH on urinary
calcium excretion. In 1961, one of the authors (CRK) first
showed that PTE administration directly increased renal
calcium reabsorption.13 Subsequently, it was shown that the
threshold serum calcium value for excreting calcium during a
calcium infusion was seen at serum calcium values between 7
and 8 mg/dl in hypoparathyroid patients.14 In 1984, Ogata and
associates showed that besides PTH, the active form of
vitamin D, calcitriol, directly increased the threshold for
renal calcium excretion and also enhanced the
responsiveness of the tubule to PTH.15 More recently,
347
10
8
6
4
Serum Ca.: Mq.%
Serum P.: Mq.%
Serum P.
12
8
Serum Ca.
4
0
700
140
600
120
500
100
400
300
200
Calcium in urine
Phosphorus in urine
800
80
P. intake
60
40
100
20
0
0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 454749 51 53 55 57 59 61 63 6567 69 71 73 75 77 79 81
* 50 Units Parathormone
Periods
The foundation of Albright’s studies of calcium and phosphorus was the balance study. Most of the time, the results were reported in long,
detailed tables, but in this early study from 1929 of a patient with hypoparathyroidism, a figure is provided to show how parathormone
(parathyroid extract) administration and changes in dietary phosphate affect the serum calcium and phosphorus concentration and urine calcium
and phosphorus excretion. Each day was divided into three-eight hour periods. The patient was given the same meal three times a day at the
beginning of each period. Fifty units of parathormone were administered at the beginnings of periods 16, 19, 22 and 25 as indicated by
asterisks. The diet was altered at period 43 and several times thereafter.5
Figure 1. Graphic representation of balance data.
Bindels and colleagues have shown that the stimulatory
effect of both calcitriol and PTH on renal calcium
reabsorption results from the activation of an epithelial
calcium channel (TRPV5) in the distal convoluted tubule.16
VITAMIN D TREATMENT AND CALCIUM INFUSION
AS PHOSPHATURIC AGENTS
In 1938 and in 1942, Albright used the newly available analog of
vitamin D, dihydrotachysterol, for the treatment of hypocalcemia
in patients with hypoparathyroidism17 and also in the newly
described disorder of pseudohypoparathyroidism in which there
was a failure to respond to administered PTE.18 Albright
observed that the correction of hypocalcemia increased urine
phosphate excretion. This observation had been made earlier by
associates of Albright19 and by Howland and Kramer.20 In 1965,
Eisenberg demonstrated in hypoparathyroid patients that the
phosphaturia was independent of vitamin D by showing that a
prolonged intravenous infusion of calcium sufficient to
348
normalize the serum calcium concentration at 48 hours was
phosphaturic and also lowered the serum phosphorus
concentration (figure 3A and B).21 Evidence has accumulated
during the past several years that the recently discovered bonederived phosphaturic hormone, fibroblast growth factor 23
(FGF23) might be involved. High dietary calcium has been
shown to stimulate FGF2322 and the correlation between the
serum calcium concentration and FGF23 seen in primary
hyperparathyroidism23-25 even remained significant after
parathyroidectomy.24 However, a study has yet to be performed
identifying the specific mechanism for the observation made
more than 70 years ago by Albright and others.
PRIMARY HYPERPARATHYROIDISM, INTESTINAL
CALCIUM ABSORPTION, AND RENAL FAILURE
In patients with primary hyperparathyroidism, Albright
showed that changes in dietary calcium and phosphate
affected calcium balance. The first patient studied was
Nefrologia 2011;31(3):346-57
10
Ca. Mq. %
P. mq. %
9
Albright concluded that in primary hyperparathyroidism: 1)
adaptation to a low calcium diet did not occur because high
urine calcium losses persisted; 2) intestinal calcium
absorption was increased; and 3) high PTH values were the
likely cause of the negative calcium balance.
Serum P.
9
8
Serum Ca.
7
40
60
30
40
20
0
Calcium in urine
Phosphorus in urine
*
80
20
10
0
7 8 9 10 11 12 1
* 75 Units Parathormone
2 3 4 5 6 7
Time
Hourly urinary calcium and phosphorus excretion are negligible
until parathyroid extract is given after which urinary phosphorus
excretion rapidly increases, serum phosphorus decreases and then
serum calcium slowly increases. Despite an increase in serum
calcium to almost 9 mg/dl, urine calcium excretion remains
negligible.5
Figure 2. Effect of parathyroid extract on urinary calcium
and phosphorus excretion in a patient with idiopathic
hypoparathyroidism.
Captain Martell,26 who was to have seven parathyroid
operations before an ectopic parathyroid gland was removed
from the anterior mediastinum.27 From the balance studies in
Captain Martell, who had serum calcium values between 13.1
and 15.3 mg/dl, Albright made the following observations: 1)
the patient’s negative calcium balance on a low calcium diet
(0.1 grams/day) was greater than in normal controls (–0.46 vs
–1.29 grams per 3 day study period); 2) the increased
negative calcium balance in the hyperparathyroid patient was
due to increased urinary calcium excretion because fecal
calcium excretion was less than in normals; 3) an infusion of
PTE in normal volunteers sufficient to increase serum
calcium to between 11.5 and 12.8 mg/dl resulted in a
negative calcium balance duplicating the results of the
hyperparathyroid patient; and 4) a calcium diet of 1.07
grams/day in the hyperparathyroid patient resulted in a
positive calcium balance (0.36 grams per day) because
urinary calcium excretion increased by only 0.06 grams/day
from that on a low calcium diet (0.1 grams/day). Thus,
Nefrologia 2011;31(3):346-57
Albright also evaluated the effect of dietary phosphate on
calcium balance in hyperparathyroidism. He showed that a
high phosphate diet improved calcium balance in
hyperparathyroid patients on both low (0.07 g/day) and
normal (0.9 g/day) intakes of dietary calcium.28 When high
dietary phosphate was given to patients with primary
hyperparathyroidism, there was: 1) almost complete
intestinal absorption of phosphate; 2) rapid excretion of the
absorbed phosphate by the kidneys; 3) a rise in the
previously low serum phosphorus; 4) a fall in the previously
elevated serum calcium; 5) a rise in the serum calciumphosphorus product; and 6) a fall in urinary calcium
excretion. While a high phosphate diet seemed to have
certain beneficial effects such as lowering the serum
calcium concentration and decreasing urinary calcium
excretion, Albright recognized that there were two potential
dangers associated with increased phosphate ingestion in
patients with primary hyperparathyroidism: 1) parathyroid
poisoning with soft tissue calcium deposition including the
kidney and lungs; and 2) calcium-phosphate kidney stones.
Today, the recognition that hyperphosphatemia in CKD
patients and perhaps even high normal serum phosphorus
values in the general population are associated with
increased vascular disease and mortality probably from
increased vascular calcification29,30 could be considered an
extension of the pioneering studies of Albright.
By 1934, Albright came to understand that renal failure had a
specific effect on calcium and phosphorus regulation.31 When
a 13 year old girl with moderate renal failure was referred
for hypercalcemia (13.6 mg/dl), bone demineralization, a
markedly elevated serum alkaline phosphatase, and a serum
phosphorus of 4.3 mg/dl, balance studies were performed
before the parathyroid surgery during which an adenoma
was removed. The balance studies showed that on a low
calcium diet (0.1 g/day), urine calcium excretion despite
hypercalcemia was only marginally greater than in controls
on a similar diet (94 mg vs 63 mg/day). This value was much
less than in non-azotemic patients with primary
hyperparathyroidism and hypercalcemia (435 mg/day). Also,
fecal calcium excretion was greater than in controls and
much greater than in hyperparathyroid patients without renal
failure. Because of the results in this young girl with renal
failure, Albright reviewed the results of the series of balance
studies which had been performed on Captain Martell before
and after he developed renal failure. As shown in table 1, for
a similar magnitude of hypercalcemia (14 mg/dl vs 14.4
mg/dl), for the same low calcium diet after the onset of renal
failure, intestinal calcium absorption was less (0.06 vs 0.26
g/day) as was urine calcium excretion (0.09 vs 0.44 g/day).
349
Tmp/ GFR (mg/100 ml GF)
8
calcitriol, which in turn enhances intestinal absorption of
calcium. With loss of renal function, calcitriol production is
decreased despite high PTH values, a result which may in
part be due to increased FGF23 values. Consequently, both
intestinal calcium absorption and renal calcium excretion are
reduced in renal failure. The latter results from both a
decrease in the glomerular filtration of calcium and
increased tubular calcium reabsorption from high PTH
values.
A
6
4
2
PRIMARY HYPERPARATHYROIDISM
In several patients in his original series of 17 patients
published in 1934,32 Albright made the diagnosis of
hyperparathyroidism only because he had the insight to
measure serum calcium and phosphorus values in all patients
who presented with kidney stones. In the first 14 patients to
undergo parathyroid surgery, parathyroid adenomas were
found. Two of these patients had ectopic parathyroid
adenomas located in the anterior mediastinum. Cases 15 to
17 had hyperplasia of all the parathyroid glands. Because
hyperplasia had not been previously recognized as an entity,
case 15 required three parathyroid operations to remove a
sufficient amount of the hyperplastic glands before the
hypercalcemia resolved. Between the second and third
operations, estrogen treatment and irradiation of the
pituitary and parathyroid glands were tried without
success.33
0
Hypoparatiroid
+Ca infusion
B
Tmp/ GFR (mg/100 ml GF)
8
6
4
2
0
4
6
8
Plasma
10
12
14
Calcium (mg/100ml)
The results shown from Robertson70 were recalculated from the
data in the study by Eisenberg.21 A. The effect of a prolonged
calcium infusion on the maximal tubular reabsorption of
phosphate factored for the glomerular filtration rate (Tmp/GFR)
in hypoparathyroid subjects is shown. The Tmp/GFR is the
classic test for evaluating the appropriateness of urinary
phosphate excretion. The dotted lines define the normal range.
B. The relationship between the Tmp/GFR and the level of
plasma calcium in hypoparathyroid subjects is shown before
treatment (open circle) and after a prolonged calcium infusion
(closed circle) or vitamin D therapy (closed triangle). The dotted
area encloses the normal range.
Figure 3. Effect of a 48 hour calcium infusion
with normalization of the serum calcium concentration
on phosphate excretion in hypoparathyroid patients.
Thus, Albright was the first to recognize that the
development of renal failure in primary hyperparathyroidism
dramatically decreased both intestinal absorption and the
renal excretion of calcium. Today, it is known that PTH
stimulates renal production of the active form of vitamin D,
350
In this series of 17 patients, the dimensions, but not the
weights of the removed parathyroid glands were provided.32
The mean amount of parathyroid tissue removed per patient
was approximately 83 times greater than the combined size
of four normal human parathyroid glands, which
subsequently were shown to have a combined weight of
approximately 140 mg.34 Based on these results, the average
estimated weight of removed parathyroid tissue for each
patient was approximately 11 grams. In severe cases of
primary hyperparathyroidism with marked hypercalcemia,
cachexia and debilitating fractures were sometimes seen and
parathyroidectomy was life saving (figure 4). The different
magnitude of primary hyperparathyroidism in patients
presenting in the 1930s and today is shown by the very high
preoperative serum calcium values in Albright’s patients
(figure 5). Finally, Albright was the first to describe the
“hungry bone syndrome” in which severe hypocalcemia
developed values shortly after parathyroidectomy (figure 6).
He also showed that the decrease in serum calcium
correlated with the pre-operative serum alkaline
phosphatase value. When the serum calcium decreased to
less than 7 mg/dl, Albright reported that tetany and visual
disturbances were often seen. In actuality, the subsequent
recognition of the “hungry bone syndrome” in dialysis
patients after parathyroidectomy is an extension of the
results in primary hyperparathyroidism by Albright.
Nefrologia 2011;31(3):346-57
Table 1. A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before
and after the development of renal impairment
Calcium (g)
Phosphorus (g)
Serum
Output
Output
(mg per 100 cc)
Urine
Feces
Total
Intake Balance
Urine
Feces
Total
Intake
Balance
Ca
P
Control Seriesa
0.13
0.32
0.45
0.33
–0.12
1.21
0.60
1.81
2.07
0.26
10.0
4.0
Average of 3
periods in 1926
before renal impairment
1.31
0.19
1.50
0.31
–1.19
2.22
0.24
2.46
2.10
–0.36
14.0
2.7
Average of 4
periods in 1932
after renal impairment
0.27
0.79
1.06
0.30
–0.76
2.12
0.66
2.78
1.77
–1.01
14.4
4.2
The results for normal individuals are included for comparison.31
a
Each collection period was three days.
In 1934, Albright also recognized that patients with primary
hyperparathyroidism presented with either bone disease or
stone disease, but rarely both together.32 In patients with
bone disease, skeletal symptoms associated with bone loss,
bone cysts, brown tumors, and fractures predominated. In
patients with stone disease, presenting symptoms were those
associated with nephrolithiasis and skeletal problems were
generally absent. Albright questioned why there should be
two separate presentations for the same disease. He
hypothesized that the extent of bone disease was proportional
to the duration of disease times the daily loss of calcium.32
Thus, according to Albright a short duration of disease would
lessen the risk of bone disease. Moreover, a high calcium
intake would make bone disease less likely because as
Albright had previously observed in studies of patients with
primary hyperparathyroidism, a high calcium diet resulted in
a positive calcium balance.26
In 1945, Keating reported 24 patients with primary
hyperparathyroidism in whom the magnitude of
hypercalcemia, hypophosphatemia and serum alkaline
phosphatase elevation was greater in patients with bone
disease than with stone disease. 35 In contradiction to the
hypothesis advanced by Albright, the patients with bone
disease had a shorter duration of symptoms before
presentation. In 1956, Dent also reported that patients
with bone disease had a shorter duration of symptoms. 36
Subsequently, Dent reported that there was no difference
in dietary intake of calcium between patients with bone or
stone disease.37
In 1968, Lloyd reviewed 138 consecutive cases of primary
hyperparathyroidism accumulated by Dent in London from
1950 to 1965.38 Patients were divided into overt bone disease
without kidney stones (Type 1, n = 44) and kidney stones
without overt bone disease (Type 2, n = 88). The remaining
six patients had neither overt bone disease nor kidney stones.
Nefrologia 2011;31(3):346-57
As shown in table 2, the adenoma weight was greater, the
growth rate of the parathyroid tissue more rapid, and the duration
of symptoms was shorter in patients with bone disease. These
results contradicted Albright’s hypothesis that patients with bone
disease have a longer duration of disease.
One explanation for the shorter duration of disease together
with more severe hypercalcemia and larger adenomas in
patients with bone disease is simply a more rapid growth rate
of the parathyroid adenomas in patients with bone disease. In
the early 1970s, both Woodhouse et al39 and Lumb and
Stanbury40 suggested that the more rapid growth of
adenomas in patients with bone disease might be from a lack
of vitamin D. In 1987, one of the authors (CRK) wrote an
editorial in support of this possibility.41 Also in 1987, Paillard
and associates reported that patients with bone disease had
lower values of the stored form of vitamin D, 25hydroxyvitamin D (25[OH]D), 3.4 ± 2.0 vs 17.6 ± 13.6
ng/ml (P <0.001) and three-fold greater PTH values than
patients with stone disease.42 In more recent studies,
Silverberg et al in a longitudinal study of patients with mild
hyperparathyroidism, found that patients in the lowest tertile
of 25(OH)D measurements (12 ± 3 ng/ml) had the highest
PTH values.43 Rao, et al., in a study of 148 consecutive
patients operated for primary hyperparathyroidism with a
mean resected parathyroid gland weight of 1.27 grams,
reported an inverse correlation between 25(OH)D and
parathyroid gland weight while the correlation between the
active form of vitamin D, calcitriol, and parathyroid gland
weight was not significant.44 These results suggest that a
suboptimal vitamin D status may stimulate parathyroid
adenoma growth. The presence of 1 alpha-hydroxylase, the
enzyme responsible for conversion of 25(OH)D to calcitriol,
in parathyroid cells suggests the possibility that 25(OH)D
may directly affect PTH secretion and parathyroid gland
growth.45,46 Also contributing to the lowering of 25(OH)D
levels in primary hyperparathyroidism is that high PTH
351
17
A
16
15
Serum calcium
14
13
12
10
32
33
29
31
16
22
11
12
34
2
5
20
25
21
3
23
7
17
4
8
24
28
1
10
6
15
27
35
14
19
22
13
16
30
11
Case number
The marked elevation of the serum calcium values in the majority
of patients at the time of surgery is shown.71
B
Figure 5. Average preoperative serum calcium values of the
first 35 patients with primary hyperparathyroidism from the
Massachusetts General Hospital series.
Silverberg and Rao in which the increased weight of the
parathyroid adenoma was modest and the diagnosis of
primary hyperparathyroidism was made relatively early in
the course of the disease, vitamin D status seemed to play
a role.43,44
A. The patient is shown on admission at which time he had fractures
of both femurs, an ischiorectal abscess, decubitus ulcers and
advanced cachexia. The preoperative serum calcium concentration
was 16.8 mg/dl. B. The same patient shown 6 months after
resection of his parathyroid adenoma had gained 42 lbs. Also, the
decubitus ulcers had healed and the fractures were healing.34
Figure 4. The same patient before and after parathyroidectomy
from original series of Albright..
levels decrease 25(OH)D levels by increasing conversion of
25(OH)D to calcitriol.47 In summary, even in the studies of
352
Since the 1970s, the clear demarcation between patients with
bone and stone disease previously seen in patients with primary
hyperparathyroidism starting with the report of Albright in 1934
and continuing through the 1960s has been lost.32,35,38,48-51
Beginning in the 1930s and continuing for the next three
decades, the sequence of events in diagnosing bone disease in
primary hyperparathyroidism often was as described by
Albright, “appearance of a bone tumor, biopsy, diagnosis of
benign giant cell tumor, local treatment, and finally recognition
of generalized disease only years later”.2 However, the
introduction of multichannel analyzers in which serum calcium
and phosphorus values were routinely measured resulted in the
detection of many asymptomatic hyperparathyroid patients
with mild hypercalcemia.
In a recent review of primary hyperparathyroidism, the
average weight of the removed adenoma was 400 to 600
mg, values which are only three to four times greater than
the combined weight of four normal parathyroid glands. 52
In contrast, the mean weight of the removed parathyroid
adenomas in the Albright study from 1934 was
approximately 11 grams. 32 In 1947, Norris reviewed 322
cases from the existing world literature and reported that
the average weight of a removed parathyroid adenoma was
8 grams.48 In 1963, Hodgkinson reported that the mean
Nefrologia 2011;31(3):346-57
weight of the removed adenoma was 5.1 grams in patients
with bone disease and 1.4 grams in patients with stone
disease.49 Similar differences in the weight of parathyroid
adenomas between patients with bone and those with stone
disease were reported by Lloyd in his analysis of Dent’s
patients38 and by O’Riordan.51 The mean weight of the
parathyroid adenoma in patients with bone disease was 5.9
grams in the former and 4.2 grams in the latter series.
In areas of the world with limited access to medical care,
vitamin D insufficiency/deficiency appears to be more
common and the duration of primary hyperparathyroidism
much longer before diagnosis and treatment. In recent
studies of primary hyperparathyroidism from India and
China, the presence of large parathyroid adenomas and
bone disease has been associated with vitamin D
insufficiency/deficiency (figure 7).53-57 In a study from China,
the presenting PTH value was 21 times greater than normal.55
Similarly, in a study from India, the mean weight of the
removed parathyroid adenoma was 10.75 g in hypercalcemic
patients and 3.9 g in normocalcemic patients.54 In another
study from India, the mean weight of the removed
parathyroid adenoma was 7.9 g.56 Moreover, the 25(OH)D
18.0
Operation
17.0
16.0
Serum calcium per 100 CC
15.0
14.0
13.0
12.0
11.0
10.0
9.0
8.0
7.0
value was less than 10 ng/ml in the majority of these
patients. In the cited studies, pathologic bone fractures, bone
cysts, and brown tumors were commonly encountered.54-56 In
summary, the severe form of primary hyperparathyroidism
characterized by large adenomas and disabling bone disease,
first described by Albright in the 1930s, is still commonly
encountered in areas of the world with limited access to
medical care. Furthermore, the severe form of primary
hyperparathyroidism seen in these patients is often
associated with vitamin D insufficiency/deficiency.
VIGNETTES IN WHICH OBSERVATIONS BY ALBRIGHT
HAVE HAD CONTINUED CLINICAL RELEVANCE
1937. Prelude to the “Trade-Off Hypothesis”
of Slatopolsky and Bricker10,58 which was Advanced
to explain the development of secondary
hyperparathyroidism
Albright made the following statement in a 1937
publication: 59 “It has been suggested above that the
parathyroid hyperplasia is a compensation for the
disturbed equilibrium occasioned by phosphate retention
resulting from the renal insufficiency. In the absence of the
hyperplasia there would probably be greater phosphate
retention in the blood with a lowering of the blood calcium
level and severe tetany. If these concepts are correct, the
hyperplasia would have to be considered beneficial. The
one reservation might have to be made that, while helping
homeostasis, the parathyroid hyperplasia may lead to bone
disease”. Confirmation of the Albright hypothesis has been
shown in many animal and clinical studies of phosphate
loading. Also in studies of patients with stage 3 and 4
CKD treated with the calcimimetic, cinacalcet, the
reduction in PTH values has increased the serum
phosphorus concentration.60
6.0
6.0
1941. Hypothesis that hypercalcemia in malignancy
could be from ectopic hormone production
5.0
Days before operation
1
2
3
4
5
10
20
30
40
50
100
150
200
250
500
1000
2000
3000
2000
1000
500
250
200
150
100
50
25
20
15
10
5
4.0
Days after operation
Serum calcium values are shown before and after
parathyroidectomy. The values connected by dotted lines are on
patients with high serum alkaline phosphatase. Albright tells the
reader to note that cases with high alkaline phosphatase values
and therefore, with bone disease, are evenly distributed
preoperatively at various levels of hypercalcemia. However, the
cases with high alkaline phosphatase values all developed
hypocalcemia postoperatively.71
Figure 6. Fall in serum calcium values after parathyroidectomy
in 35 cases of primary hyperparathyroidism (first demonstration
of hungry bone syndrome).
Nefrologia 2011;31(3):346-57
At a clinicopathological conference, a 51 year old male
presenting with hypercalcemia and hypophosphatemia was
discussed.61 A neck exploration for presumed
hyperparathyroidism was performed, but no abnormality was
found. Bone x-rays showed a destructive lesion in the right
ilium, which on biopsy was reported to originate from a
renal cell carcinoma. The comment of Albright at the end of
the conference was “Why a person should have high serum
calcium and low serum phosphorus when the cause of the
disturbance is a tumor destroying bone is an interesting
theoretical question. We treated this case by radiation of the
tumor masses; the serum calcium went down to normal, and
the serum phosphorus went up to normal. Gradually, both
values became abnormal again. I suspected that the tumor
353
Table 2. Comparison of two types of primary
hyperparathyroidism based on a series analyzed by Lloyd
Number of cases
Mean tumor weight (g)
Type Ia
Type 2b
44
88
5.90
1.05
Range
0.70-26.0
0.15-3.5
Length of history (years)
3.56 ± 4.8
6.66 ± 7.2
Doublings (from 50 mg)
6.9
4.3
Doubling time (months)
6.2
18.6
Linear growth rate (g/year)
1.64
0.15
13.36 ± 2.40
11.64 ± 0.80
Plasma Ca (mg/dl)
Plasma P (mg/dl), BUN <21 mg/dl
2.17 ± 0.40 (32) 2.36 ± 0.47 (86)
Plasma P (mg/dl), BUN >21 mg/dl
4.43 ± 1.33 (12) 3.26 ± 0.06 (2)
BUN (mg/dl)
25.8
Urinary Ca (mg per 24 h)
337
408
Nephrolithiasis
5%
100%
Nephrocalcinosis
AP (K.A.U.)
Bone disease
15.3
30%
25%
40.1 ± 23.2
8.1 ± 3.0
Osteitis fibrosa
Osteoporosis
From Lloyd.69
a
Type 1: presenting with bone disease. b Type 2: presenting with stone
disease.
might be producing parathyroid hormone. I therefore had it
assayed by Dr. J. B. Collip, but no hormone was found”. In
essence, Albright was the first to suggest the possibility of
ectopic hormone production by a tumor. Today we know the
causal agent responsible for the hypercalcemia and
hypophosphatemia to be PTH-related protein and not PTH.
1941. Pseudohypoparathyroidism in vitamin D
deficiency
A year before Albright reported the clinical entity of
pseudohypoparathyroidism in which there was a failure to
respond to PTE in patients with characteristic body
features,18 he recognized a subset of patients with vitamin D
deficiency in whom the serum calcium was low and the
serum phosphorus was normal. Albright logically but
incorrectly thought that the problem was because the
necessary compensatory increase in parathyroid function had
not taken place.62 Subsequently, there continued to be reports
of patients with vitamin D deficiency in whom hypocalcemia
was accompanied by normal or even high serum phosphorus
values.40,63-65 In 1985, Rao et, al. established that the
hypocalcemia associated with vitamin D depletion can
impair the phosphaturic response to PTH despite an
appropriately increased nephrogenous cyclic AMP
response.66 Correction of hypocalcemia with vitamin D and
calcium treatment restored the phosphaturic response to PTH
despite a reduction in nephrogenous cyclic AMP. Thus, these
354
patients had an acquired form of pseudohypoparathyroidism
type II, which was subsequently shown to be from a
postreceptor G protein defect.67 In the opinion of the authors,
another possibility which should be evaluated is that the
vitamin D deficiency and the hypocalcemia combine to
impair FGF23 production.22-25
1941. Immobilization and Hypercalcemia
Albright reported the case of a 14 year old boy who in an
athletic injury, fractured his right femur at the site of a bone
cyst.68 After an open reduction, the boy was placed in a spica
cast immobilizing him from the waist down. Shortly
thereafter anorexia and vomiting developed. Because the
presence of the bone cyst raised the possibility of primary
hyperparathyroidism, serum calcium was measured and
found to be 14.6 mg/dl with a serum phosphorus of 4.5
mg/dl. Mild renal insufficiency also developed. Because of
the persistent hypercalcemia, the boy underwent a
parathyroid exploration at which only normal parathyroid
glands were identified. Six weeks later because of persistent
hypercalemia, the anterior mediastinum was explored but
no parathyroid tissue was identified. Once the patient
was mobilized, the serum calcium decreased to normal
values. Albright concluded that the sequence of events
was: a) solitary bone cyst; b) fracture through cyst; c)
immobilization of a large part of a previously active
skeleton; d) osteoporosis from disuse with an excess of
calcium from bone being presented to the kidney; e) an
inability of the kidney to excrete promptly all the calcium; f)
resulting in hypercalcemia; and g) kidney damage from
excess of calcium being excreted through the kidney.
Albright further added that once renal insufficiency
developed, it probably increased the tendency to
hypercalcemia. From this case, Albright learned that
25
25OHD
ng/ml
20
PTH
x normal
15
10
5
0
China
India
India
New York Detroit
The markedly higher values of PTH in India and China were
associated with much lower values of 25(OH)D.53
Figure 7. A global view of vitamin D levels and the magnitude
of hyperparathyroidism as determined by the elevation in PTH.
Nefrologia 2011;31(3):346-57
immobilization of an individual with active skeletal
remodeling increases calcium efflux from bone and he also
recognized that a decreased glomerular filtration rate reduces
the capacity to excrete calcium, which in turn, exacerbates
hypercalcemia.
CONCLUSION
In the late 1920s, Albright joined Joseph Aub and Walter
Bauer to pursue studies of calcium and phosphorus
metabolism. First Aub and then Bauer were appointed to
academic positions in other subspecialties at Harvard, which
by 1930 left the young Albright as the primary investigator
of calcium and phosphorus metabolism in Boston. Through
inductive reasoning, which has been defined by the late
Jacob Bronowski as that unpredictable blend of speculation
and insight, Albright came to recognize in normal volunteers
and in hypo- and hyperparathyroid patients, the presence of
consistent patterns of response for calcium and phosphorus
metabolism. Fuller Albright was truly the first person to
establish a sense of order out of the existing chaos in the
new field of calcium and phosphorus metabolism. As one
of the 20 th century’s preeminent philosophers of science,
Karl Popper has stated, “Science does not rest upon rockbottom. The bold structure of its theories rises, as it were,
above a swamp, but not down to any natural or given base;
and when we cease our attempts to drive our piles into a
deeper layer, it is not because we have reached firm
ground. We simply stop when we are satisfied that they are
firm enough to carry the structure, at least for the time
being”. Albright was the first to establish a functional
system which explained calcium and phosphorus
metabolism. His classic book, The Parathyroid Glands and
Metabolic Bone Disease, published in 1948, became the
standard reference for a generation of students of calcium
and phosphorus metabolism. Albright trained many future
investigators and became an inspiration for the next
generation of clinical investigators studying calcium and
phosphorus disorders. As the importance of translational
research is again rightfully being emphasized, the
contributions of Fuller Albright should be recognized and
he should be celebrated as a role model for a new
generation of young clinical investigators.
REFERENCES
1. Kleeman CR, Levine BS, Felsenfeld AJ. Fuller, Albright, the consummate clinical investigator. Clin J Am Soc Nephrol 2009;4:1541-6.
2. Albright F, Reifenstein EC, Jr. The parathyroid glands and metabolic
bone disease, selected studies. Baltimore, MD: The Williams and
Wilkins Company; 1948.
3. Levine BS, Kleeman CR, Felsenfeld AJ. The journey from vitamin Dresistant rickets to the regulation of renal phosphate transport. Clin
J Am Soc Nephrol 2009;4:1866-77.
Nefrologia 2011;31(3):346-57
4. Means JH. Ward 4 Cambridge: Harvard University Press; 1958:101.
5. Albright F, Ellsworth R. Studies on the physiology of the parathyroid
glands. I. Calcium and phosphorus studies on a case of idiopathic
hypoparathyroidism. J Clin Invest 1929;7:183-201.
6. Albright F, Bauer W, Ropes M, Aub JC. Studies of calcium and phosphorus metabolism. IV. The effect of the parathyroid hormone. J Clin
Invest 1929;7:139-81.
7. Albright F, Bauer W. The action of sodium chloride, ammonium chloride, and sodium bicarbonate on the total acid-base balance of a
case of chronic nephritis with edema. J Clin Invest 1929;7:465-86.
8. Raisz LG, Niemann I. Effect of phosphate, calcium, and magnesium
on bone resorption and hormonal responses in tissue culture. Endocrinology 1969;85:446-52.
9. Coburn JW, Massry SG. Changes in serum and urinary calcium during phosphate depletion: studies on mechanism. J Clin Invest
1970;49:1073-87.
10. Slatopolsky E, Caglar S, Pennell JP, et al. On the pathogenesis of
hyperparathyroidism in chronic experimental renal insuffficiency in
the dog. J Clin Invest 1971;50:492-99.
11. Rodríguez M, Martín Malo A, Martínez ME, Torres A, Felsenfeld AJ,
Llach F. Calcemic response to parathyroid hormone in renal failure: role
of phosphorus and its effect on calcitriol. Kidney Int 1991;40:105562.
12. Krapf R, Glatz M, Hulter HN. Neutral phosphate administration generates and maintains renal metabolic alkalosis and hyperparathyroidism. Am J Physiol 1995;268:F802-7.
13. Kleeman CR, Bernstein D, Rockney R, Dowling JT, Maxwell MH. Studies on the renal clearance of diffusible calcium and the role of the
parathyroid glands in its regulation. Yale J Biol Med 1961;34:1-30.
14. Peacock M, Robertson WG, Nordin BEC. Relation between serum
and urinary calcium with particular reference to parathyroid activity.
Lancet 1969;1:384-6.
15. Yamamoto M, Kawanobe Y, Takahashi H, Shimazawa E, Kimura S,
Ogata E. Vitamin D deficiency and renal calcium transport in the rat.
J Clin Invest 1984;74:507-13.
16. Hoenderop JGJ, Muller D, Van der Kemp AWCM, et al. Calcitriol
controls the epithelial calcium channel in kidney. J Am Soc Nephrol
2001;12:1342-9.
17. Albright F, Bloomberg E, Drake T, Sulkowitch HW. A comparison of
the effects of AT10 (dihydrotachysterol) and vitamin D on calcium
and phosphorus metabolism in hypoparathyroidism. J Clin Invest
1938;17:317-29.
18. Albright F, Burnett CH, Smith PH, Parson W. Pseudo-hypoparathyroidism - An example of Seabright-Bantam syndrome. Endocrinology 1942;30:922-32.
19. Bauer W, Marble A, Claflin D. Studies on the mode of action of irradiated ergosterol IV. In hypoparathyroidism. J Clin Invest
1932;11:47-62.
20. Howland J, Kramer B. Calcium and phosphorus in the serum in relation to rickets. Am J Dis Child 1921;22:105-19.
21. Eisenberg E. Effects of serum calcium and parathyroid extracts on
phosphate and calcium excretion in hypoparathyroid patients. J Clin
Invest 1965;44:942-6.
22. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D
metabolism. Am J Physiol Renal Physiol 2005;289:F1088-95.
355
23. Yamashita H, Yamashita T, Miyamoto M, et al. Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol 2004;151:55-60.
24. Kobayashi K, Imanishi Y, Miyauchi A, et al. Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol 2006;154:93-9.
25. Kawata T, Imanishi Y, Kobayashi K, et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary
hyperparathyroidism. J Am Soc Nephrol 2007;18:2683-8.
26. Bauer W, Albright F, Aub JC. A case of osteitis fibrosa cystica (osteomalacia?) with evidence of hyperactivity of the parathyroid bodies.
Metabolic study II. J Clin Invest 1930;8:229-48.
27. Bauer W, Federman DD. Hyperparathyroidism epitomized: the case
of Captain Charles E. Martell. Metabolism 1962;11:21-9.
28. Albright F, Bauer W, Claflin D, Cockrill JR. Studies in parathyroid
physiology III. The effect of phosphate ingestion in clinical hyperparathyroidism. J Clin Invest 1932;11:411-35.
29. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality
risk in chronic hemodialysis patients: A national study. Am J Kidney
Dis 1998;31:607-17.
30. Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphorus levels associate with coronary atherosclerosis in young
adults. J Am Soc Nephrol 2009;20:397-404.
31. Albright F, Baird PC, Cope O, Bloomberg E. Studies on the physiology of the parathyroid glands. IV. Renal complications of hyperparathyroidism. Am J Med Sci 1934;187:49-65.
32. Albright F, Aub JC, Bauer W. Hyperparathyroidism: a common and
polymorphic condition as illustrated by seventeen proved cases from
one clinic. JAMA 1934;102:1276-87.
33. Albright F, Sulkowitch HW, Bloomberg E. Hyperparathyroidism due
to idiopathic hypertrophy (hyperplasia?) of parathyroid tissue. Arch
Intern Med 1938;62:199-215.
34. Churchill ED, Cope O. The surgical treatment of hyperparathyroidism. Ann Surg 1936;104:9-35.
35. Keating FR, Jr., Cook EN. The recognition of primary hyperparathyroidism. JAMA 1945;129:994-1002.
36. Davies DR, Dent CE, Willcox A. Hyperparathyroidism and steatorrhoea. Br Med J 1956;2:1133-7.
37. Dent CE, Hartland BV, Hicks J, Sykes ED. Calcium intake in patients
with primary hyperparathyroidism. Lancet 1961;2:336-8.
38. Lloyd HM. Primary hyperparathyroidism: an analysis of the role of
the parathyroid tumor. Medicine (Balt) 1968;47:53-71.
39. Woodhouse NJY, Doyle FH, Joplin GF. Vitamin-D deficiency and primary hyperparathyroidism. Lancet 1971;2:283-7.
40. Lumb GA, Stanbury SW. Parathyroid function in human vitamin D
deficiency and vitamin D deficiency in primary hyperparathyroidism.
Am J Med 1974;56:833-9.
41. Kleeman CR, Norris K, Coburn JW. Is the clinical expression of
primary hyperparathyroidism a function of the long-term vitamin D status of the patients? Miner Electrolyte Metab
1987;13:305-10.
42. Patron P, Gardin JP, Paillard M. Renal mass and reserve of vitamin D: Determinants in primary hyperparathyroidism. Kidney Int 1987;31:117480.
43. Silverberg SJ, Shane E, Dempster DW, Bilezikian JP. The effects of vi356
tamin D insufficiency in patients with primary hyperparathyroidism.
Am J Med 1999;107:561-7.
44. Rao DS, Honasoge M, Divine GW, et al. Effect of vitamin D nutrition
on parathyroid adenoma weight: Pathogenetic and clinical implications. J Clin Endocrinol Metab 2000;85:1054-8.
45. Segersten U, Correa P, Hewison M, et al. 25-Hydroxyvitamin
D3-1a-hydroxylase expression in normal and pathological
parathyroid glands. Nephrol Dial Transplant 2002;87:296772.
46. Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ. 25-Hydroxyvitamin D3 suppresses PTH synthesis and secretion by bovine parathyroid cells. Kidney Int 2006;70:654-9.
47. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, Adams PH.
Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 1987;73:659-64.
48. Norris EH. The parathyroid adenoma-a study of 322 cases. Int Abstr
Surg 1947;84:1-41.
49. Hodgkinson A. Biochemical aspects of primary hyperparathyroidism:
an analysis of 50 cases. Clin Sci 1963;25:231-42.
50. Cope O. The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 1966;274:1174-82.
51. O’Riordan JLH, Watson L, Woodhead JS. Secretion of parathyroid
hormone in primary hyperparathyroidism. Clin Endocrinol (Oxf)
1972;1:149-55.
52. Bilezikian JP, Silverberg SJ. Clinical spectrum of primary hyperparathyroidism. Rev Endocrinol Metab Dis 2000;1:237-45.
53. Silverberg SJ. Vitamin D deficiency and primary hyperparathyroidism. J Bone Miner Res 2007;22(Suppl.2):V100-4.
54. Harinarayan CV, Gupta N, Kochupillai N. Vitamin D status in primary
hyperparathyroidism. Clin Endocrinol (Oxf) 1995;43:351-8.
55. Bilezikian JP, Meng X, Shi Y, Silverberg SJ. Primary hyperparathyroidism in women: a tale of two cities-New York and Beijing. Int J Fertil Women’s Health 2000;45:158-65.
56. Mishra SK, Agarwal G, Kar DK, Gupta SK, Mithal A, Rastad J. Unique clinical characteristics of primary hyperparathyroidism in India.
Br J Surg 2001;88:708-14.
57. Rao DS, Agarwal G, Talpos GB, et al. Role of vitamin D and calcium
nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective. J Bone Miner Res
2002;17(Suppl.2):N75-N80.
58. Bricker NS. On the pathogenesis of the uremic state. An exposition
of the “trade-off hypothesis”. N Engl J Med 1972;286:1093-9.
59. Albright F, Drake TG, Sulkowitch HW. Renal osteitis fibrosa cystica.
Bull Johns Hopkins Hosp 1937;60:377-99.
60. Charytan C, Coburn JW, Chonchol M, et al. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in
patients with CKD not receiving dialysis. Am J Kidney Dis
2005;46:58-67.
61. Albright F. Case records of the Massachusetts General Hospital-case
27461. N Engl J Med 1941;225:789-91.
62. Albright F. The parathyroids-Physiology and therapeutics. JAMA
1941;117:527-33.
63. Salvesen HA, Boe J. Osteomalacia in sprue. Acta Med Scand
1953;146:290-9.
64. Taitz LS, De Lacy CD. Parathyroid function in vitamin D deficiency.
Part II. Pediatrics 1962;30:884-92.
Nefrologia 2011;31(3):346-57
65. Taitz LS, De Lacy CD. Parathyroid function in vitamin D deficiency.
Part I. Pediatrics 1962;30:875-83.
66. Rao DS, Parfitt AM, Kleerekoper M, Pumo BS, Frame B. Dissociation between the effects of endogenous parathyroid hormone on
adenosine 3’5’-monophosphate generation and phosphate reabsorption in hypocalcemia due to vitamin D depeletion: an acquired disorder resembling pseudohypoparathyroidism type II. J Clin
Endocrinol Metab 1985;61:285-90.
67. Mitchell J, Tenenhouse A, Warner M, Goltzman D. Parathyroid hormone
desensitization in renal membranes of vitamin D-deficient rats is associated with a postreceptor defect. Endocrinology 1988;122:1834-41.
68. Albright F, Burnett CH, Cope O, Parson W. Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism. J Clin Endocrinol 1941;1:711-6.
69. Parfitt AM, Kleerekoper M. Clinical disorders of calcium, phosphorus, and magnesium metabolism. In: Maxwell MH, Kleeman
CR, eds. Clinical disorders of fluid and electrolyte metabolism.
Third ed. New York: McGraw-Hill Book Company; 1980:9471151.
70. Robertson WG. Plasma phosphate homeostasis. In: Nordin BEC,
ed. Calcium, phosphate and magnesium metabolism. Edinburgh, London and New York: Churchill Livingstone; 1976:21729.
71. Albright F, Sulkowitch HW, Bloomberg E. Further experience in
the diagnosis of hyperparathyroidism, including a discussion of
cases with a minimal degree of hyperparathyroidism. Am J Med
Sci 1937;193:800-12.
Sent to review: 12 Dec. 2010 | Accepted: 14 Mar. 2011
Nefrologia 2011;31(3):346-57
357
letters to the editor
A) BRIEF PAPERS ON RESEARCH AND CLINICAL EXPERIMENTS
Prevalence of chronic
kidney disease and
arteriosclerosis in a
non-selected
population. World
Kidney Day
Nefrologia 2011;31(3):358-9
To the Editor,
Chronic kidney disease (CKD) is an
important issue for public health, given
its high incidence, prevalence, morbidity and mortality, and socio-economic
cost.1
In Spain, 2 the prevalence of replacement renal therapy is 986 patients per
million population (pmp), which
means that approximately 45 000
people need extrarenal clearance or
have received a kidney transplant.
CKD is much more prevalent in earlier stages, and is associated with a
poor prognosis, given the increased
risk of premature death caused by cardiovascular disorders and the risk of
kidney disease progressing. If this
were to occur, replacement renal
treatment is needed.
The prevalence of CKD at stages 3b
and 4 is 1.38%,3 presenting a greater
risk of death, cardiovascular disease
(CV), CV morbidity and mortality,
greater cognitive deterioration and
worse quality of life.4
CKD treated at early stages progresses
to a lesser extent and presents with less
CV complications. Therefore, the public health system should advocate for an
early CKD detection and treatment.
We saw World Kidney Day (WKD) as
the perfect opportunity to assess CKD
prevalence and its associated vascular
risk in a non-selected population in the
Galician city, Ourense.
358
We spontaneously studied a non-selected population that attended the WKD
marquee in the city centre. The following measurements were taken: anthropometrics, blood pressure (Omron®),
glucose (Reflotron®) and creatinine
(Reflotron®) rates, intima-media thickness (IMT) measured by ultrasound of
the supra-aortic trunks (LOGIQ,
12MHz probe), taken from the posterior wall and from an area free from
atheromatous plaques. An arteriosclerosis score was used (AS): AS 1:
ITM<0.8; AS 2: ITM>0.8; AS 3:
ITM><0.8 with plaques.
Statistical calculations included mean,
standard deviation and the Pearson’s regression.
We obtained the following results: 82
people came to the marquee, 75 men
(69.66 years) and 7 women (67.28
years), see Table 1. Average MDRD
was 109.38 (12.4-180), the percentage
of MDRD<60ml/min was 11.9%, and
the different degrees of arteriosclerosis
are shown in Table 2. AS correlated
with age (0.000), kidney function
(0.015), pulse pressure (0.044) and
BMI (0.069).
When the glomerular filtration rate
(GFR) is lower than 50ml/min, inflammatory response to endothelial dysfunction (ED) is initiated, the latter being
a
precursor
of
the
atherothrombotic/arteriosclerotic
process. It is initiated by an increase in
adhesion molecule expression, monocyte infiltration, and their activation
and transformation into macrophages.
When the eGFR is lower than
30ml/min, phosphorus (P) ‘retention’ is
produced and fibroblast growth factor
(FGF 23) activated. Through its specific binding with a receptor and Klotho,
it does not only reduce the kidney’s P
Table 1. Descriptive
Variable
Mean
Age
69.46
Confidence interval
47-87
BMI
28.78
19.53-28.78
SBP
148.85
90-230
DBP
76.97
45-105
ABP
136.67
73.33-101.09
PP
72.34
25-145
MDRD
109.38
12.41-180.28
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; ABP: average
blood pressure; PP: pulse pressure; MDRD: Modification of diet in renal disease
Table 2.
AS1
AS2
AS3
Correlation
P
Age
62.39
70.86
74.44
0.503
0.000
MDRD
127.75
101.96
104.30
–0.271
0.015
SBP
146.78
145.66
155.55
0.157
0.165
DBP
80.68
74.16
76.29
–0.131
0.250
PP
67.72
71.50
79.25
0.228
0.044
ABP
103.25
98.00
102.71
–0.004
0.969
BMI
27.30
24.46
29.38
0.214
0.069
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; ABP: average
blood pressure; PP: pulse pressure; MDRD: Modification of diet in renal disease
Nefrologia 2011;31(3):358-78
absorption, it also inhibits 1-alpha-hydroxylase and results in lower calcitriol
synthesis.
CKD progression, the decrease in FGF
23’s phosphaturic action and lower vitamin D rate produce a situation of resistance to FGF 23’s phosphaturic action. As a result, the P’s plasmatic rate
increases, which upregulates the gene
that codes for PTH through a “P sensor”
in the parathyroid glands. Furthermore,
in this hyperphosphataemia situation,
extracellular P is transported by the cotransporter Pit-1 to the intracellular
compartments, and once there, it acts as
an indicator of an increase in mineral
nucleation expression agents.5
Deficiency in vitamin D contributes to
this process, given that Th1 lymphocyte
action cannot be inhibited, which continue activating and perpetuating the
ED process.
To conclude, there is a high prevalence
of CKD in a non-selected and spontaneous population. Arteriosclerotic disease is not only related to kidney function, but also to age and pulse pressure.
Pathogenic mechanisms are well
known, meaning that a change is needed. Nephrology departments, in collaboration with primary care centres
should create programmes for detecting
CKD and incipient vascular lesions early, so as to reduce CKD progression and
cardiovascular morbidity and mortality.
1. Eknoyan G, Lameire N, Barsoum R, et al. The
burden of kidney disease: Improving global
outcomes. Kidney Int 2004;66:1310-4.
2. http://www.senefro.org
3. Otero A, Gayoso P, García F, De Francisco
ALM, on behalf of the EPIRCE study group.
Epidemiology of chronic renal disease in the
Galician population: Results of the pilot
Spanish EPIRCE study. Kidney Int
2005;68(Supl 99):S16-S19.
4. Go AS, Chertow GM, Fan D. Chronic kidney
disease and the risks of death, cardiovascular
events, and hospitalisation. N Engl J Med
2004;351:1296-35.
5. Rodríguez Portillo M. Alteraciones del
metabolismo óseo y mineral en la
enfermedad renal crónica: avances en
Nefrologia 2011;31(3):358-78
patogenia, diagnóstico y tratamiento. En:
Cannata JB (ed.). Lippincott Williams &
Wilkins, 2010;169.
C. Pereira Feijoo1, V.E. Martínez Maestro1,
N. Bretaña Vilanova1, L. Queija Martínez1,
A. Otero González2
1
Nephrology Department. Íñigo Álvarez de
Toledo Kidney Foundation. Ourense, Spain
2
Nephrology Department.
Ourense Hospital Complex.
Correspondence: A. Otero González
Complejo Hospitalario de Ourense. Spain.
[email protected]
Monitoring sirolimus
levels: How does it affect
the immunoassay used?
Nefrologia 2011;31(3):359-61
To the Editor,
Sirolimus, an immunosuppressive
agent used to prevent graft rejection,
has a narrow therapeutic window and
high interindivual and intraindividual
variability. Its concentration in blood
must be monitored to prevent graft rejection and some adverse effects.1 To
date, the microparticle immunoassay
(MEIA, Abbott Laboratories®) on an
IMx® analyser has been the most used
method for measuring sirolimus concentrations in blood.2-6 However, the
2010 Abbott Laboratories® stopped
marketing the reagents for this technique, replacing them with a chemiluminescent microparticle immunoassay
(CMIA) on the Architect® analyser. Different immunoassays do not always
yield the same results, given that techniques can have different sample pretreatments, drug metabolite cross-reactivity, or quantification limits.
The aim of our study was to compare
sirolimus limits in kidney transplant patients, obtained by analysing the same
blood sample with the two immunoassays (IMx® and Architect®). The
sirolimus concentration analysis includ-
ed the samples received at Del Mar
Hospital during the first half of 2010
(period in which both reagents were
available). We analysed 21 samples
from 13 kidney transplant patients (10
men, age: 57.5 years [SD=12.4], posttransplant time: 5.25 years [Q1Q3=4.13-9.44]).
Average concentrations obtained were
4.98ng/ml (SD=2.14) for IMx ® and
8.37ng/ml (SD=3.01) for Architect®.
The mean absolute difference between the techniques was +3.39ng/ml
(SD=1.76) for Architect® compared to
IMx®.
The Bland-Altman graph in Figure 1
shows the differences between the two
techniques. Figure 2 shows the correlation of least squares between both techniques. The Pearson’s correlation coefficient was r=0.819.
For 13 of the 21 samples, the difference
between the two techniques was more
than 50%, especially for samples less
than 5ng/ml (9/11 compared to 4/10;
P=.080).
Two of the samples analysed by IMx®
(9.5%) were below their quantification
limit (QL: 2.5ng/ml), while this was not
found for the Architect®-analysed samples (QL: 0.7ng/ml).
For the IMx®-analysed samples, 47.6%
(10/21) were within the therapeutic
window (5-15ng/ml), the remaining
52.4% (11/21) were at an infra-therapeutic level. However, of the Architect®-analysed samples, 76.2% (16/21)
were within the therapeutic window,
19.0% (4/21) were at an infra-therapeutic level and 4.8% (1/21) at a supratherapeutic level.
Various immunoassays have been developed, making immunosuppressive
drug monitoring easier.7,8 Immunoassays use reagents with monoclonal antibodies against the drug analysed. Depending on the antibody’s specificity,
cross-reactivity may exist with the
drug’s metabolites. This cross-reactivity varies for each technique, giving rise
359
Laboratories, IMx® presents a bias of
around -10%, and Architect ® of
+15%-20%. 10
mean
The continuous line shows the mean difference between the specific differences for each of
the techniques. Broken lines shows ± 2 SD.
Figure 1. Bland-Altman graph showing the sirolimus concentration differences between
IMx® and Architect® (n=21 samples)
to differences in the results from different immunoassays. This variance
could cause conflict in deciding upon
an immunosuppressive dose.
Our results show that Architect ®
shows 3ng/ml more than IMx ®. Courtais et al obtained similar results
with slightly lower difference
(2.28±1.28ng/ml). However, only 4
out of the 53 patients studied had un-
dergone a kidney transplant. 9 Furthermore, the difference was only
calculated for 51 out of the 100 samples analysed, meaning that the infra-therapeutic or the supra-therapeutic ones were not considered.
According to the HPLC data provided at that time by the United Kingdom External Quality Assessment
Service (UK NEQAS) for Clinical
Figure 2. Linear correlation between sirolimus concentrations of IMx® and Architect® (n=21)
360
These differences can be due to different causes. Firstly, the two techniques use different methods for extracting the drug from the protein
FKBP12.
Dimethyl
sulfoxide
(DMSO) is used in Architect ® pretreatment to heat the sample so that
more sirolimus can be extracted. 11
Secondly, Architect® has better
metabolite cross-reactivity. This
cross-reactivity is always positive
with metabolites F2 (8.7%), F3
(4.1%), F4 (36.8%) and F5 (20.3%)
(data provided by Abbott Laboratories ®). For IMx ®, these interferences
are lower: F2 (2.8%), F4 (26.2%)
and F5 (6.8%), but higher with F3,
and, also, negative (-22%). This difference was extended when we directly compare IMx® and Architect®.
The decrease in QL from 2.5ng/ml
(IMx ®) to 0.7ng/ml (Architect ®) allows for regimen adjustment when
lower levels are required.1
Recently, the laboratory that markets
sirolimus sent a communication to
health care professionals warning of
the changes made to immunoassays
and the consequences that this has on
monitoring levels. 12 This communication especially emphasised the
need for doctors to contact the laboratory to find out which assay is
used, given that changes between
different immunoassays or between
one immunoassay and HPLC could
produce clinically significant differences in results. These differences
could provoke inadequate dosage adjustments, possibly causing adverse
consequences. In our study, IMx ®
had more infra-therapeutic results
than Architect ® (52% vs. 19%),
which could mean that there more
patients’ doses would be increased
than with Architect®.
To date, therapeutic windows have
not been standardised for each measurement technique. Recently, the
Nefrologia 2011;31(3):358-78
University of Colorado Hospital
tried to adapt this therapeutic windows. 13 Given that the levels obtained by Architect ® are higher, the
window has increased from 3-8ng/ml
(with HPLC) to 4.5-13ng/ml (with
Architect®).
Our study’s most significant limitation is that we have included a small
amount of measurements in the sample, which could not have been increased as Abbott Laboratories ®
stopped marketing the IMx ® reagent.
Furthermore, our study includes the
most kidney transplant patients to
date.
It confirms that the laboratories that
determine the sirolimus levels
should inform doctors when they
make changes to the immunoassay
employed, and the consequences that
could arise. This information is of vital importance so that appropriate
dose adjustments can be made. Furthermore, this information should be
considered when conducting clinical
studies or comparisons between different hospitals. Similarly, sirolimus
therapeutic windows should be standardised for each of the techniques
in use.
1. Stenton SB, Partovi N, Ensom MH.
Sirolimus: the evidence for clinical
pharmacokinetic monitoring. Clin
Pharmacokinet 2005;44(8):769-86.
2. Johnson RN, Sargon R, Woollard G,
Davidson J. An evaluation of the Abbott
IMx sirolimus assay in relation to a highperformance liquid chromatographyultraviolet method. Ann Clin Biochem
2005;42(Pt 5):394-7.
3. Zochowska D, Bartlomiejczyk I, Kaminska
A, Senatorski G, Paczek L. Highperformance liquid chromatography versus
immunoassay for the measurement of
sirolimus: comparison of two methods.
Transplant Proc 2006;38(1):78-80.
4. Morris RG, Salm P, Taylor PJ, Wicks FA,
Theodossi A. Comparison of the
reintroduced MEIA assay with HPLCMS/MS for the determination of wholeblood sirolimus from transplant recipients.
Ther Drug Monit 2006;28(2):164-8.
Nefrologia 2011;31(3):358-78
5. Scholer A, Von Rickenbach R, Faffa G, Vetter
B. Evaluation of a microparticle enzyme
immunoassay for the measurement of
sirolimus in whole blood (Abbott IMx
sirolimus). Clin Lab 2006;52(7-8):325-34.
6. Bargnoux AS, Bonardet A, Chong G,
Garrigue V, Deleuze S, Dupuy AM, et al.
Evaluation of an immunoassay (AbbottIMX
Analyzer)
allowing
routine
determination of sirolimus: comparison
with LC-MS method. Transplant Proc
2006;38(7):2352-3.
7. Kahan BD, Napoli KL, Kelly PA, Podbielski J,
Hussein I, Urbauer DL, et al. Therapeutic
drug monitoring of sirolimus: correlations
with efficacy and toxicity. Clin Transplant
2000;14(2):97-109.
8. Holt D, Jones K, Johnston A. An
imunoassay for measurement of sirolimus.
Clin Chem 1998;44(Suppl):A94.
9. Courtais C, Dupuy AM, Bargnoux AS,
Pageaux GP, Fegueux N, Mourad G, et al.
Evaluation of two sirolimus assays using
the ARCHITECT-i1000((R)) CMIA or RxL(R))
ACMIA methods in comparison with the
IMx(R)) MEIA method. Clin Chem Lab Med
Jul 29.
10. http://www.bioanalytics.co.uk/pt/pt_information.html
(accessed 01 July 2010).
11. Schmid RW, Lotz J, Schweigert R, Lackner K,
Aimo G, Friese J, et al. Multi-site analytical
evaluation of a chemiluminescent magnetic
microparticle immunoassay (CMIA) for
sirolimus on the Abbott ARCHITECT analyzer.
Clin Biochem 2009;42(15):1543-8.
12. h t t p : / / w w w . h c - s c . g c . c a / d h p mps/alt_formats/pdf/medeff/advisoriesavis/prof/2009/rapamune_4_hpc-cps-eng.
pdf (accessed 1 September 2010).
13. http://www.uch.edu/docs/pdf/2009-11-13 Test
Update - Immunosuppressant Tests.pdf
(accessed 1 September 2010).
M. Marín-Casino1, M. Crespo2,
J. Mateu-de Antonio1, J. Pascual2
1
Hospital Pharmacy Department.
Del Mar Hospital. Parc de Salut Mar.
Barcelona, Spain.
2
Nephrology Department. del Mar Hospital.
Parc de Salut Mar. Barcelona, Spain.
Correspondence: M. Marín-Casino
Servicio de Farmacia Hospitalaria.
Hospital del Mar. Parc de Salut Mar. Passeig
Marítim, 25-29. 08025. Barcelona, Spain.
[email protected]
Good practice
guidelines on the use
of erythropoiesisstimulating agents
in 2011
Nefrologia 2011;31(3):361-2
To the Editor,
As coordinator of the Kidney, Dialysis
and Transplant Programme in Cuba, I
would be extremely grateful if you
could publish this letter. I would like to
highlight my opinions regarding the
safe use of erythropoiesis-stimulating
agents (ESA), and give my contributions on its optimal use, which is currently subject to debate.1
For me, introducing recombinant human erythropoietin (rhEPO) and ESA
to clinical practice following replacement dialysis has been one of the most
important advances in stage 5 chronic
kidney disease (CKD) treatment. These
techniques are the best example of how
biotechnology has been successfully
applied as a clinical treatment as it is
used to correct severe anaemia linked
with CKD, despite the adverse results
highlighted by the most recent prospective and controlled studies.2 Furthermore, we must remember that to do so
we have to use supraphysiological doses of erythropoietin, justified by its
non-haematopoietic effects.3
The reason why these studies report a
greater risk to negative events, mortality and cancer makes us reflect upon important questions that are yet to be completely resolved:
1. Would the population with the
greatest haemoglobin levels and
worst results show other rhEPO effects and be likely to have to a homogeneous analysis?
2. Is the maximum rhEPO dose to be
employed for each haemoglobin
level clear?
3. Have we considered that rhEPO
dose does not have to be increased
to reach any haemoglobin level?
4. Are patients with adverse effects
361
and a higher ESA dosage those with
an accepted ‘accelerated atherosclerosis’ and clinical or subclinical problems determining worse results in
terms of mortality, previously hyporesponsive to the ESA (ferric state actually representing a deficit or decreased
availability from the deposits, acute
inflammation or chronic microinflammation, secondary hyperparathyroidism, among other factors)?
Recently, we are reaching a crucial moment and are currently analysing a
prospective, phase IV, multicentre,
open, non-controlled study, to assess the
effectiveness of Cuban rhEPO. We are
assessing haemoglobin levels and rhEPO doses employed over a period of 12
months, the type of response over time
(variability), and adverse events. We included 617 patients from 15 nephrology
departments throughout Cuba.4
This study highlights problems in controlling haemoglobin levels and rhEPO
doses similar to those detected in other
international studies.5
I have summarised my opinion based
on the current evidence, as a strategy
for guaranteeing efficient ESA use with
minimum risks and in line with good
clinical practice:
1. Avoid blood transfusions.
2. Start rhEPO treatment in renal
anaemia patients with haemoglobin
of 10g/dl.
3. Keep haemoglobin levels between
11.5g/dl and 13g/dl.
4. Never try and reach the latter by increasing rhEPO doses.
5. Question rhEPO doses over
8000U/week.
6. Use the best intravenous iron products
available, depending on the elements
of iron metabolism for each patient.
7. Increase the clinical method, scientific
and rigorous search of the factors concerning a lack of response that are associated with ESA, undertake energetic and effective actions on this, and
on those well identified mortality factors for patients with stage 5 CKD.
In summary, we must be careful in our
prescription and assess the risk-benefit for
each haemoglobin level, in accordance
with each patient’s characteristics and
needs. We must consider that an inadequate EPO response or using it at a high
dosage is a risk marker for mortality.
We must not forget that stage 5 CKD
patients are becoming increasingly
more heterogeneous with regards epidemiological and clinical aspects and
related comorbidities.
1. De Bakris G, Singh A. Managing anemia in
CKD-new insights on a challenging problem.
Medscape Nephrology, December 2010.
http://www.medscape.com/viewarticle/733117
2. Solomon SD, Uno H, Lewis EF, Eckardt KU,
Lin J, Burdmann EA, et al., Trial to Reduce
Cardiovascular Events with Arasnep
Therapy
(TREAT)
Investigators.
Erytrhopoietic response and outcomes in
kidney disease and type 2 diabetes. N Engl
J Med 2010;362(12):1146-55.
3. Ortega LM, Contreras G. El impacto clínico
de los efectos fisiológicos de la
eritropoyetina (EPO) y de los agentes
estimulantes de la eritropoyetina en la
incidencia de malignidad, trombosis e
hipertensión: más allá de la anemia.
Nefrologia 2009;29(4):288-94.
4. Hasegawa T, Bragg-Gresham JL, Pisoni RL,
Robinson BM, Fukuhara S, Akiba T, et al.
Changes in anemia management and
hemoglobin levels following revisión of a
bundling policy to incorpórate recombinant
human erythroppoietin. Kidney Int.
Published online 20 October 2010.
5. Pérez-Oliva DJF. Effectiveness and Safety of
ior EPOCIM in patients with Chronic Renal
Failure on dialysis methods. Registro
Público Cubano de Ensayos Clínicos.
Reference
Number:
24-076-07-B.
Secondary Identifying Numbers: IIC RD091. http://registroclinico.sld.cu/ Centro
Nacional Coordinador de Ensayos Clínicos.
J.F. Pérez-Oliva Díaz
Kidney.
Dialysis and Transplant Programme Director.
Dr Abelardo Buch López National Institute of
Nephrology. Havana, Cuba.
Correspondence: J.F. Pérez-Oliva Díaz
Dirección de Atención al Programa de
Enfermedad Renal, Diálisis y Trasplante Renal.
Instituto Nacional de Nefrología Dr. Abelardo
Buch López, 26 y Boyeros.
10600. La Habana, Cuba.
[email protected]
[email protected]
B) BRIEF CASE REPORTS
Listeria
monocytogenes: an
infrequent cause of
peritonitis in peritoneal
dialysis
Nefrologia 2011;31(3):362-5
doi:10.3265/Nefrologia.pre2010.Sep.10631
To the Editor,
Peritoneal infections are a serious
complication in peritoneal dialysis and
362
can affect the clinical state of the patient and technique viability.1 Gram
positive bacteria are most frequently
involved (coagulase negative Staphylococcus [40%-60%], Staphylococcus
aureus [10%-20%] and Streptococcus
[10%-20%]). Of all peritonitis, 5%20% are due to gram negative organisms. Other germs, which represent
less than 5% of cases, are other bacteria, fungi and protozoa.1
There are not many cases of Listeria
monocytogenes peritonitis published
in the literature, and they generally affect immunocompromised patients.2-12
We present the case of a patient undergoing peritoneal dialysis due to heart failure resistant to diuretics. This is the first
case of Listeria monocytogenes infection
in the peritoneum in our hospital.
We present a 64-year-old man who underwent an operation for tetralogy of Fallot
when he was younger. He later developed
a severe right heart failure and eventually
became resistant to diuretics. This caused
Nefrologia 2011;31(3):358-78
him to be admitted to hospital on several
occasions for anasarca and acute renal
failure. He was rejected for a heart transplant because he had severe pulmonary
hypertension. Given this situation, he was
entered onto a peritoneal ultrafiltration
programme (May 2006), having a single
night exchange of 2l of icodextrin.
The patient arrived at the emergency department with abdominal pain, moderate
diarrhoea and cloudy peritoneal drainage
fluid. He did not complain of fever, vomiting or focal neurological or infectious
signs. He had no family history of food
borne diseases and he was not aware of
having made any mistakes with the dialysis technique, which would have caused
the equipment to become unsterile. This
patient had already suffered two other
peritonitis, with negative peritoneal fluid
culture. He was treated successfully with
wide spectrum antibiotics (vancomycin
and ceftazidime), recovering without any
major problems.
When he was admitted, signs of distension
and pain were noted upon abdominal palpation. Analytical tests showed: leukocyte
count: 8900/µl, 84% neutrophils, haemoglobin: 12.1g/dl; platelets: 163 000/µl;
urea: 60mg/dl, creatinine: 1.7mg/dl; normal hepatic enzymes; peritoneal leukocytes count: 8800/µl, 96% neutrophils.
The Gram staining of the peritoneal fluid
revealed single and short-chain bacilli.
Empirical intraperitoneal antibiotic treatment was started with vancomycin and
ceftazidime. Small, translucent, grey
colonies with a discreet beta haemolysis
area were found in the peritoneal fluid on
blood agar plate cultures following aerobic
incubation at 37ºC (pH 7.2-7.4), indicating
Listeria monocytogenes. Faecal samples
were cultivated. They were negative for
Listeria, although it was provided after antibiotic treatment had been started which
could have halted its growth. Initial antibiotics were substituted for intravenous
ampicillin and intraperitoneal gentamicin.
The infection started responding to the antibiotics after 72 hours. Specific antibiotic
therapy was maintained for three weeks.
Listeria monocytogenes is the only Listeria
among the seven known species that can inNefrologia 2011;31(3):358-78
fect human beings. It is an aerobic gram
positive germ (in certain circumstances can
also behave like an anaerobic one) which
cannot form spores. Despite being present
in the environment, it does not usually cause
humans to become ill. An incidence of 0.7
cases/100 000 has been calculated.13 The
elderly, newborns, cancer patients, cirrhotic
and immunocompromised patients are
more susceptible to contracting a Listeria
infection. The most common clinical signs
include meningitis, endocarditis, gastroenteritis, miscarriage and bacteraemia. Peritonitis caused by Listeria is a rare, dangerous form of the complication. Spontaneous
forms of peritonitis caused by Listeria are
well known, especially in cirrhosis patients.13 Around 50 cases have been published and most of them describe Spanish
patients.14 The geographical predilection in
Spain is not entirely understood, but may be
due to eating habits including the consumption of incorrectly pasteurised dairy products or raw fruit and vegetables.14
For patients undergoing dialysis, peritonitis caused by Listeria is very rare.
Table 1 shows the cases published to
date in the medical literature. All cases
have occurred in immunocompromised
patients, due to illness or medication.
It has been reported that natural killer
cells (non-antigen first line of defence) in
heart failure patients are in a situation of
anergy and respond less to the molecules
that usually stimulate them, such as interleukin-2 and interferon-gamma. These
patients are therefore considered to be at
greater risk of developing infections given their immunocompromised sitution.15
Listeria is one of the most virulent
pathogens which cause food borne diseases. It has a mortality rate of 20%-30%,
higher than almost all other food borne illnesses. It was difficult to find the source of
infection in our patient, but given that he
lives in a rural area it is possible that he ingested incorrectly pasteurised dairy products, which would have caused this germ
to colonise the intestine. The bacteria
would have then invaded the mucosa,
reaching the peritoneum. Unfortunately,
this has not been confirmed, given that the
faecal culture sample was provided after
antibiotic treatment had been started.
However, the hypothesis mentioned above
seems the most plausible.12 Furthermore,
chronic heart failure could have been involved in this process. In this situation, the
patient would have intestinal oedema, increased permeability and would be more
susceptible to bacterial invasion.16
The antibiotic treatment of choice for Listeria infection is penicillin or ampicillin,
which can be administered in combination
with aminoglycosides or not.12 However,
there is no clear indications as to which
treatment is better for peritonitis caused by
Listeria, or how long treatment should last.
Vancomycin may not be effective since
Listeria is an intracellular microorganism.5,6,9 Both trimethoprim-sulfamethoxazole and erythromycin have been used successfully for patients allergic to
penicillin.2,12 For most cases, peritonitis responds rapidly and effectively to antibiotics, without needing to withdraw the
peritoneal catheter.
In summary, we must remember that Listeria monocytogenes is a germ that can
cause peritonitis in patients undergoing
peritoneal dialysis, where rod-shaped
gram positive bacteria can be found,
even in patients considered immunocompetent. Above all, prevention is the
best weapon to combat this zoonosis.
1. Piraino B, Bailie GR, Bernardini J, et al.
Peritoneal
dialysis-related
infections
recommendations: 2005 update. Perit Dial
Int 2005;25:107-31.
2. Myers JP, Peterson G, Rashid A. Peritonitis
due to Listeria monocytogenes complicating
continuous ambulatory peritoneal dialysis. J
Infect Dis 1983;148:1130.
3. Korzets A, Andrews M, Campbell A, Feehally
J, Walls J, Prentice M. Listeria monocytogenes
peritonitis complicating CAPD. Perit Dial Int
1989;9:351-2.
4. Allais JM, Cavalieri SJ, Bierman MH, Clark
RB. Listeria monocytogenes peritonitis in a
patient on continuous ambulatory peritoneal
dialysis. Nebr Med J 1989;74:303-5.
5. Al-Wali WI, Baillod R, Hamilton-Miller JM, Kyi
MS, Brumfitt W. Listeria monocytogenes
peritonitis during continuous ambulatory
peritoneal dialysis (CAPD). Postgrad Med J
1990;66:252.
363
6. Dryden MS, Jones NF, Phillips I. Vancomycin
therapy failure in Listeria monocytogenes
peritonitis in a patient on continuous
ambulatory peritoneal dialysis. J Infect Dis
1991;164:1239-40.
7. Hart KA, Reiss-Levy EA, Trew PA. Listeria
monocytogenes peritonitis associated with
CAPD. Med J Aust 19991;154:59-60.
8. Lunde NM, Messana JM, Swartz RD.
Unusual causes of peritonitis in patients
undergoing continuous peritoneal dialysis
with emphasis on Listeria monocytogenes. J
Am Soc Nephrol 1992;3:1092-7.
9.
Banerji C, Wheeler DC, Morgan JR.
Listeria monocytogenes CAPD peritonitis:
failure of vancomycin therapy. J
Antimicrob Chemother 1994;33:374-5.
10. Tse KC, Li FK, Chan TM, Lai KN. Listeria
monocytogenes peritonitis complicated by
septic shock in a patient on continuous
ambulatory peritoneal dialysis. Clin Nephrol
2003;60:61-2.
11. Stylianou K, Passam A, Papoutsakis A,
Perakis K, Kroustalakis N, Daphnis E. Listeria
monocytogenes Peritonitis in a Peritoneal
Dialysis Patient with Severe Heart Failure.
Kidney 2008;17:238-40.
12. Ahmad M, Krishnan A, Kelman E, Allen V,
Bargman JM. Listeria monocytogenes
peritonitis in a patient on peritoneal dialysis:
Table 1. Characteristics of 11 cases of peritonitis caused by Listeria monocytogenes in patients undergoing peritoneal dialysis
Ref.
Age
/
Sex
Underlying
disorders
Drugs
used
Previous
peritonitis
episodes
Signs
Antibiotic treatment
Duration
of
treatment
Catheter
withdrawal
Results
[2]
71/F
ITP
Prednisone
None
Abdominal
pain,
cloudy fluid
I.V. and I.P. erythromycin
and I.V. co-trimoxazole
(allergic to penicillin)
Not known
No
Cure
[3]
50/F
SLE
Prednisone,
azathioprine
Staphylococcus
aureus
11 months before
Abdominal
pain,
cloudy fluid
Gentamicin +
ampicillina ampicillin
4 weeks
No
Cure
[4]
31/F
SLE
Prednisone
Not known
Abdominal pain,
cloudy fluid
Vancomycin at start;
ampicillin once
vancomycin
failed
Not known
No
Cure
[5]
53/M
Wegener’s
Granulomatosis
COX 25mg
No
Abdominal pain,
cloudy fluid
I.P. Ampicillin and
P.O. pivampicillin
following
vancomycin
failure
3 weeks
No
Cure
[6]
60/M
LLC
Prednisone
Not known
Fever, abdominal
pain, cloudy
fluid
Oral amoxicillin
1g and I.V.
following
vancomycin failure
10 days
No
Curación
[7]
67/M
Cirrhosis
None
Abdominal pain,
cloudy fluid
Ampicillin following
vancomycin
and gentamicin
failure
Not known
No
Not known
[8]
38/F
CGN, kidney
transplant lost
Negative culture
for 2 years,
gram positive
1 year ago
Abdominal pain,
cloudy fluid,
nausea, mild
diarrhoea
Tobramycin
+ amikacin
2 weeks
No
Cure
[9]
64/M
Polymyositis
Prednisone
None
Abdominal
pain,
cloudy fluid
I.P. vancomycin +
gentamicin,
after failure, I.P. ampicillin
and gentamicin
10 days +
4 weeks
No
Cure
[10]
38/F
SLE
Prednisone,
azathioprine
None
Fever,
cloudy fluid,
septic shock
I.V. ampicillin +
amikacin
4 weeks
No
Cure
[11]
68/M
Prosthetic,
valves, EHD,
ischaemic renal failure
kidney failure
None
Abdominal pain,
lcloudy fluid,
fever, nausea,
vomiting,
shock
I.P. vancomycin
and netilmicin
3 weeks
+ 6 weeks
No
Resolved but
death
due to
decompensated
heart failure
[12]
28/F
SLE
Negative culture
11 months ago,
CNS and SV
4 months ago
Abdominal pain,
cloudy fluid,
nausea,
conjunctivitis
I.P. Cephalosporins
and ampicillin
3 weeks
No
Cure
OC
64/M
TF, EHD,
ischemic renal failure
Two episodes
with negative
cultures
Abdominal pain,
cloudy fluid
and IV ampicillin
I.P. vancomycin
+ ceftazidime, then
I.P. gentamicin.
3 weeks
No
Cure
OC: our case; M: male; F: female; ITP: idiopathic thrombocytopenic purpura; SLE: systemic lupus erythematosus; CLL: chronic lymphocytic leukaemia; CGN: chronic glomerulonephritis; TF: tetralogy
of Fallot; EHD: end stage heart disease; COX: cyclophosphamide; CNS: coagulase-negative staphylococcus; SV: streptococcus viridans; IP: intraperitoneal; P.O.: per os; I.V.: intravenous.
364
Nefrologia 2011;31(3):358-78
13.
14.
15.
16.
a case report and review of the literature. Int
Urol Nephrol 2008;40:815-9.
Frachtman S, Lu L, Lau M, Greenberg S.
Spontaneous Bacterial Peritonitis Due to
Listeria monocytogenes: A Case Report and
a Review of Listeria monocytogenes
Peritonitis. Infect Dis Clin Pract 2009;17:635.
Nolla-Salas J, Almela M, Gasser I, Latorre C,
Salvadó M, Coll P. Spontaneous Listeria
monocytogenes peritonitis: a populationbased study of 13 cases collected in Spain.
Am J Gastroenterol 2002;97:1507-11.
Vredevoe DL, Moser DK, Gan XH, Bonavida
B. Natural killer cell anergy to cytokine
stimulants in a subgroup of patients with
heart failure: relationship to norepinephrine.
Neuroimmunomodulation 1995;2:16-24.
Sandek A, Bauditz J, Swidsinski A, et al.
Altered intestinal function in patients with
chronic heart failure. J Am Coll Cardiol
2007;50:1561-9.
O. Benjelloun, J.E. Sánchez Álvarez,
C. Rodríguez Suárez, I. González,
A. Fernández-Viña, M. Núñez, B. Peláez
Clinical Management Area in Nephrology and
Bone-Mineral Metabolism. Central Asturias
University Hospital. Oviedo, Asturias, Spain.
Correspondence: J.E. Sánchez Álvarez
Área de Gestión Clínica de Nefrología
y Metabolismo Óseo y Mineral. Hospital Universitario
Central de Asturias,Celestino Villamil, s/n.
33006 Oviedo. Asturias. Spain.
[email protected]
[email protected]
Arterial hypertension
induced by
pyeloureteral stenosis
in horseshoe kidney
Wilms’ tumour or urothelial tumour.1
We present the case of a 27-year-old
male, who came to the emergency department for abdominal pain located in the
left flank. From his medical record, we
discovered that he had a recent history of
arterial hypertension (AHT). His blood
pressure was 160/90mm Hg in the physical examination. We performed an abdominal ultrasound (not shown) in which
cystic images were observed on the superior pole of the left kidney, which presented with a mild cortical atrophy. Given that
a kidney disease was suspected, a computerised tomography (CT) scan was performed, showing that the cystic images
corresponded to dilation of the pyelocaliceal system (Figure 1) in a HK (Figure
2). We performed a left pyeloplasty which
resolved the obstructive problems: the patient being asymptomatic at present.
HK is the most common type of renal fusion anomaly. It appears in 1 out of every
400 births, with a higher incidence in men
A
(2:1). The isthmus is usually located anterior to the large abdominal vessels. Hydronephrosis due to obstruction in the
pyeloureteral junction is observed in a
third of all HK, being factors which contribute to the upper ureter entering the renal pelvis and isthmus or blood supply
anomalies.2 It has been documented that
Wilms’ tumours, clear-cell, neuroendocrine,3 and urothelial carcinomas and
nephroblastomas can be found in HK. It
can be associated with congenital, genitourinary,
bone,
gastrointestinal,
myelomeningocele and cardiovascular
anomalies. Pyeloureteral junction stenosis (PJS) is the most common congenital
alteration of the upper urinary tract, and
is most associated with HK. In most cases, PJS is due to a destruction of the muscular fibres and an increase in the amount
of collagen in the pyeloureteral junction.
The most common clinical sign is lumbar
back pain, but for chronic obstruction, activation of the renin-aldosterone system
would lead to vasoconstriction of the afferent arteriole, with a consequent reduction in renal blood flow and AHT developing. In spite of this, given
hydronephrosis and HK, the most common cause is lithiasis, followed by PS.4
HK is diagnosed using imaging tests. CT
with modern multidetectors can perform
a multiplanar reconstruction and confirm
B
Nefrologia 2011;31(2):365-6
doi:10.3265/Nefrologia.pre2010.Sep.10607
To the Editor,
Horseshoe kidney (HK) was first described by Berengario da Carpo in 1552.
Thirty-three percent of cases are asymptomatic and the remaining may present
with complications such as multicystic renal dysplasia, obstructive uropathies, hydronephrosis, lithiasis, infections and
neoplasias such as renal carcinoma and
Nefrologia 2011;31(3):358-78
Figure 1A y B. 1A and B. Abdominal CT scan
after administering I.V. contrast agent. A)
nephrogenic phase. Cystic formation in the left
kidney at the height of the hilum (arrow). B)
Excretory phase. The passage of the contrast
agent is observed, confirming that it corresponds
to dilation of the pyelocaliceal system.
Figure 2. 3D reconstruction of the
previous test; horseshoe kidney with
multiple accessory arteries (arrows).
365
the diagnosis given the ultrasound finding, whereas renal gammagraphy is used
to find out whether the parenchyma is
functioning correctly. Treatment is performed using laparoscopic and endoscopic pyeloplasty in any of its variants. At
present, robotic surgery has proven its
utility in obtaining good pyeloplasty results for primary and secondary stenosis,
both for children and adults and for different causes.5
In summary, when a young patient presents with AHT (related or not to HK), one
should consider that it may owe to a PJS.
Abdominal CT scans are a good diagnostic method for assessing this condition.
1. Andreu García A, Molina Burgos R, Coronel
Sánchez B, Navío Perales J, Botella Almodóvar
R Llamazares Cachá G. Carcinoma renal de
itsmo en riñón en herradura. A propósito de un
caso. Actas Urol Esp. 2008;32(2):249-52.
2. Margreiter M, Hernandez DJ, Lang EK,
Pavlovich CP. Horseshoe kidney with giant
hydronephrosis secondary to ureteropelvic
junction obstruction. J Urol 2010;183(1):329.
3. Boix Orri R, Mora Durban MJ, Sánchez Macías J,
Ruiz Domínguez J, Bernal Salguero S, Areal
Calama J et al. Tumor neuroendocrino en el
riñón en herradura: riesgo relativo de
asociación de dos entidades relacionadas. Arch
Esp Urol 2008;61(7).
4. Cruz Guerra NA, Sáenz Medina J, Tarroc Blanco A.
Hipertensión arterial asociada a estenosis
congénita unilateral de la unión pieloureteral. Arch
Esp Urol 2005; 58(5): 463-6.
5. Pereira Arias JG, Gamarra Quintanilla M,
Gallego Sánchez JA, Camargo Ibergaray I.
Cirugía renal robótica: pieloplastia. Arch
Esp Urol 2007;60(4):449-61.
J.J. Aguilar-García1, A.D. Domínguez-Pérez1,
V. Nacarino-Mejías1, C.I. Ruiz-Guerrero1,
M.A. Iribarren-Marín1, C.J. Ortega-Seda2
1
Diagnostic Radiology Department. Virgen
del Rocío University Hospital, Seville, Spain.
2
Urology Department. Virgen del Rocío
University Hospital. Seville, Spain.
Correspondence: J.J. Aguilar-García
Servicio de Radiodiagnóstico.
Hospitales Universitarios Virgen del Rocío.
Avda. Manuel Siurot, s/n. 41013 Sevilla. Spain.
[email protected]
366
Successful treatment
with sodium
thiosulfate for calcific
uraemic arteriolopathy
Nefrologia 2011;31(3):366-8
To the Editor,
A dermatological manifestation of
chronic kidney disease (CKD) is calcific uraemic arteriolopathy (CUA) or calciphylaxis. It is an anatomopathological
entity characterised by necrosis of the
skin and adipose tissue due to incorrect
calcium salt deposits.1 Morbidity and
mortality of calciphylaxis is high due to
the complications associated with it:
sepsis and ischaemia. Different clinical
entities can manifest calciphylaxis:
rheumatoid arthritis, inflammatory
bowel disease, neoplasias, CKD, systemic lupus erythematosus or HIV infection.1 Its treatment has to be aggressive. Sodium thiosulfate has shown
improvements in skin lesions caused by
calciphylaxis.
Our patient was a 78-year-old man
with history of high blood pressure, diabetes mellitus type 2, dyslipidaemia,
CKD of unknown origin treated with
haemodialysis three times a week for
3hr, mineral and bone disorder associated with CKD (MBD-CKD), auricular
fibrillation and ischaemic heart disease. His usual treatment was sevelamer, enalapril, aspirin, acenocumarol
and insulin.
He was admitted to hospital for painful
skin erythematous lesions with necrotic
edges on both lower limbs, measuring
5x6cm. Physical examination: good
general condition, body mass index: 23;
blood pressure 150/63mm Hg; heart
rate 64bpm; no fever. Cardiopulmonary
and abdominal auscultation: painless.
Lower limbs: normal pulse, with no
sign of deep vein thrombosis and showing previously described lesions.
Analyses: parathyroid hormone (PTH):
826.3pg/ml, calcium: 8.9mg/dl; phosphorus; 7.40; creatinine: 9.8mg/dl; albumin: 3g/dl; urea: 156mg/dl; C-reac-
tive protein; 4.3. A cervical ultrasound
and parathyroid gammagraphy were
performed showing parathyroid hyperplasia free of adenomas. The radiological study (bone series and supra-aortic
trunks Doppler) showed vascular calcifications on the ascending and descending aorta. Given the suspected calciphylaxis, we performed a biopsy of one of
the lesions, with results compatible
with calciphylaxis: lesion with abundant calcium deposits compared with
the walls of small vascular structures.
Swollen septa due to fibrosis (Figure 1).
No signs of necrosis are observed. Lastly, we performed a technetium-99 gammagraphy which did not show that the
calciphylaxis spread to the bones.
We considered MBD-CKD to be the
cause of calciphylaxis and intensified
the treatment for it: daily dialysis of 4hr
was started with low calcium
(2.5mEq/l) in the haemodialysis solution and high flux dialyser. The treatment was intensified with calcium-free
phosphate-binders: lanthanum carbonate: 750mg/8hr and sevelamer:
1600mg/8hr, and PTH control with calcimimetics:
60mg/24hr.
Acenocoumarol was withdrawn and treatment
was started with 80ml of sodium thiosulfate at 25% (20g) following
haemodialysis (three times per week).
Lesions improved 2 months later (Figure 2). Analytical parameters upon discharge: P: 3.6mg/dl; total Ca: 8.9mg/dl;
PTH: 406.90pg/ml.
CUA consists of a hydroxyapatite deposit in the skin and soft tissues with
Figure 1. Lesion on right leg prior to
treatment with thiosulfate.
Nefrologia 2011;31(3):358-78
risk of necrosis. In CKD, CUA physiopathology is due to an alteration in
phosphocalcic metabolism, uraemic
state, increase in PTH (although there
are CUA cases following parathyroidectomy)2, calcium-based phosphate binders and a high calcium concentration in the dialysis solution.3
Phosphate and calcium are bound
producing vascular, skin and organic
calcifications.4
Other predisposing factors are: female
sex,
obesity,5
hypoalbuminaemia
(<2g/dl), diabetes mellitus, C and S
protein deficiency,6 oral anticoagulants
(they inhibit synthesis of 4.8-gammacarboxyglumate)7, intravenous iron and
vitamin D due to its intestinal action on
calcium reabsorption.8
Lesions caused by CUA are often on
the abdomen and the calf area, given
their abundance of subcutaneous tissue. The lesion is similar to livedo
reticularis progressing to ulceration.
Calcium deposits in skin are deposited in the dermis and subcutaneous tissue. Physio-pathogenitically, high levels of urea and phosphorus cause
smooth muscle cells to convert into
osteoblast cells that also increase osteopontin levels, which together with
proinflammatory and free radical molecules, make it easier for phosphorus
to adhere to calcium.1,7,9,10 This magma
is mostly concentrated around calcium
deposits that are also found in the arterioles1 and media of the vessels.
Figure 2. Lesion on right leg after two
months of treatment with sodium
thiosulfate.
Nefrologia 2011;31(3):358-78
The diagnosis is essentially clinical.
Lesion biopsy is not recommended
given the risk of infection and ulceration.10 Gammagraphy with technetium-99 is used to diagnose whether
it has spread to the bones.10 Calciphylaxis has a morbidity and mortality of
80% given the risk of infection and
necrosis.
The CUA therapeutic approach must
be aggressive, controlling its associated alterations (BMD-CKD control),
avoiding agents that could strengthen
it, and curing the lesion and infectious
complications.2 BMD-CKD control
will be performed using calcium-free
phosphate binders, low calcium
haemodialysis and peritoneal dialysis
solutions (CUA can develop above
4mEq/l11) and implementing daily
haemodialysis. PTH control will be
performed using calcimimetics and
vitamin D, preferably vitamin D analogues given that they have a lower
calcifying and hyperphosphatemic effect.2 Parathyroidectomy will be reserved for cases resistant to drug
treatment.
Dermal CUA lesions that have no ulcerations improve with corticoids.10
However, for those with ulceration,
the hyperbaric oxygen chamber is effective against anaerobic organims.11
The sodium thiosulfate (antidote
against cynade, used in skin treatments for acne and pityriasis versicolor, and protection against carboplatin
and cisplatin toxicity) has proven a
successful therapeutic measure in
CUA lessions.5,14 Sodium thiosulfate
inhibits calcium salt precipitation and
dissolves calcium deposits.12,13 It does
not have any effects on levels of calcium, phosphorus or PTH. The recommended dose is 20g I.V., three times a
week during a minimum of 6
months.2,14 Its administration could
lead to metabolic acidosis, osteoclast
activation, volume overload and hypotension.
In summary, CUA is a serious entity
among our patients. Its treatment has
to be aggressive. Sodium thiosulfate is
a valid therapeutic agent for treating
CUA lesions. It is safe to use and the
benefits obtained mean that it can be
considered a first-line drug for CUA
lesions.
1. Cordova K, Oberg T, Malik M, et al.
Dermatologic conditions in end stage renal
disease. Semin Dial 2009;22(1):44-55.
2. Llach F, Goldblatt M, Freundlich RE, et al.
The evolving pattern of calcific uremic
arteriolopathy (calciphylaxis). J Am Soc
Nephrol 2000;11:685A.
3. Llach F. The evolving clinical features of
calciphilaxis. Kidney Int 2003;85:S122S124.
4. Massry SG, Coburn JW, Hartenbower DL,
et al. Mineral content of human skin in
uremia.
Effect
of
secondary
hyperparathyroidism and haemodialysis.
Proc Eur Dial Transplant Assoc
1970;7:146-8.
5. Coates T, Kirkland GS, Dymock RB.
Ischemic tissue necrosis (calciphylaxis) in
renal failure. Am J Kidney Dis
1998;32:384-91.
6. Gipstein RM, Coburn JW, Adams DA, et
al. Calciphylaxis in man. Arch Intern Med
1976;136:1273-80.
7. Kurban M, Boureiz A, Kivi A. Cutaneous
manifestations of chronic kidney disease.
Clin Dermatol 2008;26:255-64.
8. Zacharias JM, Fontaine B, Fine A. Calcium
use increases risk of calciphylaxis: A casecontrol study. Perioneal Dial Int
1999;19:248-52.
9. Rogers N, Teubner D, Coates T. Calcific
uremic arteriolopathy: advances in
pathogenesis and treatment. Semin Dial
2007;20(2):150-7.
10. Fine A, Zacharias J. Calciphylaxis is usually
nonulcerating: Risk factors, outcome and
therapy. Kidney Int 2002;61:2210-7.
11. Vassa N, Twaedowski ZJ, Campbell J.
Hiperbaric oxygen in calciphylaxis-induced
skin necrosis in a peritoneal dialysis
patient. Am J Kidney Dis 1994;23:878-81.
12. Yatzidis H, Agroyannis A, Digenis GE.
Sodium thiosulphate in the treatment of
soft-tissue calcifications in patients with
end-stage renal disease. Peritoneal Dial
Bull 1987;7:250-2.
13. Kyriakopoulos G, Kontogianni K. Sodium
tiosulphate treatment of tumoral
calcinosis in patients with end-stage renal
disease. Renal Failure 1990;12:213-9.
367
14. Cicone JS, Petronis J, et al. Successful
treatment
of
calciphiylaxis
with
intravenous sodium thiosulfate. Am J
Kidney Dis 2004;43(6):1104-8.
L. Salanova Villanueva1,
M. C. Sánchez González1,
J. A. Sánchez Tomero1, P. Sanz2
1
Nephrology Department. La Princesa
University Hospital. Madrid, Spain.
2
Nephrology Department. San Camilo
Hospital. Madrid, Spain.
Correspondence: L. Salanova Villanueva
Hospital Universitario de la Princesa. Plaza de
las Américas, 13, bajo C. 28770 Madrid.
Spain.
[email protected]
Spontaneous remission
of nephrotic syndrome
in a patient with
diabetic nephropathy
and Parkinson's disease
Nefrologia 2011;31(3):368-9
To the Editor,
Parkinson’s disease (PD) is a common
neurodegenerative disease that can be
caused by mitochondrial dysfunction, oxidative stress, apoptosis or inflammation.1
Between 50% and 80% of PD patients
show intolerance to glucose, which can
be exacerbated by levodopa treatment.2
We describe the case of a patient with PD
and poorly controlled diabetes mellitus,
who was initially treated with anti-diabetic drugs and later required insulin therapy and who came for consultation with a
nephrotic syndrome (NS).
The patient was a 74-year-old man with
a 9-year history of diabetes mellitus
(initially treated with anti-diabetic
drugs and for the last 3 years with insulin); diagnosed with infarctional ischaemic heart disease and post-infarction angina, he had undergone double
coronary bypass surgery. Previous
episodes of deep vein thrombosis and
368
pulmonary thromboembolism, and hypercoagulability had been confirmed
(heterozygotic mutation of homocysteine gene). For 10 years he had PD,
which was being treated with carbidopa/entacapone/levodopa, ropinirole
and rasagiline. Other medical conditions included prostate adenoma, hiatus
hernia and chronic renal failure with
previous plasma creatinine levels of
1.4-1.5mg/dl.
The patient was referred to the emergency department by his NS, owing to
symptoms of anasarca. In the days prior to his visit to the emergency department he had noticed a decrease in the
frequency of diuresis accompanied by
weight gain. He did no report bloodstained or dark-coloured urine. A week
before he had developed very itchy petechiae on his arm and the back of his
hands.
The physical examination revealed that
the patient’s general condition was
good, and he was conscious and orientated. There was slight jugular vein ingurgitation and his blood pressure was
150/78mm Hg. Body temperature was
normal. As far as the rest of the examination is concerned, notable symptoms
included pitting oedema of the lower
limbs and signs of venous insufficiency.
In the complementary tests, the blood
analysis showed: haematocrit: 44%,
leukocyte: 7060, platelets: 152 000;
pH: 7.32, bicarbonate: 28mEq/l, glucose: 241mg/dl, creatinine 2.2mg/dl
and calcium 7.7mg/dl. The rest of the
on-the-spot analysis was normal.
In the routine blood analysis the findings were as follows: uric acid:
11.8mg/dl, cholesterol: 297mg/dl,
triglycerides: 141mg/dl, albumin:
1.9g/dl, total protein: 5.2g/dl, LDH:
629U/l, glycosylated haemoglobin:
8.5%. Immunological analysis: C-reactive protein 1.9mg/dl; rheumatoid factor, ASLO, ANCA, antinuclear antibodies, anti-Ro, anti-La, anti-Sm and
anti-RNP antibodies were within normal limits. Tumour markers, including
ACE, CA19-9, AFP and PSA were acceptable. Blood electrophoresis: hypoproteinaemia, reduced albumin levels, raised alpha-2 and beta globulins
with a polyclonal increase in gammaglobulins. Thyroid hormones were normal. Serological tests for the hepatitis C
and HIV virus were negative. HBsAg
positive, anti-HBc and anti-HBs negative; hepatitis B virus DNA less than
2000 copies/ml. Herpes virus 1-2 IgG
positive.
The urine analysis on admission
showed proteins +++, blood ++ and the
presence of casts (cylindruria). Protein
quantification in 24-hour urine was
13g/24 h.
Chest X-ray: enlarged heart with no
signs of acute heart failure. Electrocardiogram: sinus bradyarrhythmia at
50bpm. A Doppler ultrasound scan
showed no pathological findings.
Given the patient’s history of poorly
controlled diabetes mellitus and his admission owing to recent fluid retention,
it was decided that a renal biopsy
should be performed. Our findings were
as follows: six glomeruli, two of which
were completely sclerotic. In two of the
other four glomeruli, focal, nodular lesions of the glomerular tuft (Kimmelstiel-Wilson nodules) were identified.
The result of the immunofluorescence
assay was negative. Moderate interstitial fibrosis associated with tubular atrophy and chronic inflammatory infiltrate was observed. The vascular
component presented no lesions. The
definitive diagnosis was nodular
glomerulosclerosis with a morphological substrate of diabetic nephropathy
(DN).
With this diagnosis, the initially established treatment, which consisted of diuretics, irbesartan, atenolol, statins and
oral anticoagulants, was maintained and
the patient was discharged.
Twelve days later the patient was re-admitted for fluid retention, and he responded favourably to diuretic treatment. Subsequent outpatient follow-up
Nefrologia 2011;31(3):358-78
showed the analytical changes depicted
in Table 1 and the patient has not presented new episodes of fluid retention.
DN is a common complication of diabetes and is currently an important public health problem, as diabetic renal disease is the main cause of terminal
chronic kidney disease in Western
countries.3 Diabetic patients with a history of DN who develop slow-onset
proteinuria, are not usually subjected to
a biopsy, on the assumption of the presence of DN. However, non-diabetic
glomerular disease may also develop in
diabetic patients, which is why a renal
biopsy may be indicated.4 In our case,
the patient had longstanding diabetes
mellitus, which was poorly controlled
metabolically. We are unaware whether
he had proteinuria prior to his first admission, although the onset of anasarca
and fluid retention was sudden, so we
decided to perform a renal biopsy and
the diagnosis was DN.
In the medical literature cases of NS
due to minimal change disease have
been reported in diabetic patients.5,6 In
the case described by Donaire et al, the
suspicion of a cause other than diabetes
was founded on the short history of diabetes, the absence of retinopathy and
the fact that a previous check-up proved
negative for proteinuria.5 Although in
our case the established diagnosis was
DN, the sudden onset of symptoms with
severe proteinuria which led to fluid retention on more than one occasion and
subsequently spontaneous remission,
and then a proteinuria of less than
0.5g/24 h during follow-up, suggested
the possibility that the patient might
have a comorbid minimal change
nephropathy. This might have gone unnoticed during the histological analysis
when an underlying DN substrate was
found and electron microscopy test was
not performed. The patient might have
had an unrelated infectious process prior to his first admission. In fact, he had
developed cutaneous lesions on his upper limbs. This process could have been
triggered by an immune mechanism,
leading to an increase in glomerular
permeability and, subsequently, severe
NS with spontaneous remission some
months later.
To conclude, we described a case of NS
with clinical symptoms indicating a
minimal change aetiology, which could
have gone unnoticed in the renal biopsy because we found a DN histological
substrate associated to the base pathology (long-term diabetes mellitus).
1. Samii A, Nutt JG, Ransom BR. Parkinson´s
disease. Lancet 2004;363:1783-93.
2. Sandyk R. The relationship between
diabetes mellitus and Parkinson´s disease.
Int J Neurosci 1993;69:125-30.
3. Van Dijk PC, Jager KJ, Stengel B,
Gronhagen-Riska C, Feest TG, Briggs JD.
Renal replacement therapy for diabetic
and stage-renal disease: data from 10
registries in Europe (1991-2000). Kidney
Int 2005;67:1489-99.
4. Castellano I, Covarsi A, Novillo R, GómezMartino JR, Ferrando L. Lesiones histológicas
Table 1. Follow-up of laboratory results
Baseline
First
Second
Visit
admission admission (first month)
Consultation
Visit
Consultation
(second month) (third month) (fifth month)
PCR (mg/dl)
1.5
2.2
2
1.8
1.7
1.6
1.6
Albumin
3.8
3
2.7
2.2
2.5
3.1
4
172
270
310
273
171
26
17
5.95
5.06
0.47
0.34
41
40
34
42
34.7
47
(g/dl)
Cholesterol
104
(mg/dl)
Proteinuria
(g/24h)
CrCl (ml/min)
PCR: plasma creatinine; CrCl: creatinine clearance.
Nefrologia 2011;31(3):358-78
renales en pacientes con diabetes mellitus
tipo II. Nefrologia 2002;22:162-9.
5. García-Donaire JA, Manzanera MJ,
Valentín MO, Espejo B, Gutiérrez Martínez E,
Praga M. Síndrome nefrótico recidivante
por lesiones mínimas en un paciente
diabético. Nefrologia 2004;24(2):179-82.
6. Enríquez R, Sirvent AE, Padilla S,
Andrada E, Amorós F, Fernández-Lozano
JA, et al. Remission of minimal change
disease
in type 2 diabetes after
streptococcus bacteremia. Clin Nephrol
2009;71(2):179-82.
M. Heras1, A. Sáiz2, M.J. Fernández-Reyes1,
R. Sánchez1, A. Molina1, M.A. Rodríguez1,
F. Álvarez-Ude1
1
General Hospital of Segovia.
2
Anatomical Pathology Department.
Ramón y Cajal Hospital . Madrid, Spain
Correspondence: M. Heras
Hospital General de Segovia.
Ctra. de Ávila, s/n. 40002. Segovia. Spain.
[email protected]
[email protected]
Immunotactoid
glomerulopathy
and tuberculosis:
a novel association
Nefrologia 2011;31(3):369-71
To the Editor,
Tuberculosis is associated with a variety
of glomerular manifestations. However,
association
with
immunotactoid
glomerulopathy has never been reported.
We encountered a case of 37-year-old
gentleman with such a novel presentation.
A 37-year-old gentleman presented with
swelling all over the body for 6 weeks. His
past history revealed recent history of
pulmonary tuberculosis 9 weeks back. He
was presently on 2 drug anti-tubercular
treatment (ATT) (isoniazid and rifampicin)
after first 8 weeks of 4 drugs, which
additionally included pyrazinamide and
ethambutol. At the time of diagnosis of
tuberculosis, he was also found to have
369
stage 1 hypertension and was started on
hydrochlorthiazide 12.5 mg daily. There
was no history of hematuria, past renal
disease or any other systemic disorder.
Physical examination revealed pitting
edema and no other notable findings.
Laboratory data showed hemoglobin
10.1 g/dl, white cell counts of 6800,
blood urea 68 mg/dl, serum creatinine
1.4 mg/dl, eGFR by MDRD formula 59
ml/min/1.73 m2, protein 4.5 g/dl,
albumin 1.7 g/dl, cholesterol 356 mg/dl,
Hepatitis-B and C and HIV-1 and 2
negative, ANA and cryoglobulins
negative, normocomplementemia, urine
–, protein 3+, RBC 4-6 and WBC 12/hpf, casts-nil and 24-hr urine protein
4.8 g (non-selective). Liver functions
tests were within normal limits. An
ultrasound guided renal biopsy was
performed.
On light microscopy, glomeruli exhibited
varying degrees of mesangial expansion,
negative silver staining and congo red
staining and some thickening of peripheral
capillary walls. Immunoflourescence was
positive only for IgG in mesangium and
peripheral capillary walls. Electron
microscopy showed microtubules >30 nm
arranged focally in parallel in mesangium
suggesting
immunotactoid
glomerulopathy (ITG) (figure 1). Further
work-up showed a negative serum and 24hr urine immuno-fixation electrophoresis.
Imaging
studies
done
for
lymphoproliferative disease as an etiology
were negative too.
He was treated with ATT for a total of
6 months. His blood pressures were
kept under control with ramipril 10 mg
daily. His proteinuria decreased to
1.1g/day at 6 months. At 2 years of
follow-up, his serum creatinine is 3
mg/dl with eGFR of 23. We offered a
repeat renal biopsy during this period
which the patent did not consent.
ITG is distinct rare morphologic entity
characterized by microtubular glomerular
deposits often ranging from 34 to 49 nm
in diameter organized in parallel arrays. It
usually occurs in older individuals
presenting with nephrotic syndrome,
370
tered and retained immunoglobulins.
This would end up in formation of
immunotactoids.
The treatment strategies for ITG have been
variable, though there has been a case of
ITG exhibiting nephrotic syndrome
successfully treated with corticosteroids
and antihypertensive therapy10. We did not
subject our patient to steroids as there was
a potential risk of flaring tuberculosis with
high doses of corticosteroids. However, we
did not try rituximab as data for this agent
is limited at present5.
Figure 1. Microtubular deposits of >30
nm seen in mesangium (on electron
microscopy magnification x15000).
hematuria and renal insufficiency. The
term was introduced by Schwartz et al in
1980’s, where they described this disease
as a glomerular disease characterized by
highly organized crystalline structure
of immune deposits in absence of
systemic diseases such as amyloidosis,
cryoglobulinemia, paraproteinemia,
and systemic lupus erythematosus1. In
most instances, an underlying
lymphoproliferative disorder is found.
Association with HIV, sickle cell
disease, hypereosinophilic syndrome
and recurrence in transplanted kidneys
has been reported2-5.
Our case showed a temporal association
with tuberculosis. Though tuberculosis or
its treatment is shown to be linked to a
variety of glomerular diseases such as
amyloidosis, minimal change disease,
IgA nephropathy, and collapsing
glomerulopathy6-9 but as causality with
ITG has never been reported. It is difficult
to prove whether tuberculosis per se
caused ITG, however treatment of
tuberculosis resulted in partial remission.
The exact pathogenesis of ITG remains to be elucidated. Like lymphoproliferative diseases, tuberculosis is
also an inflammatory disorder. It
might be possible that immune dysregulation in tuberculosis or systemic
inflammatory mediators cause defects in critical podocyte cellular
functions involved in clearance of fil-
Our patient was relatively young as
compared to most other cases and
progressed to chronic kidney disease stage
4 over a span of 2 years. The natural course
of the disease is progression to end-stage
renal disease (ESRD) within 7 months to
10 years. However, in a recent report a
patient with a diagnosis of ITG developed
acute kidney injury (AKI) and ESRD
within 1 week of initial presentation11.
To conclude, to the best of our
knowledge, our case is the first report of
an association of ITG with tuberculosis.
There could be a possible causal
relationship between mycobacterial
infections and ITG. In addition to search
for lymphoproliferative disorder and
HIV, tuberculosis as an etiology should
be kept in mind in a case of ITG.
1. Korbet SM, Schwartz MM, Rosenberg BF,
Sibley RK, Lewis EJ. Immunotactoid
glomerulopathy. Medicine (Baltimore)
1985;64:228-43.
2. Chen C, Jhaveri KD, Hartono C, Seshan SV.
An uncommon glomerular disease in an
HIV patient: value of renal biopsy and
review of the literature. Clin Nephrol
2011;75:80-8.
3. Aviles DH, Craver R, Warrier RP.
Immunotactoid glomerulopathy in sickle
cell anemia. Pediatr Nephrol 2001;16:82-4.
4. Choi YJ, Lee JD, Yang KH, Woo JY, Kim BK,
Bang BK, et al. Immunotactoid glomerulopathy
associated with idiopathic hypereosinophilic
syndrome. Am J Nephrol 1998;18:337-43.
5. Sathyan S, Khan FN, Ranga KV. A case of
recurrent immunotactoid glomerulopathy
in an allograft treated with rituximab.
Nefrologia 2011;31(3):358-78
6. Krishnamurthy S, Samanta D, Yadav S.
Renal
amyloidosis
secondary
to
childhood tuberculosis: a report of two
cases. J Postgrad Med 2009;55:121-3.
7. Mori S, Matsushita Y, Arizono K. Minimalchange nephrotic syndrome associated
with isoniazid in anti-tuberculosis
chemoprophylaxis for a patient with
rheumatoid
arthritis.
Intern
Med
2011;50:253-7.
8. Ortmann J, Schiffl H, Lang SM. Partial
clinical remission of chronic IgA
nephropathy with therapy of tuberculosis.
Dtsch Med Wochenschr 2010;135:1228-31.
9. Rodrigues CE, Sette LH, Torritani J,
Malheiros DM, Titan SM, Barros RT, et al.
Tuberculosis-associated
collapsing
glomerulopathy: remission after treatment.
Ren Fail 2010;32:143-6.
10. Kinomura M, Maeshima Y, Kodera R,
Morinaga H, Saito D, Nakao K, et al. A
case of immunotactoid glomerulopathy
exhibiting
nephrotic
syndrome
successfully treated with corticosteroids
and antihypertensive therapy. Clin Exp
Nephrol 2009;13:378-84.
11. Jain S, Chhabra D. A case of
immunotactoid glomerulopathy with rapid
progression to end-stage renal disease.
Scientific World J 2009;9:1348-54.
A. Gupta, A. Khaira
Division of Nephrology. University of Ottawa.
Ottawa, Ontario (Canada).
Correspondence: A. Gupta
Division of Nephrology.
University of Ottawa, Riverside Drive,
K1G0E8, Ottawa, Ontario. Canada.
[email protected]
[email protected]
Sarcoidosis: diagnosis
from the renal function
and hypercalcaemia
study
Nefrologia 2011;31(3):371-2
To the Editor,
Sarcoidosis is a multi-systemic granulomatous disease of unknown aetiology,
which is characterised by the presence
Nefrologia 2011;31(3):358-78
of non-caseating epithelioid granulomas. Renal involvement is uncommon
in sarcoidosis and, in cases where it
does occur, it is associated with hypercalcaemia, hypercalciuria, increased
levels of calcitriol and parathyroid hormone (iPTH) suppression.1
We present the case of a 64-year-old male
patient with a family history (patient’s father) of emphysema. Incidents of note in
his medical history include various
episodes of macrohaematuria when the
patient was 15, pleuritis at the age of 30,
rhinitis at the age of 60 and glaucoma. He
was admitted to the nephrology department with suspected renal failure. The patient presented toxic syndrome and had
been vomiting and suffering from diarrhoea for two months. The only notable
findings during the physical examination
were a painful, enlarged spleen and high
blood pressure (162/90mm Hg). The following analytical findings were of note:
haemoglobin:
11.7mg/dl,
calcium:
12.0mg/dl, phosphorus: 3.0mg/dl, iPTH:
0.3pg/ml (normal values 10-65pg/ml),
alanine aminotransferase (ALT): 22U/l,
aspartate aminotransferase (AST): 69U/l,
gamma glutamyl transpeptidase (GGT):
69U/l, ferritin: 495ng/ml, uric acid:
7.0mg/dl, urea: 56mg/dl, creatinine:
2.13mg/dl, estimated glomerular filtration
rate (eGFR): 33ml/min, proteinuria:
0.334g/24 hours and in the sediment there
were only 10-20 erythrocytes per field.
Calciuria was 896mg/24h. Angiotensin
converting enzyme (ACE) levels: 167U/l
(normal range 8-55), 25-(OH)-vitamin
D3: 69pg/ml (normal range 9-52), 1,25(OH)2-vitamin D3: 89pg/ml (normal
range 15-60pg/ml). The other biochemical
parameters, and the immunological and
tumour marker results were normal. The
chest X-ray revealed an interstitial pattern
at the base of the right lung. In the thoraco-abdominal computed tomography
(CT) scan, the lung parenchyma analysis
showed diffuse, non-specific interstitial
reinforcement in both lungs. The abdominal exploration revealed small inflammatory/reactive retroperitoneal adenopathies,
homogenous spleen enlargement and bilateral renal microlithiasis. A renal ultrasound scan confirmed the morphology,
position and size of the kidneys to be nor-
mal. Gammagraphy with gallium revealed
moderately severe inflammation of the
parotid glands and the base of the right
lung. The renal histology tests detected 13
diagnostically useful glomeruli. Three of
them were completely sclerotic, and the
rest had preserved their structure and morphology. Focal ischaemic ondulations and
minimal mesangial segmental increases
were identified. Glomerular cell proliferation was not observed. No granulomas
were observed, and patches of interstitial
fibrosis and tubular atrophy, which together accounted for 10% of the cylinder, were
identified. Two interlobular arteries without morphological changes were identified. Immunofluorescence assays using
anti-IgG, IgA, IgM and C1q, C3, kappa
and lambda sera were negative. Pulmonary histology samples obtained by fibrobronchoscopy and transbronchial
biopsy showed the presence of a noncaseating granuloma.
Sarcoidosis was diagnosed and prednisone was administered, starting with a
dose of 1mg/kg body weight and progressively reducing the dose from the first
month onwards. After three months, the
constitutional syndrome disappeared, progressive weight gain was achieved and renal function improved significantly (creatinine 1.3mg/dl and eGFR 58.8ml/m). The
patient’s calcaemia (calcium 8.9mg/dl)
and anaemia (Hb 13.0mg/dl) were corrected and his iPTH (32pg/ml) and ACE
(13U/l) levels were normal.
Sarcoidosis is a multi-systemic disease
of unknown aetiology and the pulmonary and lymphatic systems are the
most commonly affected (30%-60% of
cases). Hypercalcaemia (2%-10%) and
hypercalciuria (6%-30%) can cause
nephrocalcinosis, lithiasis and renal insufficiency. The prevalence of tubulointerstitial nephritis ranges from 7% to
27%, although chronic renal failure develops in less than 1% of cases, according to a number of retrospective studies.2 Sarcoidosis patients often have
high levels of vitamin D and ACE,
which are synthesised by the epithelioid
cells of the granuloma.3,4 In the case that
we present the clinico-radiological involvement was minimal and the diagno371
sis was confirmed by transbronchial
biopsy. The analytical profile was indicative of sarcoidosis (hypercalcaemia, hypercalciuria, high levels of vitamin D and
ACE and substantial iPTH suppression).
Membranous
glomerulonephritis
in a patient with syphilis
Nefrologia 2011;31(3):372-3
Renal function impairment in sarcoidosis
is generally due to hypercalcaemia, hypercalciuria and nephrocalcinosis, although
nephrolithiasis, glomerulopathies and interstitial nephritis (with or without sarcoid
granuloma) form part of the spectrum of
renal pathologies in sarcoidosis.1
Corticosteroids5 are the treatment of
choice and in the case presented here a
good response was obtained. Renal involvement without the lungs being affected is very rare2 and in this case it was
not possible to establish that this was the
case until the lung biopsy was performed. When we are faced with a case
of renal failure associated with hypercalcaemia, sarcoidosis should be suspected,
even though there is no clinical manifestation of lung pathology.
1. Gobel U, Kettritz R, Schneider W, Luft F.
The protean face of renal sarcoidosis. J Am
Soc Nephrol 2001;12(3):616-23.
2. Baughman RP, Teirstein AS, Judson MA,
Rossman MD, Yeager H Jr, Bresnitz EA, et al.
Clinical characteristics of patients in a case
control study of sarcoidosis. Am J Respir Crit
Care Med 2001;164(10 Pt 1):1885-9.
3. Sharma OP. Vitamin D, calcium, and
sarcoidosis. Chest 1996;109(2)535-9.
4. Romer FK. Angiotensin-converting enzyme
in sarcoidosis. Acta Med Scand 1979;206(12):27-30.
5. Nunes HBD, Valeyre D. Sarcoidosis
treatment. Rev Prat 2008;58(10):1099-104.
O. Ibrik1, R. Samon1, A. Roda1, R. Roca1,
J.C. González1, J. Viladoms1, J. Vilaseca2,
M. Serrano2
1
Servicio de Nefrología. Hospital de Mollet.
Mollet del Vallès. Barcelona. Spain.
2
Servicio de Neumología. Hospital de Mollet.
Mollet del Vallès. Barcelona. Spain.
Correspondence: O. Ibrik
Hospital de Mollet. Ada. dels Pinetons, nº 6-8,
Mollet del Vallés, 08100. Barcelona. Spain.
[email protected]
[email protected]
372
To the Editor,
La glomerulonefritis membranosa Membranous glomerulonephritis (MGN)1 is
the second most prevalent renal pathology to be identified in biopsies. One of
the most common causes of nephrotic
syndrome in the adult population, it is
characterised by the formation of immune complexes, predominantly IgG and
complement, on the subepithelial side of
the glomerular capillaries, and this is associated with increased proteinuria.2
In general, its aetiology is idiopathic or
primary and, less frequently, secondary
(immunological, infectious, drug and
medication-related, or neoplastic).
Unfortunately, it is difficult to distinguish
primary from secondary forms by histological means,2 so explicit clinical information, including the age of the patient,
history of exposure to medicines or toxic
substances, serological tests and suspected neoplasias which are linked to the
pathology, is required.
The importance of serological tests lies in
their ability to confirm the diagnosis. In the
case of syphilis screening, non-treponemal
tests are performed: the VDRL (Venereal
Disease Research Laboratory) and RPR (rapid plasma reagin) tests. If the results are positive, the more specific treponemal tests are
performed to confirm the diagnosis: FTAABS (absorption of fluorescent antibodies by
Treponema) and MHA-TP (Treponema pallidum microhaemagglutination). They must
be repeated three and six months later to ensure the response to treatment.
The case which concerns us is relevant,
owing to the small number of publications on the association between
syphilis and MGN.
The patient was a 27-year-old, white,
Caucasian male with a history of cryp-
torchidism, adenoidectomy and amygdalectomy in childhood. He was an active smoker, a social drinker and a homosexual. Two months before being
assessed by our department and, coinciding with a slight pharyngodynia, an
induration had appeared in the patient’s
right groin, as well as ulcerated serpiginous lesions on the penis and a whitish
urethral discharge, which was initially
treated with azithromycin. While waiting for the serological results, maculopapular lesions were observed in the
surrounding area on the thighs and
trunk. They spread to the patient’s feet
and hands, progressing through different phases with no signs of fever, and
accompanied by oedema of the lower
limbs and genitals, with a slight increase
in the abdominal perimeter and a decrease in diuresis, which is why the case
was reported to us. The patient’s urine
was normal in colour, with no evidence
of dysuria or blood in the urine. Blood
pressure (BP) was within normal limits.
The analytical findings of note were
as follows: urea: 61mg/dl; creatinine:
1.73mg/dl; normal ions; total protein:
4.4g/dl; albumin: 1.8g/dl; total cholesterol: 295mg/dl, HDL: 61mg/dl,
LDL:
206mg/dl,
triglycerides:
140mg/dl and normal hepatic enzyme
levels. Significant findings in the
urine analysis included proteinuria:
13.4g at 24h, 250 red blood cells per
microlitre and a negative leukocyte
count. The haemogram and coagulation were normal, except for an FTP
of 762g/l. Autoimmunity assays: antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies
(ANCA) negative; complement and
protein tests were normal. Serology
tests for hepatitis B (HBV), hepatitis
C (HCV) and human immunodeficiency (HIV) viruses were negative.
Positive 1/32 titre RPR (rapid plasma
reagin) and FTA (anti-Treponema antibody) results.
Renal ultrasound showed the kidneys to
be normal in size. The echocardiogram
was within normal limits and no lung
parenchyma changes were detected in the
chest X-ray.
Nefrologia 2011;31(3):358-78
Given that the data indicated a nephrotic
syndrome, a renal biopsy was performed
and 13 glomeruli were counted. They
were very slightly enlarged with permeable capillary lumens and no mesangial
proliferation or associated inflammatory
component. When Masson’s trichrome
procedure was used, frequent fuchsinstained deposits were observed on the
subepithelial side of the capillary walls.
With methenamine silver no spikes were
recognised. There was no increase in fibrous tissue in the interstitium. There were
areas of chronic inflammatory infiltration,
predominantly containing dispersedly distributed lymphocytes and eosinophils, located around the glomerulus. The tubules
contained occasional hyaline cylinders
and haematic material. The blood vessels
were normal. Immunofluorescence revealed intense granular IgG deposits on
the capillary walls and non-specific traces
of IgM. Anatomopathological diagnosis:
stage 1 MGN.
Treatment was initiated by administering
2.4 million units of intramuscular penicillin G benzathine, intravenous diuretics,
and anti-thrombotic and lipid (cholesterol)-lowering prophylactic drugs.
The patient responded favourably and
blood volume and renal function returned
to normal values (urea 43mg/dl, creatinine 1.28mg/dl) with a clearance rate of
85ml/min/1.73m2. At a check-up the following month the proteinuria had disappeared. 1/2 titre RPR values were obtained at three months and they were
negative at six months.
Syphilis is a sexually transmitted disease
(STD) which is caused by a spirochete
called T. Pallidum. It can be transmitted
by sexual contact (the most common
form of transmission), congenitally via
the placenta, or as a result of an infected
blood transfusion or accidental inoculation. It is known as ‘the great simulator’,
owing to its range of clinical presentations.3 Primary syphilis manifests as an
ulcerated lesion or chancre, which appears two-six weeks after infection. Secondary syphilis is the result of its dissemination via the blood or lymph and its
symptoms are highly varied. Tertiary
Nefrologia 2011;31(3):358-78
syphilis appears months or years after infection if it has not been properly treated.
In developed countries, largely due to the
discovery of penicillin, syphilis was practically wiped out in the 1950s.4 In the
1980s, owing to the concern about the
AIDS epidemic, sexual behaviour changed
and an even greater decrease in its incidence was observed. In recent years we
have been witnessing a resurgence of this
disease in Spain, with an increase in its incidence from 2.57 cases per 100 000 inhabitants in 1995 to 5.70 per 100 000 in
2008,5 and this is also happening in other
European countries and the United States.
The new cases occur predominantly in
young homosexual men and a large proportion of them present coinfection with
HIV (20%-70%, depending on the area in
question).6 Perhaps this is due to a relaxation in sexual behaviour as a result of a reduction in protective measures following
the appearance of highly active antiretroviral therapy (HAART) against HIV.4-7
Although the association between
syphilis and renal disease has been known
for over 100 years,8 there are few cases reported in Spain in reviews on the subject,
which makes diagnosis more difficult, as
it is seldom suspected in clinical practice.
Syphilis can cause a wide variety of
clinical and pathological forms of renal
disease. In addition to MGN, rapidly
progressive GN, diffuse endocapillary
GN with or without extracapillary formation or minimal change GN have
been described.8 Proteinuria is the most
common clinical manifestation. The definitive diagnosis is confirmed by renal
biopsy.
It is important to know the age of the patient and to obtain a detailed clinical history when dealing with nephrotic syndrome. Although it is more common for
MGN to be associated with HBV than
syphilis, we must not forget that, in the
battery of serological tests requested in a
case of nephrotic syndrome, diagnostic
tests for syphilis should be included, more
so knowing that there has been a substantial increase in the number of cases in
Spain in recent years.
In our case, the patient had been diagnosed with syphilis before and its association with nephropathy facilitated the aetiological diagnosis of MGN. After
starting specific treatment (penicillin G
benzathine) to eliminate the triggering
factor, the nephrotic syndrome remitted.
This experience has made us see that it is
of vital importance to conduct a detailed
assessment when dealing with a case of
nephrotic syndrome. Once we have an exact result and diagnosis, this will enable
us to adopt an economic, effective and,
above all, curative approach.
1. Registros glomerulonefritis por la Sociedad
Española de Nefrología. Pamplona, 2009.
2. Satoskar AA, Kovach P, O’Reilly K, Nadasdy T.
An uncommon cause of membranous
glomerulonephritis. Am J Kidney Dis
2010;55:386-90.
3. Lucas Costa A, Belinchón Romero I. La sífilis
hoy. Piel 2008;22:1-3.
4. Ibarra V, Oteo JA. ¿Otra vez la sífilis? Med
Clin (Barc) 2003;120:295-6.
5. Servicio de Vigilancia Epidemiológica. Centro
Nacional de Epidemiología. Vigilancia
epidemiológica de las infecciones de
transmisión sexual 1995-2008, Feb 2010, 26.
6. Simms I, Fenton K, Ashton M, Turner KME,
Crawley-Boevey EE, Gorton R, et al. The reemergence of syphilis in the United
Kingdom: the new epidemic phases. Sex
Trans Dis 2005;32:220-6.
7. Menéndez B, Ballesteros J, Clavo P, Del
Romero J. Aumento de la sífilis y de la
infección
genocócica
en
varones
homosexuales o bisexuales en Madrid. Med
Clin (Barc) 2005;125:756.
8. Hunte W, Al-Ghraoui F, Cohen RJ. Secondary
syphilis and the nephrotic syndrome. J Am
Soc Nephrol 1993;3:1351-5.
M.T. Mora Mora, M.S. Gallego Domínguez,
M.I. Castellano Cerviño, R. Novillo Santana,
J.R. Gómez-Martino Arroyo
Hospital of San Pedro de Alcántara. Cáceres,
Spain
Correspondence: M.S. Gallego Domínguez
Sección de Nefrología.
Hospital San Pedro de Alcántara. Cáceres.
[email protected]
373
Treatment with
intravenous
daptomycin for a
peritonitis relapse
caused by
Staphylococcus
epidermidis
Nefrologia 2011;31(3):374-5
To the Editor,
Peritonitis is one of the main complications for patients on kidney replacement therapy with peritoneal dialysis.
In many cases, peritonitis causes the
technique to fail, meaning that the patient has to be transferred to haemodialysis.1,2
We present here the case of a patient
with two relapses caused by the same
germ, probably caused by the colonisation of the catheter, who responded well
to treatment with intravenous daptomycin.
The patient was a 79-year-old male
with stage 5 chronic kidney disease secondary to nephroangiosclerosis and/or
diabetic nephropathy, who was on kidney replacement therapy with continuous ambulatory peritoneal dialysis. The
patient also had long-term type-2 diabetes mellitus, arterial hypertension and
pernicious anaemia.
The patient came to the emergency department 27 months after starting treatment with symptoms and a cell count in
the drainage fluid compatible with peritonitis. The empiric protocol established in our department which includes
vancomycin and ceftazidime was started and cultures were also taken.
Staphylococcus epidermidis grew in the
peritoneal fluid in the following days.
The treatment with ceftazidime was
stopped and intraperitoneal vancomycin was continued on an ambulatory basis until the treatment had been
followed for 15 days.
374
The patient once again had abdominal
pain and cloudy fluid 7 after finishing
the treatment. New cultures were taken
and the empiric treatment was restarted,
but this time it was accompanied with
prophylactic antifungal treatment. S.
epidermidis grew once again in the cultures with a similar antibiogram to the
one seen during the first episode and
with a similar minimum inhibitory concentration (MIC) for vancomycin to the
previous one (2µg/ml). Given the
growth of the same germ and the short
time period between the end of treatment and the new episode, it was considered as a relapse and antibiotic treatment was indicated for three weeks
with intraperitoneal vancomycin plus
oral rifampicin. An ultrasound of the
abdomen and the catheter tunnel was
requested at that time in order to rule
out intraperitoneal fluid collections or
collections in the pathway of the
catheter.
The patient had a new episode with exactly the same germ once the antibiotic
treatment had been completed. The
need to transfer the patient to
haemodialysis was considered at this
point in order to take out the catheter as
colonisation was suspected. As vascular access was difficult, we decided to
try treatment with intravenous daptomycin at a dose of 4mg/kg/48h for 10
days.
At present, four months after ending
treatment, the patient has not had any
new episodes. He has been able to continue with his dialysis treatment and we
were able to avoid removing the peritoneal catheter.
Peritonitis relapse is defined as a new
episode of peritonitis with the same result in the culture within four weeks of
completing treatment. It is usually associated with resistance to antibiotics and
a biofilm presence on the catheter.
Studies have been published that report
the need to increase the dose or use
multiple antibiotics to eradicate the
germ. In the case of S. epidermidis, it is
recommended that treatment is continued for at least 21 days.3-6
There is little information in the medical literature which evaluates treatment
with daptomycin in peritoneal dialysis
by intravenous or intraperitoneal route.
In our case, daptomycin was probably
able to enter inside the biofilm on the
catheter and eradicate the germ that was
causing the peritonitis and the subsequent relapses.
Although clinical studies are obviously
needed to determine how valid this
therapeutic option is, it was very useful
in our case as the patient did not have
to have the catheter removed.
As a result, intravenous daptomycin is
an option that must be taken into account when it is suspected that the
catheter has been contaminated by S.
epidermidis in patients with peritonitis
on peritoneal dialysis.
1. Woodrow G, Turney JH, Brownjohn AM.
Technique failure in peritoneal dialysis and
its impact on patient survival. Perit Dial Int
1997;17:360.
2. Holley HL, Piraino BM. Complications of
peritoneal dialysis: diagnosis and
management. Semin Dial 1990;3:245.
3. Dasgupta MK, Kowalewaska-Grochowska
K, Costerton JW. Biofilm and peritonitis in
peritoneal dialysis. Perit Dial Int
1993;13(Suppl 2):S322.
4. Piraino B, Bailie GR, Bernardini J,
Boeschoten E, Gupta A, Holmes C, et al.
Peritoneal dialysis-related infections
recommendations: 2005 update. Perit Dial
Int 2005;25:107.
5. Anwar H, Dasgupta MK, Costerton JW.
Testing the susceptibility of bacteria in
biofilms
to
antibacterial
agents.
Antimicrob
Agents
Chemother
1990;34:2043.
6. Finkelstein ES, Jekel J, Troidle L,
Gorban-Brennan N, Finkelstein FO, Bia
FJ. Patterns of infection in patients
maintained on long-term peritoneal
dialysis therapy with multiple episodes
of peritonitis. Am J Kidney Dis
2002;39:1278.
7. Goedecke VA, Clajus C, Burkhard O.
Pharmacokinetics and dialysate levels of
daptomycin given intravenously in
peritoneal dialysis patient. Scan J Infect
Dis 2009;41:155-7.
Nefrologia 2011;31(3):358-78
8. Hermsen ED, Hovde LB, Hotchkiss JR,
Rotschafer JC. Increased killing of
staphylococci and streptococci by
daptomycin compared whit cefazolin and
vancomycin in an in vitro peritoneal
dialysate model. Antimicrob Agents
Chemother 2003;47:3764-7.
F. Levy1, V. Camarero Temiño1,
A. Blasco Mollá2, M.P. Ortega Lafont2,
P. Abaigar Luquin1, M.J. Izquierdo Ortiz1,
G. Torres Torres1
1
Healthcare Complex of Burgos, Spain
2
Microbiology Department.
Healthcare Complex of Burgos, Spain
Correspondence: F. Levy
Complejo Universitario Asistencial de Burgos.
[email protected]
Intraperitoneal
daptomycin
Nefrologia 2011;31(3):375-6
To the Editor,
Peritonitis is one of the main causes of
morbidity in patients undergoing peritoneal dialysis (PD). Although the usual treatments with vancomycin, aminoglycosides or semi-synthetic penicillins
recommended in treatment guidelines
for peritonitis1 are efficient in most cases, situations such as colonisation by
methicillin-resistant microorganisms
with some degree of resistance to vancomycin are common. These treatments
are ineffective in these cases.
The proliferation of multi-resistant
gram-positive pathogens has led to the
antibiotic daptomycin being brought
back and its clinical development has
started again. It was approved by the
United States Food and Drug Administration (FDA) in 2003 for the treatment
of endocarditis caused by gram-positive
pathogens, and skin and white-tissue infections.
A case study has been published of
peritonitis which was not linked to the
Nefrologia 2011;31(3):358-78
peritoneal catheter that was treated with
intravenous daptomycin. This study
analysed the concentration of daptomycin reached in the peritoneal fluid
after intravenous administration. It was
found to be 5mg/ml (minimum inhibitory
concentration
[MIC]=4mg/ml).2 Therefore, the concentrations in the intraperitoneal fluid
as a result of intraperitoneal administration of the antibiotic would be less
close to the microorganism MIC for
daptomycin.
The clinical experience published to
date is limited to two cases. Intraperitoneal daptomycin was used in these
cases to treat peritonitis caused by vancomycin-resistant gram-positive bacteria.3 This treatment succeeded in these
cases where conventional therapies had
previously failed. The intraperitoneal
administration of daptomycin was well
tolerated in these patients and they had
no peritoneal irritation or negative effects associated with the administration
of drugs through this route.
Furthermore, daptomycin is a drug that
is currently used to treat catheter-related bacteriaemias4 due to its efficacy in
controlling biofilm growth, and that is
why it may be considered useful in the
treatment of biofilm on intraperitoneal
catheters.
We report here the clinical case of a 61year-old man who had been diagnosed
with advanced chronic kidney disease
(CKD) secondary to diabetic nephropathy since 2001. He started PD in December 2006. The patient has had three
episodes of peritonitis since February
2008 that led us to consider removing
the catheter in October 2009 due to suspected biofilm.
In May 2010 he had a new episode of
peritonitis and was started on intraperitoneal empiric treatment with vancomycin following normal dosage
guidelines (a shock dosage of 2g followed by 2g/3 days and a shock dosage
of 100mg of tobramycin and
50mg/24h). The presence of Staphylococcus epidermidis and Streptococcus
viridans which were only sensitive to
carbapenems was found four days later
when the culture results were received.
We, therefore, continued with the intraperitoneal treatment with vancomycin at a dose of 2g a week (3
weeks), and tobramycin was changed
for 1g of imipenem/24h for 14 days.
He had a new relapse in June 2010 and
S. epidermidis with intermediate sensitivity to vancomycin (MIC=2) was isolated. Treatment with vancomycin was
started according to protocol, with a
positive clinical response, although after this relapse, it was suspected that the
peritoneal catheter had been colonised
by S. epidermidis biofilm. An application was made for the compassionate
use of intraperitoneal daptomycin on
the basis of the previous experience of
two clinical cases published. Treatment
with vancomycin was maintained until
daptomycin was authorised.
We used the following treatment plan
with daptomycin:
A shock dosage of 200mg (in a 2l PD1
solution), followed by 40mg in each
change of the intraperitoneal fluid (four
times a day) for 10 days. After finishing
this treatment plan, the catheter was
then put in an antibiotic lock with
350mg in 7ml for 12h once a week for
one month. The patient responded positively to this treatment and has had no
relapses or new episodes of peritonitis.
1. Furgeson SB, Teiltelbaum I. New
treatment options and protocols for
peritoneal dialysis-related peritonitis.
Contrib Nephrol 2009;163:169-76.
2. Burklein D, Heyn J, Kirchhoff C, Ozimek A,
Traunmuller F, Joukhadar C, et al. Analysis of
plasma and peritoneal fluid concentrations
of daptomycin in a patient with
Enterococcus faecium peritonitis. Int J
Antimicrob Agents 2008;32(4):369-71.
3. Huem SC, Hall I, Topal J, Mahnenmith R,
Brewster U, Abu-alfa A. Successful use of
intraperitoneal daptomicyn in the treatment of
vancomycin-resistant enterococcus peritonitis.
Am J Kidney Dis 2009;54(3):538-41.
4. Raad I, Hanna H, Jiang Y, Dvorak T, Reitzel
R, Chaiban G, et al. Comparative activities
375
of daptomycin, linezolid and tigecycline
against
catheter-related
methicilinresistant Staphylococcus bacteremic isolates
embedded in biofilm. Antimicrob Agents
Chemother 2007;51:1656-60.
L. García-López1, L. Gómez Sayago1,
M.J. Fernández-Reyes Luis2
1
Pharmacy Department.
General Hospital of Segovia, Spain
2
General Hospital of Segovia, Spain
Correspondence: L. García-López
Servicio de Farmacia.
Relapses in patient
with microscopic
polyangiitis with
persistently positive
antimyeloperoxidase for
4 years using
maintenance
immunosuppressants
Nefrologia 2011;31(3):376-8
To the Editor,
Anti-neutrophil cytoplasmic antibodies
(ANCA) are antibodies directed against
neutrophil granulocytes and monocytes.1 These ANCA are essential markers and help to classify small-vessel
vasculitides, such as Wegener’s granulomatosis (WG), microscopic polyangiitis (MP) and renal-limited vasculitides,
which are classified as ANCA-associated systemic vasculitides.2
The diagnosis can be confirmed when
ANCA are detected. This means that
treatment with steroids and immunosuppressants can be started without delay.3 In contrast to anti-glomerular basement membrane antibody (anti-GBM)
disease, these vasculitides are chronic
diseases with a high relapse rate which
leads to increased morbidity/mortality.4
Thus, a diagnosis of relapse in a patient
with ANCA-associated small-vessel
vasculitis with persistently negative
ANCA titre at the moment of a possible
376
relapse should be questioned, requiring
either histological proof of disease activity or exclusion of other diagnoses.5
On the other hand, whether persistently
positive levels of ANCA or an increase
in their levels can predict vasculitis disease activity is more controversial.4,5
We describe here the case of a patient
diagnosed with MP with positive
ANCA at the time of diagnosis. The patient did not have any relapses for 7
years while the ANCA were negative
and then had 2 relapses in the following
4 years with persistently positive
ANCA and while under immunosuppressive maintenance therapy.
The patient was a 74-year-old male diagnosed with ANCA-positive MP (antimyeloperoxidase [anti-MPO] antibodies
at a titre of 320U/ml, negative anti-PR3
antibodies) in September 1999. He was
treated with oral prednisone at 1mg/kg
and monthly pulses of 750mg of cyclophosphamide for 6 months. He also
had a medical history of tuberculosis in
his youth; spondyloarthrosis and osteoporosis; collapse at D10 vertebra as a
complication of steroid treatment;
chronic hepatitis with positive HBs-Ag,
and positive anti-HBe coinciding with
the diagnosis of vasculitis. The patient
had been asymptomatic for 7 years with
stable kidney function (oscillations of
serum creatinine with a range of 1.31.8mg/dl), persistently negative ANCA
and without immunosuppressive maintenance therapy. From the seventh year
following diagnosis of MP, we started to
detect positive ANCA (positive antiMPO). The follow-up of the evolution
of the ANCA, kidney function parameters and the immunosuppressive treatment established is shown in Table 1.
A year and an half after detecting the
positive ANCA, the patient was admitted for a respiratory infection without
pulmonary consolidation which was
treated with levofloxacin. During this
hospitalisation, plasma creatinine was
1.4mg/dl, proteinuria 0.28g/24h, C-reactive protein 13mg/dl and an ANCA
titre that oscillated between 410 and
429U/ml was found.
The first relapse of the disease was
found two years and 3 months after the
ANCA had become positive and while
the patient was undergoing immunosuppressive treatment with oral cyclophosphamide at 50mg/day. The patient had anti-MPO at a titre of
367U/ml and the relapse appeared as
acute non-oliguric renal failure (creatinine peak at a maximum of 6.6mg/dl),
microscopic haematuria and pulmonary haemorrhage in the right lung
(Figure 1) that responded to treatment
with 500mg pulses of 6-methylprednisone i.v. (three doses) followed by
oral prednisone at 1mg/kg/day and
500mg pulses of cyclophosphamide.
Two months after this first relapse, the
patient was admitted to hospital for another respiratory infection without pulmonary consolidation that responded
well to levofloxacin.
The second relapse of the disease was
detected four years after the reappearance of the ANCA. This was also seen
in the deterioration of kidney function
(serum creatinine peak at 4.1mg/dl)
and microscopic haematuria and with
anti-MPO titres of 126U/ml. The patient responded well to treatment with
500mg pulses of 6-methylprednisolone
followed by a descending dosage of
oral prednisone starting at 1mg/kg/day
and treatment with mycophenolate
mofetil at a dose of 500mg/day. The
patient was asymptomatic three
months after this second relapse with a
serum creatinine level of 2.7mg/dl,
persistent microhaematuria (20-25 red
blood cells/field), a C-reactive protein
of 0.7mg/dl and an anti-MPO titre of
13U/ml.
Relapses are the main problem of vasculitides given that they cause mortality and morbidity to increase: chronic
organ damage (renal failure) and increased cumulative immunosuppressive
therapy toxicity.4,6 Although the value of
ANCA is well established in the diagnosis of these diseases, the usefulness
of measuring ANCA titres in assessing
disease activity is more controversial.7
Increased anti-PR3 is associated with a
relapse in patients with WG, whereas,
Nefrologia 2011;31(3):358-78
Table 1. Evolution of ANCA titre, kidney function parameters, immunosuppressive treatment and relapses
Respiratory
infection
Diagnosis
Month/year
ANCA
Anti-MPO (EliA U/ml)
9/99
3/00
4/06
+
–
–
320
0
0
CRP (mg/dl)
SCR (mg/dl)
2.5
1.5
Proteinuria (g/24 h)
1
0.5
Sediment
20-30
(red blood cells/field)
IS
S. P.O.; S. P.O.
CF. i.v.
10/06 12/06
+
First
relapse
Second
relapse
Respiratory
infection
2/08
5/08
8/08
12/08
1/09
1/10
6/10
+
+
+
+
+
+
6/09 12/09
+
+
+
+
10/10 11/10
+
+
46
361
264
300
344
367
39
209
187
98
126
54
0.67
0.30
1.07
2.09
1.1
0.9
0.8
0.6
0.7
0.2
0.55
0.64
0.38
0.52
1.3
1.5
1.4
1.3
1.4
1.6
1.7
2.1/4.8
2.1
2.6
2.8
2.7
2.7/4.1
2.4
0
0
0
0
0
0
0
10-15
0.20
>40
0.90
25-30
1.34
>40
1.4
Macro
1
2-4
2
>40
2.5
2.5
>40
2.5
>40
2.6
15-20
–
–
Aza
Aza
Aza
CF P.O.
MMF
S (I.V.
+ P.O.);
CF. I.V.
S. P.O.; S. P.O.; S. P.O.;
CF. I.V. CF. I.V.
Aza
S. P.O.; S. I.V. + S. P.O.;
Aza
P.O.
MMF
ANCA: anti-neutrophil cytoplasmic antibodies; CRP: C-reactive protein; SCR: serum creatinine; RBC: red blood cells; Macro: macrohaematuria; IS:
immunosuppression: S: steroids; I.V.: intravenous pulses; P.O.: oral; CF: cyclophosphamide; Aza: azathioprine; MMF: mycophenolate mofetil.
persistently high anti-MPO in MP is
more contentious. Lurati and Spertini
analysed the predictive value of ANCA
as a relapse marker in a retrospective
study that included 36 patients (23 with
WG and 13 with MP). They studied the
prognostic potential of an acute increase in the ANCA titre compared to a
persistently positive level of ANCA:
persistently high ANCA (over 6
months) were not found to be significantly associated with disease relapse
in their study, and the predictive value
of an acute increase in the ANCA titre
was related to the size of the increase.8
curred regardless of the level of antiMPO detected: although the first relapse
occurred with anti-MPO levels above
350U/ml, the anti-MPO levels had been
above 400U/ml a few months before at
the time of a respiratory infection, and
at this point no relapse had been noted.
In the second relapse, the anti-MPO level had been similar to the previous
month’s levels (<150U/ml). Ayada et al
also described a similar case to ours
with anti-MPO titres that had been persistently positive for 6 years. The antiMPO levels were not valuable for predicting relapse early.9
In our case, the patient had two relapses
over a period of 4 years, during which
the anti-MPO titres remained persistently high and, furthermore, the patient was
undergoing immunosuppressive maintenance therapy. Also, the relapses oc-
While monitoring ANCA in patients
with vasculitis may be helpful for the
clinician and may be useful to make a
decision on whether to start immunosuppressive treatment, the final decision must be based on clinical and his-
tological parameters in addition to other analytical parameters.9 In our case,
considering that the patient had only received induction therapy when the disease was diagnosed, and still did not
have symptoms to consider disease activity (stable kidney function without
proteinuria), preventative immunosuppressive therapy was started when the
ANCA reappeared 7 years after the diagnosis and the patient had the first relapse 2 years after starting this treatment.
Activation of T-cells, genetic and exogenous causes and infections have
been included among the factors associated with relapse. In our case, the patient had been admitted to hospital for a
respiratory infection with a maximum
peak of anti-MPO within normal levels,
although the vasculitis activity was
seen seven months later.
Furthermore, the reason for preventing
relapses is to avoid chronic organ damage. In our case, it can be seen that after the relapse, a progressive worsening
of kidney function along with an increased proteinuria was noted.
A
B
Figure 1. Pulmonary haemorrhage in the right hemithorax (A) before treatment and
(B) after receiving immunosuppressive treatment.
Nefrologia 2011;31(3):358-78
To conclude, persistently positive antiMPO in patients with MP may not be
very useful for predicting relapse, even
more so if the patients are undergoing
immunosuppressive maintenance thera377
py, although clinical monitoring must
be even stricter in patients with persistently positive anti-MPO titres.
1. Davies DJ, Moran JE, Niall JF, Ryan GB.
Segmental necrotising glomerulonephritis
with antineutrophil antibody: posible
arbovirus aetiology? Br Med J (Clin Res
Ed) 1982;285:606.
2. Savige J, Davies D, Falk RJ, Jennette JC,
Wiik A. Antineutrophil cytoplasmic
antibodies and associated diseases: a
review of the clinical and laboratory
features. Kidney Int 2000;57:846-62.
3. Savage C, Martin Lockwood C.
Autoantibodies in primary systemic
vasculitis. Adv Int Med 1990;35:73-92.
4. Rutgers A, Heeringa P, Damoiseaux JG,
Tervaert JW. ANCA and antiGMB in
diagnosis and follow-up of vasculitic
378
disease. Eur J Int Med 2003;14(5):287-95.
5. Stegeman CA. Predictive value of
Antineutrophil cytoplasmic antibodies in
small-vessel vasculitis: is the glass half full
or half empty? J Rheumatol 2005;32
(11):2075-7.
6. Sanders JS, Stassen PM, Van Rossum AP,
Kallenberg CG, Stegeman CA. Risk
factors for relapse in Antineutrophil
cytoplasmic antibody (ANCA)-associated
vasculitis: tools for treatment decisions?
Clin Exp Rheumatol 2004;22(Suppl
36):S94-101.
7. Han WK, Choi HK, Roth RM, McCluskey
RT, Niles JL. Serial ANCA titers: useful tool
for prevention of relapses in ANCAassociated
vasculitis.
Kidney
Int
2003;63(3):1079-85.
8. Lurati F, Spertini F. Predictive value of
antineutrophil cytoplasmic antibodies in
small-vessel vasculitis. J Rheumatol
2005;32(11):2167-72.
9. Ayada M, Matsuo T, Takada T, Suda S,
Okado T, Mori Y, et al. Case of immune
complex crescentic glomerulonephritis
with consistently hihg titers of MPOANCA for 6 years. Nippon Jinzo Gakkai
Shi 2007;49(5):511-6.
M. Heras1, M.J. Fernández-Reyes1,
R. Sánchez1, H. Muñoz2, M.J. Jiménez2,
A. Molina1
1
Nephrology Department. General Hospital of
Segovia, Spain.
2
Clinical Analysis Department. General
Hospital of Segovia, Spain.
Correspondence: M. Heras
Nefrologia 2011;31(3):358-78
ERRATA
In the article titled «Dispositional optimism in patients on chronic haemodialysis and its
possible influence on their clinical course» published in Nefrologia 2011;31(2):203, we would like
to correct Table 2:
Where:
Table 2. Relation of the different variables analysed with
hospital admission
Not admitted
to hospital
P
LOT-R
22.37
19.42
0.001
Age
66.14
63.43
0.27
mCCI
7.34
7.4
0.90
Time on HD (years)
5.2
5.8
0.59
19.36
23.44
<0.001
Overall CW
Should be:
Admitted
to hospital
Table 2. Relation of the different variables analysed with
hospital admission
Admitted
to hospital
N=65
Not admitted
to hospital
N=75
P
LOT-R
19.4 ± 5.7
22.3 ± 4.6
0.001
Age (years)
66.1 ± 12.1
63.4 ± 16.3
0.27
7.3 ± 2.9
7.40 ± 2.6
0.90
mCCI Charlson
Time on HD (years)
5.2 ± 6.3
5.8 ± 7.1
0.59
Overall CW
23.4 ± 6.9
19.36 ± 5.0
<0.001
Total CW: total score in the COOP-WONCA charts.
CCI: Comorbidity Index.
The higher the score obtained in the LOT-R, the higher the dispositional
optimism is and vice-versa.
The higher the score in the CW charts, the worse the perceived
health-related quality of life is.
We apologise for any inconvenience that this has caused our readers.

originals - Revista Nefrologia

Transcription

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