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WORLD KIDNEY DAY 2012: THE GLOBAL ROLE OF KIDNEY TRANSPLANTATION
EARLY DIAGNOSIS OF ATHEROSCLEROSIS BY CAROTID ULTRASOUND IN CHRONIC KIDNEY
DISEASE
LONGITUDINAL OBSERVATIONAL STUDIES AND CAUSALITY
RENAL SUPPORTIVE CARE AND PALLIATIVE CARE
HAEMODIALYSIS USING HIGH CUT-OFF DIALYSERS FOR TREATING ACUTE RENAL FAILURE IN
MULTIPLE MYELOMA
EARLY BIOMARKERS OF ACUTE KIDNEY FAILURE AFTER HEART ANGIOGRAPHY OR HEART
SURGERY
SURVIVAL ON HAEMODIALYSIS AND POVERTY LEVEL
DDAVP INTRANASAL SOLUTION FOR TREATING HYPOTENSION DURING HAEMODIALYSIS
SESSIONS
URIC ACID AS A MARKER OF ALL-CAUSE MORTALITY IN THE ELDERLY
Sociedad
Española de
Nefrología
Official Publication of the Spanish Society of Nephrology
Full version in English and Spanish at www.revistanefrologia.com
Nefrología Journal
Editor-in-Chief: Carlos Quereda Rodríguez-Navarro
Executive editor: Roberto Alcázar Arroyo
Deputy editors: Andrés Purroy Unanua, Mariano L. Rodríguez Portillo,
Ángel Luis Martín de Francisco, Fernando García López, Víctor Lorenzo Sellares
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
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M.A. Frutos
D. Jarillo
A. Mazuecos
A. Oliet
L. Pallardo
J.J. Plaza
D. Sánchez Guisande
J. Teixidó
J. Alsina
P. Barceló
J. Bustamente
A. Darnell
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M.T. González
L. Jiménez del Cerro
J. Lloveras
B. Miranda
J. Olivares
V. Pérez Bañasco
L. Revert
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F.A. Valdés
F. Anaya
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
C. Bernis
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
J. Aranzábal
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
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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)
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© Copyright 2012. Grupo Editorial Nefrología. All rights reserved.
• ISSN: 2013-2514
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President:
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Director of Nefrología Publishing Group:
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Links:
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[email protected]
contents
Volume
32 - Number 1 - 2012
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EDITORIALS
1
• The global role of kidney transplantation
Guillermo García-García, Paul Harden, Jeremy Chapman, for the World Kidney Day
Steering Committee 2012
WORLD KIDNEY DAY 2012: THE GLOBAL ROLE OF KIDNEY TRANSPLANTATION
EARLY DIAGNOSIS OF ATHEROSCLEROSIS BY CAROTID ULTRASOUND IN CHRONIC KIDNEY
DISEASE
LONGITUDINAL OBSERVATIONAL STUDIES AND CAUSALITY
RENAL SUPPORTIVE CARE AND PALLIATIVE CARE
7
• Carotid ultrasound for the early diagnosis of atherosclerosis in chronic
kidney disease
HAEMODIALYSIS USING HIGH CUT-OFF DIALYSERS FOR TREATING ACUTE RENAL FAILURE IN
MULTIPLE MYELOMA
EARLY BIOMARKERS OF ACUTE KIDNEY FAILURE AFTER HEART ANGIOGRAPHY OR HEART
SURGERY
SURVIVAL ON HAEMODIALYSIS AND POVERTY LEVEL
DDAVP INTRANASAL SOLUTION FOR TREATING HYPOTENSION DURING HAEMODIALYSIS
SESSIONS
Àngels Betriu-Bars, Elvira Fernández-Giráldez
URIC ACID AS A MARKER OF ALL-CAUSE MORTALITY IN THE ELDERLY
Sociedad
Española de
Nefrología
EDITORIAL COMMENTS
12
• Longitudinal observational studies and causality
Alfonso Muriel, Domingo Hernández-Marrero, Víctor Abraira
15
• The value of serum free light chain assay in patients with monoclonal
gammopathies and renal failure
M. Luisa Campos, Nuno M. Barbosa de Carvalho, Guillermo Martín-Reyes
Official Publication of the Spanish Society of Nephrology
Full version in English and Spanish at www.revistanefrologia.com
IMAGES ON COVER
Granulomatous interstitial nephritis
due to sarcoidosis. C. Galeano and A. Saiz.
Nephrology and Anatomical Pathology
Departments Ramón y Cajal University
Hospital. Madrid, Spain.
SHORT REVIEW
20
• Renal supportive care and renal palliative care: revision and proposal
in kidney replacement therapy
Juan P. Leiva-Santos, Rosa Sánchez-Hernández, Helena García-Llana, M. José Fernández-Reyes, Manuel Heras-Benito,
Álvaro Molina-Ordas, Astrid Rodríguez, Fernando Álvarez-Ude
SPECIAL ARTICLE
28
• Start-up of a clinical sample processing, storage and management platform: organisation
and development of the REDinREN Biobank
Laura Calleros, María A. Cortés, Alicia Luengo, Inés Mora, Brenda Guijarro, Paloma Martín,
Alberto Ortiz-Arduán, Rafael Selgas, Diego Rodríguez-Puyol, Manuel Rodríguez-Puyol
ORIGINALS
35
• Haemodialysis using high cut-off dialysers for treating acute renal failure in multiple myeloma
Guillermo Martín-Reyes, Remedios Toledo-Rojas, Álvaro Torres-Rueda, Eugenia Sola-Moyano, Lourdes Blanca-Martos,
Laura Fuentes-Sánchez, M. Dolores Martínez-Esteban, M. José Díez-de los Ríos, Alicia Bailén-García,
Miguel González-Molina, Isabel García-González
44
• Early biomarkers of acute kidney failure after heart angiography or heart surgery in patients with acute
coronary syndrome or acute heart failure
Isidro Torregrosa, Carmina Montoliu, Amparo Urios, Nisrin Elmlili, Isabel Juan, M. Jesús Puchades, Miguel Á. Solís,
Rafael Sanjuán, M. Luisa Blasco, Carmen Ramos, Patricia Tomás, José Ribes, Arturo Carratalá, Alfonso Miguel
53
• The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney injury
in patients undergoing cardiac surgery
A.M. Candela-Toha, M. Recio-Vázquez, A. Delgado-Montero, J.M. del Rey, A. Muriel, F. Liaño, T. Tenorio
59
• Early detection of chronic kidney disease: Collaboration of Belgrade nephrologists and primary
care physicians
Ljubica Djukanović, Visnja Lezaić, Nada Dimković, Gordana Perunicić Peković, Danica Bukvić, Sanja Bajcetić,
Jelena Pavlović, Ana Bontić, Nadezda Zec, Danijela Momcilović, Marina Stojanović Stanojević
67
• Serum uric acid as a marker of all-cause mortality in an elderly patients cohort
Manuel Heras, María J. Fernández-Reyes, Rosa Sánchez, Álvaro Molina, Astrid Rodríguez,
Fernando Álvarez-Ude
73
• Bone mineral density and bone metabolism in hemodialysis patients.
Correlation with PTH, 25OHD3 and leptin
A. Polymeris, K. Doumouchtsis, E. Grapsa
79
• The lack of income is associated with reduced survival in chronic haemodialysis
Sergio Marinovich, Carlos Lavorato, Guillermo Rosa-Diez, Liliana Bisigniano, Víctor Fernández, Daniela Hansen-Krogh
contents
Volume
89
32 - Number 1 - 2012
• Effect of intranasal DDAVP in prevention of hypotension during hemodialysis
Seyed S. Beladi-Mousavi, Marzieh Beladi-Mousavi, Fatemeh Hayati, Mehdi Talebzadeh
94
• Echocardiographic impact of hydration status in dialysis patients
Isabel Juan-García, María J. Puchades, Rafael Sanjuán, Isidro Torregrosa, Miguel Á. Solís, Miguel González, Marisa Blasco,
Antonio Martínez, Alfonso Miguel
SHORT ORIGINALS
103
• Vascular accesses in haemodialysis: a challenge to be met
Gloria Antón-Pérez, Patricia Pérez-Borges, Francisco Alonso-Almán, Nicanor Vega-Díaz
108
• Changes in body composition parameters in patients on haemodialysis and peritoneal dialysis
M. Cristina Di-Gioia, Paloma Gallar, Isabel Rodríguez, Nuria Laso, Ramiro Callejas, Olimpia Ortega, Juan C. Herrero, Ana Vigil
LETTERS TO THE EDITOR
A) Comments on published articles
114
• The role of interleukin 6 in the pathogenesis of hyponatremia associated with Guillain-Barré syndrome
Se Jin Park, Ki Soo Pai, Ji Hong Kim, Jae II Shin
114
• Aciclovir and valaciclovir neurotoxicity in patients with renal failure
Gloria Ruiz-Roso, Antonio Gomis, Milagros Fernández-Lucas, Martha Díaz-Domínguez, José L. Teruel-Briones,
Carlos Quereda
115
• Estimating glomerular filtration rate in order to adjust drug doses: confusion abounds
Javier Peral-Aguirregoitia, Unax Lertxundi-Etxebarria, Ramon Saracho-Rotaeche, Sira Iturrizaga-Correcher,
M. José Martínez-Bengoechea
B) Brief papers on research and clinical experiments
118
• Is peripheral and/or catheter blood necessary for performing haemoculture in haemodialysis patients
whose central venous catheter presents bacteraemia?
Juan F. Betancor-Jiménez, Francisco Alonso-Almán, Yanet Parodis-López, Beatriz Quintana-Viñau,
Sonia González-Martínez, Cristina García-Laverick, Patricia Pérez-Borges, José C. Rodríguez-Pérez
120
• Serial ultrasound of the vascular access
Juan A. Martín-Navarro, M. José Gutiérrez-Sánchez, Vladimir Petkov-Stoyanov
122
• Economic impact of estimating renal function in patients with systemic lupus erythematosus
Marco U. Martínez-Martínez, Carlos Abud-Mendoza
123
• Chronic kidney disease in the elderly: the impact of patients’ sex
Manuel Heras, Pedro García-Cosmes, M. José Fernández-Reyes, M. Teresa Guerrero, Rosa Sánchez
C) Brief case reports
124
• Adrenal myelolipoma associated with primary hyperaldosteronism
Vanesa Camarero-Temiño, Verónica Mercado-Ortiz, Badawi Hijazi-Prieto, Pedro Abaigar-Luquin
125
• Reactive haemophagocytic syndrome associated with parvovirus B19 in a kidney-pancreas transplant
patient
Maico Tavera, Jorgelina Petroni, Luis León, Elena Minue, Domingo Casadei
127
• Emphysematous cystitis resolved with medical treatment. A case report and literature review
Héctor Parra-Riffo, Juan Lemus-Peñaloza, Paula Maira
127
• Rhabdomyolysis and acute renal failure following hard physical activity in a patient treated
with rosuvastatin
Diana Martínez-López, Ricardo Enríquez, Ana E. Sirvent, M. Dolores Redondo-Pachón, Isabel Millán, Francisco Amorós
129
• Intestinal pseudo-obstruction secondary to persistent constipation due to lanthanum carbonate
Vanesa Camarero-Temiño, Verónica Mercado-Valdivia, Badawi Hijazi-Prieto, Pedro Abaigar-Luquin
130
• Acute renal failure due to gabapentin. A case report and literature
Eduardo Torregrosa-de Juan, Pau Olagüe-Díaz, Pilar Royo-Maicas, Enrique Fernández-Nájera, Rafael García-Maset
131
• Haemorrhagic fever with renal failure syndrome: a case report
Rodrigo Avellaneda-Campos
http://www.revistanefrologia.com
© 2012 Revista Nefrología. Official Publication of the Spanish Nephrology Society
editorials
The global role of kidney transplantation
Guillermo García-García1, Paul Harden2, Jeremy Chapman3, for the
World Kidney Day Steering Committee 2012*
*World Kidney Day, International Society of Nephrology. Brussels (Belgium)
1
Nephrology Department. Hospital Civil de Guadalajara, University of Guadalajara Health Sciences Center (CUCS).
Guadalajara, Jalisco (Mexico)
2
Oxford Kidney Unit and Oxford Transplant Centre. Churchill Hospital. Oxford (United Kingdom)
3
Centre for Transplant and Renal Research. Westmead Millennium Institute, Sydney University, Westmead Hospital. Sidney (Australia)
Nefrologia 2012;32(1):1-6
doi:10.3265/Nefrologia.pre2012.Jan.11333
INTRODUCTION
K
idney transplantation is acknowledged as a major advance of modern medicine which provides high-quality life years to patients with irreversible kidney failure (end-stage renal disease, ESRD) worldwide. What was an
experimental, risky and very limited treatment option fifty
years ago, is now routine clinical practice in more than 80
countries. What was once limited to a few individuals in a
small number of leading academic centers in high income
economies, is now transforming lives as a routine procedure
in most high- and middle-income countries – but can do much
more. The largest numbers of transplants are performed in the
USA, China, Brazil and India, while the greatest population
access to transplantation is in Austria, USA, Croatia, Norway,
Portugal and Spain. There are still many limitations in access
to transplantation across the globe. World Kidney Day on
March 8th 2012 will bring focus to the tremendous life-changing potential of kidney transplantation as a challenge to politicians, corporations, charitable organizations and healthcare professionals. This commentary raises awareness of the
progressive success of organ transplantation, highlight concerns about restricted community access and human organ
trafficking and commercialism, while also exploring the real
potential for transforming kidney transplantation into the routine treatment option for ESRDacross the world.
Correspondence:
World Kidney Day Steering Committee 2012.
World Kidney Day, International Society of Nephrology,
Rue des Fabriques 1, 1000 Brussels, Belgium.
[email protected]
OUTCOMES OF KIDNEY TRANSPLANTATION
The first successful organ transplantation is widely
acknowledged to be a kidney transplant between identical
twins performed in Boston on 23rd Dec 1954 which
heralded the start of a new era for patients with ESRD1.
In the development years between 1965 and 1980, patient
survival progressively improved towards 90% and graft
survival rose from less than 50% at one year to at least
60% after a first deceased donor kidney transplant, based
on immunosuppression with azathioprine and
prednisolone. The introduction of ciclosporin in the mid
1980s was a major advance, leading to one year survival
rates of more than 90% and graft survival of 80%2. In the
last 20 years, better understanding of the benefits of
combined immunosuppressant drugs coupled with
improved organ matching and preservation, as well as
chemoprophylaxis of opportunistic infections, have all
contributed to a progressive improvement in clinical
outcomes. Unsensitised recipients of first deceased donor
kidney transplants and living donor recipients can now
expect 1-year patient and transplant survival to be at least
95% and 90% respectively. 1 New developments have led
several groups to report excellent results even from
carefully selected ABO Blood group incompatible
transplants in recipients with low titre ABO-antibodies 3.
Even for those with high titres of donor specific HLAantibodies, who were previously ‘untransplantable, better
de-sensitisation protocols 4 and paired kidney exchange
programs 5 now afford real opportunities for successful
transplantation.
Group members:
World Kidney Day (WKD) is a joint initiative of the International Society of Nephrology and the International Federations of Kidney Foundations.
WKD Steering Committee members: Abraham G, Beerkens P, Chapman JR, Couser W, Erk T, Feehally J, Garcia GG, Li PKT, Riella M, Segantini L,
Shay P.
1
editorials
Guillermo García-García et al. The global role of kidney transplantation
Ethnic minorities and disadvantaged populations continue to
suffer worse outcomes; Aboriginal Canadians, for example,
have lower 10-year patient (50% vs 75%) and graft (26% vs
47%) survival compared with white patients.6 African
American kidney transplant recipients have shorter graft
survival compared to Asian, Hispanic, and White
populations in the United States of America.7 In New
Zealand, Maori and Pacific Island recipients of deceased
donor transplants have a 50% 8-year graft survival compared
to 14 years for non-indigenous recipients, in part due to
differences inmortality.8 By contrast, despite a resource poor
environment, Rizvi et alreport 1 and 5-year survival rates of
92% and 85%, respectively, among 2,249 living related
kidney transplants in Pakistan,9 whilst in Mexico, 90% and
80% one-year survival for living and deceased donor kidney
transplants, was reported among 1,356 transplants performed
at a single centre.10 But, while it is possible to achieve such
excellent long-term results, most patients and their families
in resource poor environments are not able to afford the high
cost immunosuppressants and antiviral medications needed
to reduce the risk of graft loss and mortality.11
THE PLACE OF KIDNEY TRANSPLANTATION IN
TREATMENT FOR ESRD
Kidney transplantation improves long-term survival
compared to maintenance dialysis. In 46,164 patients on the
transplant waiting list in the USA between 1991-1997,
mortality was 68% lower for transplant recipients than for
those remaining on the transplant waiting list after >3 yrs
follow-up.12 The transplanted 20-39 year old patients of both
sexes were predicted to live 17 years longer than those
remaining on the transplant waiting list, an effect that was
even more marked in diabetics.
The number of people known to have ESRD worldwide is
growing rapidly, as a result of improved diagnostic
capabilities and also the global epidemic of type 2 diabetes
and other causes of chronic kidney disease (CKD). Dialysis
costs are expensive even for developed countries, but
prohibitive for many emerging economies. The majority of
patients commencing dialysis for ESRD in low-income
countries die or stop treatment within the first 3 months of
initiating dialysis due to cost restraints.13 The cost of
maintenance hemodialysis varies considerably by country
and healthcare system. In Pakistan maintenance
hemodialysisis reported to be US$1680 per year, which is
beyond the reach of most of the population without
humanitarian financial aid.14 Despite exemplars, both
provision of hemodialysis facilities and uptake of peritoneal
dialysis remain very limited in middle and low-income
countries. Whilst the costs of transplantation exceed those of
maintenance dialysis in the first year post-transplantation
(eg. in Pakistan US$5245 vs US$1680 in the first year), the
costs are much reduced compared to dialysis in subsequent
2
years, especially with the advent of inexpensive generic
immunosuppression.15 Transplantation thus expands access
and reduces overall costs for successful treatment of ESRD.
Pre-emptive transplantation is an attractive option for both
patients and payers with both reduced costs and improved
graft survival.16 Pre-emptive transplantation is associated
with a 25% reduction in transplant failure and 16% reduction
in mortality compared to recipients receiving a transplant
after starting dialysis.17
Transplantation of the kidney, when properly applied, is thus
the treatment of choice for patients with ESRD because of
lower costs and better outcomes.
GLOBAL DISPARITIES IN ACCESS TO KIDNEY
TRANSPLANTATION
Substantial disparities in access to transplantation across the
world are demonstrated in Figure 1 (derived from the World
Health Organisation/OrganisationMondiale de la Sante
(WHO/OMS) Global Observatory on Donation and
Transplantation.18) which demonstrates the relationship
between transplant rate and Human Development Index
(HDI). There is a reduced transplant rate in low and middle
HDI countries, and a large spread of transplant rates even
amongst the richer nations. Transplant rates of more than 30
per million population (pmp) in 2010 were restricted to
Western Europe, USA, and Australia, with a slightly broader
spread of countries achieving between 20 and 30 pmp.
There are also within-country disparities in transplant rates
among minorities and other disadvantaged populations. In
Canada, all minority groups have significantly lower
transplant rates; compared to whites, rates in Aboriginal and
African Canadians, Indo Asians, and East Asians were 46%,
34%, and 31% lower respectively.19 In the US,
transplantation rates are significantly lower among AfricanAmericans, women, and the poor, compared to Caucasians,
men and the more affluent populations.20 The situation is
similar in Australia where Aboriginal Australians fare worse
than non-indigenous Australians (12% vs 45%) and in New
Zealand where Maori/Pacific Islanders are disadvantaged
(14% vs 53%).21 In Mexico, the transplant rate among
uninsured patients is 7 pmp compared with 72 pmp among
those with health insurance.22
Multiple immunologic and non-immunologic factors
contribute to social, cultural, and economic disparities in
transplant outcomes, including biological, immune, genetic,
metabolic, and pharmacological factors as well as associated
co-morbidities, time on dialysis, donor and organ
characteristics, patient socio-economic status, medication
adherence, access to care, and public health policies.23
Developing countries often have especially poor transplant
deceased organ donors, and most developed countries are
trying to emulate their success. A return to ‘donation after
cardiac death’ instead of the now standard ‘donation after
brain death’, has enhanced the deceased organ donation
numbers in several countries, with 2.8 DCD donors pmp in
the US and 1.1 pmp in Australia now emanating from this
source. Protocols for rapid cooling and urgent retrieval of
kidneys after cardiac death, and in some circumstances
other organs, have developed over the past five years to
reduce the duration and consequences of warm ischaemia.25
Another strategy for increasing the rate of transplantation
has been to extend the acceptance criteria for deceased
organ donors. Such ‘extended criteria’ donors require
additional consideration and specific consent by the
recipient. There is risk in accepting an ‘extended criteria’
kidney since the transplants are less successful in the long
term, but also a risk to waiting longer on dialysis for a
standard criteria donor.
rates not only because of these multiple interacting factors,
but also because of inferior infrastructure and an insufficient
trained workforce. Deceased donation rates may also be
impacted by lack of a legal framework governing brain death
and by religious, cultural and social constraints. When these
factors are all compounded by patient anxieties about the
success of transplantation, physician bias, commercial
incentives favoring dialysis and geographical remoteness,
poor access to transplantation is almost inevitable for most
of the world’s population.
IMPROVING ACCESS TO TRANSPLANTATION
Both living donation and deceased donor donation are now
recognized by the WHO as critical to the capacity of
nations to develop self-sufficiency for organ
transplantation.24 No country in the world, however,
generates sufficient organs from these sources to meet the
needs of their citizens. Austria, USA, Croatia, Norway,
Portugal and Spain stand out as countries with high rates of
AFR
60.0
AMR
editorials
A number of strategies have been designed and implemented
to reduce disparities among disadvantaged populations. The
EMR
Croatia
EUR
SEAR
Norway
Portugal
Spain
50.0
Deceased and Living Donor Kidney Transplants
Per Million Population
WPR
Australia
40.0
Turkey
Iran
30.0
C. Rica
20.0
Rep. of Corea
Syria
Singapore
Mauritius
Japan
10.0
India
South Africa
Thailand
Algeria
0.0
0.5
0.6
0.7
0.8
0.9
1.0
Human Development Index
Grouped by WHO Regions (AFR = Africa, AMR = Americas, EMR = Eastern Mediterranean, EUR = Europe, SEAR = South Eastern Asia,
WPR = Western Pacific)
Figure 1. Number of deceased and living donor kidney transplants in World Health Organisation Member States in 2010, correlated
with human development index.
3
editorials
Transplantation Society has established the Global
Alliance for Transplantation in an effort to reduce
worldwide disparities in transplantation. The program
includes collecting global information, expandingf
education about transplantation, and developing guidelines
for organ donation and transplantation. The International
Society of Nephrology (ISN) Global Outreach program
has catalysed the development of kidney transplant
programs across a large number of countries with targeted
fellowship training and creation of long term institutional
links between developed and developing transplant centers
through its Sister Center Program. This has led to the
establishment of successful kidney transplantation in
countries such as Armenia, Ghana and Nigeria where none
existed before and expansion of existing programs in
Belarus, Lithuania and Tunisia.
A model of collaboration for dialysis and transplantation
between government and the community in the resource
poor world has been successfully established in Pakistan
with government assistance for infrastructure, utilities,
equipment, and up to 50% of the operating budget, while
the community, including affluent individuals,
corporations and the public, donate the remainder. 14 In
2001, in Central America, a specialized unit of pediatric
nephrology and urology was opened in Nicaragua with
funds provided initially by the Associazione per il
Bambino Nefropatico, a kidney foundation based in
Milan, Italy supplemented by a consortium of private
and public organizations, including the International
Pediatric Nephrology Association and the Nicaraguan
Ministry of Health. Subsequently the Nicaraguan
government and a local kidney foundation recognized
the success of the program and accepted gradual transfer
of the costs of treatment, including the provision of
immunosuppressive
medications
for
renal
transplantation. A similar successful partnership between
government and private sector has recently been
reported in India. 26
ETHICAL CHALLENGES AND THE LEGAL
ENVIRONMENT
The impact of the global organ donor shortage and the
dramatic disparities demonstrated by the WHO data, are
experienced in many different ways requiring varied
responses. But one common factor is the relative wealth of
the nation and the individual. The poor receive the fewest
transplants and the rich are most often transplanted either in
their own country or through finding an organ through illegal
purchase from the poor or an executed prisoner. Trafficking
in human organs and commercialisation of the beneficial act
of organ donation were unusual and extremely hazardous in
the 1980’s, became frequent but still very hazardous in the
1990’s, then becoming a gruesomely burgeoning trade from
the turn of the century. The WHO has estimated that up to
10% of all organ transplants were of commercial origin by
2005.27
The first WHO Guiding Principles in this field were agreed
in 1991 and made clear by the decision of national
governments to ban commercialization of organ donation
and transplantation.28 This principle was reaffirmed
unanimously by theWorld Health Assembly in 2010 when
the updated WHO Guiding Principles for human organ and
tissue donation and transplantation, were endorsed.29 Almost
all countries with transplantation programs and even some
without active programs have carried that ban on
commercialism through to their own legislation, making it
illegal to buy or sell organs. Sadly this has not prevented
continuation of the trade illegally in countries such as China
and Pakistan, nor has it prevented new entrants to this
lucrative trade from taking advantage of their own or other
nations’ impoverished and vulnerable populations to provide
kidneys and even livers for the desperate wealthy in need of
transplantation.
There are tremendous opportunities to correct disparities in
kidney disease and transplantation worldwide, but it is
important to recognize that funding of ESRD treatment
should be associated with funding for early detection and
prevention of the progressive kidney diseases that lead to
ESRD. Comprehensive programs should include community
screening and prevention of CKD, especially in high-risk
populations, as well as dialysis and transplantation for
ESRD.
Iran, alone, claims to have resolved national self sufficiency
for kidney transplantation through a scheme of part
government, part patient-funded sale of kidneys by vendors.
The resultant slow development of deceased organ donation
in Iran restricting liver, heart and lung transplant programs,
as well as the disparity of socioeconomic status between
donors and recipients, both testify to the universality of the
problems that arise from organ transplant commercialisation.
The restriction of transplantation to Iranian nationals only
under this program has however largely ensured that this
national experiment has not flowed on to create commercial
organ trafficking across Iranian national borders.
An integrated approach to the expansion of transplantation
requires training programs for nephrologists, transplant
surgeons, nursing staff, and donor coordinators; nationally
funded organ procurement organizations providing
transparent and equitable retrieval and allocation; and the
establishment of national ESRD registries.
The Transplantation Society and the ISN have taken a joint
stand against the despoiling of transplantation therapy and
victimization of the poor and vulnerable by doctors and other
providers operating in these illegal programs. In 2008, more
than 150 representatives from across the world from
different disciplines of health care, national policy
4
development, law and ethics came together in Istanbul to
discuss and define professional principles and standards for
organ transplantation. The resultant Declaration of Istanbul30
has now been endorsed by more than 110 professional and
governmental organizations and implemented by many of
these organizations with a goal to eliminate transplant
tourism and enhance the ethical practice of transplantation
globally.31
SUMMARY
There remain major challenges to providing optimal
treatment for ESRD worldwide and a need, particularly in
low income economies, to mandate more focus on
community screening and implementation of simple
measures to minimize progression of CKD. The recent
designation of renal disease as an important noncommunicable disease at the UN High Level Meeting on
NCDs is one step in this direction.32 But early detection and
prevention programs will never prevent ESRD in everyone
with CKD, and kidney transplantation is an essential, viable,
cost-effective and life-saving therapy which should be
equally available to all people in need. It may be the only
tenable long-term treatment option for ESRD in low-income
countries since it is both cheaper and provides a better
outcome for patients than other treatment for ESRD.
However, the success of transplantation has not been
delivered evenly across the world, and substantial disparities
still exist in access to transplantation, we remain troubled by
commercialization of living donor transplantation and
exploitation of vulnerable populations for profit.
There are solutions available. These include demonstrably
successful models of kidney transplant programs in many
developing countries; growing availability of less expensive
generic immunosuppressive agents; improved clinical
training opportunities; governmental and professional
guidelines legislating prohibition of commercialization and
defining professional standards of ethical practice; and a
framework for each nation to develop self sufficiency in
organ transplantation through focus on both living donation
and especially nationally managed deceased organ donation
programs. The ISN and TTS have pledged to work together
in coordinated joint global outreach programs to help
establish and grow appropriate kidney transplant programs
in low and middle income countries utilizing their
considerable joint expertise. World Kidney Day 2012
provides a focus to help spread this message to
governments, all health authorities and communities across
the world.
Conflicts of interest
Authors declare no potential Conflicts of interest.
editorials
REFERENCES
1. Murray JE. Ronald Lee Herrick Memorial: June 15, 1931-December
27, 2010. Am J Transplant 2011;11(3):419.
2. Clayton P, Excell L, Campbell S, McDonald S, Chadban S. Transplantation. In: McDonald S, Excell L, Livingston B (eds.). ANZDATA Registry Report 2010. Australia and New Zealand Dialysis and Transplant Registry. Adelaide, South Australia; p. 8.1-8.31. Available at
http://www.anzdata.org.au/anzdata/AnzdataReport/33rdReport/Ch
08.pdf. [Accessed nov 29, 2011].
3. Shimmura H, Tanabe K, Ishida H, Tokumoto T, Ishikawa N, Miyamoto N, et al. Lack of correlation between results of ABO-incompatible
living kidney transplantation and anti-ABO blood type antibody titers under our current immunosuppression.Transplantation
2005;80(7):985-8.
4. Peng A, Vo A, Jordan SC. Transplantation of the highly human leukocyte antigen–sensitized patient: long-term outcomes and future
directions. Transplantation Reviews 2006;20:46-156
5. Warren DS, Montgomery RA. Incompatiblekidney transplantation:
lessons from a decade of desensitization and paired kidney exchange. Immunol Res 2010;47(1-3):257-64.
6. Weber CLC, Rush DN, Jeffery JR, Cheang M, Karpinski ME. Kidney
transplantation outcomes in Canadian aboriginals. Am J Transplant
2006;6:1882-9.
7. Gordon EJ, Ladner DP, Caicedo JC, Franklin J. Disparities in kidney
transplant outcomes: A review. Semin Nephrol 2010;30(1):81-9.
8. Collins JF. Kidney disease in Maori and Pacific people in New Zealand. Clin Nephrol 2010;74:S61-S65.
9. Rizvi SA, Naqvi SAA, Zafar MN, Hussain Z, Hashmi A, Hussain M, et
al. Living related renal transplants with lifelong follow-up. A model
for the developing world. Clin Nephrol 2010;74 Suppl 1:S142-9.
10. Monteón FJ, Gómez B, Valdespino C, Chavez S, Sandoval M, Flores
A, et al. The kidney transplant experience at Hospital de Especialidades, Centro Médico Nacional de Occidente, IMSS, Guadalajara
México. In: Cecka JM, Terasaki P (eds.). Clinical Transplants 2003.
Los Angeles: UCLA Inmunogenetics Center; 2003. p. 165-74.
11. Jha V. Current status of end-stage disease care in South Asia. Ethn
Dis 2009 Spring;19(1 Suppl 1):S1-27-32.
12. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY,
et al.Comparison of mortality in all patients on dialysis, patients on
dialysis awaiting transplantation and recipients of a first cadaveric
transplant. N Engl J Med 1999;341:1725-30.
13. Sakhuja V, Sud K. End-stage renal disease in India and Pakistan: Burden
of disease and management issues. Kidney Int Suppl 2003;(83):S115-8.
14. Rizvi SAH, Naqvi SAA, Zafar MN et al. A Renal Transplantation Model for developing countries. Am J Transplant 2011:11:2302-7.
15. Sud K, et al. Indian J of Nephrology 1999;9:83-91.
16. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes. Transplantation 2002;74(10):1377-81.
17. Kasiske BL, Snyder JJ, Matas MD, Ellison MD, Gill JS, Kausz ATl.Preemptive kidney transplantation: The advantage and the advantaged.
J Am Soc Nephrol 2002;13:1358-6.
18. World Health Organization. Global Knowledge Base on Transplantation. Available at http://www.who.int/transplantation/knowledgebase/en/. [Accessed nov 29, 2011].
5
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19. Yeates K. Health Disparities in renal disease in Canada. Semin Nephrol 2010;30:12-8.
20. Alexander GC, Sehgal AR. Barriers to cadaveric renal transplantation among blacks, women, and the poor. JAMA 1998;280:114852.
21. McDonald S. Incidence and treatment of ESRD among indigenous
peoples of Australasia. Clin Nephrol 2010;74:suppl 1:S28-31.
22. Garcia-Garcia G, Renoirte-Lopez K, Marquez-Magaña I. Disparities
in renal care in Jalisco, Mexico. Semin Nephrol 2010;30:3-7.
23. Gordon EJ, Ladner DP, Caicedo JC, Franklin J. Disparities in kidney
transplant outcomes: A review. Semin Nephrol 2010;30:81-9.
24. 3rd Global WHO Consultation March 2010. Organ Donation and
Transplantation: Striving to Achieve Self-Sufficiency. Transplantation
2011;91 11S:S27-S114.
25. Bernat JJ, D’Alesandro AM, Port FK, Bleck TP, Heard SO, Medina J,
et al. Report of a National conference on donation after cardiac death. Am J Transplant 2006;6:281-91.
26. Abraham G, John GT, Sunil S, Fernando EM, Reddy YNV. Evolution
of renal transplantation in India over the last four decades. NDT Plus
2010;3:203-7.
27. Shimazono Y. The state of the international organ trade: a provisio-
28.
29.
30.
31.
32.
nal picturebasedonintegration of availableinformation. Bull World
Health Organ 2007;85(12):955-62.
World Health Organization. Forty-fourth World Health Assembly, resolution and decisions. Geneva, Switzerland: World Health Organization; 1991 (WHA 44/1991/REC/1). Annex 6.
World Health Organization. Sixty-third World Health Assembly. Geneva, Switzerland: World Health Organization; 2010. Available at:
http://www.who.int/transplantation/Guiding_PrinciplesTransplantation_WHA63.22en.pdf. [Accessed nov 29, 2011].
Participants in the International Summit onTransplantTourism and
Organ Trafficking Convened by the Transplantation Society and International Society of Nephrology in Istanbul, Turkey, April 30-May
2, 2008. The Declaration of Istanbul on organ trafficking and transplanttourism. Transplantation 2008;86(8):1013-8.
Delmonico FL, Domínguez-Gil B, Matesanz R, Noel L. A call for government accountability to achieve nationalself-sufficiency in organdonation and transplantation. Lancet 2011;378(9800):1414-8.
United Nations General Assembly. Political declaration of the
High-level Meeting of the General Assembly on the Prevention
and Control of Non-communicable Diseases A/66/L. 1, September 16, 2011.
Sent for review: 9 Jan. 2012 | Accepted: 9 Jan 2012.
6
editorials
Carotid ultrasound for the early diagnosis
of atherosclerosis in chronic kidney disease
Àngels Betriu-Bars1, Elvira Fernández-Giráldez2
Unitat de detecció i tractament de les malalties aterotrombòtiques (UDETMA) del Servicio de Nefrología. Hospital Universitari Arnau
de Vilanova. Institut de recerca biomèdica de Lleida. Universidad de LLeida. Spain
2
Servicio de Nefrología. Unitat de detecció i tractament de les malalties aterotrombòtiques (UDETMA) del Servicio de Nefrología.
Hospital Universitari Arnau de Vilanova. Institut de recerca biomèdica de Lleida. Universidad de LLeida. Spain
1
Nefrologia 2012;32(1):7-11
doi:10.3265/Nefrologia.pre2011.Dec.11258
A
therothrombotic disease (ATD) is a progressive
disorder and its most common clinical
manifestations, acute myocardial infarction and
stroke, are responsible for the highest morbidity and
mortality rates in the Western world. Sudden death due to
infarction with no prior symptoms occurs in 50% of men and
64% of women.1
One of the main tools to control the incidence of vascular disease is prevention. Formulas are available to estimate cardiovascular risk (Framingham risk score, etc.)2 They are based
on epidemiological studies that determine the risk of suffering a cardiovascular event (fatal or non-fatal) within 5 to 10
years.3 While the available system to calculate cardiovascular
risk is easily generalisable, and universal, it does present
some difficulties. The main drawback is its low sensitivity for
detecting individuals at a high risk to suffer a cardiovascular
event. Large epidemiological studies show that 62% of subjects with a prior history of myocardial infarction present
none or only one of the cardiovascular risk factors,4 which,
undoubtedly, prevents them from being properly identified at
a time to take effective preventive actions.
In recent years, there have been significant technological
advances in medical imaging techniques, particularly in
the field of vascular disease. Below, we describe the advantages, disadvantages and uses of imaging techniques in
the general population and in chronic kidney disease
(CKD) patients.
Correspondence: Àngels Betriu Bars
Servicio de Nefrología.
Unitat de detecció i tractament de les malalties aterotrombòtiques.
Rovira Roure, 80. 25198 Lleida. Spain.
[email protected]
[email protected]
GENERAL POPULATION
Various methods have been used for the diagnosis and
prevention of cardiovascular disease (CVD). Studies on the
calcification of coronary arteries using helicoidal or
multidetector computed tomography (CT) accurately
measure coronary calcium content (coronary calcium
score). However, this method is not useful in patients at a
low cardiovascular risk according to traditional estimation
methods. 5 Although coronary CT has a high specificity to
diagnose coronary atherosclerosis, and some studies
suggest that it directly correlates to mortality over time,6
this is a costly technique that requires advanced
technology, and therefore, it cannot be used for the early
detection of ATD in the general population. More
significantly, coronary calcium scores measure the
presence of calcium deposition in the coronary arteries, and
therefore, it fails to diagnose early stages of vascular
disease, as ATD is a progressive vascular disorder, and
calcification only occurs in its advanced stages.
Coronary arteriography has recently been complemented
with the use of intravascular ultrasound7 techniques that
offer a more precise diagnosis of coronary atherosclerosis.
However, this method is painful and expensive, and
therefore cannot be considered a good option for the early
detection of ATD in the general population.
Carotid ultrasound has several advantages compared to the
previously described methods, but the use of this technique
for early diagnosis of atherosclerosis is not generalised.
Ultrasound of supra-aortic trunks is used in patients with
symptomatic atherosclerosis, particularly those who have
suffered a stroke. As these patients have already suffered an
event due to arterial disease, we can only provide a diagnosis
or confirmation of a suspected diagnosis and establish the
surgical indication, rather than implementing preventive
therapeutic interventions.
7
editorials
Applying this technique in early diagnosis of ATD requires
rigorous training of the technician and the specialist reading
of the properly acquired images in order to obtain accurate
parameters for the early diagnosis of the disease.
Carotid intima-media thickness (cIMT) measured by
carotid ultrasound was described by Pignoli et al in 1984
and validated by the same authors in 1986. They
conclusively established a strong correlation between the
thickness of the arterial wall, measured by ultrasound,
with the histological findings in these patients.8 Since then,
carotid ultrasound has been known as a technique with
potential applications in the field of atherosclerosis, but 20
years later, it is not part of the routine clinical practice to
diagnose vascular disease, mainly due to the high
variability in the resulting parameters, highly dependent
on the acquisition technique employed. The
recommendations of the XIII European Stroke Conference
in 2004 (Manheim IMT Consensus) 9 pconstitute a definite
step forward in generalising the proper technique for
clinical practice.
Carotid artery ultrasound, which measures cIMT and detects
atheromatous plaques (Figure 1 A and B), is a strong indicator
of overall vascular health. cIMT is a well recognized and
accepted marker to predict cardiovascular disease.10
In clinical trials, the cIMT is used alongside traditional risk
factors. These trials highlight the usefulness and importance
of using non-invasive techniques to evaluate the effect of
risk factors on the vascular wall. Through the years, clinical
trials have provided evidence corroborating the importance
of measuring cIMT to prevent cardiovascular events (the
thicker the cIMT, the higher the risk of myocardial infarction
and cerebral infarction).11
cIMT was accepted as a surrogate marker of atherosclerosis
by the US Food and Drug Administration (FDA) and the
European Agency for the Evaluation of Medicinal Products.
At present, cIMT is the noninvasive technique most
frequently used in clinical trials to determine atherosclerosis.
Clinical guidelines and medical societies recommend it to
obtain a more precise evaluation of cardiovascular health in
selected populations,12 and in cardiovascular disease
prevention programmes.13 Upon adjustment for age and sex,
an increase of 0.1 mm in cIMT, indicates a 10%-15%
increase in the risk of myocardial infarction, and a 13%-18%
increase in the risk of stroke.11
Davidsson14 and coworkers have recently shown, in a
multivariate analysis of 391 men in Sweden, odd ratios for
cardiovascular events of 2.09 (95% confidence interval (CI)
1.05-4.16; p= 0.03) in subjects with atheromatous plaques in
the carotid artery. Nambi et al15 published the latest results
from the ARIC study, demonstrating a correlation between
an increase in cIMT , or the presence of atheromatous
8
Àngels Betriu-Bars et al. Early diagnosis of atherosclerosis
plaques, and the incidence of cardiovascular events. They
reported the predictive role of carotid ultrasound (cIMT and
plaques) in a large epidemiological study of 13,145 healthy
individuals, who presented 1,812 adverse cardiovascular
events over a 15-year follow up. The area under the curve
estimating the sensitivity and accuracy of their logistic
regression analysis increased significantly when cIMT and
the presence of atheromatous plaque were added to the list of
conventional cardiovascular risk factors.
CAROTID
DISEASE
ULTRASOUND
IN
CHRONIC
KIDNEY
Current tables to estimate cardiovascular risk have not been
designed for CKD patients, whose main cardiovascular risk
factors are different from those in the general population.
CKD patients experience the so-called “reverse
epidemiology”. In studies in haemodialysis patients, no
association was found between serum cholesterol levels or
systolic blood pressure with coronary artery disease,
cerebrovascular disease or peripheral vascular disease.16,17
Furthermore, there are other “non-traditional” and
“emerging” factors that play a role in the pathogenesis of
atherosclerosis in CKD, such as anaemia, chronic
inflammation, oxidative stress, and abnormalities in mineral
metabolism that are not taken into account when using
traditional predictors of cardiovascular risk.
This evidence, along with the high incidence rate of CVD
among CKD patients,18 supports the use of new, more
sensitive tools for the early detection and prevention of
cardiovascular disease.19 Guidelines from the European
Society of Cardiology recommend a close monitoring of
traditional cardiovascular risk factors in patients with
chronic kidney disease.20 , Furthermore, the National Kidney
Foundation (NKF) recommends the use of carotid ultrasound
for a more precise assessment of cardiovascular health in
kidney disease.21
Because cardiovascular disease is the main cause of
morbidity and mortality in CKD,22 early diagnosis of vascular
disease using ultrasound techniques is becoming
increasingly widespread in this patient population.
We lack conclusive evidence on how changes in cIMT relate
to cardiovascular risk factors in CKD, but it has been
reported that cIMT increases as glomerular filtration rate
decreases.23
Our group has confirmed the high prevalence and severity
of atherosclerosis in patients with different stages of
kidney disease (n=409). 24 The diagnostic methods used
were carotid ultrasound and the ankle-brachial index
(ABI). Both tests have been validated as predictors of
adverse cardiovascular events. 25 We have developed a
Nefrologia 2012;32(1):7-11
A
editorials
B
(A) View of the artery wall for measuring carotid intima-media thickness (cIMT) or the distance between the tunica adventitia
and the intima layer of the arterial wall, at the level of the common carotid artery. Arrows delimit the cIMT; (B) Plaque along
the upper wall of the common carotid artery (plaque defined as cIMT >1.5mm).
Figure 1. Ultrasound image of carotid arteries
classification of vascular disease based on the results of
ABI and carotid ultrasound, using for the cIMT reference
intervals adjusted for age and sex. We found that a high
percentage of kidney patients had atheromatous vascular
disease, and this percentage was much higher than in ageand sex-matched control subjects with a normal kidney
function (n=851). Relevant findings from this study were
the higher prevalence of ATD in patients on dialysis
compared to those at earlier CKD stages, and the lack of
correlation between vascular disease and LDL cholesterol
levels. The presence of atheromatous plaque was higher in
dialysis patients (78.3%) 26 compared to pre-dialysis
patients (55.6%) 27 or the normal control group (43.2%).
Variables with a positive association with atherosclerosis
included age, dialysis treatment, and serum levels of
plasma C-reactive protein. Being a female was a protective
factor also in CKD.
Carotid ultrasound also offers a critical additional
information, the assessment of vascular calcification.
Vascular calcification is a strong predictor of morbidity and
mortality in the general population and in CKD. In CKD
patients, vascular calcification is more prevalent, appears at
an earlier age, and is more severe.28 The degree of arterial
calcification can be measured using CT to obtain the
Agatston score, which is the only quantitative method
currently available, and therefore it is the gold standard,
mostly used in clinical research. Semi-quantitative methods
have been proven useful, as those described by Adragao and
Kauppila. They employ simple radiology, are more adapted to
Nefrologia 2012;32(1):7-11
clinical practice, and have proved to have a good predictive
power of cardiovascular events in CKD.
Carotid ultrasound is also the only available technique to
localise the site of calcium deposition within the arterial
wall. Our group has completed an ultrasound study
examining the location of calcium in carotid and femoral
artery wall. The brachial artery served as a negative control
since this area is free of atherosclerosis.29 We observed that
calcification was localized exclusively in the intimal layer,
following two distinct patterns: 1) Calcification of the
atheromatous plaque (Figure 2 A) and 2). Linear
calcification of the intimal layer, anatomically unrelated to
the atheromatous plaque (Figure 2 B). Multivariate analysis
associated this previously unrecognized intimal calcium
location with age, serum levels of phosphate and C-reactive
protein, and with the presence of atheromatosis. These
results underscore the contribution of inflammation and
atheromatosis to the calcification of elastic arteries.
Although serum phosphate levels remain a not fully resolved
issue, we must start focussing on preventing atheromatosis
and decreasing the pro-inflammatory status of CKD patients
as much as possible.
CONCLUSIONS
Carotid ultrasound is a tool with a number of advantages
compared to other methods. First, it is easy to use and does
not require complex equipment. It can be performed in
9
editorials
A
B
Arrows indicate the calcified areas: (A) linear calcification in the intima; (B) calcified or type 5 plaque (with posterior acoustic
shadow). Clin J Am Soc Nephrol 2010;6(2):303-10.
Figure 2. Calcification patterns depicted by ultrasound.
outpatient clinics or at the bedside; and is inexpensive and
non invasive. Secondly, it provides doctors with valuable
information for treatment, including the atheromatous
burden, the severity of the calcification, and the location of
calcium deposition within the vascular wall. Thirdly, it
detects ATD at early stages, prior to the appearance of
atheromatous plaque. Therefore, it constitutes an ideal
technique to obtain evidence-based recommendations for
ATD prevention.
At present, we lack studies addressing the prognostic value
of either the calcification of atheromatous plaques (type V
plaque according to the American Heart Association) or the
new linear profile of intima calcification in kidney disease
patients.
The Spanish study NEFRONA (www. nefrona.es) has been
designed to answer important questions on the pathogenesis
and progression of ATD at all CKD stages compared to ageand sex- matched controls with normal renal function
through measurements of the distinct atherosclerosis and
calcification patterns between groups using arterial
ultrasound.
Conflicts of Interest
Authors declare potential conflicts of interest
Honoraria as speaker: Shire, Abbott, Genzyme and Amgen
10
Acknowledgements:
Grants: FIS (Carlos III Health Institute).
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thickness of the arterial wall: a direct measurement with ultrasound
imaging. Circulation 1986;74(6):1399-406.
Toboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P,
Bornstein N, et al. Manheim carotid intima-media thickness
consensus (2004-2006). An Update of behalf of the advisory board
of the 3er and 4th watching the risk symposium 13th and 15th
European Stroke conferences, Mannheim, Germany, 2004 and
Brussels, Belgium 2006. Cerebrovasc Dis 2007;23:75-80.
Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et
al.; American Society of Echocardiography Carotid Intima-Media
Thickness Task Force. Use of carotid ultrasound to identify
subclinical vascular disease and evaluate cardiovascular disease
risk: a consensus statement from the American Society of
Echocardiography Carotid Intima-Media Thickness Task Force.
Endorsed by the Society for Vascular Medicine. J Am Soc
Echocardiogr 2008;21:93-111.
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction
of clinical cardiovascular events with carotid intima-media
thickness: a systematic review and meta-analysis. Circulation
2007;115:459-67.
Bots ML, Dijk JM, Grobbee OA, Diederick E. Carotid intima-media
thickness, arterial stiffness and risk of cardiovascular disease
current evidence. J Hypertens 2002;20:2317-25.
Verhamme P, Kerkhof F, Buysschaert I, Rietzschel E, de Groot E.
Carotid intima-media thickness: more than a research toal? Review
Article. Acta Cardiol 2010;65(1):59-66.
Davidsson L, Fagerberg B, Bergström G, Schmidt C. Ultrasoundassessed plaque occurrence in the carotid and femoral arteries are
independent predictors of cardiovascular events in middle-aged men
during 10 years of follow-up. Atherosclerosis 2010;209:469-73.
Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al.
Carotid intima-media thickness and presence or absence of plaque
improves prediction of coronary heart disease risk: the ARIC
(Atherosclerosis Risk In Communities) study. J Am Coll Cardiol
2010;55:1600-7.
Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is
a significant predictor of death in a cohort of chronic hemodialysis
patients. Kidney Int 2002;61:1887-93.
Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV,
et al. Atherosclerotic cardiovascular disease risks in chronic
hemodialysis patients. Kidney Int 2000;58:353-62.
editorials
18. Go AS, Chertow GM, Fan D, McCullock CE, Hsu CY. Chronic
kidney disease and the risks of death, cardiovascular events, and
hospitalization. N Engl J Med 2004;351:1296-1305.
19. Tuttle KR, Short RA. Longitudinal relationships among coronary
artery calcification, serum phosphorus, and kidney function. Clin J
Am Soc Nephrol 2009;12:1968-73.
20. European Guidelines on Cardiovascular Disease Prevention in
clinical practice: executive summary. Eur J Cardiovasc Prev Rehabil
2007;14 Suppl 2:E1-40.
21. KDIGO clinical practice guideline for the diagnosis, evaluation,
prevention and treatment of chronic kidney disease-mineral and
bone disorder (CKD-MBD). Kidney Int Suppl 2009;(113):S1-130.
22. Go AS, Chertow GM, Fan D, McCullock CE, Hsu CY. Chronic
kidney disease and the risks of death, cardiovascular events, and
hospitalization. N Engl J Med 2004;351:1296-305.
23. Desbien AM, Chonchol M, Gnahn H, Sander D. Kidney function
and progression of carotid intima-media thickness in a community
study. Am J Kidney Dis 2008;51:584-93.
24. Coll B, Betriu A, Martínez-Alonso M, Borràs M, Craver L, Amoedo
ML, et al. Cardiovascular risk factors underestimate atherosclerotic
burden in chronic kidney disease: usefulness of non-invasive tests
in cardiovascular assessment. Nephrol Dial Transplant
2010;25:3017-25.
25. Ix JH, Katz R, de Boer IH, Kestenbaum IR, Allison MA, Siscovick DS,
et al. Association of chronic kidney disease with the spectrum of
ankle brachial index the CHS (Cardiovascular Health Study). J Am
Coll Cardiol 2009;54:1176-84.
26. Krasniak A, Drozdz M, Pasowicz M, Chmiel G, Michalek M, Szumilak
D, et al. Factors involved in vascular calcification and atherosclerosis
in maintenance hemodialysis patients. Nephrol Dial Transplant
2007;22:515-21.
27. Leskinen Y, Lehtimäki T, Loimaala A, Lautamatti V, Kallio T, Huhtala H,
et al. Carotid atherosclerosis in chronic renal failure-the central role
of increased plaque burden. Atherosclerosis 2003;171:295-302.
28. Nolan RL, Morton AR, Pickett W. Prevalence and associations of
coronary artery calcification in patients with stages 3 to 5 CKD
without cardiovascular disease. Am J Kidney Dis 2008;52:849-58.
29. Coll B, Betriu A, Martínez-Alonso M, Amoedo ML, Arcidiacono MV,
Borrás M, et al. Large Artery Calcification on Dialysis Patients Is
Located in the Intima and Related to Atherosclerosis. Clin J Am Soc
Nephrol 2010;6(2):303-10.
30. Junyent M, Martínez M, Borrás M, Betriu A, Coll B, Craver L, et al.
Utilidad de las técnicas de imagen y biomarcadores en la predicción del
riesgo cardiovascular en pacientes con enfermedad renal crónica en
España: Proyecto NEFRONA. Nefrologia 2010;30(1):119-26.
Send to review: 28 Nov. 2011 | Accepted: 6 Dec. 2011
Nefrologia 2012;32(1):7-11
11
editorial comments
See original article in Nefrologia Sup Ext 2011;2(7):7-13
Longitudinal observational studies and causality
Alfonso Muriel1, Domingo Hernández-Marrero2, Víctor Abraira1
1
2
Unidad de Bioestadística Clínica. Hospital Universitario Ramón y Cajal, IRYCIS, CIBERESP. Madrid. Spain
Servicio de Nefrología. Hospital Universitario Carlos Haya. Málaga. Spain
Nefrologia 2012;32(1):12-4
doi:10.3265/Nefrologia.pre2011.Nov.11167
R
esults from randomised clinical trials (CT) and CT
meta-analyses provide the best scientific evidence for
evaluating the effect of a treatment according to the hierarchical rankings for clinical research methods. Observational studies (OS) hold a lower position in the evidence rankings, and are considered to have less probative force for the
following reasons: a) they may overestimate the effects of the
treatment due to patient heterogeneity; b) they may contain
biases that are inherent to their design and nature; and c) on
some occasions, the interpretation of results may be confusing. However, the controlled conditions found in a CT mean
that their results may not be directly applicable to patients in
clinical practice. An OS, on the other hand, measures effectiveness that cannot feasibly be obtained in any other way. In
clinical research, and in the field of nephrology in particular,
the analysis of large patient registers or clinical databases
provides information whose usefulness should not be underestimated,1,2 and which may complement CT results. Using
this strategy, we can perform medical research that is closer
to daily clinical practice, and focuses on the normal conditions experienced by the patients themselves.3
Generally speaking, OS, and cohort studies in particular, are
useful for assessing the effect of a treatment that was not
assigned at random. Here, treatment is established based on
common medical practice or on the patient’s individual
characteristics. Establishing a link between a treatment and a
certain result may depend on a number of biases, including
confounding by indication, since in this type of study,
treatment is not assigned at random and may be related to
health results. One obvious example is when the indication
for the treatment in some situations is determined based on
clinical guidelines or consensus for a specific disease.
A number of statistical models have been created to assess
the effect of a treatment and to check for potentially
Correspondence: Alfonso Muriel García
Unidad de Bioestadística Clínica, Hospital Universitario Ramón y Cajal,
IRYCIS, CIBERESP, Ctra. Colmenar, km 9.100, 28034 Madrid. Spain.
[email protected]
[email protected]
12
confounding co-variables. For example, regression models
can offer measures to associate a treatment with a result, but
they cannot establish causality measures due to the lack of
interchangeability among patients. Causal relationships can
be established in a CT, since the patients are interchangeable
and assigned to different groups at random.
Interchangeability cannot be assumed in an OS, since the
assigned group depends on the patient’s conditions,
expressed as co-variables that change over time, and on the
treatment the patient receives according to the co-variables
that were analysed. It may therefore occur that timedependent variables are affected by the treatment itself. This
means that both the co-variables and the treatment may
change the patient’s prognosis.
Marginal structural models (MSM) were proposed in the
late 1990s by members of the Harvard School of Public
Health3,4 to evaluate causal relationships and avoid biases in
longitudinal studies. MSM are an alternative to classical
regression models when there is a time-dependent
confounder that is associated with the event in question, but
it is also related to the treatment being evaluated. These
models are called “structural” because they study causality,
rather than simple association. Causal inference is
performed by means of comparing, theoretically, the results
of treating all patients with the results of treating none of
the patients. Marginal structural models use a weighted
form of the propensity score, called IPTW (inverse
probability of treatment weight), in such a way as to
simulate a population in which treated and untreated
patients do not differ in any of their co-variables, therefore
allowing us to assume interchangeability for treated and
untreated patients. MSM are used in clinical research in
order to resolve questions of causality. As noted by Hernan,
the scenario is typically represented by observational
studies that are analysed like CT.5 This type of model can be
implemented by using common statistical software
applications. The journal NBE published an article entitled
“Modelos estructurales marginales: una herramienta útil
que proporciona evidencia a los estudios observacionales”
(marginal structural models: a tool for studying causal
relationships in observational studies)6 which provides
Alfonso Muriel et al. Observational studies and causality
practical information about this type of statistical tool. This
article also provides an in-depth account of the conceptual
bases of an MSM, the assumptions and conditions it must
contain, and the way to implement it by using specifically
designed statistical software.
In many medical specialties, including nephrology, patients
are monitored over long periods of time as part of their care
requirements, and they receive a number of treatments that
are added according to their condition at a specific time. An
MSM is ideal in this type of situation for avoiding
confounding by indication biases. To cite an example, MSM
were applied in OS of HIV-positive patients receiving antiretroviral drugs7-10; in patients taking aspirin due for
cardiovascular disease11; and in patients who received
corticosteroids for asthma12 or rheumatoid arthritis.13
In nephrology, MSM have also been used to determine the
causal relationship between multiple treatments or
exposures and the final outcome of a disease. In this respect,
multiple OS have shown that patients on high doses of
erythropoietin (EPO) could have higher mortality rates,
although it was also suspected that patients requiring higher
doses of EPO could have more co-morbidities. Likewise,
the efficacy of restricting phosphorus in a diet or using a
certain dialysis technique (haemodialysis vs peritoneal
dialysis) to decrease mortality in kidney patients are also
topics of considerable debate.
Although a preliminary analysis shows that very high
doses of EPO are associated with higher mortality, this
effect disappeared with the implementation of a more
complete MSM. 14 Use of MSM also revealed that neither
restricting dietary phosphate in these patients nor the type
editorial comments
of dialysis (haemodialysis or peritoneal dialysis) had a
decisive influence on mortality in this patient group. 15,16
Lastly, the use of MSM in a multi-centre OS from the
Netherlands showed that loss of residual renal function
was associated with higher mortality rate, 17 which
supports the possibility of implementing kidney
replacement therapy that is personalised according to the
urinary volume of the patient at the start of chronic
dialysis.
In the field of kidney transplantation, the main purpose of
MSM is to estimate the impact of metabolic changes on
mortality and to evaluate the efficacy of
immunosuppressive and cardioprotective drugs on both
patient and kidney graft survival. In fact, the use of Cox
regression models and MSM, adjusted for confounders,
showed that high glycaemia and more intense insulin
treatment was associated with higher mortality. 18 At the
same time, with the help of MSM, it was shown that the
use of mycophenolate mofetil was a more effective aid to
kidney graft survival than azathioprine. 19 Lastly, a recent
OS performed by our group by MSM found that the use of
renin-angiotensin system blockers in kidney transplant
patients is associated with a lower risk of mortality, but
does not guard against losing the graft. 20 These findings
confirm the usefulness of implementing an MSM in
cohort OS of renal patients, but it remains unclear
whether carrying out randomised CT on these patients
will support these results.
As we await new evidence, use of MSM in cohort OS
employing time-dependent variables provides results that
are valid and complementary to CT results for evaluating
the clinical efficacy of specific treatments.
KEY CONCEPTS
1. OS results may be comparable to those from
clinical trials in terms of therapeutic efficacy,
given adequate, rigorous OS design and data
analysis methods.
2. The presence of time-dependent clinical
confounders can result in overestimating or
underestimating the effect of treatment
when conventional regression models are
used, due to confounding by indication.
4. The choice of confounders for implementing
MSM must be done from a clinical standpoint,
using the appropriate statistical support.
Faulty choice of these variables can result in a
bias that changes the estimator variance.
5. When using an OS to assess the efficacy of a
treatment, employing MSM can increase the
level of evidence, making it applicable and
extendable to daily clinical practice.
3. MSM can prevent confounding by indication
biases, but their assumptions and conditions
must be verified.
Nefrologia 2012;32(1):12-4
13
editorial comments
Acknowledgements
The authors would like to thank Ramón y Cajal University Hospital’s Biostatistics Unit (IRYCIS, Madrid, Spain; CIBER Epidemiology and Public Health CIBERESP) and the kidney transplant teams at University Hospital of
the Canary Islands (Tenerife) and Carlos Haya Hospital (Málaga) for their
participation.
Conflict of interest
The authors declare they have no potential conflicts of
interest related to the contents of this article.
REFERENCES
1. Dreyer NA, Garner S. Registries for robust evidence. JAMA
2009;302(7):790-1.
2. Hernández D, Pascual J, Abraira V, Lorenzo V, Quereda C. Estudios
observacionales y registros como fuentes de evidencia en el trasplante renal. Nefrologia 2006;26 Suppl 5:66-76.
3. Hernán MA. With great data comes great responsibility: publishing
comparative effectiveness research in epidemiology. Epidemiology
2011;22(3):290-1.
4. Robins JM, Hernán MA, Brumback B. Marginal structural models
and
causal
inference
in
epidemiology.
Epidemiology
2000;11(5):550-60.
5. Hernán MA, Alonso A, Logan R, Grodstein F, Michels KB, Willett
WC, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology 2008;19(6):766-79.
6. Muriel A, Hernández D, Abraira V. Modelos estructurales marginales: una herramienta útil que proporciona evidencia a los estudios
observacionales. Nefrologia Sup Ext 2011;2(7):7-13.
7. Edmonds A, Yotebieng M, Lusiama J, Matumona Y, Kitetele F, Napravnik S, et al. The effect of highly active antiretroviral therapy on
the survival of HIV-infected children in a resource-deprived setting:
a cohort study. PLoS Med 2011;8(6):e1001044.
8. Petersen ML, Wang Y, van der Laan MJ, Guzman D, Riley E, Bangsberg DR. Pillbox organizers are associated with improved adherence
to HIV antiretroviral therapy and viral suppression: a marginal structural model analysis. Clin Infect Dis 2007;45(7):908-15.
Alfonso Muriel et al. Observational studies and causality
9. Petersen ML, Wang Y, van der Laan MJ, Rhee SY, Shafer RW, Fessel
WJ. Virologic efficacy of boosted double versus boosted single protease inhibitor therapy. AIDS 2007;21(12):1547-54.
10. Hernán MA, Brumback BA, Robins JM. Estimating the causal effect
of zidovudine on CD4 count with a marginal structural model for
repeated measures. Stat Med 2002;21(12):1689-709.
11. Cook NR, Cole SR, Hennekens CH. Use of a marginal structural model to determine the effect of aspirin on cardiovascular mortality in
the Physicians’ Health Study. Am J Epidemiol 2002;155(11):104553.
12. Kim C, Feldman HI, Joffe M, Tenhave T, Boston R, Apter AJ. Influences of earlier adherence and symptoms on current symptoms: a marginal structural models analysis. J Allergy Clin Immunol
2005;115(4):810-4.
13. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate
and mortality in patients with rheumatoid arthritis: a prospective
study. Lancet 2002;359(9313):1173-7.
14. Wang O, Kilpatrick RD, Critchlow CW, Ling X, Bradbury BD, Gilbertson DT, et al. Relationship between epoetin alfa dose and mortality: findings from a marginal structural model. Clin J Am Soc Nephrol 2010;5(2):182-8.
15. Lynch KE, Lynch R, Curhan GC, Brunelli SM. Prescribed dietary phosphate restriction and survival among hemodialysis patients. Clin J
Am Soc Nephrol 2011;6(3):620-9.
16. Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients
with end-stage renal disease. Arch Intern Med 2011;171(2):110-8.
17. van der Wal WM, Noordzij M, Dekker FW, Boeschoten EW, Krediet
RT, Korevaar JC, et al. Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural
model. Nephrol Dial Transplant 2011;26(9):2978-83.
18. Wiesbauer F, Heinze G, Regele H, Horl WH, Schernthaner GH, Schwarz
C, et al. Glucose control is associated with patient survival in diabetic
patients after renal transplantation. Transplantation 2010;89(5):612-9.
19. Kainz A, Heinze G, Korbely R, Schwarz C, Oberbauer R. Mycophenolate mofetil use is associated with prolonged graft survival after
kidney transplantation. Transplantation 2009;88(9):1095-100.
20. Hernández D, Muriel A, Abraira V, Pérez G, Porrini E, Marrero D, et
al. Renin-angiotensin system blockade and kidney transplantation:
longitudinal cohort study. Nephrol Dial Transplant. 2011 May
28.doi:10.193/ndt/gfr276. [Epub ahead of print].
Sent for Review: 2 Nov. 2011 | Accepted: 30 Nov. 2011
14
Nefrologia 2012;32(1):12-4
editorial comments
See original article on page 35
The value of serum free light chain assay in patients
with monoclonal gammopathies and renal failure
M. Luisa Campos1, Nuno M. Barbosa de Carvalho1, Guillermo Martín-Reyes2
1
2
The Binding Site Spain. Barcelona. Spain
Servicio de Nefrología. Hospital Regional Universitario Carlos Haya. Málaga. Spain
Nefrologia 2012;32(1):15-9
M
onoclonal gammopathies (MG) are blood dyscrasias that result from a neoplastic process in plasma
cell (PC) clones, and are usually associated with an
elevated production of a monoclonal protein (MP). This paraprotein can be an intact immunoglobulin or a light chain
(LC). The immunoglobulins are composed of an identical
pair of heavy chains joined to two identical kappa (κ) or
lambda (λ) LC. The heavy and light chains are produced separately, and are later joined and secreted into the bloodstream. In order to ensure correct conformation of the immunoglobulins, PC produce an excess of LC, whose surplus is
secreted along with the completed immunoglobulins. In this
manner, 40% of LC are found free in the serum, not joined to
heavy chains.1 These serum free light chains (sFLC) have a
different conformation: κ FLC present as 25kDa monomers,
whereas λFLC form 50kDa dimers.
their equivalents in serum samples1,4; however, they are
affected by the renal function of the patient, which is their
primary disadvantage (Figure 1). Nephelometric techniques
are the most precise and sensitive analytical methods
available, but they do not make the distinction between
monoclonal and polyclonal background. A recent addition to
the last techniques has been the sFLC assay, which allows
for measuring sFLC and determining monoclonality by
establishing the ratio of κ vs λ sFLC.2 This assay allows the
detection of κFLC and λFLC separately using polyclonal
antibodies produced in sheep that specifically recognise
epitopes in the constant region of LC that are hidden in
intact immunoglobulins, but are exposed in sFLC.1 The
sFLC assay is the most sensitive assessment technique
currently available. However, no technique can provide by
itself a diagnosis of the various types of MG, and so they
must be used together in order to provide a high sensitivity
in the diagnosis.5
DIAGNOSING MONOCLONAL GAMMOPATHIES
The diagnosis of MG is based on detecting the circulating
paraprotein. Serum protein electrophoresis (SPE) is the most
commonly used technique for measuring monoclonal bands,
but its sensitivity is limited: it is incapable of detecting MP
at concentrations <400mg/l, levels that are frequently
observed in cases of Bence-Jones (BJ) or light chain multiple
myeloma (BJMM).2 Immunofixation electrophoresis (IFE) is
a more sensitive technique for characterising the type of MP
but not to quantify it, and therefore it is of limited
application during the MG follow-up. Both urine
electrophoresis and immunofixation are more sensitive than
Correspondence: M. Luisa Campos
The Binding Site Spain.
Balmes, 243, 4º 3a. 08006 Barcelona. Spain.
[email protected]
For the first time, sFLC assay allowed for measuring normal
serum levels and determining a reference range for normal
subjects. The normal range of κFLC is 3.3-19.4mg/l, and the
normal range for λFLC is 5.7-26.3mg/l, with a normal
interval for the κ/λ sFLC of 0.26-1.65.6 Using this range in a
retrospective study, Bradwell demonstrated that 100% of
patients with BJMM have an altered κ/λ ratio, suggesting
monoclonality.7 In the field of MG, sFLC assay has shown a
greater sensitivity for detecting the monoclonal component,
with special relevance in non-secretory MM, in which it is
now possible to measure and monitor MP without having to
recurre to invasive techniques, and in the case of AL
amyloidosis, where international guidelines recommend
measuring sFLC as part of the diagnostic process.8,9
Additionally, measuring sFLC at the moment of diagnosing
MM and other MG takes on a role in prognosis and will
provide a valuable baseline value for monitoring the patient
during treatment.8,10 Recently, Katzmann performed a study
15
M. Luisa Campos et al. The value of serum FLC assay
editorial comments
The quantity of circulating FLC depends on the level of production by PC and the rate of
metabolisation by the kidneys. The renal glomerulus works as a filter with a cut-off point of
40-60kDa, which is easily passed by low molecular weight molecules. sFLC pass the pores
of the glomerulus towards the proximal tubule of the nephron, where they are reabsorbed
and metabolised. The capacity of reabsorption for sFLC by the kidney is 10-30g/day, and so
normal individuals that produce 0.5-1g/day reabsorb all FLC, and they do not reach the
urine. As a result of this metabolisation pathway, the half-life of these molecules in serum is
considerably short (2-6 hours) when compared with the half-life of intact immunoglobulins
(5-21 days). This difference in half-life is one of the primary advantages of sFLC assay in
monitoring MG.
AL AMYLOIDOSIS
LCDD
ACUTE TUBULAR NECROSIS
FALCONI SYNDROME
Proximal
tubule
Distal tubule
5-10mg/day in
urine
sFLC filtrated:
glomerulus
CAST
NEPHROPATHY
Absorption:
10-30g/day
sFLC+ Tamm-Horsfall
precipitate and produce
waxy casts
Cast
nephropathy
50 000
5.000
5000
500
Bence-Jones
proteinuria
250
100
2000
Urine
FLC in urine (mg/l)
50.000
FLC in serum (mg/l)
Serum levels of FLC depend on their metabolisation by the kidneys, but at
the same time, an excess in FLC affects kidney function. In this paradox, we
find the reason for analysing serum samples instead of urine samples in
patients with MG and increased sFLC. The sFLC assay has high sensitivity, and
can detect dyscrasia earlier, since serum levels will increase and exceed the
normal range before they can be detected in urine samples. With the
progression of the pathology, serum FLC levels will saturate the metabolic
capacity of the kidney, and only after this point of Bence-Jones proteinuria
will FLC be detectable in the urine. However, this saturation is associated
with a high risk of nephropathy, and with time kidney function will decrease
and less sFLC will be filtered, thus accumulating at a greater rate in serum,
with a greater half-life. As such, from the moment of renal failure, free light
chain assays using urine samples no longer show the true clinical situation of
the patient.
1000
Serum
10
10
0
6
12
18
Time (months)
24
30
Normal range serum
Normal range urine
(Adapted from: Bradwell AR, courtesy of R Johnson and J Feehally.)
FLC: free light chains; sFLC: serum free light chains; LCDD: light-chain deposition disease.
Figure 1. Free light chains and the kidney
with 1877 patients with MG, showing that a higher sensitivity
for diagnosis could be achieved for the majority of malignant
MG using a protocol of serum analyses (SPE + sFLC + sIFE).
Based on their results, these authors proposed replacing IFE in
24-hour urine samples with the sFLC assay.11 This simple
algorithm allows for orientating the diagnosis towards cast
nephropathy (Figure 2). In a similar manner, the International
Myeloma Working Group recommended using a combination
of SPE, sFLC, and sIFE for tracking MG, and suggested that
the sFLC assay could substitute IFE in 24-hour urine samples.
This last test, however, still remains necessary in the case of
strong, unconfirmed suspicion of AL amyloidosis.8
the normal range. This abnormal value in the κ/λ coefficient
is proportional to the progression of the renal disease, and
can pose a challenge when diagnosing patients with renal
failure prior to MG.12,13 In order to avoid this issue,
Hutchison measured κ and λ sFLC in 688 patients with renal
failure and no MG, establishing a new range of normality for
patients with renal failure at 0.37-3.1.12,13 The new “renal
range” has been validated, and maintains a sensitivity of
100%, improving the specificity for the assay in cases of
renal failure from 93% to 99%.13,14
NEPHROTOXIC PROPERTIES OF SERUM FREE LIGHT
CHAINS
RENAL FAILURE AND THE NEW RANGE OF
NORMALITY FOR PATIENTS WITH A PRIOR
ABNORMAL RENAL FUNCTION
One important consideration for clinical practice is that the
renal failure itself affects sFLC levels due to the reduced
filtration rate. However, the sFLC assay has shown that, in
the majority of cases of renal failure not derived from MG,
the sFLC coefficient remains within its normal range. Some
patients with renal failure have values that fall just outside of
16
MG are frequently associated with renal disease, and up to
50% of patients with MM already have altered renal function
at the time of diagnosis (10%-20% dependent on
dialysis).15,16 The nephrotoxic properties of sFLC are well
known, and are attributed with the increased risk of suffering
renal damage in patients with MG. Their toxicity can
develop at different levels: 1) glomerular: formation of
amyloid fibrils, usually λsFLC, or deposits in the basal
membrane associated with κsFLC; 2) proximal tubule: the
Nefrologia 2012;32(1):15-9
editorial comments
Suspected MG
Acute renal failure
SPE
sFLC
Altered
Normal
No MG
Clonal FLC
<500mg/l
No cast nephropathy,
alternative MG?
Clonal FLC
>
_500mg/l
Probable
cast
nephropathy
Consider renal biopsy:
collaboration with haematology/oncology departments
Altered
Normal
Strong
clinical
suspicion of AL
sIFE
No MG
MG identified and
classified
IFE
in serum and
24-hour urine
No MG
MG identified and
classified
(Adapted from Dispenzieri, et al.8 and Cockwell, et al.21)
AL: AL amyloidosis; FLC: free light chain; PC: plasma cells; SPE: serum protein electrophoresis; MG: monoclonal gammopathies.
Figure 2. Proposed protocol for the diagnosis and follow-up of acute renal failure/monoclonal gammopathy
exacerbated process of reabsorption stimulates the
production of cytokines and, consequently, the inflammatory
response and fibrosis produced can lead to acute tubular
necrosis; or, even, by the incapacity of cells to degrade FLC
that accumulate intracellularly, forming crystals
characteristic of Fanconi syndrome17; 3) the distal tubule:
once the absorption capacity of the proximal tubule is
surpassed, the FLC precipitate with Tamm-Horsfall proteins,
causing cast nephropathy with the formation of waxy casts
that eventually block the nephron and produce renal failure
(Figure 1). Cast nephropathy, or “myeloma kidney,” is the
most commonly seen nephropathy in MM. This condition is
irreversible as long as the tumour remains active, and is
associated with a worse prognosis, making effective tools for
an early diagnosis essential, so as to detect MG before the
appearance of this renal lesions.18
nephrology department, 100% of which are identifiable
using sFLC assays.13,22 Recent studies have shown that a
rapid decrease in sFLC allows for a greater rate of renal
recovery. This is due to the progression of the disease
towards interstitial fibrosis, which results in irreversible
renal damage.20 Once more, the delay before clinical
intervention will determine the prognosis, since 80% of
patients require a reduction in sFLC >60% by day 21 in
order to reach renal recovery, and this renal recovery entails
a significant improvement in survival.23
A rapid diagnosis and start of treatment are possible through
good interaction between nephrologists, haematologists, and
oncologists, leading to improved survival. Given the high
sensitivity of the test, sFLC measurement allows for a rapid
identification of nephrotoxic monoclonal proteins in patients
with acute renal failure.23
IMPACT OF AN EARLY DIAGNOSIS
MONITORING TREATMENT
The amount of time elapsed before a diagnosis is established
and treatment is started is very important. A prolonged time
until MM is diagnosed increases the probability of
complications, among which stands out renal lesions.19,20 The
nephrologist plays a central role in the early diagnosis of the
disease as a substantial portion of patients develop acute
renal failure without known MG.21 Particularly in relation to
myeloma kidney, 50% of patients will seek treatment in the
Nefrologia 2012;32(1):15-9
In addition to providing a tool for the early diagnosis of MG,
sFLC assay plays an important role in monitoring the
elimination of sFLC in patients with MG. The strategy for
treating MM is based on the application of chemotherapy to
eliminate the malignant PC clone, and at the same time,
direct elimination of the circulating sFLC in the
bloodstream.
17
editorial comments
The treatment of MM has evolved substantially in recent
years due to the development of more effective and faster
drugs, such as thalidomide, lenalidomide, and bortezomib,
with higher response rates and better long-term results.
Bortezomib is approved by the FDA, is well-tolerated by
patients with renal failure, and its pharmacokinetics is not
affected by the level of renal failure, so it can be
administered with no need for readjusting the dose.
Bortezomib with dexamethasone is the recommended
treatment for patients with MM and renal failure of any
level.24
Plasmapheresis has not shown to be as effective as expected
for eliminating sFLC.25,26 The fact that a large part of the
circulating sFLC are located in the extravascular space,
along with limits to the duration and frequency of
plasmapheresis cycles, may be the basis for the lack of
effectiveness observed with this treatment. However, the
studies performed until now have supported the relationship
between a reduction in sFLC levels and renal recovery.21,26
More recently, different haemodialysis filters have been
developed with a high cut-off point (HCO), which allows for
the passage of sFLC without an excessive loss of albumin.16,27
The HCO 1100 membrane has demonstrated its high
effectiveness that, in combination with proper chemotherapy,
produces promising results for the recovery of patients with
myeloma kidney.28,29 A swift and constant decrease in sFLC
was associated with recovery of the kidney in 74% of
patients in the study by Hutchison,28 and 50% in the study
published by Martin-Reyes29 in this same issue of Nefrología.
Given the short half-life of sFLC in comparison to intact
immunoglobulins, measuring sFLC allows for determining
levels before and after each cycle of haemodialysis almost in
real time.29 In this manner, measuring sFLC is important in
monitoring the treatment of these patients because it allows
us to: 1) evaluate the efficient elimination of sFLC during
dialysis; 2) analyse the efficiency of chemotherapy during
treatment, with the option of adjusting the treatment regimen
as needed; 3) determine the moment in which the patient has
recovered renal function, starting to metabolise the sFLC
anew; and 4) early diagnosis of recurrence.
Each year, the incidence of MM increases, but we have the
possibility of providing more effective treatment to these
patients. This is due to the development of more effective
new-generation chemotherapies, in addition to the possibility
of offering a rapid decrease in circulating sFLC, thus
reducing the probability of irreversible renal damage, which
reduces survival.30 As such, this is an important time of great
advancements and expectations in the treatment of MM and
the recovery of these patients, in which the clinician still
plays an important role in providing attentive care and quick
action. However, no therapy provides effective results after a
late diagnosis, and the major advantage that we have today is
a simple protocol that allows us to identify patients with
clinically relevant MG efficiently and earlier.
18
The authors M. Luisa Campos and Nuno M. Barbosa de
Carvalho work for Binding Site Spain.
REFERENCES
1. Bradwell AR. Serum Free Light Chain Analysis (plus Hevylite). 6.ª ed.
Birmingham, UK: The Binding Site Group Ltd.; 2010.
2. Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ,
Drayson MT, et al. Highly sensitive, automated immunoassay for
immunoglobulin free light chains in serum and urine. Clin Chem
2001;47(4):673-80.
3. Keren DF. Procedures for the evaluation of monoclonal
immunoglobulins. Arch Pathol Lab Med 1999;123(2):126-32.
4. Hutchison CA, Basnayake K, Cockwell P. Serum free light chain
assessment in monoclonal gammopathy and kidney disease. Nat
Rev Nephrol 2009;5(11):621-8.
5. Katzmann JA. Screening panels for monoclonal gammopathies:
time to change. Clin Biochem Rev 2009;30(3):105-11.
6. Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell
AR, et al. Serum reference intervals and diagnostic ranges for free
kappa and free lambda immunoglobulin light chains: relative
sensitivity for detection of monoclonal light chains. Clin Chem
2002;48(9):1437-44.
7. Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT.
Serum test for assessment of patients with Bence Jones myeloma.
Lancet 2003;361(9356):489-91.
8. Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et
al. International Myeloma Working Group guidelines for serumfree light chain analysis in multiple myeloma and related disorders.
Leukemia 2009;23(2):215-24.
9. López-Corral L, García-Sanz R, San Miguel JF. [Value of serum free
light chains assay in plasma cell disorders]. Med Clin (Barc)
2010;135(8):368-74.
10. Kyle RA, Durie BGM, Rajkumar SV, Landgren O, Blade J, Merlini
G, et al. Monoclonal gammopathy of undetermined
significance (MGUS) and smoldering (asymptomatic) multiple
myeloma: IMWG consensus perspectives risk factors for
progression and guidelines for monitoring and management.
Leukemia 2010;24(6):1121-7.
11. Katzmann JA, Dispenzieri A, Kyle RA, Snyder MR, Plevak MF, Larson
DR, et al. Elimination of the need for urine studies in the screening
algorithm for monoclonal gammopathies by using serum
immunofixation and free light chain assays. Mayo Clin Proc
2006;81(12):1575-8.
12. Hutchison CA, Harding S, Hewins P, Mead GP, Townsend
J, Bradwell AR, et al. Quantitative assessment of serum
and urinary polyclonal free light chains in patients with
ch ro n i c k i d n e y d i se a se . C l i n J A m S o c Nep h ro l
2008;3(6):1684-90.
13. Hutchison CA, Plant T, Drayson M, Cockwell P, Kountouri M,
Basnayake K, et al. Serum free light chain measurement aids the
diagnosis of myeloma in patients with severe renal failure. BMC
Nephrol 2008;9:11.
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14. Abadie JM, van Hoeven KH, Wells JM. Are renal reference intervals
required when screening for plasma cell disorders with serum free
light chains and serum protein electrophoresis? Am J Clin Pathol
2009;131(2):166-71.
15. Bladé J, Fernández-Llama P, Bosch F, Montolíu J, Lens XM, Montoto
S, et al. Renal failure in multiple myeloma: presenting features and
predictors of outcome in 94 patients from a single institution. Arch
Intern Med 1998;158(17):1889-93.
16. Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J,
et al. Efficient removal of immunoglobulin free light chains by
hemodialysis for multiple myeloma: in vitro and in vivo studies. J
Am Soc Nephrol 2007;18(3):886-95.
17. Reyes GM, González IG, Alférez MJ, González JMM, Frutos MA.
Cristales intracitoplasmáticos y síndrome de Fanconi en un paciente
con mieloma IgA Kappa. Nefrologia 2001;XXI(2):213-6.
18. Herrera GA, Joseph L, Gu X, Hough A, Barlogie B. Renal pathologic
spectrum in an autopsy series of patients with plasma cell dyscrasia.
Arch Pathol Lab Med 2004;128(8):875-9.
19. Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB. Multiple
myeloma: causes and consequences of delay in diagnosis. QJM
2007;100(10):635-40.
20. Basnayake K, Cheung CK, Sheaff M, Fuggle W, Kamel D, Nakoinz S,
et al. Differential progression of renal scarring and determinants of
late renal recovery in sustained dialysis dependent acute kidney injury
secondary to myeloma kidney. J Clin Pathol 2010;63(10):884-7.
21. Cockwell P, Hutchison CA. Management options for cast nephropathy
in multiple myeloma. Curr Opin Nephrol Hypertens 2010;19(6):550-5.
22. Hutchison CA, Bridoux F. Renal impairment in multiple myeloma:
time is of the essence. J Clin Oncol 2011;29(11):e312-313; author
reply e314.
editorial comments
23. Hutchison CA, Cockwell P, Stringer S, Bradwell A, Cook M, Gertz
MA, et al. Early reduction of serum-free light chains associates
with renal recovery in myeloma kidney. J Am Soc Nephrol
2011;22(6):1129-36.
24. Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N,
Ludwig H, Jagannath S, et al. Renal impairment in patients
with multiple myeloma: a consensus statement on behalf of
the International Myeloma Working Group. J Clin Oncol
2010;28(33):4976-84.
25. Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett
BJ, et al. Plasma exchange when myeloma presents as acute renal
failure: a randomized, controlled trial. Ann Intern Med
2005;143(11):777-84.
26. Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A,
Fervenza FC, et al. Improvement of cast nephropathy with plasma
exchange depends on the diagnosis and on reduction of serum free
light chains. Kidney Int 2008;73(11):1282-8.
27. Ward RA. Protein-leaking membranes for hemodialysis: a new class
of membranes in search of an application? J Am Soc Nephrol
2005;16(8):2421-30.
28. Hutchison CA, Bradwell AR, Cook M, Basnayake K, Basu S,
Harding S, et al. Treatment of acute renal failure secondary to
multiple myeloma with chemotherapy and extended high cutoff hemodialysis. Clin J Am Soc Nephrol 2009;4(4):745-54.
29. Martín-Reyes G, Toledo R, Torres A, et al. Tratamiento con
hemodiálisis del fracaso renal agudo en el mieloma múltiple
con filtros de alto poro. Nefrologia 2012;32(1):35-43.
30. Reyes GM, Valera A, Frutos MA, Ramos B, Ordónez V, Novales
EL. Supervivencia de pacientes con mieloma tratados con
diálisis. Nefrologia 2003;XXIII(2):131-6.
Sent for review:20 Jul. 2011 | Accepted: 9 Nov. 2011
Nefrologia 2012;32(1):15-9
19
short review
Renal supportive care and palliative care: revision
and proposal in kidney replacement therapy
Juan P. Leiva-Santos1, Rosa Sánchez-Hernández2, Helena García-Llana3,
M. José Fernández-Reyes2, Manuel Heras-Benito2, Álvaro Molina-Ordas2, Astrid Rodríguez2,
Fernando Álvarez-Ude2
Cuidados Paliativos-MIR MFyC. Hospital General de Segovia. Spain
Servicio de Nefrología. Hospital General de Segovia. Spain
3
Servicio de Nefrología. Hospital Universitario La Paz, IdiPAZ. Madrid. Spain
1
2
Nefrologia 2012;32(1):20-7
ABSTRACT
Patients with chronic kidney disease may receive sustained
renal supportive care and renal palliative care (RPC) starting with the diagnosis of the disease, throughout the various stages of renal replacement therapy (RRT), the cessation of the RRT, and in the decision of whether to provide
conservative treatment or non-initiation of RRT. This article reviews the literature on the development of renal palliative care and proposed RPC models. We describe the
progression of disease in organ failure, which is very different from other areas of palliative care (PC). We describe
important components of resident nephrology training in
PC. We discuss the management of pain and symptom control, as well as communication skills and other psychological and ethical aspects in the renal patient. We conclude
that in chronic renal patients, a palliative care approach
can provide a positive impact on the quality of life of patients and their families, as well as optimizing the complex
treatment of the renal patient.
Keywords: Renal Palliative Care. Opioids and Renal
Failure. Renal Palliative Care and Organization.
Cuidados de soporte renal y cuidados paliativos renales:
revisión y propuesta en terapia renal sustitutiva
RESUMEN
El paciente con enfermedad renal crónica es susceptible de
recibir tratamiento de soporte y cuidados paliativos renales (CPR) desde el diagnóstico de la enfermedad, durante
las distintas etapas de tratamiento sustitutivo renal (TSR),
en el cese de dicho TSR y también si se decide tratamiento
conservador o no inicio de TSR. Este artículo revisa la literatura referente al desarrollo de cuidados CPR y los modelos propuestos. Exponemos la trayectoria de la enfermedad en el fallo de órgano, que marca diferencias respecto
a otros campos de los cuidados paliativos (CP). Se describen componentes de formación importantes para el residente de nefrología en CP. Abordamos el manejo del dolor y el control de síntomas, así como habilidades de
comunicación y otros aspectos psicológicos y éticos en el
paciente renal. Concluimos que en la atención al paciente
renal crónico, un enfoque desde la medicina paliativa puede suponer un provechoso impacto en la calidad de vida
del paciente y su familia, además de optimizar el complejo tratamiento nefrológico del paciente.
Palabras clave: Cuidados paliativos renales. Opioides en
insuficiencia renal. Organización en cuidados paliativos renales.
INTRODUCTION
The 21st century should be second nature to health
professional has two obligations when performing his/her
Correspondence: J.P. Leiva Santos
Hospital General de Segovia.
Carretera de Ávila s/n. 40002 Segovia. Spain.
[email protected]
20
job: to cure disease, and to alleviate suffering.1 In the case of
chronic incurable diseases, the objective of treatment is to
improve or preserve body function so as to avoid a
premature death. This objective is carried out through
palliative care (PC), defined by the World Health
Organisation (WHO) in 20022 as total, active, and continued
care of the patient and the patient’s family by a multiprofessional team when the medical expectation is no longer
Juan P. Leiva-Santos et al. Renal supportive care and palliative care
one of curing the disease. The primary objective of this
medicine field is not to prolong survival, but to achieve the
highest possible quality of life for patients and their families.
As such, PC practitioners must cover their patients’ physical,
psychological, social, and spiritual needs.2 If necessary, this
support must also be extended to the grieving process.
Palliative medicine (PM) is not synonymous with terminal
illness, although it does include it. There is a large
knowledge base for the application of PM, but this
experience is not benefiting the majority of people that have
a need for it. Despite the efforts made in the last two
decades, the majority of patients that require PC do not
receive it.3 Recently, dramatic changes have occurred in the
demographics of patients with advanced chronic kidney
disease (ACKD).4 In 2009, the incidence of RRT in Spain
was 126 patients per million population (pmp).5 Currently,
approximately 1.5 million patients are receiving
haemodialysis globally, and this value is growing at a 7%
yearly rate in those populations that have the privilege of
access to this type of treatment.6
Chronic kidney disease (CKD) follows a progressive
deterioration through various stages, in which RRT is the
final stage that only a small portion of CKD patients arrive
at7; with this in mind, we performed a review focusing on the
development of renal palliative care (RPC) and renal
supportive care (RSC), areas of new and growing interest for
nephrology in Spain.
For a better analysis of the subject, we will focus on the
following aspects:
1) Concepts of RSC and RPC
2) Bioethics: fundamental basis for RRT
3) Progression and stages of the disease
short review
the concept of life expectancy previously held by the
patient, placing them in a scenario of uncertainty where
the perception of control is lost and quality of life is
threatened. However, this psychological situation is
rarely recognised or discussed. Experts in PM should
work together with nephrologists in order to provide the
best possible care and quality of life for patients and
their families.9
The future course of this type of treatment will involve
integrating the principles and practices of PC in the
different areas of nephrology including haemodialysis,
peritoneal dialysis, renal transplants when necessary,
dealing with patients with CKD where the indicated
approach is a conservative treatment, and, of course,
patients that require end of life care. The objective is to
ensure that all renal patients with a limited life
expectancy receive high quality care with the help of the
most appropriate professionals.
The concept of RSC has been analysed by Noble et al,
using the Rogers method, which is based on the idea that
concepts are dynamic, with constant modification and
change. With this in mind, the following attributes of the
concept of RSC were laid down 8:
1) RSC must be available from the moment of
diagnosis to patient death, with emphasis on a clear
prognosis and the impact of the advanced renal
disease. One difference with respect to oncology is that,
in the case of oncology, some patients may recover but
CKD patients have a very high probability of death due
to the complications associated with their disease.
2) Interdisciplinary approach to treatment. This
facilitates avoiding the medicalisation of the
psychological and existential needs associated with
RRT patients.
4) Organisational models
5) Guidelines for training in PC for nephrology residents
6) Pain and symptom control
7) Psychological aspects and counselling
A NEW CONCEPT: RENAL SUPPORTIVE CARE
The term RSC is emerging as a central topic in
nephrology. It deals with a concept that is similar to PC,
end of life care, and conservative patient management, 8
but with several differences. Although very similar, they
are not synonymous, and as such it requires a definition.
To tell a patient that he/she has advanced renal failure
and needs dialysis involves very bad news that shatters
Nefrologia 2012;32(1):20-7
In addition, the concept of a nephrologist with extensive
training in RPC has emerged, with great importance at
centres where palliative care units (PCU) do not cover
all the patients with non-oncological pathologies.
3) Attention given to the patient’s caretaker and family.
The support of patient caretakers is essential in RSC.
The pressures felt by financial budgets are one
important factor, making the patient the central focus.10
In family renal disease, unaffected caretakers tend to
have an added emotional burden that may go unnoticed
at first.11
4) Therapeutic communication skills, which ensure
proper and opportune shared decision making. The
objectives of RSC are not reachable without proper
training in communication skills.12
21
short review
BIOETHICS: A FUNDAMENTAL BASIS FOR RENAL
REPLACEMENT THERAPY
Within the sphere of RPC interventions, we must pay special
attention to certain clinical situations with a high emotional
impact that can generate difficulties in shared decision
making, such as the withdrawal of a patient from dialysis or
the decision not to start it, among others.6 At this point in the
development of the field of nephrology, we know that not all
that is technically possible is ethically admissible. Modern
bioethics is based on the development of four fundamental
principles that should be second nature to doctors attending
to patients on RRT (Table 1). A detailed study of these
principles falls outside the aims of this review.
PROGRESSION AND STAGES OF DISEASE
Most of patients with ACKD die due to non-renal causes,
and although the renal disease may contribute to exitus, it is
not directly responsible.12 Four different progressions have
been described for disease (Figure 1).13,14
1) Sudden death may occur at any point during the
progression of the disease, with no previous diagnosis
(Figure 1A).
2) Following diagnosis of the terminal disease, function is
preserved initially, followed by a rapid deterioration in
advanced stages (Figure 1B); which is the typical pattern
in oncology.
3) This pattern involves recurrences of acute episodes,
requiring hospitalisation occasionally, with no recovery
of previous functional states (Figure 1C), which poses a
risk of death. This is the typical pattern in organ failure.
4) There is a gradual decrease in function prior to death,
which is characteristic of dementia and advanced age
(Figure 1D). These patterns may overlap in a patient on
RRT.
Implications of the disease progressions
For ACKD patients and their families, as well as for the health
professionals that treat them, it is of vital importance to
understand these disease progressions towards death.12 This is
consistently becoming more important for nephrologists, who
currently manage patients on RRT at more advanced ages and
with more associated comorbidities. The disease progressions
allow health care providers to: realise that “to do all that one
can do may be the wrong choice,” carry out a practical plan
for a good death, support both the patients and their
caregivers, and avoid a “prognostic paralysis”.15 These
implications lead us to the following conclusions: 1) that one
single model does not work for all cases: the typical
oncological PC model may not be adjustable to gradual and
progressive patient decline with unpredictable exacerbations.
Patients with non-malignant diseases may have more
prolonged needs than, although similar in nature to, those of
cancer patients; 2) transferable lessons: PC in oncology
Table 1. The four principles of modern bioethics
A
patient, to not do damage (primum non nocere). Tends to be interpreted as the lex artis and the obligation to carry out only indicated
actions and never contraindicated actions.
2. Principle of justice: equitable distribution of the costs and benefits of
treatment, with no discrimination of patients based on any cause
that might have to do with their social condition, sex, race, etc. The
principle of justice has to do with equal opportunity and equitable
allocation of available resources.
Level II, or maximum:
3. Principle of autonomy: all people are, inherently and unless otherwise demonstrated, capable of making their own decisions regarding
Terminal illness
High
Functional state
1. Principle of non-maleficence: the obligation to do no harm to the
B
Sudden death
C
High
Death
Death
Low
Organ failure
D
Fragile elderly patient
Functional state
1. Level I or minimal:
Death
Death
Low
Time
Time
whether or not to receive treatments that will affect their health.
4. Principle of beneficence: we are obliged to aid our patients, provi-
(Source: Lunney et al20)
ding them with the greatest possible benefit.
(Source: TL Beauchamp y JF Childress, 1979).
22
Figure 1. Typical progressions of disease, identified in different
patients.
Nefrologia 2012;32(1):20-7
provides experiences that we can benefit from; 3) challenges
for research: patients receiving PC are an especially
vulnerable group, for which there is not usually a “second
opportunity” that allows for improving the care given to them.
As such, the idea of assigning patients to sub-optimal
conditions of health care is unacceptable.15 Research is
difficult to carry out in this field of medicine, but even so
should be given more emphasis.
ORGANISATIONAL MODELS
Spanish authors have proposed a PC programme for
terminal uraemia in patients with stage 5 CKD that do not
respond to dialysis, with glomerular filtration rates (GFR)
<15ml/min and who refuse RRT.16 In the model we propose
in this review, we extend this concept, considering clinical
and psychological criteria to be paramount above
laboratory parameters for including a patient on RSC and
RPC programmes; for example, a patient with a
functioning renal graft and a GFR of 60ml/min but with
musculoskeletal pain may benefit from the aid of an expert,
multi-disciplinary team that manages this pain and
immunosuppression therapy without compromising the
patient’s GFR. A PC programme for terminal uraemia
patients is only part of the proposed approach (Figure 2).
Tejedor et al also propose the creation of a PCU for ACKD
patients. We believe it to more economically sound, safer,
and more effective to train nephrology teams in RSC and
RPC. Anyway, the essential step is to incorporate expert
Renal supportive care
ACKD
C
K
D
HD
R
R
T
Conservative ACKD
treatment
Cessation
of RRT
S
L
Terminal
uraemia
D
PD: peritoneal dialysis; CKD: chronic kidney disease; ACKD:
advanced chronic kidney disease; HD: haemodialysis; SLD:
situation during last days; RRT: renal replacement therapy; RTx:
renal transplant.
Shaded boxes show the scenarios in which supportive and
palliative renal care intervention is most intense.
Figure 2. Proposed model for the application of renal
supportive care and renal palliative care.
Nefrologia 2012;32(1):20-7
doctors in PM and psychologists, who can offer RSC and
RPC from the hospital PCU, in the context of the
nephrology department. They can provide aid to the
patients and their families, as well as direct support for the
nephrologist.9 As such, it is essential to adapt the PM model
to the nephrology context and to incorporate RSC.4 This
proposed model is in accordance with a recent publication
in nephrology regarding the sustainability and equity of
RRT in Spain,17 and is a humble addition to this shared
task. PC could be developed and carried out by
interdisciplinary teams that would also include the patient’s
family and friends (Figure 3),4 who appreciate and
recognise the importance of this type of care before and
after the death of the patient.18
In some countries such as in Canada and the United States,
the approval of recent guidelines and national publications
have established the role of PC in the field of nephrology.19
Similar experiences have been described in England, Poland,
Australia, Portugal, and Hong Kong.
GUIDELINES FOR TRAINING NEPHROLOGY
RESIDENTS IN PALLIATIVE CARE
In Spain there are no recommendations from the national
committee on nephrology for residents to carry out a specific
rotation period for PC. A Canadian study concluded that
residents that had contact with PM specialists had better
training in situations dealing with the final stages of disease
and are considered more competent for providing necessary
end of life care,20 and proposed a programme for PM training
directed towards nephrology residents that covers the
following aspects21:
Renal palliative care
KTx
PD
short review
G
R
I
E
V
I
N
G
Nephrologist
Renal nurse
Nutritionist
Geriatrics
Family and friends
Primary care doctor
Primary care nurse
–
Physiotherapist
–
Dentist
–
Neurologist
–
Ophthalmologist
Renal patient
Palliative medicine
specialist
Social worker
Occupational therapist
Psychologist
priest/spiritual
advisor
Palliative care nurse
(Source: Lichodziejewska et al2)
Figure 3. Diagram of the interactions amongst the multidisciplinary team in renal palliative care.
23
short review
1) Impact on the patient upon reaching the final stage of
renal disease: life expectancy, survival, mortality, and
comorbidity
2) PM-based focus in haemodialysis units
3) Living wills and cardiopulmonary resuscitation
4) Communication skills: counselling
5) Pain management in renal patients
and intensity of pain during dialysis is higher than outside of
dialysis, according to the VAS scale.26 The revised Edmonton
Staging System (rESS),27 designed for the evaluation of
oncological pain, could be a clinically useful tool for the
study and treatment of pain in renal patients. This system has
the advantage of predicting analgesic response, considering
that a “difficult” pain does not necessarily mean that it
cannot be controlled. In order to make a simple of effective
evaluation, it is enough to know whether the pain is
neuropathic, incidental episodes, or if it associated with
emotional suffering and/or altered cognitive state, or drug
abuse.27
6) Controlling symptoms in renal patients
7) Transferral to specialised PC units and grieving support
8) Clinical, ethical, and legal issues when starting and
withdrawing dialysis treatment
PAIN AND SYMPTOM CONTROL
Arteriovenous fistulas are punctured an average of 300 times
per year in haemodialysis patients, and are qualified as
medium-intensity pain using the VAS scale.28 The
postoperative treatment of pain in patients with ACKD poses
a problem due to the fear of accumulating metabolites that
would depress the respiratory system. This also has been
described by anaesthesiologists, and several drugs are being
researched for their efficacy and safety in postoperative
ACKD patients.29
Pain
Chronic pain is suffered by 50%-63% of dialysis patients,
and 42%-55% of them classify their pain as severe.22 The
evidence provided by dialysis guidelines suggest that little
recognition is given to this pain and other symptoms in
dialysis patients, with consequent under-treatment.23 The use
of opioid analgesics is not very widespread, due to the threat
of toxicity and a lack of experience in their use. This leads to
inadequate treatment of pain in CKD patients. In a recent
review on the use of opioids and benzodiazepines in dialysis
patients, the effectiveness of treatment was variable and low;
in 17%-38% of patients, the years spent on dialysis were
correlated with the presence of pain, and 72%-84% of
patients with severe pain did not receive any analgesia.24
Recent research into the use of cannabinoids has motivated
the evaluation of their potential use in controlling symptoms
in renal patients on RRT. Although they had promising
results, at the moment this option is limited due to the
absence of long-term results.25
Evaluation of pain
The quantification and later follow-up of pain using scales
should be an added parameter for monitoring the
management of renal patients. Several different validated
pain measurement scales have been applied to groups of
haemodialysis patients: the Visual Analogue Scale (VAS),
the Pain Management Index (PMI), the McGill Pain
Questionnaire (MGPQ), and the Brief Pain Inventory (BPI).
The most common aetiology of pain observed during
dialysis is ischaemic pain, and the most common extradialysis pain is chronic musculoskeletal pain. The prevalence
24
Opioids in chronic kidney disease
We have dedicated this section solely to opioid compounds
listed for analgesia by the WHO, given the difficulty in their
use and their notable usefulness in renal patients. The
complex pharmacokinetics of opioid analgesics in patients
with kidney disease, as well as a lack of familiarity with the
medical use of these drugs, presents a barrier to the effective
alleviation of pain.30 The development of renal failure as a
consequence of opioid use has not been described.31 A
prospective study performed with 12 patients on
haemodialysis concluded that hydromorphone could provide
a safe and effective option in certain patients on
haemodialysis.32 Similar conclusions were reached in a study
comparing the use of hydromorphone in patients with
normal urea and creatinine vs patients with renal failure.33
The pharmacokinetic and pharmacodynamic profiles of
hydromorphone, methadone, and fentanyl are apparently
safe in patients with renal failure, making them
recommendable in these cases. The dose should be adjusted
when GFR<10ml/min.31 It has also been recommended to
reduce the dose and/or increase the dosing interval in renal
failure patients on dialysis. Frequent patient monitoring is
also indicated, and may even include home telephone
follow-up. It is also recommended not to use morphine or
codeine due to the difficulty of managing the adverse effects
and complications produced in these patients.31 Morphine
metabolites could accumulate between dialysis sessions.
Methadone metabolites are inactive and are not dialysed, and
so do not require adjusted doses in dialysis patients.31 These
studies are limited to populations with poor statistical
significance, and so we must use the recommended drugs
Nefrologia 2012;32(1):20-7
under close monitoring and perform
clinical/laboratory evaluation of our patients.
a
complete
short review
Table 2. Stressors in advanced chronic kidney disease
treatable through psychological interventions
1. Secondary effects of ACKD and its treatments
Symptom control
2. Diet management and hydration restrictions
3. Anxiety and depression
The general load of symptoms in CKD patients is high and
similar to those produced at the end of life in cancer
patients.34
4. Insomnia
In patients with stage 5 CKD that are treated without the
use of dialysis, the prevalence and severity of symptoms
during the last month prior to death have been studied
using the Memorial Symptom Assessment Scale-Short
Form (MSAS-SF) 35; of the 74 patients that participated in
the study, with a mean age of 81 years, 86% had severe
asthenia, 84% had pruritus, 82% had somnolence, 80%
had dyspnoea, 76% had difficulties concentrating, 73%
suffered from pain, 71% had reduced appetite, 71% had
oedema of the arms or legs, 69% had dry mouth, 65%
had constipation, and 59% had nausea. The SMILE
(Symptom Management Involving End-Stage Renal
Disease) randomised clinical trial demonstrated that
patients suffered from pain, sexual dysfunction, and
depression when on haemodialysis, these being underdiagnosed symptoms even though they are very
prevalent.36
7. Main caregiver burnout
PSYCHOLOGICAL ASPECTS AND COUNSELLING
The interest in incorporating psychological aspects into the
care of these patients and their families has been part of
PC since its beginning. However, the integration of
psychologists into nephrology teams is not widespread. As
such, the importance of these variables in PC of renal
patients is shown at an earlier stage at the end of their
lives. The field of RPC poses an ideal space in which
psychologists could exercise their specialty.37
Depression is a psychological issue with a very high
prevalence (10%-66%) in ACKD patients, and can be
approached through psychological and/or combined
intervention. 38 In certain scenarios, such as in peritoneal
dialysis units, depression is under-diagnosed and difficult
to treat. 38 Few controlled studies and even fewer
randomised studies have considered this issue. Renal
patients at the end of their lives are a special high-risk
group, given their high vulnerability and dependence.39
In a similar manner, anxiety disorders can be quite
common among renal patients at the end of their lives if
preventative treatment is not given. The prevalence rate of
anxiety disorders in haemodialysis patients is
approximately 45.7%, with negative effects on patient
quality of life.40
Nefrologia 2012;32(1):20-7
5. Social alienation
6. Functional limits and dependency
8. Spiritual crisis
9. Complicated grieving process: prevention and treatment
10. Exhaustion of the health care team. Prevention of burnout
ACKD: advanced chronic kidney disease
According to Cukor et al, ACKD entails a large number
of stressors that the patient and his/her close friends and
relatives must face (Table 2). Preventative measures in
RPC must be the gold standard for avoiding
psychopathologyzation at the end of patients’ lives.
Renal patients have a history of disease associated with
multiple losses that intensifies upon reaching advanced
phases. It is normal to encounter scenarios such as those
in hospital haemodialysis units, where “biographical
death,” associated with reduced quality of life, can occur
before “biological death.” In order to deal with these
differences, psychological intervention in chronic
advanced diseases requires protocols for maximising
resources rather than models orientated towards
psychological pathologies.41
Psychological therapies in RPC include support for the
family and after the patient has died.23 In 10%-20% of cases,
those grieving can have significant difficulties and even
associated physical comorbidities in the process of adapting
to the loss.42
One therapeutic tool that has demonstrated its effectiveness
in PC is counselling, since this is an ideal method for
therapeutic communication in circumstances of intense
emotional reactions.43
There are several definitions of counselling available.
According to Dietrich,44 at its core, it is a form of a helpful,
interventional, and preventative relationship in which an
advisor, through communication, attempts in a relatively
short span of time to provoke an active process of cognitiveemotional learning in a disorientated or overloaded person,
during the course of which this person can improve his/her
disposition towards self-help, his/her capacity for selfdirection, and operational competence.
25
short review
KEY CONCEPTS
1. The introduction of PC and its values within
the field of nephrology generates a
significant impact on the quality of life of
renal patients and their families.
2. Clinical, psychological, and laboratory criteria
are orientated towards including patients in
RSC and RPC programmes, although this is not
exclusively for terminal stage patients.
3. RSC and RPC involve a multidisciplinary team
and can be improved by the inclusion of
lessons learned in other fields of PC.
4. Training in PC for nephrology residents should
be promoted within the teaching and
research areas.
5. The study and management of pain in renal
patients is a priority that should be promoted
both within clinical practice and research.
6. Nephrology teams should be trained to
develop communication skills such as
counselling.
To our knowledge, there is no term in Spanish that translates
the full conceptual richness of the English word. Counselling
is not an assessment, nor is it assisted or clinical advice, but
it is the opposite of giving advice. Perhaps the most closely
related term would be “helping relationship.”
Counselling is not just an interventional tool based on
problem solving and emotional management, but also a way
of conceiving interpersonal relationships through an ethical
concept based on recognising the capacity in others to make
their own decisions. Counselling is the art and science of
making open, focused questions in order to explore threats
and detect resources. It is based on listening rather than
talking, empathy rather than judgement, and a fundamental
respect of the patient’s values rather than imposing our own.
All of this is of the utmost importance during the end of a
renal patient’s life.
REFERENCES
CONCLUSIONS
It has been clearly demonstrated that the application of the
principles of PC in the field of nephrology generates major
benefits for the patient, the patient’s family, and the
nephrologist. We are faced with a significant challenge in
carrying out studies that offer better safety in the use of paincontrolling drugs and those used to treat other symptoms in
these patients. The nephrologist also should learn to
masterfully use the different options available for managing
pain and suffering in advanced phases of renal disease, as
well as communication skills for supporting the patients and
their families. The development of PC in nephrology
departments is a large and important development that we
must strive for, involving the dedication of several different
disciplines.
26
Authors declare no potential conflicts of interest .
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34. Davison SN, Jhangri GS, Johnson JA. Cross-sectional validity of
modified Edmonton symptom assessment of symptom burden.
Kidney Int 2006;69:1621-5.
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36. Weisbord SD, Shields AM, Mor MK, Sevick MA, Peternel J, Porter
P, et al. Methodology of randomized clinical trial of symptom management strategies in patients receiving chronic hemodialysis:
The SMILE study. Contemp Clin Trials 2010;31(5):491-7.
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40. Cukor D, Cohen SD, Peterson RA, Kimmel P. Psychosocial aspects
of chronic disease. ESRD as a paradigmatic illness: J Am Soc
Nephrol 2007;18:3042-3055.
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42. Prigerson HG, Bierhals AJ, Kasl SV, Reynolds CF, Shear MK, Day N,
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Sent for review: 28 Jun. 2011 | Accepted: 27 Aug. 2011
Nefrologia 2012;32(1):20-7
27
special article
Start-up of a clinical sample processing, storage and
management platform: organisation and
development of the REDinREN Biobank
Laura Calleros*1, María A. Cortés*1, Alicia Luengo1, Inés Mora1, Brenda Guijarro1, Paloma Martín1,
Alberto Ortiz-Arduán2, Rafael Selgas3, Diego Rodríguez-Puyol4, Manuel Rodríguez-Puyol1
Departamento de Fisiología. Facultad de Medicina. Universidad de Alcalá. Instituto Reina Sofía de Investigaciones Nefrológicas
(IRSIN). Madrid. Spain
2
Laboratorio de Investigación Renal y Vascular. IIS-Fundación Jiménez Díaz. Universidad Autónoma de Madrid. Instituto Reina Sofía
de Investigaciones Nefrológicas (IRSIN). Madrid. Spain
3
Servicio de Nefrología. Hospital Universitario La Paz-IdiPAZ. Instituto Reina Sofía de Investigaciones Nefrológicas (IRSIN). Madrid. Spain
4
Sección de Nefrología y Unidad de Investigación. Hospital Príncipe de Asturias. Instituto Reina Sofía de Investigaciones Nefrológicas
(IRSIN). Madrid. Spain
* Both authors have contributed equally to this work
1
Nefrologia 2012;32(1):28-341(6):XX
doi:10.3265/Nefrologia.pre2011.Oct.11121
ABSTRACT
Background: The creation of the Biobank, a resource
pertaining to the Spanish Renal Research Network
(REDinREN) promotes advances in clinical research on
kidney disease in Spain. The Biobank’s aims are to generate
an archive of clinical samples and associated data, furnish
those samples to research teams, and coordinate with
European biobanks. Method: Applicable legislation had to
be complied with in order to launch the Biobank project
(Biomedical Research Law, Data Protection Law and
Biological Sample Transport Regulations). A strict work
protocol and a new database for the Network’s clinical data
were also implemented. Results: Over time, the Biobank
has acquired additional infrastructure and qualified
personnel. In 2010, 2953 new patient samples were
collected, giving a total of 37 043 stored vials containing
different types of samples. Furthermore, the Biobank is
currently participating in eleven research projects.
Discussion: Although the Biobank was originally designed
for REDinREN use, we must take joint action to make this
biological sample storage system and the many possibilities
it offers available to the entire nephrological community
with a view to promoting kidney disease research.
Puesta en marcha de una plataforma de proceso,
almacenamiento y gestión de muestras clínicas:
organización y desarrollo del Biobanco de REDinREN
RESUMEN
Antecedentes: La creación del Biobanco, como una plataforma dentro de la Red de Investigación Renal (REDinREN), impulsa el avance de la investigación clínica de la enfermedad
renal en España. Los objetivos del Biobanco son la generación
del archivo de muestras clínicas y de datos asociados, para su
cesión a los grupos de investigación, y la coordinación con
biobancos europeos. Métodos: Para su puesta en marcha, fue
necesaria la implementación de la normativa vigente (Ley de
Investigación Biomédica y de Protección de Datos y la Normativa del Transporte de Sustancias Biológicas), un estricto protocolo de trabajo y la creación de una base de datos clínicos
de la Red. Resultados: En su evolución, el Biobanco ha adquirido infraestructura y personal cualificado, lo que permitió
que en el año 2010 se obtuviera un total de 2.953 pacientes,
lo que hace un total de 37.042 viales almacenados con muestras de diferentes naturalezas. Además, hasta la fecha, el Biobanco está incluido en 11 proyectos de investigación. Discusión: Aunque el Biobanco fue diseñado como una plataforma
de soporte de la REDinREN, es necesario con una acción conjunta poner a disposición de toda la comunidad científica nefrológica las posibilidades que otorga este sistema de almacenamiento de muestras biológicas para potenciar la
investigación de la enfermedad renal.
Key Words: Biobank. Chronic kidney disease. Network
Palabras clave: Biobanco. Enfermedad renal crónica.
Support. Medical samples.
Plataforma de red. Muestras clínicas.
Correspondence: Laura Calleros
Departamento de Fisiología.
Facultad de Medicina. Universidad de Alcalá, Ctra. Madrid-Barcelona
km 33.600. 28871 Alcalá de Henares, Madrid. Spain.
[email protected]
INTRODUCTION
28
The Biobank of the REDinREN (Spanish Renal Research
Network) is a public, non-profit entity that stores a collection
Laura Calleros et al. Evolution of the REDinREN Biobank
of samples intended for use in biomedical research into
kidney disease. Its purpose is to contribute to advancing
scientific knowledge of nephrological diseases as one of the
activities coordinated by REDinREN, which is dependent on
the Carlos III Institute of Health (RD6/0016/0002). This
network is made up of groups of researchers from different
regions in Spain. It enables researchers to undertake
interdisciplinary, multi-centre research projects in strategic
areas that focus on gaining a better understanding of kidney
disease, with an emphasis on providing solutions for real,
current problems in the field of nephrology. The Biobank is
currently an essential platform for undertaking joint research
activities in REDinREN. The Biobank’s initial list of
objectives is found in Table 1, and all of its objectives are
still in force. The Biobank is therefore a cross-sectional
resource that provides support to nephrological research, and
it may be considered as a complement to other biobanks that
were created in the frameworks of a range of institutional
initiatives.
METHOD
Aspects fundamental to the creation of the
REDinREN Biobank
The REDinREN Biobank’s organizational structure and
workings are based on four basic pillars: compliance with
legislation, dedicated staff members, the development of
standardised technical procedures, and a formal system to
record and access clinical data. Each of these components is
listed below.
1) Legal requirements: The REDinREN Biobank was
designed according to the regulations stated in the Spanish
Law for Biomedical Research (Law 14/2007 of 3 July).1 This
Law states that patients must be informed by their doctors
and give written consent before any samples may be sent to
the Biobank. As a result, in one of the first steps toward
creating the Biobank, the Ethics Committees at each hospital
belonging to the network approved the Informed Consent
forms that are provided to patients. Information is given in
Table 1. Biobank objectives
Create the REDinREN archive of biological samples by processing all
extracted samples.
Coordinate technical procedures that health centres must follow in
order to donate samples to the Biobank.
Create a system to organise samples and provide a computerised
platform for their associated information.
Coordinate action procedures with similar European Union
organisations.
Nefrologia 2012;32(1):28-34
special article
writing, and it covers the details, significance, implications
and risks of donating samples to the Biobank, and mentions
the donor’s right to revoke consent at any time. To obtain the
samples, the Biobank depends on the free will of people who
may choose to donate their biological samples to science.
The Biobank reserves the right to audit the samples that are
sent in to ensure that consent was properly given.
On a parallel note, the clinical database containing coded
data pertaining to patients whose samples are stored in the
Biobank has been registered with both the Spanish Data
Protection Agency and the Madrid Data Protection Agency.
The Biobank complies with the security requirements set
forth by the Spanish regulation on security measures for
computer files containing personal data, approved by Royal
Decree 994/1999 of 11 June, in fulfilment of Organic Law
15/1999 of 13 December on Personal Data Protection.2
Lastly, all technical procedures described below were
designed in accordance with the legally established
requirements. All biological samples are stored in such a
way that long-term preservation, quantity, and quality are
assured, so that they can be used for current research projects
and any future projects that may be undertaken as our
knowledge of kidney disease and biotechnology increases.
2) Dedicated staff and associated Committee: The
Biobank’s organisational structure is shown in Figure 1.
During an early step in the process, the Biobank also trained
specific personnel from each centre that would be sending
samples. This was done so that the process would be
standardised according to the protocols established for the
entire network. The Biobank continues to train researchers
and support staff that are new to the Network and will be
providing samples.
3) Technical procedures: In order to guarantee quality
sample processing and storage, the Biobank has established a
Standard Working Procedure based on a quality management
system similar to UNE-EN-ISO 9001:2008. Figure 2 shows
a sample processing diagram. The Biobank receives blood
and urine samples. At times, depending on the active lines of
research, it also receives tissue samples. These samples are
sent to the Biobank by courier. Taken from whole blood
samples, it routinely stores plasma aliquots and cell samples
from which DNA and proteins can be extracted. If there are
enough cells with good viability (more than 80%), some of
them are cryopreserved. By using the Qiagen automated
system, RNA is isolated from blood that was extracted with
PAXgene® tubes. Vials are stored in such a way as to
guarantee that all aliquots can be found in the Biobank’s
locator database.
For purposes of storing samples, the Biobank has storage
systems set to –80 ºC and –180 ºC. Storage units are
protected by a three-fold safety system: uninterruptible
29
special article
Technical and
Scientific Committee
Lead
Researcher
Dossier
Authority
Technical
Subdirector
Technical
Assistant 1
Technical
Assistant 2
Technical
Assistant 3
Technical
Assistant 4
Figure 1. Biobank organisational structure.
power supply (UPS), temperature sensors with remote alarm
monitoring, and a connection to the Faculty of Medicine’s
generator set. In this way, biological samples are guaranteed
to be completely protected in the event of an electrical or
computer system failure.
4) Quality of the clinical data record system and linking
data correctly with stored samples: While the biological
sample collection was being created, the Biobank also made
a clinical database for the Network. It covers all of the
patients with samples stored in the Biobank and contains all
information needed in order to make full use of the
biological samples. Although the initial design allowed for a
single document (Figure 3), supplementary documents may
be included in the different specific studies.
Patients selected to send samples to the Biobank are
assigned a Biobank Number which allows entering their
clinical data in the database. Patients’ personal data are not
linked to clinical data, and they are not included in the same
database. This archive is found online within the intranet of
the Network’s webpage (www.redinren.eu). Members can
gain access by using their personal passwords. Each
hospital’s access is limited to the clinical data of its own
patients, and the hospital providing the data is the only one
to know the patient’s name and clinical history number.
Every time a sample is extracted from a patient, it is given a
Label Number and sent to the Biobank. Upon reaching the
Biobank, the samples are coded (the samples are
disassociated from identified donors, or made unidentifiable
30
by using a code to substitute or disassociate the donor’s
identifying information. The code is also used to recover that
information. The clinical database on the Network’s
webpage records the Biobank Number and Label Number.
The link between the sample and the patient is maintained in
order to have the possibility of contacting the patient to
obtain samples representing different moments in the
progression of his or her kidney disease. In cases in which
more than one sample will be extracted from the same
patient, there will be multiple Label Numbers
corresponding to the same Biobank Number (the opposite
cannot occur.) The researcher who gains access to the
sample receives only the Label Number, and never the
Biobank Number. This provides additional protection for
patient confidentiality throughout the entire procedure and
complies with current security regulations.1-2
5) Sending and requesting samples: Meanwhile, the
Biobank has finished designing both its webpage and its
intranet area. Here, all Network members enjoy a range of
computerised mechanisms for accessing Biobank
information: forms for sending or requesting samples, the
calendar to reserve a dispatch date, and a summary of the
Biobank’s inventory available to research teams.
Collecting, transporting, handling and dispatch of
samples all take place under biosecure conditions that
comply with applicable legislation (WHO regulations on the
Transport of Infectious Substances).3 The Biobank
guarantees the following in sample transport: sample
Nefrologia 2012;32(1):28-34
Urine in 50ml
tubes with
protease inhibitors
special article
Whole blood
tubes (EDTA)
3 10ml-tubes
PAXgene tubes
(2.5ml blood)
®
Each patient's sample
arriving at the Biobank
Biobank action protocol
Urine centrifuged and
divided into small aliquots
RNA extraction
(automated method)
Stored at -80ºC
Stored at -80ºC
3 aliquots of 4x106
cells (DNA)
Stored at -80ºC
20ml of whole blood.
Separate mononuclear
cells (Ficoll method)
10ml of whole blood.
Separated into 4 plasma
aliquots (500µl)
Stored at -80ºC
3 aliquots of
4x106
cells (Proteins)
Stored at -80ºC
Cryotubes of
viable cells
(8-10x106) (Proteins)
Stored at -180ºC
The whole blood is processed by diluting and separating peripheral mononuclear blood cells, which are subjected to Ficoll density gradient.
Figure 2. Biobank action protocol.
identification and traceability, a definition of the
preparation conditions, handling and transport
conditions required by each type of sample, and proper
training for the personnel handling and preparing the
samples. When transporting samples abroad, the
Biobank will transmit all of the required documents in
accordance with Spanish Royal Decree 65/2006 4 for
exporting biological samples and sending them through
customs checkpoints.
purposes of the approved project; not to store, return, or
transfer it to a third party; and to use the minimum
quantity possible), the possibility of Biobank running an
audit to verify that contractual conditions have been met,
and the requirement of including Biobank’s name in
publications (material and methods). Lastly, upon
completion the project, researchers are required to report
their final results.
In addition, the Biobank’s Scientific and Technical
Committee has drawn up and approved the documents
needed by researchers in order to donate and/or
provide Biobank samples (Figure 4). Requests for
samples and/or data will be evaluated by the Biobank
Scientific and Technical Committee; a Clinical Research
Ethics Committee must necessarily support the study in
question. Biological samples stored in the Biobank may
be used in research projects undertaken by REDinREN
members. If permission is granted by the Scientific and
Technical Committee, they may be used in research
projects with third-parties, provided that a REDinREN
member is participating in the project. The provision of
a sample can be accompanied by the associated clinical
information from the Network’s clinical database, with
the necessary guarantees for personal data protection. If
provision of the sample is approved following the
evaluation, a cession agreement is signed. This
agreement stipulates the regulations for collecting
samples, the samples for which access is provided, the
lead researcher and the project in which the samples will
be used, the researcher’s obligations (use for exclusive
RESULTS
Nefrologia 2012;32(1):28-34
Evolution and description of the current state of
the Biobank
1) Infrastructures: The REDinREN Biobank is located
within the Faculty of Medicine of the University of
Alcalá (Madrid). Launching the biobank involved
facility remodelling, purchase of a complete set of
equipment and start-up of the entire laboratory. From the
time it was created to the present, the REDinREN
Biobank infrastructure has grown considerably. Since its
inception, it has added 2 new –80 ºC vertical laboratory
freezers to bring its total to 3, as well as the
corresponding temperature probes, a higher-powered
UPS system and 3 times as much physical capacity as
was found in the original laboratory.
2) Personnel: The substantial increase in the workload
arising from the greater number of samples and requests
for material for a variety of projects has resulted in the
need for more supporting technicians. These tasks were
31
special article
samples were added to the Biobank at the end of 2010.
These include plasma and serum samples that are
separated at the hospital of origin and arrive at the
Biobank ready to be stored. This guarantees the
preservation of a number of biomarkers that may change
in the transport of whole blood samples.
Lastly, based on data entered by researchers on the
Website, we have a list of all pathologies for which
samples are kept in the Biobank (Figure 5C). Those in
white were gathered by the Nefrona project.
Research projects linked to the Biobank
1) General strategy: prospective inclusion of patients
meeting the following criteria: although patient
inclusion criteria were originally very general, samples
are currently being taken from patients with specific
characteristics that are matched to each project.
(Source: www.redinren.eu)
Figure 3. Clinical data sheet for the REDinREN biobank
2) Specific strategies: the Biobank as a resource for
specific research projects. The Biobank is currently
involved in several collaborative scientific projects with
Network members. Collaborative projects in the
framework of the Spanish National Plan: 6 projects;
Collaborative projects with a European Network: 1;
research projects receiving private funding: 3; clinical
trials: 1. The Biobank has also applied to be included in a
European Biobank Network for dialysis patients (ERAEDTA. EURECA-m BIOBANK).
DISCUSSION
originally carried out by 1 person, but we currently have
4 staff members dedicated to the different phases of
sample processing. Maintaining qualified personnel is a
continuous training task that is essential to make the
Biobank work properly.
3) Stored samples and recorded patients: The
dispatch, collection, processing and storage system is
currently working correctly; having received biological
samples from all hospitals within the Network. As
shown in Figure 5A, the Biobank stored 518 vials in
2007; this number has increased considerably, reaching
37 042 in 2010. Of the total of vials that are categorised
by type (Figure 5B), we have plasma vials (30%), vials
for DNA isolation (28%), and vials for protein
extraction (28%). We must consider that urine vials
(1%) are only collected in specific cases and that as
RNA extraction with the PAXgene ® system is very
expensive, it is only performed in a few selected
patients (4%). Meanwhile, through Biobank’s
collaborative efforts with the Nefrona project, new
32
Future prospects
Our Biobank was designed to strictly comply with all
applicable legislation. This will grant us access to the
National Biobank Register as soon as it is created, as
provided for by Law 14/2007, and the relevant Royal Decree
has been issued. The register will aid us in publicising our
Biobank on a national level and foster access to biological
material by the scientific community.
Furthermore, all of our procedures are managed with a view
to obtaining top quality, and we are now beginning to launch
our quality management programme so as to be certified by
AENOR under ISO standard 9001:2008 in the near future.
Although the Biobank was initially designed as a
support platform for the REDinREN, the aim of the
Network members and Biobank administrators is to
place all of the possibilities contained in this biological
sample storage system at the disposal of the
nephrological research community.
Nefrologia 2012;32(1):28-34
special article
Hospital
Patient
NETWORK
Visit
Signature
I.C.
Biobank
Processing and
storage
Sample provision
process
(DOC. 5)
(DOC. 6)
Sample
Extraction
(DOC. 2)
Data
Recorded
in network
database
Hospitals
and/or
research
centres
Request
material
and/or
clinical data
from biobank
Extraction,
quantification and
preparation of
nucleic acids and
proteins
Scientific and
technical
committee
(DOC. 3)
Project
evaluation
(DOC. 4)
I.C.: inform consent; DOC. 2: sample transfer agreement with donor centre; DOC. 3: application form for samples or data from the Biobank;
DOC. 4: Committee evaluation; DOC. 5: cession agreement between the Biobank and the researcher; DOC. 6: results report by the researcher.
Red arrows indicate the sample transfer process to the Biobank. Green arrows indicate the process to gain access to the Biobank samples.
Figure 4. Summary of the main steps for donating and gaining access to biobank samples
Lastly, integrating our Biobank in a European network of
biobanks with kidney patient samples may be a key step towards
facilitating the export of samples to other countries This would
promote collaborative efforts in international research projects.
37042
A
12582
7447
518
2007
2008
2009
2010
C
B
DNA
Paxgene RNA
Cells
Urine
Plasma
Plasma by origin
Proteins
Serum by origin
Underlying kidney disease
Amyloidosis
Glomerulonephritis
Nephroangiosclerosis
Diabetic nephropathy
Ischaemic nephropathy
Lupus nephritis
Tubulo-interstitial nephritis
None
Other
Polycystosis
Vasculitis
(left blank)
Total
3
128
83
121
19
5
78
28
131
57
6
2 294
Total samples
2 953
A) Total of vials that the Biobank has stored over years. B) Vials by type of sample. C) Total of samples by patient pathology as entered into the
Website. Data to January 2011.
Figure 5. REDinREN Biobank inventory.
Nefrologia 2012;32(1):28-34
33
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ECONOMIC CONSIDERATIONS IN CREATING THE
BIOBANK
Most of REDinREN’s Biobank infrastructures and
personnel are financed by the Biobank’s parent entity Carlos
III Health Institute (REDinREN, Spanish Renal Research
Network from the Carlos III Institute of Health, FEDER
funds, RD6/0016/0002). With the permission of this
institution, the Biobank has applied for specific grants from
private organisations or projects. These include FRIAT
(Íñigo Álvarez Renal Foundation of Toledo) and the Nefrona
project which is supported by the S.E.N. (Spanish Society of
Nephrology) and by Abbott Laboratories. On the other hand,
the cost of processing the samples requested for a specific
project, whether public or private, is borne by the project
itself.
Acknowledgements
Carlos III Health Institute: (REDinREN, Spanish Renal Research Network
from the Carlos III Institute of Health, FEDER funds, RD6/0016/0002).
FRIAT (Íñigo Álvarez Renal Foundation of Toledo).
Reina Sofía Institute of Renal Research (IRSIN).
Nefrona project, supported by the S.E.N. and Abbott laboratories.
REFERENCES
1. Ley 14/2007, de 3 de julio, de Investigación Biomédica. MadridEspaña: Boletín Oficial del Estado N.º 159; 2007. p. 28826-48.
2. Ley orgánica 15/1999, de 13 de diciembre, de Protección de Datos
de Carácter Personal. Madrid-España: Boletín Oficial del Estado N.º
298; 1999. p. 43088.
3. WHO/EMC/97.3. Guía para el transporte seguro de substancias
infecciosas y especímenes diagnósticos. Organización Mundal
de la Salud. División para la Vigilancia y el Control de Enfermedades
Emergentes y Otras Enfermedades Transmisibles. Transporte seguro
de Substancias Infecciosas 2005:1-15.
4. Real Decreto 65/2006, de 30 de enero, por el que establecen
requisitos para la importación y exportación de muestras
biológicas. Madrid-España: Boletín Oficial del Estado N.º 32;
2006. p. 4626-36.
Sent to:17 Aug. 2011 | Accepted: 22 Oct. 2011
34
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See editorial comment on page 15
Haemodialysis using high cut-off dialysers for
treating acute renal failure in multiple myeloma
Guillermo Martín-Reyes1, Remedios Toledo-Rojas1, Álvaro Torres-Rueda1, Eugenia Sola-Moyano1,
Lourdes Blanca-Martos1, Laura Fuentes-Sánchez1, M. Dolores Martínez-Esteban1,
M. José Díez-de los Ríos2, Alicia Bailén-García3, Miguel González-Molina1, Isabel García-González4
Servicio de Nefrología. Hospital Regional Universitario Carlos Haya. Málaga. Spain
Laboratorio de Análisis Clínicos. Hospital Regional Universitario Carlos Haya. Málaga. Spain
3
Servicio de Hematología. Hospital Regional Universitario Carlos Haya. Málaga. Spain
4
Servicio de Anatomía Patológica. Hospital Regional Universitario Carlos Haya. Málaga. Spain
1
2
Nefrologia 2012;32(1):35-431(6):XX
ABSTRACT
Introduction: Acute renal failure (ARF) occurs in 12%-20%
of all multiple myeloma (MM) cases, and the survival of
these patients depends on renal function recovery. Renal
function is not recovered in 75% of dialysis-dependent patients, and their mean survival with replacement therapy
is less than one year. Renal tubular disease is the most frequent cause of renal failure. It is present in more than 55%
of renal failure cases and in 75% of those requiring dialysis. Rapid reduction of free light chain levels in the blood
is necessary in order to recover renal function. One coadjuvant measure in treating the disease is reducing light
chain levels with plasmapheresis, but its efficacy has not
yet been clearly proven. Our proposal was therefore to use
extended haemodialysis sessions with high cut-off dialysers
(HCO-HD), obtaining a recovery rate of more than 60%.
We present the progress of 6 patients with myeloma and
acute renal failure who were treated with HCO-HD and
the complications associated with using this type of haemodialysis. Then, we review the pros and cons of this technique. Method: Six patients diagnosed with MM and ARF
requiring dialysis and with serum free light chain levels
above 500mg/l were treated with 8-hour haemodialysis
sessions with an HCO-HD filter. Before and after each session, serum free light chain levels were measured by nephelometry; other parameters were recorded as well. At
the same time, patients underwent chemotherapy according to protocols. Results: The symptom onset times of the
Correspondence: Guillermo Martín Reyes
Hospital Regional Universitario Carlos Haya.
Almirante Enríquez, 10, Bajo D, 29017 Málaga. Spain.
gmartí[email protected]
3 men and 3 women diagnosed with MM and ARF were
highly variable, from 7 days to more than 1 year. We performed 90 extended sessions with HCO-HD filters, and
each patient underwent between 6 and 40 sessions. Free
light chain levels decreased by a mean of 65% between
treatment onset and completion, except in one patient
who experienced a 12.6% reduction. The mean percentage of reduction of light chain levels per session was
54.98%±17.27%. A complication occurred during 28% of
the sessions. Of these complications, 48% were due to
system coagulation. There were no major changes in predialysis albumin, calcium, phosphorous or magnesium levels, although lower values that were not clinically relevant were recorded in one case. Renal function was
recovered in 3 patients, they are alive and dialysis-free. In
biopsied cases that recovered renal function, the specimen
showed tubular nephropathy only. Those patients who
took longer to be diagnosed did not recover their renal
function, and when biopsied, they were diagnosed with
renal tubular disease and light chain deposition disease.
Conclusion: We found extended haemodialysis with HCOHD filters to be a reasonable alternative in ARF caused by
renal tubular disease, and achieved a recovery rate of 50%
in our cases. Function recovery was influenced by the elapsed time between symptom onset and myeloma diagnosis,
histological findings, promptness of starting chemotherapy, response to chemotherapy, and effectiveness of light
chain extraction. In any case, further studies are needed to
examine new chemotherapy agents and new direct free
light chain removal techniques.
Keywords: Haemodialysis, High cut-off dialysers, Acute renal failure, Multiple myeloma
35
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Tratamiento con hemodiálisis del fracaso renal agudo en
el mieloma múltiple con filtros de alto poro (high cut-off)
RESUMEN
Introducción: El fracaso renal agudo (FRA) en el mieloma
múltiple (MM) se presenta entre el 12-20% de los casos y la
supervivencia de estos pacientes depende de la recuperación
de la función renal. El 75% de los pacientes dependientes de
diálisis no recuperan la función renal y su supervivencia media en situación de tratamiento sustitutivo es inferior al año.
La nefropatía por cilindros es la causa más frecuente de fracaso renal y acontece en más del 55% de los casos, y en el
75% de aquellos que requieren diálisis. Para facilitar la recuperación de la función renal es imprescindible la disminución
rápida de los niveles en sangre de cadenas ligeras. Una medida coadyuvante al tratamiento específico de la enfermedad ha sido la reducción de estas cadenas ligeras con plasmaféresis, sin que se haya demostrado claramente su
eficacia, por lo que se ha propuesto el uso de hemodiálisis
largas con filtros de alto poro (HCO), consiguiendo una tasa
de recuperación superior al 60%. Presentamos la evolución
en seis casos de pacientes con mieloma y fracaso renal agudo que fueron tratados con dichos filtros HCO, las complicaciones con este tipo de hemodiálisis y revisamos los pros y los
contras de esta técnica. Metodología: Seis pacientes diagnosticados de MM y FRA con necesidad de diálisis y niveles circulantes de cadena ligera por encima de 500 mg/l fueron tratados con hemodiálisis de 8 horas con filtro HCO. Al
comienzo y al final de cada sesión se medían las cadenas ligeras séricas por nefelometría, así como otros parámetros.
Al mismo tiempo los pacientes fueron tratados con quimioterapia según protocolos. Resultados: A tres hombres y tres
mujeres diagnosticados de MM y FRA, con inicio de los síntomas muy variable, desde 7 días a más de un año, se les realizó 90 sesiones de hemodiálisis largas con filtros HCO con un
rango de entre 6 y 40 sesiones. El porcentaje de reducción
de las cadenas ligeras desde el inicio del tratamiento hasta
su finalización fue el 65% de media, excepto en un paciente, que fue del 12,6%. La media del porcentaje de reducción
de la cadena ligera por sesión fue de 54,98 ± 17,27%. En el
28% de las sesiones se registró alguna complicación. El 48%
de las complicaciones se debieron a la coagulación del sistema. No hubo grandes cambios en los niveles de albúmina
prediálisis, calcio, fósforo y magnesio, aunque en algún caso
se registraron valores disminuidos que no comportaron relevancia clínica. En tres pacientes la función renal se recuperó
y permanecen vivos e independientes de la diálisis. En los casos biopsiados y que recuperaron función renal, la nefropatía por cilindros fue pura. Los pacientes que tardaron más en
ser diagnosticados fueron los pacientes que no recuperaron
función renal, y cuando se les efectuó biopsia el diagnóstico
fue de nefropatía por cilindros más enfermedad por depósitos. Conclusión: En nuestra experiencia, la hemodiálisis larga con filtros HCO es una alternativa razonable en el FRA
causado por nefropatía por cilindros, alcanzando en nuestros casos una tasa de recuperación del 50%. En la recupera36
Guillermo Martín-Reyes et al. Acute renal failure in multiple myeloma
ción influyeron: el tiempo transcurrido desde el inicio de los
síntomas al diagnóstico de mieloma, los hallazgos histológicos, la rapidez de instauración del tratamiento quimioterápico y su respuesta y la eficacia en la extracción de cadenas
ligeras. En cualquier caso, son necesarios nuevos estudios con
nuevos agentes quimioterápicos y las nuevas técnicas de extracción directa de cadenas ligeras.
Palabras clave: Mieloma múltiple. Fracaso renal agudo.
Hemodiálisis. Filtros de alto poro.
INTRODUCTION
Multiple myeloma (MM) is a plasma cell neoplasm that
causes acute renal failure (ARF) in 12%-20% of cases,
whether as an initial manifestation of the myeloma or during
the course of evolution of the disease following diagnosis.1
The survival of these patients will depend on whether or not
they recover renal function, not only due to the
complications derived from the renal failure itself, but also
from the reduced possibility of access to more effective
treatments.2,3 Renal function is not recovered in 75% of
dialysis-dependent patients,4-7 and their mean survival on
renal replacement therapy is less than 1 year.8
Cast nephropathy is the most common cause of ARF and plays
a role in over 55% of cases, and 75% of those that require
dialysis.9,10 The formation of casts in the distal tubules, caused
by the deposition of light chains and Tamm-Horsfall protein, is
the main cause of renal failure in these patients11-14; as such, it is
essential to rapidly reduce blood levels of free light chains in
order to facilitate the recovery of renal function.15
Chemotherapy treatments for MM have improved
greatly in the last decade, and regimens involving
bortezomib, melphalan, thalidomide, and lenalidomide
have improved the prognosis of these patients. 16 One
coadjuvant therapy for this disease has been reducing
free light chain levels using extracorporeal purifying
techniques. Plasmapheresis has been used for many
years to reduce the circulating levels of light chains,
although the efficacy of this treatment in recovering
renal function has not been clearly demonstrated. 17 This
has caused researchers to search for new techniques that
can effectively remove light chains and improve the
recovery rate of renal function. To this end, Hutchison et
al, using high cut-off (HCO) dialysers and long
haemodialysis sessions (8 hours), have achieved good
results in these patients, with recovery rates over 60%. 18
We present the evolution of six patients with myeloma and
acute renal failure that were treated with these HCO filters,
as well as the complications that arise with this type of
haemodialysis, and review the pros and cons of this
technique.
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MATERIAL AND METHOD
We also used a Congo red stain test.
Six patients diagnosed with MM and ARF requiring dialysis
and with serum light chain levels >500mg/l were treated
with haemodialysis using HCO 1100® (1m2) or Theralite®
(2.1m2) high cut-off filters made from polyaryl ether
sulfone/polyvinyl pyrrolidone (Gambro Dyalisatorem,
Henchingen, Germany).19 These filters are designed to
increase the permeability of substances smaller than 60kD.
The only difference between them is the greater surface area
of the membrane, which increases the efficacy in removing
light chains and produces a greater loss of albumin. We used
Theralite® (2.1m2) filters when they were commercially
available. The haemodialysis sessions involved standard
haemodialysis monitors, lasted for 8 hours, involved a blood
flow of 200ml/min-250ml/min, and had an ultrapure
dialysate flow rate of 500ml/min. Sodium heparin was
applied at 3000IU to start with, and 500IU at each hour. At
the end of each session, 20% albumin was administered
(100cc) along with monosodium phosphate (10ml) and
magnesium sulphate (10ml), following the protocol set out
by Hutchison et al.20 The goal was to perform 5 sessions on
consecutive days, followed by sessions on alternating days
until renal function was recovered or until light chain levels
fell below 500mg/l. Ultrafiltration was programmed
according to the clinical needs of each patient.
At the same time, patients were treated with chemotherapy
regimens according to the protocols of the haematology
department.
Before and after each session, mean free light chain levels
were measured in terms of mg/l using nephelometry
(FREELITE®; The Binding Site, Birmingham, UK),21 and
creatinine, albumin, phosphorous, calcium, and magnesium
were measured before each session. These measurements
were also taken after each session in the first patient. In
cases requiring a renal biopsy, an analysis was performed
using a light microscope and immunofluorescence with
standard techniques, including the detection of anti-kappa
and lambda light chain antibodies by immunofluorescence.
RESULTS
Three men and three women were admitted to the
nephrology department for ARF of an unknown cause and
were finally diagnosed with MM. The characteristics of the
patients are summarised in Table 1. Three patients were
younger than 60 years, and the other three were older than
70. The initial symptoms were bone pain in four cases, one
patient sought treatment for constitutional syndrome, and the
sixth patient was admitted under the diagnosis of
unconfirmed pancreatitis and renal failure. The start of
symptoms varied greatly, between 7 days and over a year (6th
patient). In this patient, a review of the clinical history
revealed that a monoclonal gammopathy and bone infarcts
had been detected one year before, requiring health care, but
with an incomplete analysis. The patients that took the
longest time to be diagnosed were those that did not recover
renal function.
Three patients had kappa light chain myeloma, two had
lambda IgG myeloma, and one had IgA kappa myeloma.
The bone marrow was infiltrated to a varying degree by
plasma cells of an anomalous phenotype that are
characteristic of the disease. Four patients underwent a renal
biopsy: two were diagnosed with cast nephropathy and the
other two were diagnosed with cast nephropathy and light
chain deposition disease. Immunofluorescence was positive
in glomerular samples for light chains in two of the
deposition disease cases, and in the tubules and cylinders of
all four cases. Interstitial damage was mild, and tubular
Table 1. Characteristics of the six patients diagnosed with multiple myeloma
Patient
Age
Sex
Syntoms
Time
Type of
Renal
Bone marrow,
from start of
chain
biopsy
% plasma cells
symptoms
Free light
Recovery
chain
of renal
levels mg/l
function
12 600
Yes
to admission
1
54
M
Lumbar pain
7 days
Kappa
CN
72%
2
3
52
F
Constitutional syndrome
79
M
Shoulder pain
120 days
Kappa
CN + DD
15%
683
No
15 days
IgA Kappa
NB
NB
1080
Yes
4
70
5
82
F
M
Side pain
60 days
IgG Lambda
NB
80%
13 000
No
Lumbar pain
45 days
IgG Lambda
CN
15%
3470
Yes
6
50
F
Pancreatitis,
1 year
Kappa
CN + DD
10%
3140
No
renal failure
DD: deposition disease; M: male; F: female; CN: cast nephropathy; NB: no renal or bone marrow biopsy
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reactivity with marked regenerative changes was similar in
all cases. None of the Congo red stain tests resulted positive.
One patient refused the biopsy (case 3), and the health of
another (case 4) negated that possibility. Proteinuria ranged
between 6680mg/dl and 570mg/dl, with no correlation
observed with serum free light chain levels or histological
findings.
The number of days of hospitalisation, days to diagnosis,
days to start of HCO-HD, as well as the number of days
elapsed between hospitalisation and the start of
chemotherapy are shown in Table 2. The first three patients
were treated with vincristine, adriamycin, and
dexamethasone, and the last three were given bortezomib
and melphalan and/or prednisone, according to the protocols
of the haematology department.
It total, the six patients underwent 90 sessions of
haemodialysis, with a range of 6-40 sessions each. The
HCO-HD was interrupted due to: a) renal function recovery
in three cases (cases 1, 3, and 5); b) in case 2, the start of
HCO-HD was delayed several days since the patient had a
large inguinal haematoma following catheterisation of the
femoral vein, and a posteriori analysis showed that light
chain levels had fallen below 500mg/l; c) in case 4,
treatment was interrupted upon finding that the patient’s
light chain levels remained above 700mg/l and anuria
continued even after 7 sessions of haemodialysis; and d) in
case 6, treatment was discontinued after 40 sessions of
HCO-HD and three cycles of bortezomib and prednisone in
the absence of a response, with light chains remaining at
2760mg/l and persistent oliguria.
The percentage reduction in light chain levels from the start
of treatment to the end of treatment in each patient is
summarised in Figure 1, and was very high in all patients
except for patient 6, who did not respond to chemotherapy
treatment, with a small reduction in light chain levels
(12.6%). In the other five patients, levels decreased by over
65%. In 56 sessions in which pre and post-HD light chain
levels were measured, the mean percentage reduction in light
chain levels was 54.98%±17.27% (Figure 2 and 3). There
were no differences in the reduction of lambda and kappa
light chains (kappa: 53.52%±18.6% vs lambda
57.82%±14.2%), or between results when using 1.1m2 HCO
or 2.2m2 Theralite® filters (56%±19% vs 53%±15%,
respectively).
In 25 haemodialysis sessions (28%), several complications/events
were registered. These are discussed in Table 3. On 12 occasions
(48%), the complications were due to system coagulations (8
episodes in patient 6), requiring a suspension of the session on
three occasions. Reduced flow and catheter obstruction were the
causes of 8 other episodes (32%). Other complications were
irrelevant.
There were no major changes in predialysis albumin levels
when using this method, although patients that were treated
using the 2.1m2 Theralite® filter had a greater decrease in
albumin, requiring increased doses after dialysis (cases 5 and
6). Although calcium, phosphorous, and magnesium levels
were slightly reduced in several cases, this change had no
clinical significance (Table 4). Other complications in the
evolution of our study patients were: two infections (one
resulted in a positive blood culture for Escherichia coli, the
other one testing negative) and one stroke with complete
recovery.
In three patients, renal function was recovered (cases 1, 3,
and 5), and these patients remain alive and free of dialysis.
Case 1 received a bone marrow transplant and has had
favourable evolution for three and a half years; case 3 has
Table 2. Days to diagnosis and to treatment with HCO, chemotherapy used in the six patients diagnosed with multiple
myeloma
Patient
Days
Days to
Days from
No. of HCO
Days on
Days from
in hospital
diagnosis
admission to
sessions
HCO
admission to
1
36
6
15
8
12
8
VAD
2
56
16
26
6
11
22
VAD
3
19
5
6
13
12
6
VAD
4
24
3
7
9
27
9
Bortezomib-
5
57
6
13
14
28
14
Bortezomib-
6
36
8
11
40
86
14
start of HCO-HD
Chemotherapy
start of chemoth
melphalan
dexamethasone
Bortezomibdexamethasone
CT: chemotherapy; VAD: vincristine, adriamycin, and dexamethasone
38
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100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Figure 1. Percentage reduction in free light chain levels in the
six patients treated with HCO haemodialysis at the end of
treatment.
been monitored for two years 8 months, and case 5 for 8
months. Of the three cases that did not recover renal
function, one patient died 4 months after starting
haemodialysis; in the other two cases, the patients are still
alive, although they continue to depend on dialysis (case 2: 2
years, 10 months; case 6: 4 months). In the two cases that
did not recover renal function and had undergone a renal
biopsy, cast nephropathy was accompanied by deposition
disease, whereas in the two cases that underwent a biopsy
and recovered renal function, the cast nephropathy was the
sole diagnosis.
DISCUSSION
Based on our experience, patients with MM and ARF with
cast nephropathy can recover renal function through
combined treatment with chemotherapy and long
haemodialysis sessions with HCO filters, as occurred in at
least 50% of the patients in our small study.
Recent studies have demonstrated that a rapid decrease in
free light chain levels with chemotherapy and extracorporeal
techniques is associated with recovered renal function.15,22-24
Several studies have evaluated the efficacy of
plasmapheresis in the treatment of myeloma-related renal
failure. The study by Zucchelli et al,23 and more importantly,
the study by Johnson24 demonstrated a better patient
evolution in those cases that were treated with
plasmapheresis vs those that were not; however, the small
sample size, the fact that not all patients had cast
nephropathy, and the use of different dialysis methods
significantly limited the conclusions made in this study.
Afterwards, Clark17 published a randomised, controlled study
involving 97 patients, the largest study available in the
literature. In this study, plasmapheresis did not achieve
superior results in terms of death, dependence on dialysis,
and glomerular filtration rate (<30%ml/min/1.73m2).
However, Leung15 found that plasmapheresis was effective at
recovering renal function (mean time: 2 months) if the renal
damage was due to cast nephropathy and the level of free
Nefrologia 2012;32(1):35-43
originals
light chains decreased by at least 50%. In summary, the
efficacy of plasmapheresis in myeloma kidney is uncertain at
best, and has yet to be fully upheld as a valid treatment after
the publication of only a small number of studies with few
patients. The reason for this is that plasmapheresis only
purifies the intravascular space (17%) and not at the quantity
necessary to provide a benefit to many patients, since the
reduction in light chain levels depends primarily on the level
of production.5 Furthermore, plasmapheresis cannot be
sustained for a very long time.
Since 2007, the use of long haemodialysis sessions with
membranes that are permeable to proteins has been proposed
in order to increase the extraction rate of light chains up to
90% during three weeks.20 In this study, HCO filters
(Gambro) with a cut-off of 45kD were superior to four
different high-flux dialysers (10kD) and two super-flux
dialysers (20kD) in clearing light chains (22.5-31kD). In this
same study, the HCO filter was tested in 11 patients with
myeloma and requiring haemodialysis who underwent
different chemotherapies. Of the 11 patients diagnosed with
cast nephropathy based on a renal biopsy, 5 underwent
dialysis on a daily basis for one week and afterwards on
alternating days; 3 recovering renal function. In the 2
patients that did not recover renal function, infections forced
an interruption of the chemotherapy provided, with a
consequent rebound in light chain levels. Later, these same
authors reported their experience with 19 patients with renal
biopsies showing cast nephropathy, 13 of which recovered
renal function. Of the 6 patients in which chemotherapy had
to be suspended, only one recovered renal function, which
appears to suggest that the extraction of light chains using
this method is only useful when accompanied by a response
to chemotherapy.18
Following the first experience by Hutchison et al, we started
treating patients with MM and ARF from cast nephropathy
with this method of haemodialysis, with similar results to
those from previous authors. In our six patients, the
extraction of light chains in each long haemodialysis session
with HCO filters reduced light chain levels by 53%-57%,
similar to the results reported by Hutchison. At the end of the
treatment, our patients had experienced decreases of over
70% over the initial values, except for patient number 6,
who, despite the fact that haemodialysis was effective in
reducing light chain levels, did not respond to chemotherapy
and never recovered renal function, as occurred in
Hutchison’s patients.18
We did not observe severe complications during
haemodialysis sessions in our study, and with the
replacement of lost albumin, calcium, phosphates, and
magnesium, we reached acceptable levels in all these
parameters. The use of 2.1m2 filters did result in a greater
loss of albumin, which required increased doses to replenish
albumin levels after dialysis sessions, using a double filter.25
39
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originals
Patient 2
Patient 1
160
14 000
140
12 000
120
10 000
100
8000
pre K FLC mg/L
6000
post FLC mg/L
pre K FLC mg/L
80
post FLC mg/L
60
4000
40
2000
20
0
0
1
2
3
4
5
6
7
1
8
2
3
5
6
Patient 4
Patient 3
1200
14 000
1000
12 000
10 000
800
600
pre K FLC mg/L
8000
pre K FLC mg/L
post FLC mg/L
6000
post FLC mg/L
400
4000
200
2000
0
0
1
2
3
4
5
6
7
8
1
9
2
3
Patient 5
3500
3000
2500
pre K FLC mg/L
1500
post FLC mg/L
1000
500
1 2
3 4
5 6 7
4
5
6
7
8
9
10 11
Patient 6
4000
0
4
8 9 10 11 12 13 14
5000
4500
4000
3500
2500
2000
1500
1000
500
0
pre K FLC mg/L
post FLC mg/L
1
3
5
7
9 11 13 15 17 19 21 23 25 27
FLC: free light chains
Figure 2. Serum free light chain levels before and after haemodialysis in the six patients
The two infectious complications produced were not
significant, and did not require halting the chemotherapy
regimen.
With regard to the recovery of renal function, our results are
similar to Hutchison’s18: approximately 60% of patients
recovered renal function using this technique.22 Several
factors influenced these results: 1) the time elapsed between
the start of symptoms and the diagnosis of myeloma. In our
study, the three patients that did not recover renal function
were those that had suffered symptoms for the longest
amount of time (60 days, 120 days, and 1 year). 2)
Histological findings: the 2 patients that underwent a renal
biopsy and did not recover renal function had deposition
disease, in addition to cast nephropathy. This situation
involves a poor prognosis and short life expectancy.26 3) The
40
speed with which chemotherapy treatment is started and the
response to this treatment. 4) The efficacy in removing light
chains in haemodialysis using high cut-off filters. The
possibility of recovery was 80% in patients whose light
chain levels decreased by 60% after three weeks of
treatment.18
There is still no proven evidence that this technique clearly
contributes to improve survival in patients with MM and cast
nephropathy, or that this type of treatment is superior to
plasmapheresis, which has not demonstrated its effectiveness
either. Currently, a randomised controlled study (EuLITE) is
underway, involving 90 newly diagnosed patients with
myeloma caused by cast nephropathy and dialysis-dependent
renal failure. All patients will receive bortezomib and will be
randomised to treatment with standard haemodialysis or
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originals
Patient 2
Patient 1
60
90
80
50
70
40
60
50
30
40
30
20
20
10
10
0
1
2
3
4
5
6
7
0
8
1
2
3
35
70
30
60
25
50
20
40
15
30
10
20
5
10
0
2
3
4
5
5
6
Patient 4
Patient 3
1
4
6
7
8
0
9
1
2
3
4
Patient 5
5
6
7
8
9
10
11
Patient 6
80
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9
10 11 12 13
1
14
3
5
7
9
11 13 15 17 19 21
23 25
27
Figure 3. Percentage reduction in serum free light chains in the haemodialysis sessions of all six patients
HCO filter haemodialysis. The primary variable is
independence from dialysis after three months of treatment.27
If results are favourable for this technique, it will then be
compared with plasmapheresis.
Additionally, one limitation for the use of this technique is
its high economic cost. Grima28 recently presented a costeffectiveness model comparing the treatment of myeloma
kidney with HCO filters vs standard haemodialysis. This
study found that the treatment of myeloma kidney with long
haemodialysis sessions using HCO filters could substantially
improve renal recovery in patients with multiple myeloma,
Nefrologia 2012;32(1):35-43
Table 3. Complications in HCO haemodialysis
Complication
No.
%
Low flow
7
28%
Catheter obstruction
1
4%
System coagulation
12
48%
Other
5
20%
Total
25
100%
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originals
Table 4. Maximum, minimum, mean, and standard deviation of phosphorous, calcium, magnesium, albumin,
and creatinine values before haemodialysis sessions
Phosphorous (mg/dl)
Patient Max Min M
1
±
Calcium (mg/dl)
SD Max Min M
±
±
Magnesium (mg/dl)
SD Max Min
M
±
Albumin (mg/dl)
SD Max Min
M
±
Creatinine (mg/dl)
SD Max Min
M
±
SD
9.4 8.9 9.1
±
0.2
2.1 1.7
1.9
±
0.1
3.2 2.7
2.9
±
0.2
8.2
5.4
6.4
±
1.0
2
3.0
1.3 2.0
±
0.7
9.7 7.7 8.5
±
0.7
2.3 1.7
2.0
±
0.3
4.4 3.2
3.8
±
0.5
5.9
2.7
3.9
±
1.2
3
6.4
4.6 5.4
±
0.8 10.0 7.8 9.0
±
0.9
2.8 1.8
2.1
±
0.4
4.5 2.6
3.5
±
0.7
2.6
1.1
1.7
±
0.6
4
6.7
1.9 3.7
±
1.5
7.5 6.3 6.8
±
0.4
2.3 2.0
2.1
±
0.1
3.3 1.9
2.5
±
0.4
6.5
1.7
3.2
±
1.4
5
6.1
2.7 3.9
±
1.1
8.0 6.1 7.0
±
0.6
2.6 1.4
2.1
±
0.3
2.3 1.7
2.0
±
0.2
9.2
3.5
5.8
±
1.8
6
6.3
2.3 3.8
±
1.1
9.5 6.3 8.4
±
0.7
3.8 2.0
2.6
±
0.5
3.3 2.7
3.0
±
0.2
7.1
2.4
4.6
±
1.4
SD: standard deviation; Max: maximum values; M: mean; Min: minimum values
compared to the standard haemodialysis. This results in an
improved life expectancy and overall savings, without the
need for chronic haemodialysis. The model predicts a mean
survival of 19.92 months in patients treated with standard
haemodialysis vs 33.9 months using the new technique, with
a total savings of 6000 pounds sterling per patient.
4.
5.
6.
In conclusion, the poor prognosis of patients with MM
and ARF due to cast nephropathy requiring dialysis, the
relationship between reduced light chain levels and the
recovery of renal function suggest the potential benefit
of early chemotherapy combined with a method for the
extra-corporeal removal of light chains that is effective
and can be maintained over time. Long haemodialysis
sessions with HCO filters are a reasonable option,
although new studies involving new chemotherapy
agents and new direct extraction methods of light chains
are needed.
7.
8.
9.
10.
The authors declare potential conflicts of interest:
11.
The author(s) are paid for conferences.
The author(s) receive a travel bursary/allowance.
12.
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16. Dimopoulos MA, Richardson PG, Schlag R. VMP (Bortezomib,
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Sent for review:19 Jul. 2011 | Accepted: 3 Nov. 2011
Nefrologia 2012;32(1):35-43
43
originals
Early biomarkers of acute kidney failure after heart
angiography or heart surgery in patients with acute
coronary syndrome or acute heart failure
I. Torregrosa1, C. Montoliu2, A. Urios2, N. Elmlili2, I. Juan1, M.J. Puchades1, M.A. Solís1,
R. Sanjuán3, M.L. Blasco3, C. Ramos1, P. Tomás1, J. Ribes1, A. Carratalá4, A. Miguel5
Nephrology Department. Valencia University Clinical Hospital. Spain
Research Fundation of the Valencia University Clinical Hospital. INCLIVA. Spain
3
Coronary Unit. Valencia University Clinical Hospital, Spain
4
Laboratory. Valencia University Clinical Hospital. Spain
5
Nephrology Department. Valencia University Clinical Hospital. University of Valencia. Spain
1
2
Nefrologia 2012;32(1):44-52
doi:10.3265/Nefrologia.pre2011.Sep.10988
ABSTRACT
Background: Acute kidney injury (AKI) is a common complication in cardiac surgery and coronary angiography, which
worsens patients’ prognosis. The diagnosis is based on the
increase in serum creatinine, which is delayed. It is necessary
to identify and validate new biomarkers that allow for early
and effective interventions. Aims: To assess the sensitivity
and specificity of neutrophil gelatinase-associated lipocalin
in urine (uNGAL), interleukin-18 (IL-18) in urine and cystatin
C in serum for the early detection of AKI in patients with
acute coronary syndrome or heart failure, and who underwent cardiac surgery or catheterization. Methods: The study
included 135 patients admitted to the intensive care unit for
acute coronary syndrome or heart failure due to coronary or
valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement. The
biomarkers were determined 12 hours after surgery and
serum creatinine was monitored during the next six days for
the diagnosis of AKI. Results: The area under the ROC curve
(AUC) for NGAL was 0.983, and for cystatin C and IL-18 the
AUCs were 0.869 and 0.727, respectively. At a cut-off of
31.9ng/ml for uNGAL the sensitivity was 100% and the specificity was 91%. Conclusions: uNGAL is an early marker of AKI
in patients with acute coronary syndrome or heart failure
and undergoing cardiac surgery and coronary angiography,
with a higher predictive value than cystatin C or IL-18.
Biomarcadores precoces de fracaso renal agudo tras
angiografía coronaria o cirugía cardíaca en pacientes con
síndrome coronario o fallo cardíaco agudos
RESUMEN
Antecedentes: El fracaso renal agudo (FRA) es una complicación
frecuente tras la cirugía cardíaca y la angiografía coronaria que
ensombrece el pronóstico de estos pacientes. El diagnóstico se
basa en el ascenso de la creatinina sérica, que es tardío. Es necesaria la identificación y validación de nuevos biomarcadores
precoces que permitan intervenciones más tempranas y eficaces. Objetivos: Evaluar la sensibilidad y especificidad de interleuquina-18 (IL-18) en orina, neutrophil gelatinase-associated
lipocalin en orina (uNGAL) y cistatina C en suero para la detección precoz del FRA en una población de pacientes con síndrome coronario agudo o fallo cardíaco y sometidos a cirugía cardíaca o cateterismo. Métodos: Se incluyeron en el estudio 135
pacientes ingresados en una unidad de cuidados intensivos por
síndrome coronario agudo o fallo cardíaco por patología coronaria o valvular y a los que se realizaron una angiografía cardíaca o una cirugía cardíaca de revascularización o recambio valvular. Se determinaron los biomarcadores a las 12 horas de la
intervención y se monitorizó la creatinina sérica durante los siguientes seis días para el diagnóstico del FRA. Resultados: Para
NGAL se obtuvo un área bajo la curva ROC (AUC) de 0,983 y
para cistatina C e IL-18 de 0,869 y 0,727, respectivamente. Para
un punto de corte de NGAL en orina de 31,9 ng/ml la sensibilidad fue del 100% y la especificidad del 91%. Conclusiones: uNGAL es un marcador precoz de FRA en pacientes con síndrome
coronario o fallo cardíaco agudo y sometidos a cirugía cardíaca
y angiografía cardíaca, con una capacidad predictiva superior a
cistatina o a IL-18.
Keywords: Acute kidney injury. NGAL. Interleukin-18.
Cystatin C. Cardiac surgery. Coronary angiography. Acute
coronary syndrome. Heart failure.
Palabras clave: Fracaso renal agudo. NGAL. Interleukina18. Cistatina-C. Cirugía cardíaca. Angiografía coronaria.
Síndrome coronario agudo. Fallo cardíaco.
Correspondence: Isidro Torregrosa
Hospital Clínico Universitario de Valencia. Spain.
Avda. Blasco Ibáñez, 17. 46010 Valencia.
[email protected]
INTRODUCTION
44
Acute kidney injury (AKI) is a common complication following
cardiovascular surgery, with varying incidence rates evidenced
I. Torregrosa et al. Biomarkers of AKI in acute cardiac patients
in the medical literature that depend both on the definition of
AKI used and the population studied, but most estimates are
close to 30%.1-3 AKI prolongs the duration of hospital stays and
increases the risk of mortality by three to nine times, depending
on its severity.2,3 Even small increases in creatinine levels
worsen the situation for these patients.4 The mechanisms that
contribute to kidney injury include exogenous and endogenous
toxins, metabolic factors, ischaemia and reperfusion,
neurohumoral activation, inflammation, and oxidative stress.5
The diagnosis of AKI is based on the detection of increased
serum creatinine levels, which is delayed and does not properly
show glomerular filtration rates in acute patients.6 However,
experimental studies have demonstrated that although AKI can
be prevented or treated with several different therapies, it should
be started immediately after the renal damage is produced.7 The
ineffectiveness of these interventions in clinical trials with
humans has been attributed to significant delays in diagnosing
AKI. As such, it is clear that in order to be effective, the
treatment of AKI must start as early as possible.
The incidence of AKI following percutaneous coronary
operations can be placed between 5% and 20%, according to
the definition of AKI and the population studied, and
constitutes a potentially serious complication.8,9 Peak serum
creatinine values tend to arise within the first 5 days
following the surgery, and return to baseline values within 3
weeks (although permanent damage can be caused). As in
AKI following heart surgery, increased serum creatinine
values are late markers of kidney damage.
To try and resolve these problems, different research groups
have attempted in recent years to identify new markers for the
early diagnosis and stratification of the AKI risk. Despite the
effort invested and the progress made, the actual usefulness
of these markers has yet to be established in the different
clinical contexts of AKI.10,11 The most commonly studied
markers are cystatin-C, which is not a marker of kidney
damage but rather glomerular filtration rate, neutrophil
gelatinase-associated lipocalin (NGAL), interleukin-18 (IL18), kidney injury molecule-1 (KIM-1), and liver fatty acidbinding protein (L-FABP), in serum or urine samples.
The objective of this study is to evaluate the sensitivity and
specificity of IL-18 in urine, NGAL in urine (uNGAL), and
serum cystatin for the early detection of acute kidney injury
in a population of patients with acute coronary syndrome or
heart failure and undergoing heart surgery or catheterization.
MATERIAL AND METHOD
Study sample
Our study included 135 patients admitted between May 2008
and December 2009 to the intensive care unit of the Valencia
Nefrologia 2012;32(1):44-52
originals
University Clinical Hospital for acute coronary syndrome or
heart failure due to coronary or valvular pathologies, and
who underwent a heart angiography with or without
angioplasty and/or an implanted endoprosthesis (group 1,
n=89), or cardiac surgery involving revascularization or
valve replacement (group 2, n=46). The exclusion criteria
were: being younger than 18 years of age, pre-existing
chronic kidney disease on renal replacement therapy with
dialysis or transplant, and acute renal failure due to
cardiogenic shock upon hospitalisation. We also excluded
patients that had consecutively undergone both angiography
and surgery in order to avoid confusion.
All patients were monitored prospectively starting at their
inclusion in the study. We monitored creatinine levels from
the day prior to the procedure to six days after, and followed
the clinical evolution of each patient until they were
discharged from the hospital. We also took serum and urine
samples 12 hours after the procedure for assessing the
biomarkers. Baseline creatinine levels were established as
the value measured the day before the intervention.
Blood and urine samples were centrifuged for 10 minutes at
1500g. Several 0.5ml aliquots were taken from each serum
and urine sample for storage at -80ºC for later analysis. We
took urine samples from 20 healthy volunteers in order to
obtain normal urine NGAL values.
Table 1. Clinical and demographic characteristics of
patients that underwent coronary angiography
Patients without AKI Patients with AKI
No. patients
77
12
Age
61 (13)
73 (9)
Sex (M/F)
59/18
8/4
81 (24)
58 (18)a
Previous creatinine (mg/dl)
0.94 (0.22)
1.2 (0.3)ª
Maximum creatinine (mg/dl)
1.0 (0.23)
2.03 (0.56)a
Previous eGFR (MDRD)
(ml/min/1.73m2)
RIFLE (R/I/F)
6/2/1
AKI (day)
4 (3)
Deaths
3.9%
25%
Hospital stay (days)
10 (6)
21 (15)
AKI: acute kidney injury; previous eGFR (MDRD): estimated glomerular
filtration rate using MDRD before intervention. AKI (day): day of the
diagnosis of AKI using creatinine levels. Values are given as mean (SD).
The values for patients with AKI that were significantly different from
those of patients without AKI had P-values of a P<.01; b P<.001.
45
originals
The following information was also collected from each
patient: demographic variables and comorbidities,
parameters of the surgical procedure, and complications
during or after the catheter placement or heart surgery
(Table 1 and Table 2). The endpoint used for evaluating our
patients was the appearance of AKI, defined as creatinine
levels increasing by 50% or more, in keeping with the
RIFLE (Risk, Injury, Failure, Loss, End-stage renal
disease) classification system.12 The secondary criteria were
in-hospital mortality rates and duration of stays in the ICU
and hospital.
We measured IL-18 levels from urine samples using ELISA
kits (Human IL-18 ELISA, Bender MedSystems), and used
50µl of each urine sample for the analysis. The detection
limit for this test was 9pg/ml.
Measurements of biomarkers
Statistical analysis
NGAL and IL-18 in urine
We analysed the results using SPSS (version 17.0) and
GraphPad PRISM (version 4.0) software. The KolmogorovSmirnov tests were used for verifying that the variables had
a normal distribution. We compared the means of more than
two variables using a one-way ANOVA test with post-hoc
Bonferroni analysis, and used Student’s t-tests for comparing
two means, or Mann-Whitney U-tests in the case of nonnormal distributions. We used Pearson’s correlation
coefficients to analyse the relationship between the different
variables. The significance level was set at P<.05. We
evaluated the sensitivity and specificity of each marker using
ROC (Receiver Operating Characteristic) curves.
NGAL was measured from urine samples using ELISA kits
(Human NGAL ELISA, Hycult biotechnology b.v.). The
urine samples were diluted at 1:20 in a dilution buffer
provided by the manufacturing laboratory, and 0.1ml
aliquots were taken for analysis. The minimum detection
level for this test is 0.4ng/ml.
Table 2. Clinical and demographic characteristics of
patients that underwent cardiac surgery
Patients without AKI Patients with AKI
No. patients
32
14
Age
70 (9)
66 (15)
Sex (M/F)
22/10
12/2
(ml/min/1.73m2)
70 (32)
64 (28)
Previous creatinine (mg/dl)
1.1 (0.4)
1.23 (0.5)
Maximum creatinine (mg/dl)
1.2 (0.4)
2.12 (0.7)a
Previous eGFR (MDRD)
RIFLE (R/I/F)
9/5/0
AKI (day)
3 (1)
Deaths
0
29%
Type of surgery:
- By-pass
19
4
- Valvular
13
9
- By-pass and valvular
1
0
Time on ECC (min)
65 (25)
91 (59)
Hospital stay (days)
14 (8)
30 (24)
AKI: acute kidney injury; previous eGFR (MDRD): estimated glomerular
filtration rate using MDRD before intervention. ECC: time on
extracorporeal circulation (minutes). AKI (day): day of the diagnosis of
AKI using creatinine levels. Values are given as mean (SD). The values
for patients with AKI that were significantly different from those of
patients without AKI had a P-value of a P<.001.
46
Cystatin-C in serum
We measured cystatin-C in serum samples using a
standardised immunonephelometry analysis using a BNII
nephelometer (Siemens Healthcare Diagnostics).
RESULTS
Clinical characteristics
The clinical and demographic characteristics of our study
patients are summarised in Table 1 and Table 2. A total of 26
patients developed AKI, 12 of which were in the
angiography group (13%, 12/89) and 14 were from the
cardiac surgery group (30%, 14/46). Six patients that
underwent catheterization died, three of which had
developed AKI, and four patients died from the cardiac
surgery group, all of which had AKI. The patients with AKI
had a longer mean hospital stay than those that did not in
both groups of patients.
In the group of patients that underwent catheterization,
creatinine values prior to the procedure were significantly
higher in patients with AKI (P<.001) (Table 1), and we did
not observe any significant differences in the group of
patients that underwent cardiac surgery.
NGAL values in urine samples from healthy controls
and patients
We observed a significant difference in the values of NGAL
from urine samples between patients that developed AKI and
Nefrologia 2012;32(1):44-52
originals
those that did not, allowing us to clearly distinguish between
the two groups (P<.001) (Figure 1).
The mean urine level of NGAL in the control group (healthy
volunteers) was 18 (5) ng/ml. We observed a significant
difference in NGAL (P<.001) between patients with AKI
and the control group (catheters: 96 [24]; cardiac surgery:
129 [28]) (Figure 1A, Figure 1B, and Table 3).
The NGAL values in the group of patients without AKI were
not significantly different from the control group (catheter:
17.4 [1.5]; cardiac surgery: 27.4 [3.7]) (Figure 1A, Figure
1B, and Table 3). Figure 1C shows how patients without
AKI did not have significantly different urine NGAL values
from the control group.
NO AKI
AKI
NO AKI
AKI
NO AKI
AKI
Cystatin-C serum values
The cystatin-C serum values were significantly different
(P<.001) between AKI and non-AKI patients. In the catheter
group, the mean value for patients with AKI was 1.22 (0.16)
mg/dl, and 0.71 (0.02) mg/dl in patients without AKI. In the
cardiac surgery group, the values for patients with and
without AKI were 1 (0.1) mg/dl and 0.78 (0.04) mg/dl,
respectively. The overall results were 1.1 (0.09) mg/dl and
0.7 (0.02) mg/dl in patients with and without AKI,
respectively (Table 3).
Urine IL-18 values
In the case of the IL-18 inflammatory marker, AKI patients
had significantly higher values than those without AKI
(Table 3).
In both the catheter and cardiac surgery groups, we observed
a significant difference between patients with and without
AKI (P<.05). This significant difference was greater when
we analysed all values together (P<.001).
Relationship between cystatin, IL-18, and NGAL
We tested for correlations between these parameters and
observed a significant correlation between NGAL in urine
samples and cystatin in serum samples (r=0.311; P=.001)
and between NGAL and IL-18 in urine samples (r=0.448;
P<.001).
A: patients undergoing catheterization; B: patients that
underwent cardiac surgery; C: graph corresponding to both
study groups together (catheter + cardiac surgery). Values are
given as mean (SD). Asterisks (***) indicate that the difference
between the two groups is significant (P<.001).
NGAL: Neutrophil Gelatinase-Associated Lipocalin.
.
Figure 1. Measurements of NGAL in urine samples from
controls, patients without acute kidney injury (no AKI), and
patients with acute kidney injury (AKI) in the different study
groups
ROC curves for NGAL, cystatin-C, and IL-18
In order to determine whether these markers are good
predictors for the appearance of AKI in patients that undergo
catheterization or cardiac revascularisation surgery, we
Nefrologia 2012;32(1):44-52
carried out a sensitivity/specificity analysis using ROC
curves (Figure 2). Figure 2A shows the ROC curve of the
three markers that were analysed in the catheter group.
NGAL, cystatin-C, and IL-18 were good markers for AKI,
47
The ROC curve for patients that underwent cardiac surgery
is displayed in Figure 2B. In these patients, although the
incidence of AKI was higher than in the catheter group
(Table 1 and Table 2), the ROC AUC were lower for all three
markers (Table 4). NGAL continued to be the best predictor
(AUC: 0.773) with sensitivity and specificity values of 64%
and 80% respectively, considering 31.9ng/ml as the cut-off
point for urine NGAL. Cystatin-C produced an AUC of
0.675, with sensitivity and specificity of 64% for the cut-off
point of 0.8mg/l, and the ROC curve for IL-18 produced an
AUC of 0.676, with the best cut-off point for urine IL-18 at
249pg/ml, with a sensitivity of 64% and specificity of 60%
(Table 4).
Figure 2C shows the ROC curve for the three markers,
considering the two groups of patients studied. NGAL
produced an AUC of 0.881, and was capable of detecting
80% of AKI cases with a specificity of 86%, considering the
cut-off point for urine NGAL to be 31.9ng/ml. Cystatin-C
produced an AUC of 0.774, detecting 75% of AKI cases with
a specificity of 71% for a cut-off point of 0.8mg/l of
cystatin-C in serum samples. The cut-off point for IL-18 was
201pg/ml, with sensitivity and specificity values lower than
the other markers (70% and 61%, respectively) and an AUC
of 0.722 (Table 4).
DISCUSSION
In this study we evaluated the usefulness of NGAL and IL18 in urine samples and cystatin-C in serum samples for the
early (within 12 hours of the intervention) detection of AKI
in a group of emergency patients in the ICU with acute
coronary syndrome or heart failure, who underwent cardiac
surgery or coronary angiography with or without angioplasty
or endoprosthesis implantation with the following results:
Sensitivity
NGAL
CISTATINE C
IL 18
1-Specificity
Sensitivity
and NGAL was the best predictor, with an area under the
curve (AUC) of 0.983, followed by cystatin-C (0.869) and
IL-18 (0.727) (Table 4). For a cut-off point of urine NGAL at
31.9ng/ml, sensitivity was 100% and specificity was 91%.
For cystatin-C, the cut-off point of 0.8mg/l in serum samples
yielded a sensitivity of 89% and specificity of 76%. The cutoff point of 202pg/ml for IL-18 yielded a sensitivity of 67%
and a specificity of 73%.
NGAL
CISTATINE C
IL 18
1-Specificity
Sensitivity
originals
NGAL
CISTATINE C
IL 18
1-Specificity
Cystatin in serum samples and IL-18 in urine samples also
offer good options, although not quite as strong (AUC of
0.774 and 0.722, respectively).
A: patients undergoing catheterization (AUC for NGAL: 0.983;
cystatin: 0.869; IL-18: 0.727); B: patients that underwent cardiac
surgery (AUC for NGAL: 0.773; cystatin: 0.675; IL-18: 0.676);
C: ROC curve corresponding to both study groups together
(catheter + cardiac surgery) (AUC for NGAL: 0.881; cystatin: 0.774;
IL-18: 0.722).
ROC: Receiver Operating Characteristic; AUC: area under the
curve; NGAL: Neutrophil Gelatinase-Associated Lipocalin.
Of the 46 patients that underwent cardiac surgery, 14 (30%)
developed AKI, 9 of which had a status of R on the RIFLE
classification system, and five of which were I. This 30% is
Figure 2. ROC curves for the different markers analysed in each
patient group
uNGAL is useful for the early detection of AKI with an AUC
of 0.881.
48
Nefrologia 2012;32(1):44-52
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Table 3. Values for the three markers analysed
Catheter
Cardiac surgery
No AKI
AKI
NGAL (ng/ml)
17.4 (1.5)
Cystatin-C (mg/ml)
IL-18 (pg/ml)
No AKI
AKI
95.8 (24)
27.4 (3.7)
0.71 (0.02)
1.22 (0.16)b
196 (18)
292 (39)a
b
Catheterization +
cardiac surgery
No AKI
AKI
129 (28)
20.5 (1.6)
115 (19)b
0.78 (0.04)
1.01 (0.12)b
0.73 (0.02)
1.10 (0.09)b
217 (20)
319 (38)a
203 (14)
305 (27)b
b
No AKI: patients that do not develop acute kidney injury; AKI: patients that do develop acute kidney injury. Cystatin-C was measured in serum
samples; NGAL and IL-18 were measured in urine samples. Values are given as mean (SDM). The values for patients with AKI that were significantly
different from those of patients without AKI had P-values of a P<.05; b P<.001.
in accordance with the data previously published on the
subject. Of the 89 patients that underwent angiography, 12
(13%) developed AKI, six of which were stage R, two were
I, and one was F. These results were also within expected
ranges. The delay for AKI diagnosis using creatinine took 3
(1) days in the cardiac surgery group and 4 (3) days in the
angiography group.
Of all the biomarker for AKI that are being studied, NGAL
has probably inspired the greatest amount of interest. NGAL
is a 25 kD protein that is covalently bound to neutrophil
gelatinase. It is normally expressed in very low
concentrations in several different tissues such as the
kidneys, lungs, stomach, and colon, but is found at very high
levels in kidneys with ischaemic or toxic damage.13-15 It has
been most heavily researched as a marker for AKI following
cardiac surgery. In a study published in The Lancet in 2005,16
Mishra et al carried out a study using paediatric patients that
underwent cardiac surgery with extracorporeal circulation,
and showed that NGAL is useful both in serum and urine
samples for the early (in the first few hours following the
procedure) detection of patients that will develop AKI in the
coming days, with extremely high sensitivity and specificity
levels. The usefulness of NGAL (in blood or urine samples)
for the early detection of AKI following cardiac surgery was
later confirmed both in children17,18 and adults,19-24 although
the results are more varied and are clearly worse in adults. In
other studies, however, NGAL was predictive for AKI in
urine samples, but not in serum,25,26 and some studies have
even produced negative results from using urine NGAL.27
Probably, the reason for the lower specificity observed in
adults than in children is related to the existence of other
associated conditions. For instance, it has been shown that
NGAL values are higher in hypertensive28 and diabetic29
patients, and that they also increase with age.30 Sepsis can
also affect NGAL values.31 It has also been shown that the
relationship between NGAL and AKI after cardiac surgery
varies according to baseline glomerular filtration rate, and
the predictive capacity of NGAL is lost in patients with an
estimated glomerular filtration rate (eGFR) below
60ml/min.32 Although the strength of the results are variable
in both urine and blood tests, it appears that urine samples
Table 4. Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study
groups
N-GAL
Study group
Cystatin C
IL-18
Cut-off pointa
AUC
Cut-off pointa
AUC
Cut-off pointa
AUC
(S-s)b
(95% CI)c
(S-s)b
(95% CI)
(S-s)b
(95% CI)
Angiography
Cardiac surgery
Angiography + cardiac surgery
31.9
0.983
0.8
0.869
202
0.727
(100-91)
(0.954-1.012)
(89-76)
(0.676-1.06)
(67-73)
(0.566-0.888)
31.9
0.773
0.8
0.675
249
0.676
(64-80)
(0.580-0.96)
(64-64)
(0.46-0.88)
(64-60)
(0.49-0.86)
31.9
0.881
0.8
0.774
201
0.722
(80-86)
(0.784-0.977)
(75-71)
(0.626-0.92)
(70-61)
(0.609-0.835)
Cut-off points for each marker are expressed in ng/ml for NGAL, mg/l for cystatin-C, and pg/ml for IL-18.
S-s: sensitivity (%) specificity (%), respectively, for the cut-off point indicated. AUC: area under the ROC curve.
c
95% CI: 95% confidence interval
a
b
Nefrologia 2012;32(1):44-52
49
originals
are generally superior.25,26 The best time to obtain and analyse
the samples has not been defined yet.
2. Whether blood or urine samples should be used, and the
optimal moment for obtaining the sample.
NGAL has also been shown to be useful for the early
diagnosis of AKI following coronary angiography,33-38
although fewer studies have been published in support, and
the predictive power of this analysis, the cut-off point, and
the optimal time for measurement are not well established.
3. Extrinsic factors that may influence the results and
viability of the measurements in different clinical
contexts.
In our study, the results from the overall group of patients
were very positive for the measurement of uNGAL 12 hours
after the procedure, with an AUC of 0.881. In the cardiac
surgery group, AUC was 0.773, somewhat higher than the
results published in other studies with adult cardiac surgery
patients (0.62-0.72).19-25 The AUC for patients that underwent
coronary angiography was higher too (0.983). The cut-off
point for better sensitivity and specificity in the overall
group was 31.9ng/ml, with a sensitivity of 80% and a
specificity of 86%.
Urine IL-18 has also been studied as a possible early marker
for the detection of AKI in patients that undergo cardiac
surgery, yielding both positive39 and negative40 results, as
well as following coronary angiography,36 although this
measurement has inspired less interest as a possible
biomarker for AKI.
In contrast to NGAL and IL-18, cystatin is not a marker of
kidney damage, but rather glomerular filtration rate. CystatinC is a small endogenous protein that is freely filtered in the
glomerulus, and is reabsorbed and catabolised in the proximal
tubule, such that only a small quantity is excreted in the
urine. Its usefulness as a possible substitute for creatinine as a
method of measuring glomerular filtration rate has been
examined in recent years, both in chronic and acute kidney
disease, because of its lower dependence on muscle mass.
However, its value does depend on other variables such as
age, sex, race, and the presence of diabetes or inflammation.41
The results using this measure are also variable in patients
that undergo cardiac surgery, with positive,21 modest,42 and
negative results,26 although in this latter study, urine cystatin
was capable of predicting the appearance of AKI, compared
to serum samples. The published studies with cardiac
catheters are also inconsistent, with varying and occasionally
contrasting results.35, 43-45 In our study, the AUC for cystatin
was 0.774 in all patients, 0.869 in the coronary angiography
group, and 0.675 in the cardiac surgery group. The results for
IL-18 were quite similar (Table 4).
Therefore, the search for the ideal biological marker for the
early detection of AKI still has the following important
questions pending:
1. The best biomarker (or combination of biomarkers) and
cut-off point that offers optimal sensitivity and
specificity.
50
4. The prognostic power in addition to the diagnostic
capacity.
In this study, we have attempted to contribute a response to
some of these questions. This study differs from those
previously published by including both cardiac surgery and
catheter patients, as well as the fact that all patients were
admitted to intensive care units for coronary syndrome or
acute heart failure, making them unstable patients. This is
important because we need to know how these biomarkers
work in large groups of the population with different
characteristics, not just in homogeneous groups, and also
because of the need to observe how other factors influence
these measurements.
We took all of our samples 12 hours after the procedure. We
were interested in testing the usefulness of samples at this
time since it is the simplest option for collecting and
processing samples in a normal clinical context (if the
procedure takes place in the afternoon, the samples would be
taken first thing the next morning).
We decided not to take samples for the biomarkers before the
procedure, since the ultimate objective is to have a reliable
marker in a specific situation, regardless of baseline values.
For instance, when troponin or D-dimer are measured in
clinical practice, it is without a baseline value for
comparison. In any case, NGAL was measured in a
population of healthy individuals with normal renal function
in order to provide a reference value for comparison with the
study groups.
The results from the markers in urine samples were not
adjusted to urinary creatinine levels since, although some
authors do defend this normalisation, the majority of studies
have preferred not to do so because the evidence is not clear.
We preferred to measure NGAL in urine samples over serum
samples since, although currently there are rapid methods for
determining NGAL in blood samples with a good correlation
with the results obtained in blood samples by ELISA,16 the
results from previously published studies show a better yield
in urine samples.
In conclusion, urine NGAL taken 12 hours after the
procedure is a good marker for the early detection of AKI in
adult patients with acute heart failure or coronary syndrome
that undergo cardiac surgery or coronary angiography, with a
predictive power superior to cystatin and IL-18.
Nefrologia 2012;32(1):44-52
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injury after cardiac surgery. Ren Fail 2008;30:904-13.
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and conventional serum biomarkers predicting acute kidney injury
in adult cardiac surgery-A prospective cohort study. Crit Care Med
2009;37:553-60.
22. Tuladhar SM, Püntmann VO, Soni M, Punjabi PP, Bogle RG. Rapid
detection of acute kidney injury by plasma and urinary neutrophil
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23. Han WK, Wagener G, Zhu Y, Wang S, Lee HT. Urinary biomarkers in
the early detection of acute kidney injury after cardiac surgery. Clin
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baseline renal function on diagnostic performance. Clin J Am Soc
Nephrol 2010;5:211-9.
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acute kidney injury after cardiac surgery. Ren Fail 2008;30:904-13.
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2008;74:1059-69.
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Comparative analysis of urinary biomarkers for early detection of
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Dobrzycki S. Urinary and serum biomarkers after cardiac catheterization in diabetic patients with stable angina and normal serum creatinine. Ren Fail 2009;31:910-9.
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by eGFR, cystatin C and NGAL (neutrophil gelatinase-associated lipocalin) in relation to age in heart allograft recipients. Med Sci Monit 2010;16:440-4.
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and without acute kidney injury. Int Care Med 2010;36:1333-40.
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NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography. Nephron Clin Pract
2008;108:176-81.
37. Bachorzewska-Gajewska H, Poniatowski B, Dobrycki S. NGAL
(neutrophil gelatinase-associated lipocalin) and L-FABP after
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IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199-203.
Haase M, Bellomo R, Story D, Davenport P, Haase-Fielitz A. Urinary
interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study. Critical Care
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glomerular filtration rate affect serum cystatin C levels. Kidney Int
2009;75:652-60.
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S. Plasma cystatin C and acute kidney injury after cardiopulmonary
bypass. Clin J Am Soc Nephrol 2010;5:1373-9.
Rickli H, Benou K, Ammann P, Fehr T, Brunner-La Rocca HP. Time
course of serial cystatin C levels in comparison with serum creatinine
after application of radiocontrast media. Clin Nephrol 2004;61:98102.
Briguori C, Visconti G, Rivera NV, Focaccio A, Golia B. Cystatin C and
contrast-induced acute kidney injury. Circulation 2010;121:2117-22.
Merkle M, Sauter M, Argirov M, Wörnle M. Cystatin C and creatinine as markers for radio contrast-induced nephropathy in patients treated with N-Acetylcysteine. Ren Fail 2010;32:85-90.
Sent for review: 11 Jun. 2011 | Accepted: 21 Sep. 2011
52
Nefrologia 2012;32(1):44-52
originals
The calculation of baseline serum creatinine
overestimates the diagnosis of acute kidney injury
in patients undergoing cardiac surgery
A.M. Candela-Toha1, M. Recio-Vázquez2, A. Delgado-Montero2, J.M. del Rey3, A. Muriel4,
F. Liaño5, T. Tenorio6
Anaesthesiology and Resuscitation Department. Ramón y Cajal University Hospital. Ramón y Cajal Institute of Health Research
(IRYCIS). Acute Kidney Failure Research Consortium (CIFRA). Madrid, Spain
2
Cardiology Department. Ramón y Cajal University Hospital. Madrid, Spain
3
Biochemistry Department. Ramón y Cajal University Hospital. Madrid, Spain
4
Biostatisitics Unit. IRYCIS. Networked Consortium of Biomedical Research on Epidemiology and Public Health (CIBERESP). Ramón y
Cajal University Hospital. Madrid, Spain
5
Nephrology Department. Ramón y Cajal University Hospital. IRYCIS. CIFRA. Medicine Department, University of Alcalá. Madrid, Spain
6
Nephrology Department. Ramón y Cajal University Hospital. CIFRA. Madrid, Spain
1
Nefrologia 2012;32(1):53-8:XX
ABSTRACT
Introduction and objectives: The current definition and
classification of acute kidney injury is based on consensus criteria (RIFLE and AKIN systems). Creatinine is the
most commonly used of the recommended parameters
(creatinine, glomerular filtration rate and diuresis). If the
baseline value is not known, it can be calculated based
on the simplified MDRD equation, assuming a filtration
rate of 75ml/min/1.73m2 for the calculation. The aim of
this study was to evaluate the diagnostic impact of using
estimated baseline creatinine compared to the actual value measured in patients undergoing cardiac surgery.
Methods: Analysis of patients undergoing major cardiac
surgery, who were prospectively included in a database.
The maximum RIFLE stage reached was calculated for
each patient using the measured and estimated baseline
creatinine levels. The impact on the diagnosis was
analysed using intraclass correlation coefficients, concordance analysis and Bland-Altman plots. Results: The incidence of postoperative acute kidney injury in 2103 cases
between 2002 and 2007 was 29.1%, according to estimated creatinine (14.3% with the measure). This represents
an overestimation of 104%, with an intraclass correlation
Correspondence: A.M. Candela-Toha
Servicio de Anestesia y Reanimación.
Hospital Universitario Ramón y Cajal.
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS).
Consorcio de Investigación del Fracaso Renal Agudo.
Ctra. de Colmenar, km 9,1. 28034 Madrid. Spain.
[email protected]
of 0.12. By excluding patients with known chronic kidney
disease (glomerular filtration rate [<60ml/min/1.73m2),
both the overestimation (2.4%) and the correlation (0.57)
improved. Conclusions: The calculation of baseline creatinine using the MDRD equation overestimates the incidence of acute kidney injury after cardiac surgery, and is
an inadequate method for detection when the baseline
value is unknown.
Keywords: Cardiac surgery. Acute renal failure. Acute
kidney injury. Serum creatinine. RIFLE.
El cálculo de la creatinina sérica basal sobrestima el
diagnóstico de alteración renal aguda en pacientes
operados de cirugía cardíaca
RESUMEN
Introducción y objetivo: La definición y clasificación actual
de insuficiencia renal aguda se basa en criterios de consenso (sistemas RIFLE y AKIN). De los parámetros recomendados (creatinina, tasa de filtración glomerular y diuresis), la
creatinina es el más empleado. En ausencia de valor basal
conocido se recomienda su estimación a partir de la ecuación MDRD simplificada, asumiendo en el cálculo una tasa
de filtración de 75 ml/min/1,73 m2. El objetivo del presente
trabajo fue evaluar la repercusión diagnóstica del empleo
de la creatinina basal estimada frente al valor real medido
en pacientes operados de cirugía cardíaca. Métodos: Análi53
originals
sis de pacientes operados de cirugía cardíaca mayor incluidos de forma prospectiva en una base de datos. Para cada
paciente se calculó el estadio RIFLE máximo alcanzado usando la creatinina basal medida y la estimada. Se analizó la repercusión sobre el diagnóstico mediante coeficientes de correlación intraclase, análisis de concordancia y gráficas de
Bland y Altman. Resultados: La incidencia de insuficiencia
renal aguda postoperatoria en 2.103 casos operados entre
2002 y 2007 fue del 29,1% al utilizar la creatinina estimada
(14,3% con la medida). Esto supone una sobrestimación del
104%, y la correlación intraclase es de 0,12. Excluyendo a los
pacientes con insuficiencia renal crónica conocida (tasa de
filtrado glomerular [TFG] <60 ml/min/1,73 m2), tanto la sobrestimación (2,4%) como la correlación (0,57) mejoraron.
Conclusiones: El cálculo de la creatinina basal a partir de la
ecuación MDRD sobrestima la incidencia de insuficiencia renal aguda tras la cirugía cardíaca, y es un método inadecuado para su detección cuando el valor basal se desconoce.
Palabras clave: Cirugía cardíaca. Insuficiencia renal aguda.
Alteración renal aguda. Creatinina sérica. RIFLE.
A.M. Candela-Toha et al. RIFLE-AKIN in cardiac sugery
and perhaps for non-scientific reasons,8 the RIFLE
classification is very popular. The number of publications
exceeds 150, and a fairly recent systematic review included
24 studies covering more than 70 000 patients.9 Among the
problems associated with this classification is the diagnosis
and classification of patients whose baseline serum
creatinine is unknown. This occurs quite often in patients
with an altered SCr value who are admitted to critical care
units for acute problems (e.g., septic shock, acute coronary
syndrome and heart failure). The ADQI recommendation is
to assume that patients with a previously unknown renal
function, with no known kidney disease, have a GFR of 75100ml/min/1.73m2, and then to back-calculate the SCr value
using the simplified MDRD equation.10 This method has
been used in several epidemiological studies despite its lack
of validation.11,12
The aim of this study is twofold: 1) To assess the agreement
between estimated baseline SCr (est SCr) against the known
baseline SCr in patients undergoing cardiac surgery, and 2)
To analyse the impact of differences in baseline SCr on AKI
frequency and severity for those episodes observed in
cardiac surgery.
INTRODUCTION
MATERIAL AND METHODS
Acute kidney injury (AKI) is a common complication
following cardiac surgery. Its appearance leads to a significant
increase in both morbid-mortality and hospital stay. AKI
frequency varies depending on the definition used. When the
most severe forms, those requiring renal replacement therapy
(RRT), are considered the range is 2%-5%.1 In recent years
there has been a consensus in new definitions for this
syndrome and a change in the nomenclature.2,3 The English
term acute renal failure, traditionally translated into Spanish
as insuficiencia or fracaso renal agudo has changed to acute
kidney injury to broaden the spectrum of the syndrome and
include milder cases. Liaño et al. suggested that AKI should
be coined as alteración renal aguda (ARA) in Spanish.4 Since
Lassnig’s study on patients undergoing cardiac surgery, it is
known that even slight increases (0.3mg/dl) in serum
creatinine (SCr) with respect to baseline have an impact on
postoperative morbidity and mortality.5,6 These results have
been confirmed in hospitalised patients.7
In 2004, the Acute Dialysis Quality Initiative (ADQI)
proposed the use of the RIFLE system (Risk, Injury, Failure,
Loss and End stage renal disease) with 3 diagnostic (R, I and
F) and 2 prognostic (L and E) categories. The diagnosis is
made based on SCr increases compared to baseline,
decreases in the glomerular filtration rate (GFR), or absolute
decreases in diuresis.2 Patients are diagnosed and classified
using the criteria that placed them in the most severe stage.
These criteria were reviewed in 2007 and modified by the
Acute Kidney Injury Network (AKIN), this latter
classification being recognised as the current one.3 However,
54
Perioperative data from cardiac surgery patients operated on
in our hospital were compiled prospectively in a database
kept by the Anaesthesiology Department. We used data from
patients operated on between 2002 and 2007. All patients
older than 14 years who underwent major cardiac surgery
with or without extracorporeal circulation were included.
Patients were excluded if they were on dialysis prior to
surgery, were kidney transplant recipients, had died within
24 hours of surgery or if they underwent second major
surgery during the same hospitalisation period.
The measured baseline SCr (act SCr) was considered as the
last SCr measurement before surgery, usually within 24
hours for patients undergoing elective surgery. The kinetic
Jaffe method was used. The GFR was estimated from the
simplified MDRD formula using four variables (SCr, age,
sex and race). To calculate baseline serum creatinine (est
SCr) from this equation, considering a GFR of
75ml/min/1.73m2 (the lower normal limit), the ADQI
recommendations were followed by using the following
formula:
Estimated SCr=(75/[186x(age-0,203)x(0.742 for women)x(1.21
for black people)])-0,887
Patients were assigned the highest stage by the RIFLE
classification from SCr determinations during the first
week after surgery. The criterion based on percentage
GFR decreases was not used, due to its lack of linearity
Nefrologia 2012;32(1):53-8
and consistency when compared with increases in SCr.13 The
diuresis criterion was also not used due to lack of data.
The agreement between act SCr and est SCr was assessed
by the intraclass correlation coefficient 14 and Bland and
Altman plot. 15 The bias, the overall mean of the
differences between act SCr and est SCr, was also
calculated; as well as precision, defined as the bias
standard deviation. The estimated error was calculated as
the percentage of patients diagnosed with AKI using est
SCr (estAKI) with respect to those diagnosed from act
SCr (actAKI), using the formula below:
originals
Table 1. Main demographic variables, comorbidity,
surgical variables, postoperative variables and hospital
stay in the studied cohort (n=2103)
Age, years, mean (SD)
66.1 (11.3)
Females, %
40.7
Baseline SCr observed, mg/dl, mean (SD)
1.12 (0.38)
eGFR, ml/min/1.73m , mean (SD)
68.26 (19.9)
2
- Normal: GFR>
_90ml/min/1.73m (%)
221 (10.5)
- Slightly impaired: GFR 60-89ml/min/1.73m2 (%)
1187 (56.4)
2
- Moderately impaired: GFR 30-59ml/min/1.73m2 (%)
(estAKI – actAKI)/actAKI
46 (2.2)
- End stage renal disease: GFR<15ml/min/1.73m (%)
4 (0.2)
2
A positive value showed an overestimation while a
negative one implied underestimation. An initial analysis
of the global sample and a second analysis, excluding
patients with stage 3 or higher chronic kidney disease
(CKD) according to the National Kidney Foundation
K/DOQI classification, were performed. 16 The mean and
standard deviation or median and interquartile range,
depending on the distribution of the quantitative variables
studied, were used as measures of central tendency and
dispersion. A statistical analysis of the data and plots was
performed using SPSS version 18.0.
RESULTS
A total 2167 operations were performed on 2131 patients
during the study period. Those patients excluded were: 31
patients (32 surgeries) for undergoing preoperative dialysis
or being kidney transplant recipients; 27 who died soon after
surgery (<24 hours); and 5 for having a second surgery
during the same hospitalisation period. The final sample
consisted of 2103 operations on 2067 patients, and the main
features are shown in Table 1.
645 (30.7)
- Severely impaired: GFR 15-29ml/min/1.73m (%)
2
Hypertension, %
53.6
CHF History, %
22.1
COPD, %
6.4
Diabetes, %
- With medical treatment
19.6
- Insulin-dependent
7.7
Previous cardiac surgery, %
11.7
Type of surgery, %
- Isolated CABG
34.4
- Valvular
47.7
- Combined (CABG and valvular)
10.2
- Aortic
4.5
- Others
3.2
Off-pump ECC, %
10
Ischaemia time, min, mean (SD)
59.4 (33.5)
Perfusion time, min, mean (SD)
81.5 (43.2)
Mechanical ventilation, h, median (P25-P75)
Need for postoperative RRT, %
9 (7-20)
3.4
Hospital stay, days, median (P25-P75)
Table 2 shows the number and percentage of patients who
reached each RIFLE stage during the first week after
surgery, according to the type of baseline SCr used, either
actual or estimated; the correlation between both; and the
bias and precision. The global overestimation rate was 104%
(29.1% vs 14.6%). The diagnosis of AKI whith est SCr
showed a false positive rate of 14.8%. After excluding
patients with a GFR<60ml/min/1.73m2, the correlation was
better. The overestimation decreased to 2.4% with a false
positive rate of 0.28%.
Figure 1 shows the correlation between est SCr and act SCr
via Bland and Altman plots. The point cloud arrangement
indicates that the degree of agreement decreases when the
baseline SCr increases. Graphically, there is greater
agreement between both creatinine values after excluding
patients with any CKD stage prior to surgery (Figure 2).
Nefrologia 2012;32(1):53-8
- In ICU
- Outside ICU
3 (2-5)
10 (7-15)
CHF: chronic heart failure;COPD: chronic obstructive pulmonary
disease; est GFR: estimated glomerular filtration rate; GFR: glomerular
filtration rate; ICU intensive care unit; CABG: coronary artery bypass
graft; RRT: renal replacement therapy; SCr: serum creatinine;
SD: standard deviation.
DISCUSSION
This study shows that the recommendation to calculate
baseline SCr from the MDRD-4 equation assuming a GFR
of 75ml/min/1.73m2 overestimates the incidence of AKI in
55
originals
Table 2. Renal function stratified by RIFLE category
RIFLE stage
Act SCr
Est SCr
sepsis, trauma or cardiac arrest. Our study was the first to
focus on postoperative cardiac surgery patients, therefore it
is not possible to make direct comparisons with other
studies.
Overall cohort (n=2103)
None
1803 (85.7%)
1493 (71%)
R
178 (8.5%)
319 (15.2%)
I
77 (3.7%)
191 (9.1%)
F
45 (2.1%)
100 (4.8%)
Any criteria
300 (14.3%)
610 (29.1%)
Total
2103 (100%)
2103 (100%)
Correlation
0.605
Bias (mg/dl)
0.16
Precision (mg/dl)
0.38
Patients with eGFR >_60ml/min/1.73m2 (n=1408)
None
1247 (88.6%)
1243 (88.3%)
R
103 (7.3%)
103 (7.3%)
I
43 (3.1%)
51 (3.6%)
F
15 (1.1%)
11 (0.8%)
Any criteria
161 (11.5%)
165 (11.7%)
Total
1408 (100%)
1408 (100%)
Correlation
0.845
Bias (mg/dl)
-0.02
Precision (mg/dl)
0.13
Both the prevalence of CKD or preoperative renal
dysfunction and the incidence of AKI have a clear impact on
the percentage of overestimation. To some extent, the first
may be influenced by age (generally higher in surgical
patients) and other cardiovascular risk factors (particularly
hypertension and diabetes), which were significantly present
in our sample. It is worth noting that the best definition of
preoperative renal dysfunction for patients undergoing
cardiac surgery was established by Wijeysundera,21 as
creatinine clearance (CrCl) lower than 60ml/min. The odds
ratio for developing severe AKI (with a need for RRT) in a
random sample of 2000 patients operated on over a period of
16 months was 5 (confidence interval [CI] 95%; 2-12.6)
when presenting this degree of renal dysfunction. The
prevalence of preoperative renal dysfunction in this sample
was 27%. The prevalence of moderate or severe CKD
(GFR<60ml/min/1.73m2) in the Pickering study cited above
was 28%, while that of Bagshaw was 46%, which left our
study between them (33.1%). Excluding these patients the
6
5
4
56
3
Act Cr – est Cr (mg/dl)
patients undergoing cardiac surgery. A similar conclusion
was reached by several authors using more heterogeneous
cohorts than ours. In the BEST Kidney study, Bagshaw17
found an overestimation of 42% using the same formula to
calculate baseline SCr from a prospective study of over 1300
patients from 54 intensive care units (ICUs) in 23 countries.
In a cohort study of almost 5000 patients hospitalised during
a year, Siew18 compared 3 different methods to estimate the
baseline serum creatinine with values obtained from preadmission renal function for diagnosing AKI. The methods
were SCr calculated from MDRD with a GFR of 75ml/min,
the minimum SCr value during admission and the SCr value
on admission. The first 2 methods overestimated the
incidence by almost 50%, while the use of SCr on admission
underestimated the diagnosis by 46%. More recently,
Závada19 found similar results when comparing 3 different
methods, including the one recommended by ADQI, in nonselected patients from 3 different hospital ICUs. Finally,
after prospectively analysing 224 patients from 2 general
ICUs used as controls in the EARLYRAF study, Pickering
and Endre20 found an overall overestimation of 35.7% with
an assumed GFR of 75ml/min, which increased to 92.8%
when a baseline GFR of 100ml/min was considered. Unlike
our cohort study, only 23% of the patients underwent cardiac
surgery, and the rest had thoracic surgery, vascular surgery,
2
1
0
-1
-2
-3
-4
-5
-6
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
(Act Cr – est Cr)/2 (mg/dl)
The thick line represents the average difference (bias), and
the two thin lines above and below it show its standard
deviation (precision). The higher the baseline creatinine, the
greater the difference between both values, i.e. the degree of
agreement decreases.
Figure 1. Bland and Altman plot for the global cohort
(n=2103) showing the degree of agreement between both
creatinine values
Nefrologia 2012;32(1):53-8
originals
0.8
0.6
Act Cr – est Cr (mg/dl)
0.4
0.2
0.0
–0.2
–0.4
–0.6
–0.8
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
(Act Cr – est Cr)/2 (mg/dl)
The agreement between both creatinine values improves
significantly. Note the difference in scales compared to Figure 1.
CKD: chronic kidney disease
Figure 2. Bland and Altman plot after excluding patients with
impaired renal function, stage 3 CKD (n=1408)
overestimation decreased in all 3 studies. This effect is easily
explained, as a significant number of cases where the patient
is given a GFR above the real one are excluded. Another
concept worth mentioning, which was also described by
Wijeysundera, is that of occult renal insufficiency.22 This is
defined as preoperative renal function with a CrCl<60ml/min,
but with a preoperative baseline SCr<1.13mg/dl. In a cohort
of over 10 000 patients undergoing cardiac surgery, the
prevalence of occult renal failure was 9%, and was very
similar to our sample (8.5%). This concept stresses the
importance of estimating GFR or CrCl in addition to baseline
SCr in a preoperative analytical evaluation.
The risk factors for AKI in the context of cardiac surgery have
been extensively studied, with several grading systems
established to calculate RRT preoperative risk.23-25 Preoperative
renal function appears constantly among the factors considered.
The incidence of AKI was 14.2% in our sample, lower than
both the Pickering (31.2%) and BEST (44.9%) studies. Since
the number of diagnosed cases is the denominator in the
overestimation calculation, the smaller this number is, the
higher the overestimation. Together with the different
prevalence of CKD, this situation may explain our findings.
We believe that the main limitation of this study is the use of
baseline SCr taken as part of the preoperative evaluation:
this value need not necessarily reflect the subject’s SCr at
Nefrologia 2012;32(1):53-8
baseline. A significant number of patients admitted to the
emergency department with symptoms of ischaemic heart
disease or heart failure undergo cardiac surgery several days
later, once the patient has been stabilised. However, similar
approaches have been used in the above studies. Although
the current recommendation is to use a SCr value obtained in
the 3 months before admission, there is no known best
method for calculating baseline SCr when a baseline
measurement is not available. In the study by Pickering and
Endre,20 the random assignment of SCr values from a
lognormal distribution curve adjusted to the parameters of
central tendency and dispersion of the source population was
the method that most closely approximated to the actual
incidence (with an AKI underestimation of 2.9%). Failing
that, and as a more practical method, the authors recommend
using the lowest SCr observed during the first 7 days of
hospital stay (an AKI overestimation of 5.7%). This
recommendation, of course, should only be done for an
epidemiological analysis; as such a delay in diagnosis is not
acceptable from a healthcare point of view.
A second limitation of this study is the use of SCr criterion only
for AKI diagnosis, excluding patients diagnosed from a decrease
in diuresis. This is a problem for all retrospective analyses using
the RIFLE system, which are the vast majority of those
published. This is because this parameter is rarely reflected in
databases with sufficient detail to be applied (i.e., on an hourly
basis). Therefore, we did not give sensitivity and specificity
values, as all criteria must be used to make the diagnosis reliably
and to classify those patients with the most severe stage.
CONCLUSIONS
Using baseline creatinine calculated from the MDRD equation
in the diagnosis of AKI overestimates the incidence in patients
undergoing cardiac surgery. This is common in populations with
an increased prevalence of mild CKD, with the intensity
depending both on this factor and the incidence of AKI.
However, this is acceptable in patients whose premorbid GFR is
normal or nearly normal. This observation must be considered,
especially in hospital-based epidemiological studies.
REFERENCES
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Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute
kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-70.
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Buenos Aires: Editorial Médica Panamericana; 2008. p. 733-8.
Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute
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M, et al. A comparison of observed versus estimated baseline creatinine for determination of RIFLE class in patients with acute kidney
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G, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant 2010;25:39118.
20. Pickering JW, Endre ZH. Back-calculating baseline creatinine with
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Sent for review: 25 Jul. 2011 | Accepted: 3 Oct. 2011
58
Nefrologia 2012;32(1):53-8
originals
Early detection of chronic kidney disease:
Collaboration of Belgrade nephrologists and primary
care physicians
Ljubica Djukanović1, Visnja Lezaić2, Nada Dimković2, Gordana Perunicić Peković3,
Danica Bukvić4, Sanja Bajcetić5, Jelena Pavlović6, Ana Bontić6, Nadezda Zec3,
Danijela Momcilović7, Marina Stojanović Stanojević8 8
Academy of Medical Science. Serbian Medical Society. Belgrade (Serbia)
Medical Faculty. Belgrade University. Belgrade (Serbia)
3
Department of Nephrology. Clinical Centre Zemun. Belgrade (Serbia)
4
Special Hospital for Endemic Nephropathy. Lazarevac (Serbia)
5
Department of Nephrology. Clinical Centre Zvezdara. Belgrade (Serbia)
6
Department of Nephrology. Clinical Centre of Serbia. Belgrade (Serbia)
7
Hemodialysis Center of Health. Obrenovac (Serbia)
8
Hemodialysis Center of General Hospital. Mladenovac (Serbia)
1
2
Nefrologia 2012;32(1):59-66
ABSTRACT
Background: Belgrade screening study was undertaken in
order to detect persons with CKD markers in at risk
populations and to educate primary care physicians how to
carry out CKD screening. Methods: The study was
performed by primary care physicians from thirteen
Belgrade health centers in collaboration with nephrologists
from clinical centers. Subjects without previously known
kidney disease were enrolled: 1316 patients with
hypertension without diabetes, 208 patients with type 2
diabetes and 93 subjects older than 60 years without
hypertension or diabetes. The survey consisted of an
interview, estimation of glomerular filtration rate
(eGFR–MDRD), single urine dipstick detection of proteinuria,
hematuria,
glucosuria,
microalbuminuria. Results:
Microalbuminuria with or without proteinuria in
combination with eGFR>60ml/min/1.73m2 was detected in
17% , 41% and 24% of patients with hypertension, diabetes
and those above 60 years, respectively. Reduced eGFR (<60
ml/min/1.73m2 ) was found in 23%, 12% and 22% of the
same patient groups. The prevalence of CKD markers
increased with increasing number of risk factors.
Conclusion: High prevalence of CKD markers in at risk
population detected by primary care physicians in this
collaborative study seems to be the best way to encourage
primary care physicians to carry out regular CKD screening.
Keywords: Chronic kidney disease. Screening. Primary care.
Correspondence: Ljubica Djukanović
Academy of Medical Science.
Serbian Medical Society. Pasterova 2. 11000 Belgrade. Serbia.
[email protected]
[email protected]
Detección precoz de la enfermedad renal crónica:
colaboración entre nefrólogos y especialistas de atención
primaria de Belgrado
RESUMEN
Antecedentes: El estudio de Belgrado se realizó para detectar personas con marcadores de ERC en poblaciones de riesgo y formar a los especialistas de atención primaria sobre
cómo realizar proyecciones de ERC. Métodos: El estudio fue
realizado por especialistas de atención primaria de trece
centros de salud en colaboración con nefrólogos de centros
clínicos. Se incluyó a personas sin enfermedad renal previa
conocida: 1316 pacientes con hipertensión sin diabetes, 208
pacientes con diabetes tipo 2 y 93 pacientes de más de 60
años sin hipertensión ni diabetes. El estudio consistía en
una entrevista, determinación de la tasa de filtración
glomerular estimada (TFGe-MDRD) y detección de proteinuria, hematuria, glucosuria y microalbuminuria con una
única tira reactiva de orina. Resultados: Se detectó microalbuminuria con o sin proteinuria en combinación con una
TFGe >60 ml/min/1,73m2 en el 17%, el 41% y el 24% de los
pacientes con hipertensión, diabetes y mayores de 60 años,
respectivamente. Se encontró una TFGe reducida (<60
ml/min/1,73m2 ) en el 23%, el 12% y el 22% de estos mismos grupos de pacientes. La prevalencia de los marcadores
de ERC aumentaba cuanto mayor era el número de factores
de riesgo. Conclusión: La elevada prevalencia de marcadores de ERC en una población de riesgo detectada por
los médicos de atención primaria en este estudio de colaboración parece ser la mejor forma de motivar a estos especialistas para que realicen cribados de ERC con regularidad.
Palabras clave: Enfermedad renal crónica. Proyección.
Atención Primaria.
INTRODUCTION
The steady increase in the incidence of patients on renal
replacement therapy (RRT) was first noted in developed
59
originals
countries and thereafter all around the globe.1-3 Over the
same period diabetes and hypertension became the leading
causes of chronic kidney disease (CKD) and the number of
elderly patients in end-stage renal disease increased steadily3.
It became obvious that more attention should be directed to
prevention and early detection of CKD. Recent data
indicated stabilization of incidence rates of RRT patients in
many developed countries.4-6 Although different factors
might have led to this stabilization, greater emphasis on
early detection and prevention of CKD is doubtless one of
them. However, our country is among those European
countries where the incidence rate of patients on RRT is
continuing to increase.7,8 The experience of developed
countries in primary and secondary prevention of CKD has
taught us that attention must be moved from treating
advanced stages of CKD towards treatment of the early
stages. As early stage of CKD in most patients is
asymptomatic and undiagnosed, detection can be achieved
only by active screening. It was proposed that prevention
and early detection of CKD would be best managed in a
partnership between primary and secondary care.9 Therefore,
we undertook the first study for early detection of CKD in
Serbia in which primary care physicians from thirteen
Belgrade health centers collaborated with nephrologists from
Belgrade clinical centers. The aim was to detect persons with
CKD markers in populations at risk and also to educate
primary care physicians how to carry out screening for CKD
and how to interpret the results and manage subsequent
treatment alone or in collaboration with nephrologists.
SUBJECTS AND METHODS
The present paper presents the results of screening for CKD carried
out in Belgrade under the leadership of the Academy of Medical
Science of the Serbian Medical Society. The study included three
steps: (1) Education. Educative meetings for primary care
physicians on prevention and early detection of CKD were
organized by the Academy in 2008. (2) Organization of study for
detection of persons with CKD markers. At the beginning of 2009
primary care physicians from all 13 Belgrade Health Centers were
invited to participate in the screening study. After their positive
response nephrologists from three clinical centers presented the
study design to primary care physicians who carried out
investigations from April to June 2009. (3) Results presentation
and guideline distribution. In November 2009, the Academy
organized a meeting where the results from each health center were
presented by general practitioners and the overall findings were
collated and reported by nephrologists, coordinators of the study. At
the same time a guideline for early detection and treatment of
chronic kidney disease, prepared by members of the Academy was
presented and distributed to all participants.10
This study enrolled 1617 adult patients without previously
known renal disease who came for regular check-ups to
their primary care physicians in Belgrade Health centers
60
Ljubica Djukanović et al. Belgrade screening study
over a three month period. The patients were enrolled in
the study according to the following criteria: patients with
hypertension for more than 5 years, patients with type 2
diabetes mellitus for more than 5 years regardless of the
presence or not of hypertension, and persons older than 60
years without hypertension or diabetes. Exclusion criteria
involved: previously known kidney diseases, malignant
disease, congestive heart disease, pregnancy, any acute
illness, as well as persons younger than 18 years.
Informed consent was obtained from all patients and the
Ethics Committee of the Clinical Center of Serbia
approved the study.
The survey started with an interview in which the
participants answered a detailed questionnaire on
demographic issues, personal medical and family history
with special attention to duration and treatment of
hypertension and diabetes and data on smoking. After the
interview the primary care physicians examined all
selected subjects physically, including measurement of
body weight, height and blood pressure. In addition, they
analyzed the medical records of each subject and
calculated the average systolic and diastolic blood
pressure as well as the average serum glucose level using
all values registered in the year preceding the study.
These data were also noted in the questionnaire.
All participants were sent to the laboratory where serum
creatinine level was measured by a kinetic Jaffé method and
glomerular filtration rate (eGFR) estimated using the original
Modification of Diet in Renal Disease (MDRD) Study
formula.11 Proteinuria, hematuria, glycosuria and
microalbuminuria were assessed semiquantitatively in spot
urine samples using the urine dipstick test. Proteinuria,
hematuria, glycosuria were defined when dipstick analysis
quantified them as 1+ or more. Microalbuminuria (MAU)
was detected with Micral-test® strips (ACCU-CHEK
product, Roche Diagnostics). These immunoassay reagent
strips (monoclonal antibodies to human albumin) reveal a
distinctive color corresponding to a scale on the vial label
giving a range of albumin concentrations as follows:
negative, 20mg/L, 50mg/L and 100mg/L. According to the
manufacturer’s instructions albumin concentrations detected
as _> 20mg/L are consistent with microalbuminuria _>
30mg/day. This was confirmed in 100 patients with MAU
detected by the Micral-dipstick test during the screening and
subsequent determination of albumin in a 24h urine
collection by immunonephelometry and Micral-dipstick.
Therefore, the finding of MAU _> 20mg/L was considered as
the presence of MAU. Nephrologist coordinators collected the
questionnaire lists and laboratory results from all health
centers participating in the study and analyzed the results.
A person was considered as having arterial hypertension if
systolic blood pressure was _>140mmHg and/or diastolic
Nefrologia 2012;32(1):59-66
pressure was _>90mmHg or if antihypertensive treatment had
been previously prescribed. Patients with known and treated
type 2 diabetes were considered diabetic regardless of their
glycemic control. Body mass index (BMI) was calculated
using the formula: weight (kg)/height2 (m2) and, depending
on the obtained BMI value, patients were classified
according to the WHO recommendations.12 Smoking was
defined as actual use of cigarettes (not ex-smokers).
The estimated GFR (eGFR) was used to classify subjects into
Kidne Disease Outcomes Quality Initiative (K/DOQI) stages
of CKD.13 In addition, stage 3 CKD was divided into two substages:14 sub-stage 3a with a GFR between 45 mL/min/1.73m2
and 59 mL/min/1.73m2 and sub-stage 3b with a GFR between
30 mL/min/1.73m2 and 44 mL/min/1.73m2.
Descriptive statistics were presented as mean values ±
standard deviation (SD) for the continuous variables, or as
frequencies for categorical variables. Analysis of variance
accompanied by Bonferroni multiple comparison tests and
chi-square analysis were used for between-group
comparisons of continuous and categorical variables,
respectively. Pearson correlation coefficients were used to
detect associations among eGFR and other variables. A p
value of <0.05 was considered to be statistically significant.
All analyses were performed using the SPSS statistical
software package (Version 10; SPSS).
RESULTS
Out of 1617 subjects enrolled into the study, 1316 were
patients with hypertension without diabetes, 208 patients had
type 2 diabetes and 93 were subjects older than 60 years who
had neither hypertension nor diabetes. Thus, patients with
hypertension formed the largest group, but the relatively low
number of individuals with type 2 diabetes enrolled in the
study could have been due to way their health care is
organized in our health centers. Namely, the majority of
patients with diabetes are not controlled by the general
practitioners who recruited patients for our screening studies
but in special advice centers for diabetics. In addition, the
number of enrolled subjects older than 60 years without
hypertension and diabetes was also low, because people of
that age frequently had hypertension or a comorbidity
excluding them from the present study.
Inclusion criteria allowed patients with hypertension older
than 60 years to be included in the hypertension group, while
patients with type 2 diabetes regardless of having
hypertension or not or being above 60 years old were
included in the diabetes group. Therefore, some subjects
could have had more than one of the three risk factors for
CKD. The Venn diagram presented in figure 1 shows that
759 (57.6%) of the patients with hypertension were older
Nefrologia 2012;32(1):59-66
originals
than 60 years, while among patients with diabetes 93
(44.7%) were above 60 years old and had hypertension, 61
(29.3%) had hypertension but were younger than 60 years
and only 10 (5%) diabetics were normotensive and younger
than 60 years.
The demographic and clinical characteristics of the study
population are shown in table 1. Patients with diabetes had
significantly higher mean BMI and, as expected, the groups
of patients with hypertension and diabetes had significantly
higher systolic and diastolic blood pressure than the group of
subjects older than 60 years.
The results of laboratory analyses are presented in table 2.
Patients with diabetes had significantly higher mean eGFR
and most of them were in stage 1 and the least in stage 3 of
CKD. When the patients in stage 3 of CKD were divided
into two substages only one seventh of them belonged to
substage 3b. Table 2 also shows that patients with diabetes
had the highest prevalence of both MAU and proteinuria, but
patients with hypertension had a significantly lower
prevalence of MAU than the other two groups.
Calculation of the Pearson correlation coefficient revealed
significant associations between eGFR and systolic blood
pressure (r=-0.163, p=0.023), duration of hypertension
(r= -0.276, p=0.0001) and age (r=-0.383, p=0.0001).
Different combinations of laboratory findings were detected
in the examined subjects (figure 2). The most frequent
pathological finding was MAU with or without proteinuria
in combination with eGFR above 60ml/min/1.73m2. In
patients with diabetes this was detected in the majority
(41%) of patients with pathological laboratory findings,
while in two other groups this percent was about two times
lower. In the group with hypertension and with subjects
older than 60 years the percentage of patients with
Patients with
diabetes
Patients with
hypertension
Subjects > 60
years
Figure 1. Venn diagram presenting the distribution of patients
depending on the presence of three risk factors.
61
originals
Table 1. Demographic and clinical characteristics of the study groups
Variable
1
2
3
Patients with hypertension (HTA)
Patients with type 2 diabetes (DM)
> 60 yrs without HTA and DM
1316
208
93
Total number
Gender: females, no (%)
801 (60.8)
101 (48.5)
54 (58.1)
Age, years
62.4±10.4
64.1±10.2
69.6±5.8a
Body mass index, kg/m2
27.5±5.1b
33.9±3.6
25.4±5.2c
15.61-46.88
19.37-49.95
18.38-49.59
Range
<18.5
4 (0.3)
0
2 (2.3)
18.5–24.9
328 (24.9)
37 (18.1)
42 (44.7)
25–29.9
616 (46.2)
95 (45.2)
39 (42.3)
>30
368 (28.0)
76 (36.6)
10 (10.6)
Systolic
140.1±17.8
138.0±19.34
125.3±10.1c
Diastolic
85.7±9.9b
82.0±8.67
78.4±6.3c
-
126 (60.6%)
-
11.2±7.4
8.03±7.7
980 (74.5)
138 (66.3)
0
266 (25)
53 (25)
17 (18.3)
Hypertension
171 (14)
124 (59.6)
23 (24.7)
Type 2 diabetes mellitus
936 (77)
110 (52.8)
17 (18.3)
Blood pressure, mmHg
HbA1c > 7.5%
Duration of
Hypertension, yrs
Type 2 diabetes mellitus, yrs
No of patients treated with ACEi
Smokers
9.4±6.7
Positive family history for
Kidney disease
22 (10.6)
Data are means ± SD or numbers (percentages). a p=0.0001, 1 vs.3; b p=0.005, 1 vs.2; c p<0.0001 3 vs.1,2.
MAU/proteinuria and eGFR above 60ml/min/1.73m2 was
similar to that of patients with normal urinary finding and
eGFR below 60 ml/min/1.73m2.
As many of our subjects had more than one of the three risk
factors for CKD (hypertension, diabetes, older age), the
frequency of MAU and reduced eGFR was examined
depending on the number of risk factors. The analysis
showed that in subjects with one, two or three risk factors
MAU was present in 135 (21.0%), 215 (25.2%) or 44
(46.3%) subjects, but eGFR below 60ml/min/1.73m2 in 101
(15.4%), 241 (28.4%) or 26 (26.8%) subjects, respectively.
DISCUSSION
The present study aimed to detect persons with CKD
markers in at risk population was carried out in Belgrade
through the collaboration of nephrologists and primary
care physicians and involved 1617 subjects. Among
them there were 1316 patients with hypertension without
diabetes, 208 patients with type 2 diabetes and 93
62
subjects older than 60 years without either hypertension
or diabetes. Pathological findings were revealed in 4656% of the subjects the most frequent being MAU with
or without proteinuria in combination with eGFR above
60ml/min/1.73m 2 that was found in 17%, 41% and 24%
of the subjects with hypertension, diabetes and those
older than 60 years, respectively
The dramatic increase of CKD prevalence has directed
the attention of nephrologists towards prevention and
early detection, so numerous screening programs have
been running all over the world. Nevertheless, the
methods used in these studies have differed widely. In
some the screening was limited to determination of
serum creatinine level and eGFR 15-17 but, with time, the
opinion prevailed that, besides GFR, screening should
also include a measure of proteinuria or even better
microalbuminuria. 18-20 In addition, low eGFR and
albuminuria are two basic markers for CKD
classification proposed by the Kidney Disease
Outcomes Quality Initiative of the National Kidney
Foundation13. In the present study dipstick measurement of
Nefrologia 2012;32(1):59-66
originals
Table 2. Kidney function and urinary findings in the three studied groups
Variable
1
2
3
Patients with hypertension (HTA)
Patients with type 2 diabetes (DM)
>60 yrs without HTA and DM
70.56±16.04a
78.1±16.1
69.5±13.3b
18.3-128.6
41.3-129.9
40.9-123.3
142 (10.8)
54 (26)a
6 (6.5)
2. 60-89.9ml/min/1.73m
848 (64.4)
130 (62.5)
67 (72.0)
3. 30-59ml/min/1.73m2
304 (23.1)
24 (11.5)b
20 (21.5)b
3a. 45-59.9ml/min/1.73m2
262 (20)
19 (9.1)a
17 (18.3)
3b. 30-44.9ml/min/1.73m
42 (3.2)
5 (2.4)
3 (3.1)
22 (1.7)
0
0
Microalbuminuria
279 (21.2)
99 (47.6)a
41 (44.3)c
Proteinuria
119 (9.0)
35 (16.8)
9 (10.2)
Hematuria
50 (3.8)
10 (4.8)
8 (8.6)
eGFR, ml/min/1.73m2
range, ml/min/1.73m
2
Number (%) of patients with eGFR:
1. > 90ml/min/1.73m2
2
2
4. <30ml/min/1.73m2
Number (%) of patients with:
b
Glycosuria
68 (32.9)
Data are means ± SD or numbers (percentages). a p=0.0001, 1 vs.3; b p=0.005, 1 vs.2; c p<0.0001 3 vs.1,2.
urine protein and albumin was used together with
estimation of GFR by MDRD equation and different
combinations of these markers were found in the examined
persons.
The second methodological question is who should be
included in screening for CKD. Universal screening of
unselected populations not already known to be at risk has
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Hypertension
Diabetes
eGFR >60ml/min/1.73m + neg. urine
eGFR >60ml/min/1.73m2 + MAU+H
eGFR <60ml/min/1.73m2 + MAU/P
2
>60 years
eGFR >60ml/min/1.73m2 + MAU/P
eGFR <60ml/min/1.73m2 + neg.urine
eGFR <60ml/min/1.73m2 + H
MAU/P – MAU and/or proteinuria, H – hematuria
Figure 2. Distribution of subjects according to eGFR and urinary
findings.
Nefrologia 2012;32(1):59-66
not been shown to be cost-effective, so targeted screening for
CKD was proposed as more economical than universal
screening.21-23 In different guidelines diverse at risk
populations have been proposed for screening but patients
with hypertension or diabetes were generally accepted as
relevant ones.13,24 Therefore, these two at risk groups were
included here in addition to subjects older than 60 years
without hypertension or diabetes as also proposed as a target
population by KDOQI guidelines11. Our inclusion criteria
enabled some subjects to have more than one of these three
risk factors for CKD. More than a half of the patients with
hypertension or diabetes were above 60 years old and
majority of patients with diabetes had hypertension. Analysis
of the results revealed that subjects with two or three risk
factors had almost double the prevalence of reduced eGFR
and MAU compared with those with only one risk factor.
Reduced eGFR (<60ml/min/1.73m2), a criterion for CKD
stage 3 according to KDOQI guidelines,13 was found in 15%
to 23% of subjects in the three at risk groups. These values
are comparable to those obtained in other studies that
targeted different at risk populations.25-27 However, as GFR
declines with normal ageing, it was indicated that using
KDOQI guidelines classification large numbers of the
elderly and females would be classified in CKD stage 3
without other objective evidence of kidney disease.28 In
addition, several epidemiological studies showed that the
risk of progressive decline in renal function or of
cardiovascular events was not equal for all subjects with
stage 3 CKD, being low for subjects with eGFR29,30 between
30 to 59ml/min/1.73m2. Therefore, it was proposed to
subdivide CKD 3 into stage 3a (eGFR between
63
originals
45–59ml/min/1.73 m2) and stage 3b (eGFR between
30–44ml/min/1.73 m2).14,29,31 This classification was used in
the present study and most of the 348 subjects with stage 3
CKD belonged to substage 3a (298; 85.6%). If the subjects
with eGFR in this range had neither MAU nor proteinuria,
they were considered to be not at risk for renal disease
progression.31 Figure 2 showed that in the group of subjects
older than 60 years without hypertension and diabetes there
were six times more subjects with eGFR below
60ml/min/1.73m2 and normal urinary findings than with
pathological urinary findings. In the group with hypertension
in which 56.6% of the patients were older than 60 this ratio
was 2.3:1. Nevertheless, there are many arguments that the
decline in kidney function with age cannot be considered as
normal physiology. Therefore, although the subdivision of
CKD 3 is useful to focus the attention of health care
professionals on patients in substage 3b with worse
cardiovascular and CKD outcomes, it does not mean that
persons in stage 3a, even with normal urinary findings, could
be excluded from the measures for prevention of CKD
progression. Also, eGFR, regardless of classification into
two substages, should be taken into account in medication
dosing, so avoiding drug-induced kidney toxicity.
As CKD in its earliest stages is usually asymptomatic, it is
often overlooked and most patients, even in at risk
populations, were unaware of the CKD diagnosis.32-34
One exclusion criterion in our study was previously known
kidney disease and all patients denied any knowledge of
kidney disease. Also, their primary care physicians had no
data on previous kidney disease, although more than 80% of
the patients had checked serum creatinine level and urine
analysis in the year preceding the study.35 However,
examination of MAU is not available in our health center
laboratories, while estimation of GFR has not been
introduced in the regular practice of general practitioners, so,
despite laboratory control, many CKD patients might remain
undetected. Therefore, one of the aims of this screening
study was to educate primary care physicians about
screening for CKD. The educative meeting that preceded the
study, the collaboration of nephrologists and primary care
physicians during the study, and especially the results
obtained clearly suggested the general practitioners on the
necessity of regular screening in at risk populations. As
already stressed by other authors, prevention and early
detection of CKD cannot be managed by an insufficient
number of nephrologists and in nephrology outpatient clinics
and it would be best managed in a partnership arrangement
between primary and secondary care.9,36 However, it was
shown that primary care physicians did not have enough
knowledge for this task.37,38 Our results also indicated
insufficient attention of primary care physicians to CKD
prevention and management. Although, most patients with
hypertension used ACEi, average blood pressure in the year
preceding the study was above the target value proposed by
64
guidelines. At inclusion in the study 54.5% of patients had
systolic blood pressure above 140mmHg and 40.2% had
diastolic blood pressure above 90mmHg. A similar state was
found concerning control of glycemia in diabetics and 60.6%
of these patients had average HbA1c above 7.5%. In
addition, the majority of patients, especially those in the
hypertension and diabetes groups, were overweight.
Therefore, additional education of primary care physicians
on risk factors, prevention, early detection and management
of CKD is necessary and nephrologists should have the main
role in this education. That directed us to organize the
presented project and prepare guidelines for prevention,
early detection and treatment of CKD patients for primary
care physicians10. Nevertheless, guidelines alone are not
sufficient and they can be implemented only in close
collaboration between primary care physicians and
nephrologists.
This study has some limitations. First, it was a crosssectional study and CKD markers were measured just
once. That might cause false positive and false negative
errors. Secondly, both proteinuria and MAU were
detected by urine dipstick test with limited accuracy. The
use of a single measurement of dipstick proteinuria might
lead to overestimation as described for a study population
in the United States, where in a repeat measurement only
63% of subjects with proteinuria had a positive result.39
Despite these limitations, the present study carried out in
Belgrade is the first study for early detection of CKD in
Serbia. Moreover, the study was carried out in
nephrologists with the aim to encourage primary care
physicians to carry out regular control of CKD markers in
patients at risk for CKD and to established better
corresponding nephrologists. At the same time similar
screening studies are being prepared in several other
Serbian towns in order to spread knowledge about the
significance and necessity of early detection of CKD as a
task of primary care.
The authors have no conflicts of interest to declare.
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Sent for Review: 25 Jul. 2011 | Accepted: 3 Oct. 2011
66
Nefrologia 2012;32(1):59-66
originals
Serum uric acid as a marker of all-cause mortality
in an elderly patients cohort
Manuel Heras, María J. Fernández-Reyes, Rosa Sánchez, Álvaro Molina, Astrid Rodríguez,
Fernando Álvarez-Ude
Nephrology Department. General Hospital of Segovia. Segovia, Spain
Nefrologia 2012;32(1):67-72
ABSTRACT
Introducción: There is growing evidence of the role of serum
uric acid (SUA) as a risk factor for cardiovascular and renal
disease. We analyze the association between baseline SUA
and overall mortality in a cohort of elderly patients followed
prospectively for 5 years. Patients and Methods: 80 clinically
stable patients, median age 83 years (range 69-97), 31.3%
men, 35% diabetic, 83% hypertensives, randomly recruited in
Geriatrics and Nephrology consultations between January and
April 2006, were followed for 5 years. We measured baseline
SUA and serum creatinine and we estimated glomerular
filtration rate (GFR) with MDRD abreviated. In patient of
Nephrology Department we measured proteinuria in
collection urine 24 hours and patients Geriatrics department
we measured proteinuria (mg/dl)/creatinine (mg/dl) in urine
(first miccion). Predictive variables were: baseline SAU and
plasma creatinine; estimated GFR (abbreviated MDRD
formula); recorded age, gender, baseline comorbidity
(Charlson index), cardiovascular disease individualized,
treatment and mortality. Statistical analysis: SPSS15.0. Results:
baseline SUA was normally distributed and its median was
5.85 mg/dl. We found not significant differences in levels of
SUA by gender, history of diabetes mellitus, hypertension,
diuretic use, heart disease, peripheral arterial disease or
stroke. Patients with an history of heart failure had
significantly higher SUA (7.00±1.74 vs. 5.90±1.71, P=0.031). 41
deaths occured during follow-up (15 men and 26 women): 15
general deterioration, 8 infections, 4 stroke, 4 tumors, 3
cardiovascular disease, 2 complications of fractures and 5
unknown. Patients with SUA higher than the median had
significantly lower GFR and higher mortality at 5 years. In Cox´
analysis for overall mortality (independent variables: age,
gender, Charlson Index, history of heart failure, SUA,
creatinine, proteinuria and GFR:MDRD), only SUA levels
(HR:1,35; 1,17-1,56 p=0,000) were independently associated
with mortality. Conclusions: In our study, levels of SUA are
shown as independent risk factor for mortality in elderly
patients.
Keywords: Serum uric acid. Mortality. Glomerular
filtration rate. Chronic kidney disease. Elderly.
Utilidad del ácido úrico como marcador de mortalidad
global en una cohorte de ancianos
RESUMEN
Introducción: Existe evidencia creciente del papel del ácido úrico (AU) como factor de riesgo cardiovascular y renal. En este
trabajo analizamos la asociación entre niveles basales de AU y
mortalidad global en una cohorte de ancianos seguidos prospectivamente durante 5 años. Pacientes y métodos: 80 pacientes clínicamente estables; mediana de edad, 83 años (rango 6997); 31,3% varones; 35% diabéticos; 83% hipertensos;
reclutados aleatoriamente en consultas de Geriatría y Nefrología entre enero y abril de 2006 y seguidos durante 5 años. Medimos basalmente AU y creatinina en plasma y estimamos filtrado glomerular (FG) con fórmula MDRD abreviada.
Asimismo, en los pacientes de Nefrología se midió la proteinuria mediante la recogida de orina de 24 horas, y en los vistos
en Geriatría se estimó a partir del cociente proteínas
(mg/dl)/creatinina (mg/dl) en primera orina de la mañana. Registramos edad, género, comorbilidad basal (Índice de Charlson), patologías cardiovasculares individualizadas, tratamientos y mortalidad. Estadística: SPSS15.0. Resultados: El AU basal
presentaba una distribución normal y su mediana era de 5,85
mg/dl. No encontramos diferencias significativas en los niveles
de AU según género, antecedentes de diabetes méllitus, hipertensión arterial, uso de diuréticos, cardiopatía isquémica, arteriopatía periférica o ictus. Los pacientes con antecedentes de
insuficiencia cardíaca tenían AU significativamente mayor (7,00
± 1,74 vs. 5,90 ± 1,71, p = 0,031). 41 pacientes (15 varones y 26
mujeres) fallecieron: 15 por deterioro en el estado general; 8
por infecciones; 4 por ictus; 4 por tumores; 3 por causas cardiovasculares; 2 por complicaciones de fracturas y 5 por causas desconocidas. Los pacientes con AU superior a la mediana tenían
un FG significativamente menor y una mortalidad a los 5 años
más elevada. En el análisis de Cox para mortalidad global (variables independientes: edad, género, Charlson, antecedentes
de insuficiencia cardíaca, AU, creatinina, proteinuria y filtrado
glomerular-MDRD) sólo los niveles de AU (riesgo relativo: 1,35;
1,17-1,56, p = 0,000) se asociaban de forma independiente a
la mortalidad. Conclusiones: en nuestro estudio, los niveles de
AU se muestran como factor de riesgo independiente de mortalidad en ancianos.
Palabras clave: Ácido úrico. Mortalidad.
glomerular. Enfermedad renal crónica. Ancianos.
Filtrado
INTRODUCTION
Correspondence: Manuel Heras
Hospital General de Segovia. 40002 Segovia. Spain.
[email protected]
[email protected]
Uric acid (UA), a waste product of purine metabolism, is
degraded by urate oxidase (uricase) to allantoin, which is
freely eliminated in urine. One of the consequences of the
67
Manuel Heras et al. Uric acid and mortality
originals
absence of uricase in humans is the appearance of higher
levels of UA in humans than in other species. It may even
reach plasma UA concentrations fifty times higher than in
other mammals. This condition, far from being a drawback,
has been postulated to be an evolutionary advance related to
the protective ability of UA against oxidative damage of free
radicals.1,2
Hyperuricaemia is generally defined by UA levels >6.5mg/dl
or 7mg/dl in men and >6mg/dl in women.3
Although recent epidemiological studies have focused on
gout, which has been increasing in prevalence particularly
among elderly individuals, the studies suggest that the
incidence of hyperuricaemia has also increased during this
time.4
In addition to the role of UA in the onset of rheumatism and
gout, it has been postulated for some time that it is a possible
determinant of the onset of hypertension (AHT), diabetes
mellitus and chronic kidney disease (CKD).2,5
In recent years, there has been growing evidence of a
relationship between high levels of UA in blood and renal
and cardiovascular disease, endothelial lesions being the
proposed pathogenic mechanism.2,6
Prospective epidemiological studies have shown the
association between baseline levels of UA and the incidence
of CKD (with increasing risk as UA levels increase).7,8
Regarding cardiovascular comorbidity, some studies found
an association between UA and increased risk of heart
attacks and coronary ischaemic strokes. However, other
studies have not confirmed these results in multivariate
analyses.2
On the other hand, some studies have shown that UA levels
behave as a risk factor for both cardiovascular and overall
mortality.9
In this study, we analysed the role of UA as an overall
mortality marker in a cohort of elderly patients monitored for
a period of 5 years. We also examined the association
between baseline UA levels and cardiovascular history, the
use of diuretics and renal function (RF).
and General Nephrology departments during the period
January-April 2006. Patients were in a period of clinical
stability when they were selected and were monitored
prospectively for 5 years (re-evaluation between JanuaryApril 2011). These patients had a mean age of 82.4±6 years
(range 69-97 years) at baseline recruitment. Of these, 68.8%
were women, 82.5% had histories of AHT, 35% were
diabetic, 19.5% had histories of heart failure (HF), 15% had
histories of ischaemic heart disease (IHD) and 68.4% were
receiving diuretic therapy.
Laboratory analysis
A baseline analysis was performed one week before patients
attended scheduled visits at the Geriatrics and Nephrology
departments. According to the standard procedures of our
hospital’s laboratory, we measured creatinine, UA, albumin,
cholesterol and triglycerides in venous blood. We also
analysed creatinine and proteinuria in 24-hour urine
(Nephrology visits) or in first morning urine (Geriatrics
visits).
Methods
This was a prospective observational study. Glomerular
filtration rate (GFR) was calculated with the abbreviated
MDRD formula.13 Based on the median baseline UA, we
established two study groups: Group 1 consisting of 40
patients with UA <5.85mg/dl, and group 2 consisting of 40
patients with UA >5.85mg/dl. We also examined the possible
association between high levels of UA (P75) and
demographic characteristics, RF and mortality.
After five years, we analysed mortality according to
study group.
Statistics
Statistical analysis was performed using the SPSS 15.0
program. Data are expressed as mean and standard deviation,
or median and percentiles. Comparison of means was made
with the Student’s t-test and comparison of proportions with
the chi-squared test. To analyse the simultaneous effect of
several variables on mortality, we used a Cox analysis.
PATIENTS AND METHODS
RESULTS
Patients
This study was performed by analysing 5-year outcomes for
a cohort of patients included in a study of elderly patients
with CKD10,11,12 at the General Hospital of Segovia. Patients
were recruited randomly while they visited the Geriatrics
68
UA showed a normal distribution. Mean baseline levels of
UA were 6.11±1.7mg/dl (range 2.8-11) and their median was
5.85mg/dl (P25=4.90mg/dl, P75=7.07mg/dl). Regarding the
use of diuretics, 42.6% used loop diuretics and 29.5% used
thiazides. Potassium-sparing diuretics were the least
Nefrologia 2012;32(1):67-72
originals
prescribed, at a rate of 11.5%. Table 1 shows the association
between uric acid levels and gender, cardiovascular history
and use of diuretics. Patients with histories of HF had
significantly higher levels of UA (7.00±1.74mg/dl vs
5.90±1.71mg/dl, P=.031).
Table 2 shows the comparison between demographic
characteristics, RF parameters, comorbidity and mortality at
5 years, according to median UA. Patients with UA higher
than the median had significantly lower GFR and higher
mortality at 5 years.
Twenty patients had UA greater than P75 (7.07mg/dl). Table
3 compares the variables according to this percentile.
Table 1. Baseline levels of uric acid (mg/dl) according to
gender, cardiovascular history and use of diuretics
No
Yes
P
Gender (men/women)
6.51 (1.55)
5.93 (1.78)
0.167
AHT
5.87 (1.81)
6.16 (1.72)
0.56
DM
6.25 (1.85)
5.84 (1.53)
0.314
HF
5.90 (1.71)
7.00 (1.74)
0.031
IHD
5.96 (1.66)
6.93 (1.94)
0.075
Diuretics
6.00 (1.84)
6.17 (1.70)
0.70
Loop diuretics
5.80 (1.53)
6.36 (1.80)
0.20
IHD: Ischemic heart disease; DM: diabetes mellitus; HF: heart failure;
AHT: Hypertension.
There were no patients lost to follow-up that were not due to
death.
Overall, 41 patients died during the 5-year follow-up: 15 due
to general deterioration, 8 due to infections, 4 due to stroke,
4 due to tumours, 3 due to cardiovascular problems, 2 due to
fracture complications and 5 due to unknown reasons. In the
multivariate Cox analysis, the only predictor of overall
mortality after adjusting for age, gender, Charlson score,
history of HF, use of diuretic and creatinine, presence of
proteinuria and GFR-MDRD was UA level (mg/dl) (relative
risk 1.35; 1.17-1.56; P=.000). Figures 1A and 1B show the
Kaplan-Meier mortality curves according to the median uric
acid and P75. Both figures show significantly higher
mortality in patients with UA greater than P50 and P75.
DISCUSSION
Overall mortality in the patient group with UA levels higher
than the median was significantly higher. Moreover, if we
analyse patients with UA levels >P75 (7.07mg/dl), their
mortality increases even further, reaching 80%, results that
are consistent with other recent studies.9
In this cohort of longer-lived patients, the most frequent
cause of mortality was progressive deterioration rather than
cardiovascular disease, and baseline UA levels were found
to be the only predictors of mortality in the Cox analysis.
Hyperuricaemia has been linked to various diseases in
humans.4 Gout is a disease that predominantly affects men,
with an increase in prevalence in both genders as age
increases. In our study, men also had higher levels of UA,
although these differences were not significant, which may
Table 2. Comparison of variables according to the median uric acid (5.85mg/dl)
Group 1: UA <5.85 mg/dl
n = 40
Group 2: UA >5.85 mg/dl
n = 40
P
Baseline uric acid (mg/dl)
4.77 (0.86)
7.45 (1.27)
0.000
Creatinine (mg/dl)
1.15 (0.45)
1.46 (0.51)
0.005
Albumin (g/dl)
4.01 (0.3)
3.92 (0.48)
Not significant
Cholesterol (mg/dl)
186.56 (31)
187.90 (36)
Not significant
Triglycerides (mg/dl)
100.56 (36)
114.38 (72)
Not significant
MDRD (ml/min)
56.94 (15)
45.60 (16)
0.001
Proteinuria (g/24 h)
0.09 (0.38)
0.27 (0.63)
Not significant
81.55 (6)
83.42 (6)
Not significant
10/30
15/25
Not significant
Charlson index
1.62 (1)
1.32 (1.11)
Not significant
DEATH 5 years
32.5%
70%
0.001
Age (years)
Gender (m/f)
UA: uric acid; f: female; MDRD: Modification of Diet in Renal Disease; m: male.
Nefrologia 2012;32(1):67-72
69
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Table 3. Comparison of variables according to P75 of uric acid (7.07mg/dl)
Patients with UA <7.07 mg/dl
(n = 60)
Patients with UA >7.07 mg/dl
(n = 20)
P
Creatinine (mg/dl)
1.16 (0.38)
1.75 (0.51)
0.000
Albumin (g/dl)
4.01 (0.32)
3.92 (0.4)
Not significant
Cholesterol (mg/dl)
186.80 (33)
188.43 (34)
Not significant
Triglycerides (mg/dl)
105.44 (58)
113.00 (52)
Not significant
MDRD (ml/min)
55.27 (14)
39.27 (17)
0.000
Age (years)
81.61 (6)
85.10 (6)
0.037
Gender (m/f)
Charlson score
15/45
10/10
0.037
1.75 (1)
1.95 (1)
Not significant
Diuretics use (%)
69.5%
65%
Not significant
EXITUS 5 years
41.7%
80%
0.003
UA: uric acid; f: female; MDRD: Modification of Diet in Renal Disease; m: male.
CKD has been associated with hyperuricaemia.2 In
experimental studies in rats with hyperuricaemia, renal
lesions included afferent arteriolopathy, mild interstitial
fibrosis, glomerular hypertrophy and/or glomerulosclerosis.15
We also found in our study that elderly patients with greater
levels of UA had significantly worse RF. This association
may be valid in both directions, that is, the high levels of UA
may be explained by renal ischaemia and reduced RF, and/or
reduced GFR in patients with higher levels of UA may be
due to the direct toxic effects of UA.
Diuretics, widely used to treat AHT with the additional
benefit of preventing HF episodes,16 increase UA by
stimulating the reabsorption of sodium and urate in the
proximal tubule.3 Moreover, the increase in UA has also
been observed in conditions that are accompanied by
hypoxia (obstructive pulmonary disease, congestive HF).17,18
Leyva et al first studied UA concentrations in patients with
chronic HF and found an inverse relationship between UA
levels and oxygenation, suggesting that damage from
oxidative metabolism may play a role in the pathogenesis of
HF.19 In the SHEP study, diuretics were demonstrated to
reduce cardiovascular mortality in the elderly. However, a
recent subanalysis found that cardioprotection was lower in
those patients who had high levels of UA.20
increase associated with diuretics. Similarly, patients with
history of IHD have higher levels of UA, although in this
case it was not statistically significant, possibly due to the
low number of patients who had this disease.
Lastly, ischaemia determines an increase in xanthine
oxidase, which leads to an increase in UA levels.3 Treatment
with xanthine oxidase inhibitors, such as allopurinol, has
shown to reduce cardiovascular complications after coronary
bypass and in patients with dilated cardiomyopathy.21
1.0
Uric acid
< 5.85 mg/dl
> 5.85 mg/dl
0.8
Cumulated Survival
be due to the fact that we treated postmenopausal women in
whom estrogenic activity had ceased.14
0.6
0.4
0.2
0.0
In our study, we found that UA levels were similar among
those who received diuretics and those who did not.
Moreover, elderly patients with histories of HF, who
generally require higher doses of diuretics, had significantly
greater levels of UA. It is therefore conceivable that the
increase in UA levels in elderly patients with histories of HF
is showing the effect of a local ischaemia rather than the
70
0
500
1000
1500
2000
Follow-up Days
P = 0.002
Figure 1. Kaplan-Meier mortality curve according to the
median uric acid (P50).
Nefrologia 2012;32(1):67-72
originals
REFERENCES
1.0
P75 Uric acid
< 7.07
> 7.07
Cumulated Survival
0.8
0.6
0.4
0.2
0.0
0
500
1000
1500
2000
Follow-up Days
P=.007
Figure 2. Kaplan-Meier mortality curve according to P75 of uric
acid (P50).
Recently, Goicoechea et al found that treatment with
allopurinol in patients with chronic renal failure reduced the
decline in RF.22
With the data from our study, we cannot confirm that there is
a causal relationship between high levels of UA and
mortality. A step forward in our study would have been to
confirm whether the reduction in UA levels with allopurinol,
or more recently with febuxostat (a new inhibitor of the
xanthine oxidase),23 contributes to reduced mortality in these
patients.
An important prognostic factor of morbidity and mortality is
the presence of proteinuria.24,25 In our follow-up study of RF
in the elderly, the presence of proteinuria at 36 months was
an independent factor of mortality.12 This did not occur in our
analysis at five years, either proteinuria is included in the
model as a qualitative variable (yes/no) or if its numerical
value is used. This may be explained by the lack of
proteinuria in the baseline sample and by the fact that the
patients with higher proteinuria died in the first years of
follow-up.
In conclusion, our data show that UA is an independent risk
factor for overall mortality.
The authors have no potential conflicts of interest to declare.
Nefrologia 2012;32(1):67-72
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18. Woolliscroft JO, Colfer H, Fox IH. Hyperuricemia in acute illness: a
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23. Bruce SP. Febuxostat: a selective xanthine oxidase inhibitor for the
treatment of hyperuricemia and gout. Ann Pharmacother
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24. García de Vinuesa S. Factores de progresión de la enfermedad renal
crónica. Prevención secundaria. Nefrologia 2008;S3:17-21.
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implications of proteinuria: an indicator of chronic kidney disease.
Nat Rev Cardiol 2009;6(4):301-11.
Sent for Review: 21 Jun. 2011 | Accepted: 1 Nov. 2011
72
Nefrologia 2012;32(1):67-72
originals
Bone mineral density and bone metabolism in
hemodialysis patients. Correlation with PTH,
25OHD3 and leptin
A. Polymeris1, K. Doumouchtsis1, E. Grapsa2
1
2
Second Division of Endocrinology. Alexandra Hospital. Athens (Greece)
Renal Unit. Alexandra Hospital. Athens (Greece)
Nefrologia 2012;32(1):73-8
doi:10.3265/Nefrologia.pre2011.Jul.10916
ABSTRACT
Background: Bone metabolism disorders in hemodialysed
patients (HD) involve several humoral factors, of which
PTH plays the central role. Leptin is usually found increased in renal failure and its link with bone metabolism has
not been elucidated. We investigated the BMD and bone
metabolism in association with serum PTH, 25OHD3 and
leptin in HD patients. Methods: We measured bone alkaline phosphatase (bSAP), Cross linked N telopeptide of type
1 collagen (NTx), PTH, 25OHD3 and leptin in 37 HD patients. We also evaluated BMI and BMD in lumbar spine
(LS) and in femoral neck (FN) by DXA. Statistical evaluations were based on simple regression analysis. Results: 1)
Osteopenia was found in 32,1% in LS and 50% in FN and
osteoporosis in 14.3% and 21.4% of our patients, respectively. LS or FN Z score was not related to HD duration. 2)
Bone markers, PTH, phosphorus and leptin levels were increased. 3) 25OHD3 was low and was not related to NTx,
bSAP or PTH. 4) PTH correlated with bone markers and Z
score in LS and FN. 5) Leptin had no correlation with bone
markers or Z score (except BMI). Conclusions: In our hemodialysed patients bone metabolism markers were increased in relation with high serum PTH levels. The observed
high serum leptin was not associated with bone metabolism. Additionally the duration of hemodialysis did not appear to affect bone density.
Keywords: Bone mineral density. Bone metabolism. Hemodialysis. Leptin. PTH. Vitamin D3.
Densidad mineral y metabolismo óseo en pacientes en
hemodiálisis. Correlación con la hormona paratifoidea, el
25(OH)D3 y la leptina
RESUMEN
Antecedentes: Los trastornos del metabolismo óseo en pacientes en hemodiálisis (HD) implican varios factores humorales, de
los cuales la función central recae sobre la hormona paratiroidea. Cuando hay insuficiencia renal normalmente se detectan
niveles elevados de leptina y su relación con el metabolismo
óseo está aún por esclarecer. Investigamos la densidad mineral
ósea (DMO) y el metabolismo óseo en relación con la hormona
paratiroidea sérica, el 25(OH)D3 y la leptina en pacientes en HD.
Métodos: Medimos la fosfatasa alcalina ósea (FAO), el telopéptido N, la hormona paratiroidea, el 25(OH)D3 y la leptina en 37
pacientes en HD. Asimismo, evaluamos el IMC y la DMO en la
columna lumbar (CL) y en el cuello femoral (CF) mediante DXA.
Las evaluaciones estadísticas se basaron en análisis de regresión
simples. Entrecruzamiento del telopéptido N del colágeno óseo
tipo I. Resultados: 1) De nuestros pacientes, el 32,1% presentaba osteopenia en CL y 50% en CF y el 14,3% y el 21,4% osteoporosis, respectivamente. El puntaje Z en CL o CF no estaba relacionado con la duración de la HD. 2) Los marcadores óseos, la
hormona paratiroidea, y los niveles de fósforo y leptina se vieron incrementados. 3) El 25(OH)D3 era bajo y no estaba relacionado con el telopéptido N, la FAO o la hormona paratiroidea.
4) La hormona paratiroidea estaba correlacionada con los marcadores óseos y con el puntaje Z en CL y CF. 5) La leptina no presentaba correlación con los marcadores óseos o con el puntaje
Z (con excepción del IMC). Conclusiones: En nuestros pacientes
en hemodiálisis, los marcadores del metabolismo óseo se vieron
incrementados en relación con los niveles elevados de hormona paratiroidea sérica. La elevada leptina sérica observada no
estaba asociada al metabolismo óseo. Además, la duración de
la hemodiálisis no pareció afectar a la densidad ósea.
Palabras clave: Densidad mineral ósea. Metabolismo óseo.
Hemodiálisis. Leptina. Hormona paratiroidea. Vitamina D3.
INTRODUCTION
Correspondence: Antonis Polymeris
Second Division of Endocrinology. Alexandra Hospital.
20 Karditsis str. 15231. Athens. Greece.
[email protected]
[email protected]
Chronic renal failure is almost always associated with
alterations in mineral and bone metabolism.1,2 With the
starting of haemodialysis (HD), histological signs of
secondary hyperparathyroidism can be seen in bones in over
50% of patients.3 In end stage renal disease (ESRD)
73
originals
patients, skeletal abnormalities known as Chronic Kidney
Disease-Mineral and Bone Disorder (CKD-MBD) (the so
called renal osteodystrophy) include several types of bone
tissue lesions, such as the most prevalent high bone turn
over disease but also the adynamic bone disease.4,5 Other
less frequent bone diseases such as osteomalacia,
aluminum-related bone disease, fluorosis, strontium
overload or mixed types have also been described3.
A. Polymeris et al. BMD in HD. Relation to PTH, D3 and leptin
derivative (one alpha) orally. None of the patients received
vitamin K or aluminum hydroxide. There was no clinical or
biological evidence for other bone disease such as osteomalacia
or Paget’s disease. All patients were measured for BMD at
lumbar spine and at femoral neck and for body weight and
height and their body mass index (BMI) was calculated.
Biochemistry
It is well known that bone mineral density (BMD) is reduced
in patients with chronic renal failure and they are at higher
fracture risk6,7. Uremic patients usually exhibit high plasma
intact PTH and high serum concentration of biochemical
markers of bone metabolism such as bone specific alkaline
phosphatase (bSAP) and collagen breakdown products.8
Some studies showed low 25OHD3 levels in uremic
patients, which is probably implicated in CKD-MBD.9
Leptin, a hormone produced by fat tissue, decreases appetite
and increases basal metabolic rate. Besides that, leptin
induces in vitro stem cells differentiation to osteoblasts and
reduces osteoclastogenesis, also having an in vivo positive
effect on bone mass in mice10-13. Intracerebroventricular
administration of leptin in wild or ob/ob leptin deficient
mice resulted in bone loss14. In renal failure serum leptin
levels are increased, as leptin is cleared by the kidneys15. In
ESRD patients, in particular, the blood purification modality
appears to affect leptin concentrations16. This fact might
contribute to the development of CKD-MBD.17-19
Pre-midweek dialysis blood sampling was collected in the
morning from the arteriovenus fistula after a 12h fast. The serum
obtained after centrifugation was stored in aliquots at –20 oC until
assayed, with measurements made immediately after thawing.
Serum calcium, phosphorus, total protein, albumin, urea,
creatinine, magnesium and total alkaline phosphatase were
determined routinely using an automatic analyzer. Serum bSAP
was measured by ELISA (Metra BAP EIA, sensitivity 0.7U/l,
intra-assay variation 5.8%, inter-assay variation 5.2%) and serum
NTx was also measured by ELISA (Wampole Laboratories,
USA, intra-assay variation 4.6%, inter-assay variation 6.9%).
Serum bioactive PTH and 25OHD3 were measured by
chemiluminescence’s assay (Nichols advantage, functional
sensitivity ≤4ng/ml, CV 20% for bioactive PTH and functional
sensitivity ≤7ng/ml, CV 20% for 25OHD3). Serum leptin was
measured by RIA (Linco Research, sensitivity 0.5ng/ml, intraassay variation 4.6%, inter-assay variation 5%).
Bone mineral density
The aim of current study is to investigate, the bone mass density
and the bone metabolism in hemodialysed patients as estimated
by serum markers of bone metabolism (bSAP and NTx) and to
correlate with serum Ca, P, PTH, 25OHD3 and leptin.
SUBJECTS AND METHODS
Patients
Thirty seven patients, 18 postmenopausal female and 19 male,
on maintenance HD were included in the present study after
their informed consent. The study was performed during the
period April-May. Females were 43-73 years old, mean age
56.7 years and were on HD for 6-222 months with mean HD
duration 68.1 months. Males were 41-79 years old, mean age 58
years and were on HD for 24-207 months with mean HD
duration 67.1 months. All the patients were treated by
conventional HD 4-5 hours, three times a week. None of the
patients had a past history of parathyroidectomy or renal
transplantation, of fracture or radiographic evidence of
vertebral, rib or hip fracture. At the moment of the evaluation
none of the patients, in particular the postmenopausal women,
was receiving or had received previous to the study, oestrogen
or raloxifene, calcitonin, bisphosphonates, PTH or
corticosteroids. Thirteen patients received an active vitamin D
74
Bone mineral density (BMD) of the lumbar spine, total hip,
femoral neck and trochanter were measured using Lunar
DPX-L densitometer (Lunar, Madison, Wis, USA). All BMD
measurements were performed by the same experienced
operator. The densitometer was calibrated everyday with a
standard phantom specimen. BMD results were obtained in
absolute values (g/cm2), in T score and in Z score. T score is
the number of standard deviations from the mean of a
healthy young adult population (20-40 years old) and is used
to determine osteoporosis or osteopenia. Z score is the
number of standard deviations from the mean of a healthy
age- and gender-matched normal population, which allows
the comparison of BMD between patients of different age
and gender. Osteoporosis was defined as a BMD T score at
any site less than –2,5 and osteopenia as a BMD T score
between –1 and –2,5. The reference values were obtained
from an Italian normal population, similar to Greek normal
population, provided by Lunar.
Statistical analysis
All results are shown as means±SD, unless otherwise
indicated. Correlations between variables were assessed
using simple linear regression and p<0.05 was accepted as
Nefrologia 2012;32(1):73-8
statistically significant. Comparison of categorical variables
was performed using chi-square analysis.
Bone densinometric data
The prevalence of osteoporosis (T score <–2.5) at lumbar
spine and femoral neck was 14.3% and 21.4% respectively.
The prevalence of osteopenia (T score between –1 and –2.5)
at the same sites was 32.1% and 50% respectively. Lumbar
spine Z score (m±SD) was –0.09±1.69 and femoral neck Z
score was –0.76±1.14.
RESULTS
Demographic and biochemical data
Table 1 depicts the demographic data for the 18 female
patients and table 2 for the 19 male patients. Table 3 depicts
the biochemical data for all 37 patients.
Table 1. Demographic data in 18 female patients
Mean±SD
Range
Age (years)
56.7±10.4
43-73
Duration of HD (months)
68.1±46.7
6-222
BMI (kg/m2)
24.8±4.82
18.9-39.1
SD: standard deviation; HD: hemodialysis; BMI: body mass index.
Table 2. Demographic data in 19 male patients
Mean±SD
originals
Range
Age (years)
58.4±16.4
41-79
Duration of HD (months)
67.1±50.1
24-207
BMI (kg/m2)
24.1±3.01
19.8-31.7
SD: standard deviation; HD: hemodialysis; BMI: body mass index.
Bone markers, PTH, 25OHD3 and leptin
Serum levels of bone markers (NTx and bSAP) were very
high (table 3). Serum PTH and phosphorus levels were also
high as expected. Serum 25OHD3 levels were low and the
prevalence of vitamin D deficiency was 89.2% among
patients. Only 4 patients had normal 25OHD3 levels. Serum
leptin was increased particularly in women (table 3).
Correlation of BMD with PTH, leptin, duration
of hemodialysis, body weight and BMI
Lumbar spine and femoral neck Z score correlated
significantly in a negative manner with serum PTH (p
<0.025) (figure 1 and 2). Lumbar spine and femoral neck
Z score was not related with serum leptin or with the
duration of hemodialysis. We found that 10% of lumbar
spine Z-score and 22.9% of femoral neck Z score variability
is due to serum PTH levels. No correlation was found
between body weight or BMI and Z score at any site.
Table 3. Biochemical data in all patients
Mean±SD
Total protein (g/dl)
Albumin (g/dl)
Urea (mg/dl)
Creatinine (mg/ml)
Calcium (mg/dl)
Phosphorus (mg/dl)
Magnesium (mEq/l)
Total alk phosphatase (U/l)
PTH (pg/ml)
25OHD3 (ng/ml)
Leptin (ng/ml)
Leptin in females
Leptin in males
NTx (nMBCE/l)
bSAP (U/l)
Range
Normal values
6.92±0.57
3.93±0.44
173.1±42.1
10.6±2.3
9.4±0.7
6.1±1.3
2.7±0.4
87.2±49.8
100.5±85.1
15.7±13.3
25.85±30.67
43.8±38.4
15.4±13
263.1±235.2
5.7-7.4
2.9-5.3
60-264
5-15.2
7.9-10.7
3.8-9
1.9-3.3
25-250
4-320.6
7.5-57
1.6-169.2
4.1-169.2
1.6-60.2
19.1-958
6.4-8.4
3.5-5
18-48
0.5-1.5
8.5-10.5
2.5-4.6
1.3-2.1
100-290
14-72
10-68
27.6±44.9
8.7-72.1
7.4±3.7
3.8±1.8
(Males) 5.4-24.2
(Females) 6.2-19
15-41
SD: standard deviation.
Nefrologia 2012;32(1):73-8
75
originals
Lumbar spine Z score
that 48.5% of serum leptin variability is due to BMI. Leptin
levels had no correlation with age or hemodialysis duration.
Serum leptin had a positive correlation with serum creatinine
(R=0.419; =0.012).
R=0.398
p<0.025
DISCUSSION
PTH
Femoral neck Z score
Figure 1. Lumbar spine Z score vs PTH.
R=0.396
p<0.025
The data on the effect of hemodialysis in end stage renal
disease patients on bone density are limited. To date most of
the work has been focused on predialysis, HD and kidney
transplanted patients and scarce information is available for
patients on peritoneal dialysis, haemofiltration and
haemodialfiltration.20-23 The prevalence of osteoporosis in
hemodialysed patients is quite variable and depends on
several factors including the method used for BMD
measurement, the skeletal site and patients’ characteristics.
Nonetheless, most of the studies showed reduced BMD in
HD patients, which appears to be more pronounced than in
peritoneal dialysis patients24. The prevalence of osteoporosis
in HD patients has been estimated to be 13-29% at lumbar
spine4,5,24 and 16-19% at femoral neck.4 Our findings are in
accordance with these studies. Additionally, we found a high
prevalence of osteopenia particularly at femoral neck. In
CKD-MBD bone loss is site specific and in patients with
PTH
Figure 2. Femoral neck Z score vs PTH.
Serum PTH correlated significantly in a positive manner
with serum NTx and bSAP (R=0.715; p<0.001 and R=0.690;
p<0.001 respectively) (figure 3 and 4). We found that 50%
of serum NTx and bSAP variability is due to PTH levels. No
correlation was found between serum PTH and 25OHD3 or
leptin levels.
NTx
Correlation of PTH with bone markers, 25OHD3
and leptin
R=0.715
p<0.001
PTH
Figure 3. PTH vs NTx.
Correlation of 25OHD3 with bone markers
and leptin
R=0.69
p<0.001
bSAP
No correlation was found between 25OHD3, bone markers
(NTx and bSAP) or leptin levels.
Correlation of leptin with bone markers, BMI,
body weight, age and duration of hemodialysis
Serum leptin was not correlated with bone markers (NTx
and bSAP). As expected, serum leptin levels were positively
correlated with BMI (R=0.697; p<0.001) and with body
weight (R=0.577; p<0.001) (figure 5 and 6). We also found
76
PTH
Figure 4. PTH vs bSAP.
Nefrologia 2012;32(1):73-8
Leptin
R=0.697
p<0.01
BMI
Figure 5. Leptin vs BMI.
Body weight
R=0.577
p<0.001
Leptin
Figure 6. Leptin vs body weight.
uremic hyperparathyroidism, PTH has a preferential effect
on cortical bone.25,26
It has been reported that serum NTx is significantly higher in
HD patients than in healthy individuals27 and appears to be
the most reliable and useful bone resorption marker in renal
osteodystrophy.28 In the present study we found extremely
high levels of serum NTx and a significant positive
correlation between serum NTx and PTH which is in line
with previous published results.27,28
The clearance of bSAP is not performed by the kidney and
serum bSAP concentration is therefore not affected by renal
function. In our study a number of patients exhibited slightly
increased serum bSAP. The significant positive correlation
between serum bSAP and NTx with PTH probably suggests
that the increased bone turnover is due to secondary
hyperparathyroidism.
Plasma 25OHD3 levels are often abnormally low in normal
population, particularly in the elderly29 and in unselected
medical inpatients,30 as well as in HD patients.31 In our cohort
of patients there was also a high prevalence of vitamin D
deficiency. Ghazali, et al. in their study found that low
Nefrologia 2012;32(1):73-8
originals
plasma 25OHD3 appears to be a major risk factor for
hyperparathyroidism and Looser’s zones independent of
calcitriol levels.9 Interestingly, and in contrast, we found no
correlation between 25OHD3 and PTH or bone markers.
Leptin, an adipocyte-derived hormone, is cleared by the kidney,
and thus, plasma leptin levels are elevated in HD patients17. We
also found increased serum leptin levels in our HD patients,
particularly in women, which is in accordance with previous
studies. It has been reported that there is a link between leptin
and bone metabolism in vitro and in vivo experiments.10-12
Furthermore some studies in humans have shown a positive
relationship between leptin and bone parameters,32-34 while
others have not.35-37 In our study simple regression analysis
showed no correlation between serum leptin and Z score at
lumbar spine and femoral neck. Similarly, no correlation was
found between leptin and bone markers (NTx and bSAP).
Serum leptin showed a significant positive correlation only with
BMI and body weight as expected.
In conclusion the prevalence of osteoporosis/osteopenia is
increased in HD patients and bone mineral density appears to
correlate with high serum levels of bioactive PTH but not
with 25OH vitamin D or high serum leptin. Interestingly, the
duration of hemodialysis does not appear to affect bone
density. The impact of leptin on bone metabolism in HD
patients remains to be elucidated with further studies.
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Sent for review: 28 Mar. 2011 | Accepted: 7 Jul. 2011
78
Nefrologia 2012;32(1):73-8
originals
The lack of income is associated with reduced
survival in chronic haemodialysis
Sergio Marinovich1, Carlos Lavorato1, Guillermo Rosa-Diez1, Liliana Bisigniano2,
Víctor Fernández2, Daniela Hansen-Krogh3
Comité de Estadísticas y Registros. Sociedad Argentina de Nefrología. Ciudad Autónoma de Buenos Aires (Argentina)
Comisión Científico-Técnica. Instituto Central Único Coordinador de Ablación e Implante. Ciudad Autónoma de Buenos Aires
(Argentina)
3
Departamento de Informática. Instituto Central Único Coordinador de Ablación e Implante. Ciudad Autónoma de Buenos Aires
(Argentina)
1
2
Nefrologia 2012;32(1):79-88
ABSTRACT
La falta de ingresos económicos se asocia a menor
supervivencia en hemodiálisis crónica
Introduction: Poor socioeconomic status in the patient population is one of the causes of the lack of primary and secondary prevention of chronic kidney disease and negatively affects the survival of patients on chronic haemodialysis (HD).
Objective: To confirm whether the low or absent income of
the incident population on HD is a factor of poor prognosis.
Methods: We used the incident HD population of the Argentine Registry of Chronic Dialysis. Follow-up lasted 12 months,
performing an intention to treat analysis. We applied the Cox
model to assess the association between income and survival
of patients after adjusting for age, sex, diabetes, comorbidities, initial laboratory results, and first vascular access. Results:
We analysed 13466 adult patients (age at onset: 60.4±15.6 years; 57.2% were male, and 39.2% diabetic) who were assigned to 2 groups: 1) «no income» group, 5661 patients (age
at onset: 60.3±15.4 years; 53.1% were male and 41.4% diabetic), 2) «with income» group, 7805 patients (age at onset,
60.5±15-8] years; 60.1% were male and 37.5% diabetic). The
«no income» group had a hazard ratio of 1.19 (95% confidence interval [CI]: 1.11-1.28) in the univariate analysis, 1.23
(95% CI: 1.14-1.32 ) considering age and gender, 1.22 (95%
CI: 1.13-1.31) by adding diabetes mellitus, 1.26 (95% CI: 1.181.36) by adding comorbidities, 1.25 (95% CI: 1.16- 1.35) by adding the initial laboratory results, and 1.24 (95% CI: 1.151.33) if temporary vascular access is included. All models resulted in a significance of P=.000. Conclusions: Low or no income of patients at the time of entry into HD is an independent risk factor for immediate lower survival.
RESUMEN
Introducción: Las pobres condiciones socioeconómicas de la
población es uno de los causales de la falta de prevención primaria y secundaria de la enfermedad renal crónica e influiría
negativamente en la sobrevida de los pacientes en hemodiálisis (HD) crónica. Objetivo: Confirmar si el bajo o nulo ingreso
económico de la población incidente en HD es un factor de
mal pronóstico vital. Métodos: Utilizamos la población incidente en HD del Registro Argentino de Diálisis Crónica. El seguimiento fue de 12 meses, realizándose un análisis por intención de tratar. Se aplicó el Modelo de Cox para evaluar la
asociación entre ingresos económicos y la sobrevida de los pacientes ajustando por edad, sexo, diabetes, comorbilidades, laboratorio inicial y primer acceso vascular. Resultados: Analizamos 13.466 pacientes adultos (edad al inicio: 60,4 [±15,6] años,
57,2% varones, 39,2% diabéticos) que fueron asignados a 2
grupos: 1) «Sin ingresos», 5.661 pacientes (edad al inicio: 60,3
[±15,4] años, 53,1% varones, 41,4% diabéticos); 2) «Con ingresos», 7.805 pacientes (edad al inicio: 60,5 [±15,8] años, 60,1%
varones, 37,5% diabéticos). «Sin ingresos» mostró un hazard
ratio de 1,19 (intervalo de confianza [IC] 95%: 1,11-1,28) en
el univariado; de 1,23 (IC 95%: 1,14-1,32) considerando edad
y género; de 1,22 (IC 95%: 1,13-1,31) agregando diabetes mellitus; de 1,26 (IC 95%: 1,18-1,36) agregando comorbilidades;
de 1,25 (IC 95%: 1,16-1,35) adicionando laboratorio inicial y
de 1,24 (IC 95%: 1,15-1,33) si se incluye acceso vascular transitorio. En todos los modelos la significación resultó en una p =
0,000. Conclusiones: Los bajos o nulos ingresos económicos
del paciente en el momento del ingreso a HD es un factor de
riesgo independiente de menor sobrevida inmediata.
Keywords: Haemodialysis. Income level. Socioeconomics
status. Survival.
Palabras clave: Hemodiálisis. Nivel de ingresos. Estado
socioeconómico. Sobrevida.
Correspondence: Sergio Marinovich
Comité de Estadísticas y Registros.
Sociedad Argentina de Nefrología
Superí, 370. 2000 Rosario. Argentina.
[email protected]
[email protected]
INTRODUCTION
The total population in Argentina reached 39 745 613
inhabitants in the year 2008, an approximate 1% population
increase since 2004.1 The incidence rate of patients on
79
originals
chronic dialysis (CD) increased by 4.38% during this time
period, from 137.5 to 143.1 patients per million population
(pmp), a 1.1% increase each year. The prevalence rate of
CD increased by an even greater percentage (3.2% annual),
increasing from 550.3pmp in 2004 to 623.4pmp in 2008.2,3
Chronic kidney disease (CKD) causes very high rates of
morbidity and mortality, proportional to the CKD stage,
with 30 times higher rates of cardiovascular mortality in
stage V patients. This depends, among other factors, on the
availability of access to renal replacement therapy and to a
greater extent on access to primary and secondary kidney
disease prevention measures in early stages of the disease.
Sergio Marinovich et al. Income and survival in haemodialysis
survival of 5360 new incident patients on chronic
haemodialysis, giving a score of 1 for the final score
obtained, where a higher score indicates a lower survival
rate.5 Additionally, Abraham et al in India and Caskey et al
in England-Wales found an association between poor
socioeconomic conditions and a higher mortality rate on
dialysis. In this last study, the authors observed a lower
probability of transplant in the group with the greatest
economic need.6,7 However, Eisenstein et al, in a study from
the USA based on estimated income by housing area and
race, found no significant differences in mortality rates
while on haemodialysis among the different income level
groups (low, middle, and high).8
It can be said that there are no restrictions on the availability
of chronic dialysis treatment in Argentina. Any citizen that
reaches a stage of terminal renal failure (TRF) with the need
for dialysis is accepted by both public and private health
centres. Even so, the low adjusted incidence rates of
patients entering CD in some Argentine provinces lead us to
strongly suspect that the health systems in these areas suffer
some level of deficit in communication with chronic kidney
disease patients.2,3 Consequently, it is quite probable that the
totality of the Argentine population is not being contacted in
time using the correct methods in order to carry out primary
and secondary prevention measures for kidney disease.
The aim of this study was to analyse whether a low or
absent income in the incident population on chronic
haemodialysis is a factor for a poor prognosis, adjusting for
the variables that have been shown to influence 1-year
survival.
In addition to this inequality in the detection of kidney
disease, over one third of the incident population on CD
lives in poverty.2,3 Major epidemiological studies carried out
at the national level have shown that poverty indicators are
observed in between 30% and 33% of the general
population. The study carried out by the Catholic University
of Argentina (Universidad Catolica Argentina) also shows
that 14.6% of homes have a severe housing deficit. As of
2009, 31.6% of homes had no seweage system, 9.8% were
without running water, and 8.8% of households were
overcrowded (a strong indicator in the “unsatisfied basic
needs index”); additionally, 15.9% of homes have incomes
that do not satisfy their basic food needs (10.8% moderate
and 5.1% severe).4
Selection
Life in situations where basic needs are not met, more
commonly known as poverty, has not been examined
thoroughly as a risk factor for mortality in the population of
patients on CD using indexes or adequate multivariate
studies, since, in order to understand its true effect, the
socioeconomic variable must also be adjusted for other
variables known to affect mortality in these patients. The
few studies that have mentioned the poor conditions of CD
patients suggest that these conditions have negative effects
on survival, as well as on the probability of having access to
a kidney transplant. By using a multivariate analysis to
design a new prognostic index, we were able to demonstrate
that insufficient income for patients and their family
members was a variable of negative prognosis for the 1-year
80
METHODS
Observational, retrospective, longitudinal and predictive
analytical study.
We used the data obtained through the National Registry of
Chronic Dialysis. In Argentina, it is mandatory to register
patients when they enter or exit a CD programme. When the
patient is admitted into a programme, a questionnaire called
the first registry of a chronic dialysis patient (primer ingreso
de paciente a dialisis cronica, DRI) which, signed under
oath by the CD Centre Director, must be submitted to the
central office of the Registry under the Central Coordinating
Institute for Ablation and Implants (Instituto Central Único
Coordinador de Ablación e Implante, INCUCAI). The
questionnaire includes demographic variables, pre-existing
diseases, initial laboratory results, and socioeconomic and
occupational variables from when the patient first started
chronic dialysis treatment. This form must be completed by
the attending nephrologists and social workers.9 Insufficient
or absent income is very closely checked through the
evaluations made by the social workers both through a
review of paperwork and on-site evaluation of the living
conditions at the patient’s home in order to corroborate or
disprove the information provided.
Our study included patients 18 years of age or older that
started for the first time a chronic haemodialysis (HD)
programme in any of the haemodialysis centres (n=462) in
Argentina (24 provinces) between 1 April 2004 and 31
December 2008. The observation period came to a close on
31 December 2009, in order to guarantee a theoretical
Nefrologia 2012;32(1):79-88
follow-up period of one year. We excluded all patients that
did not have complete data for all variables considered in
the study. The patients were censored in the case of
recovered renal function, and event was defined as the death
of a patient. As such, we performed an intention to treat
analysis, with follow-up until patient death, whether or not
the patient underwent a transplant. The start time for the
follow-up period was day 1, and so all patients were
included, even those with less than 90 days of follow-up.
The population was divided into two groups: 1) “No
income,” including patients that did not have any income
declared, from neither the patients themselves or those who
shared their home, at the start of treatment. 2) “With
income,” including patients with declared income at the
start of treatment.
STATISTICAL METHOD
originals
background of myocardial infarction”, “presence of arterial
hypertension”, “presence of cardiac arrhythmia”, “presence
of congestive heart failure”, “presence of chronic
pulmonary disease”, “presence or background of
cerebrovascular disease (including dementia, hemiplegia)”,
“presence of peripheral vascular disease (including
amputated patients)”, “solid cancer without metastasis in
the last 5 years (excludes basal/squamous skin cancer)”,
“solid cancer with metastasis in the last 5 years”, “acute and
chronic leukaemia”, and “lymphoma (includes myeloma
according to the Charlson criteria)” (15 covariates).
Model 4. In addition to the Model 3 variables, we added
the following variables from the initial laboratory results:
“positive HIVAb”, “positive HBsAg”, “positive HBVAb”,
“initial albumin <3.5g/dl”, “initial haematocrit”, and “initial
glomerular filtration rate” (glomerular filtration rate
according to the abbreviated Levey formula MDRD-7)10 (21
covariates).
Continuous variables were expressed as mean and standard
deviation, and categorical variables were expressed in terms
of frequency and proportion. For the comparison of
numerical variables from both groups, we used Student’s ttests for parametric variables and Wilcoxon tests for nonparametric variables; we used Pearson’s chi-square test for
qualitative variables, and considered a P-value <.05 to be
statistically significant.
Model 5. In addition to the Model 4 variables, we added
“starting haemodialysis with a temporary vascular access
(non-tunnelled catheter)” (22 covariates).
In the survival analysis, we used the Kaplan-Meier (KM)
method. We used the log-rank test (Mantel-Cox) for a
simple comparison between the two populations.
RESULTS
We applied five different Cox proportional hazards models
to test for differences between the two groups, adjusting for
covariates that were considered to be predictive a priori
based on previous studies.3,5 We determined hazard ratio
(HR) or Exp (B) values for the independent variable
“income” (dichotomous: no income and with income) after
adjusting for the effect of other independent variables in the
equation. The variable “income” was present in all models.
In all cases, variables were considered as pre-existing
conditions or conditions at the start of the therapy. We
excluded those independent variables that were highly
correlated with each other. The proportional hazard was
calculated based on log (-log) survival.
Model 1. “Age at start of treatment” and “Male” (3
covariates).
Model 2. To the previous variables we added: “Diabetes
mellitus as a cause of TRF” (4 covariates).
Model 3. In addition to the previously mentioned variables,
we added the following comorbidities as dichotomous
variables (yes/no): “Presence of persistent angina or
Nefrologia 2012;32(1):79-88
We performed all statistical analyses using SPSS version
15.0 statistical software for Windows (SPSS Inc., Chicago,
IL).
We evaluated a total of 13,466 patients. Table 1 summarises
the characteristics of the study population. Upon starting
HD, 56.7% of our patients were 60 years of age or older.
Diabetes was present as a cause of TRF in 35.9% of the
total, although 39.2% of the incident population was
diabetic. The patients that reported no income within their
household were 42.0% of the total. Overall mortality at 1
year was 22.3%, and 1-year survival was 77.7%. Only 1.8%
of patients had to be censored from the study, with 245
recovering renal function.
Table 2 displays general patient variables, comorbidities,
laboratory results, type of initial vascular access, and the
socioeconomic conditions for both groups and the
corresponding statistical comparisons between them. The
“no income” group had a significantly higher proportion of
males, foreigners, people residing outside of Buenos Aires,
and a similar mean age as compared to the other group.
Upon analysis of the comorbidities present, although the
“no income” group had a significantly higher percentage of
diabetic patients, we found only one variable (a priori with
a worse prognosis) that yielded a significantly higher
percentage for this group: the presence of peripheral
vascular disease. On the other hand, we observed a
significantly lower percentage of angina and previous heart
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originals
Table 1. Basic patient characteristics
Characteristics
Values
No. of patients
13466
Male
7698 (57.2%)
Mean age (years)
60.4 (±15.6)a
Age groups
<50 years
3090
_>50<60 years
2710
_>60<70 years
3526
_>70<80 years
3075
_>80<90 years
1022
_>90 years
43
Causes of TRF
Diabetic nephropathy
4839 (35.9%)
Nephroangiosclerosis
2919 (21.7%)
Unknown
2429 (18.0%)
Glomerulonephritis
974 (7.2%)
Obstructive nephropathy
695 (5.2%)
Polycystic kidney disease
627 (4.7%)
Chronic tubulointerstitial nephritis
191 (1.4%)
Lupus nephritis
180 (1.3%)
Multiple myeloma
94 (0.7%)
Amyloidosis
47 (0.3%)
Haemolytic uremic syndrome
44 (0.35)
Other
427 (3.2%)
Diabetes as a cause of TRF or lack of income
5272 (39.2%)
No income
5661 (42.0%)
With income
7805 (58.0%)
Deaths
3002 (22.3%)
Censored
Completed the follow-up period
245 (1.8%)
10 219 (75.9%)
attack, arrhythmia, chronic pulmonary disease, cancer, and
tobacco use in the “no income” group.
In terms of laboratory results, the “no income” patients
started treatment with significantly worse conditions for
almost all variables: lower glomerular filtration rate, lower
albuminaemia, lower haematocrit, greater percentage of
HBsAg positive, etc. Additionally, the use of a temporary
non-tunnelled catheter was significantly more common in
this group as the first vascular access point established.
The variables associated with socioeconomic status were
also significantly worse for the “no income” group: lower
82
level of education, greater instability in their living situation,
and a larger number of people in each home (ratio of
inhabitants/rooms), among others.
The mortality rate after one year was significantly greater in
the “no income” group: 24.2% vs 20.9%. We observed a
very significant difference (P=.000) between the two groups
in the number of patients that underwent transplants. In the
“no income” group, 0.25% (14/5661) of patients underwent
transplants, and in the “with income” group, 1.18%
(92/7805). This difference was the basis for performing an
intention to treat analysis, considering all transplant
recipients with a maximum follow-up period of 12 months.
The KM survival curves for the overall population and by group
are displayed in Figure 1: total survival after one year was 77.71%.
Survival in the “with income” group was significantly higher than
in the “no income” group: 79.12% vs 75.76%, and the log-rank test
(Mantel-Cox) resulted in a chi-square value of 22.49 (P=.000).
To confirm these findings, we used a univariate Cox
regression model that yielded an Exp (B) or hazard ratio
(HR) of 1.19 for the “no income” group (95% confidence
interval [CI]: 1.11-1.28). Considering other covariates in the
equation, we will see whether the result is the same.
Table 3 displays the HR for the variables included in each of
the five multivariate regression models used, with special
emphasis on the variable “no income.”
Figure 2 shows the Cox predictive curves for models 3 and 5
for a typical individual (theoretical predictive survival) after
adjusting for all covariates for the categorical variable of
“with or without income.”
The HR for the “no income” group did not change
significantly in any of the five multivariate models. It did
improve compared to the univariate model, although this
difference did not reach statistical significance. The presence
of comorbidities in model 3 produced the highest HR value
(1.26), which decreased when the initial laboratory analysis
values were added in model 4, and even more so when
adjusting for vascular access in model 5. However, the
differences are small, which implies that whether with or
without adjustment, the lack of income for patients on HD is
an immediate factor for a poor prognosis, regardless of the
presence of other factors.
Additionally, we performed a sixth Cox multiple regression
model, which considered 4 variables: “no education or only
incomplete primary school, “unstable living situation”,
“male sex”, and “age at the start of treatment”. The two first
variables did not enter into models 1 and 5 because of their
close correlation with “no income”; for the same reason, “no
income” was not evaluated in this sixth model. “Unstable
living situation” had an HR of 1.38 (95% CI: 1.21-1.58;
Nefrologia 2012;32(1):79-88
originals
Table 2. General variables, comorbidities, initial laboratory results, and socioeconomic conditions of each group
Variables
No income
With income
P
(n=5661)
(n=7805)
60.32 (±15.4)
60.53 (±15.8)
0.440
Male (%)
53.1
60.1
0.000
Foreign-born (%)
6.7
5.7
0.017
Does not reside in the city of Buenos Aires (%)
96.6
89.0
0.000
General
Age at start (years)
Comorbidities (%)
Previous myocardial infarction or persistent angina
9.1
12.1
0.000
Arterial hypertension
86.4
84.8
0.306
Cardiac arrhythmia
9.0
11.5
0.000
Congestive heart failure
22.8
22.9
0.930
Chronic pulmonary disease
6.4
7.7
0.005
Diabetes Mellitus
41.4
37.5
0.000
Cerebrovascular disease
7.7
7.4
0.545
Peripheral vascular disease
24.9
22.6
0.002
Solid cancer without metastasis in the last 5 years
3.3
5.3
0.000
Solid cancer with metastasis in the last 5 years
0.18
0.56
0.000
Acute or chronic leukaemia
0.07
0.12
0.410
Lymphoma (includes multiple myeloma)
0.79
1.09
0.085
Tobacco use in the last 5 years
16.0
17.8
0.007
Creatinemia (mg/dl)
7.81 (±4.20)
7.54 (±3.85)
0.000
Glomerular filtration rate (ml/m)
8.48 (±4.17)
8.90 (±4.32)
0.000
0.001
Initial laboratory results and vascular access
Glomerular filtration rate >
_15ml/m (%)
Albuminaemia (g/dl)
Albuminaemia <3.5g/dl (%)
Haematocrit
7.1
8.6
3.35 (±0.62)
3.43 (±0.60)
0.000
54.1
48.8
0.000
26.49 (±5.26)
27.14 (±5.40)
0.000
Haematocrit <30 % (%)
71.9
69.1
0.000
Positive HIVAb (%)
0.35
0.36
0.958
Positive HBsAg (%)
0.79
0.42
0.005
Positive HCVAb (%)
1.97
1.67
0.202
Started haemodialysis with a temporary catheter (%)
64.2
60.2
0.000
No education or incomplete primary school (%)
34.1
18.9
0.000
Precarious household (not made with concrete or strong materials) (%)
11.5
5.7
0.000
Socioeconomic
Number of rooms per home
2.65 (±1.19)
2.86 (±1.26)
0.000
Number of inhabitants per home
3.40 (±2.36)
3.32 (±2.27)
0.038
Ratio of inhabitants/rooms
1.40 (±0.87)
1.27 (±0.78)
0.000
91.3
96.1
0.000
Bathrooms installed in home (%)
Water pipes (%)
92.0
96.5
0.000
First-year mortality (%)
24.2
20.9
0.000
Transplant recipients within the first year (%)
0.25
1.18
0.000
Recovery of renal function (%)
1.82
1.82
1.000
Mean values for numerical variables with corresponding standard deviation (±); %: percentage of patients in each dichotomous variable.
P=.000). “No education or only incomplete primary school”
had an HR of 1.09 (95% CI: 1.00-1.18; P=.046). This is simply
another manner of evaluating poverty-indigence and its
Nefrologia 2012;32(1):79-88
repercussions on immediate survival on HD: the absence of an
adequate home significantly increased the relative risk of death
by 38%, after adjusting for age, sex, and level of education.
83
originals
1.00
1.00
0.95
Total population
Cumulative survival
Cumulative survival
0.95
0.90
0.85
0.80
With income
No income
0.90
0.85
0.80
Log rank (Mantel-Cox)
Chi-square 22.49 (P = .000)
Months on haemodialysis
0.75
0
13.466
3
12.063
6
11.267
9
10.678
0.75
12
0
10.219 With income7.805
No income 5.661
3
7.058
5005
6
6.628
4.639
9
6.305
4.373
12
6.033
4.186
Figure 1. Kaplan-Meier survival curves. Left: total population. Right: by group: “with income” and “no income.” The numbers
below each curve show the number of patients that continued haemodialysis treatment each year.
.
DISCUSSION
A home is considered to be poor if the “per capita” income is
insufficient to cover the basic needs for food and other
amenities (total basic needs) of its inhabitants, including
clothing, education, transportation, and health. Additionally,
if the home does not have sufficient income to provide
adequate sustenance to its members (basic dietary needs), the
inhabitants are considered to be indigent or extremely poor.
We cannot consider the declarations of patient income to be
absolutely correct; however, this declaration was certified by
on-site evaluations in plain view of the living situations in
the majority of cases where patients declared that they did
not have any income in their households. We have observed
in this study that the differences in education and households
are notable between those that declare income and those that
do not. This variable, therefore, is strongly associated with
indigence or poverty. It is quite probable that patients that do
not declare income do receive some type of economic
subsidy after starting renal replacement therapy. However,
this cannot be determined here for lack of data on the
subject. Even so, we could observe in our study that the
relative risk of death in the first year of hemodialysis
treatment was significantly higher (19% to 26%) in patients
that declared no income as compared to those that did
declare an income.
Diabetes mellitus is a poverty-linked disease; as Table 2
shows, this condition was significantly more prevalent in the
“no income” group. Confirming the results from our study,
Caskey et al in England and Wales observed that diabetes
was a cause of TRF at a much higher rate in the population
84
living in areas of greater social deprivation.7 Also, Lorenzo
et al performed an evaluation of the high prevalence of
diabetes in the Canary Islands (Spain), and found that,
among other causes, poverty and social inequality were
causative forces for reduced use of health resources, lower
rates of compliance with treatment, and inadequate hygienediet habits, leading to increased prevalence of diabetes
mellitus in predisposed individuals.11 The initial laboratory
results and a greater frequency of non-tunnelled temporary
catheters as the first vascular access point provided showed
that “no income” patients had worse conditions than “with
income” patients, all of which is probably related to delayed
contact with the health system.
The location of the patient’s residence is also an influential
factor: the city of Buenos Aires (not including the outlying
urban areas) has been considered in other studies2,3 as the
“gold standard” for renal health in Argentina, since it has the
best indicators in the entire country: more advanced age upon
starting a CD programme (which implies a better treatment of
kidney disease and consequent delay in reaching stage 5
TRF), lower incidence rate of CD (due to better prevention
methods), a higher rate of kidney transplant, and a better
adjusted survival rate of patients on CD. Buenos Aires has the
best health infrastructure in Argentina, especially for poor and
indigent patients. In our study, we have found that this city is
one of the four districts that have the lowest rates of “no
income” patients in the entire country, 18.2%, significantly
lower than the national mean of 42%.
Observing a map of Argentina (Figure 3), we can see major
inequality between the different provinces in income in the
homes of incident patients on HD. The majority of the northNefrologia 2012;32(1):79-88
originals
Table 3. Multivariate Cox proportional hazards models
Variables
Model 1
Model 2
Model 3
Model 4
Model 5
Age at start (per each year)
1.04 (1.04-1.05)
1.04 (1.04-1.05)
1.04 (1.04-1.04)
1.04 (1.04-1.05)
1.04 (1.04-1.04)
Male
1.05 (0.97-1.13)
1.07 (0.99-1.15)
1.02 (0.94-1.09)
1.03 (0.95-1.11)
1.03 (0.95-1.11)
No income
1.23 (1.14-1.32)
1.22 (1.13-1.31)
1.26 (1.18-1.36)
1.25 (1.16-1.35)
1.24 (1.15-1.33)
P=.000
P=.000
P=.000
P=.000
P=.000
*
1.36 (1.27-1.46)
1.31 (1.21-1.42)
1.24 (1.14-1.35)
1.22 (1.12-1.32)
Diabetes Mellitus
Previous myocardial infarction/angina
*
*
1.04 (0.93-1.16)
1.07 (0.96-1.19)
1.06 (0.95-1.17)
Arterial hypertension
*
*
0.70 (0.63-0.77)
0.72 (0.64-0.79)
0.75 (0.67-0.83)
Cardiac arrhythmia
*
*
1.16 (1.05-1.29)
1.19 (1.07-1.32)
1.19 (1.08-1.32)
Congestive heart failure
*
*
1.30 (1.19-1.41)
1.27 (1.17-1.38)
1.22 (1.13-1.33)
Chronic pulmonary disease
*
*
1.18 (1.04-1.33)
1.18 (1.05-1.34)
1.16 (1.02-1.31)
Cerebrovascular disease
*
*
1.32 (1.18-1.49)
1.34 (1.20-1.51)
1.34 (1.19-1.51)
Peripheral vascular disease
*
*
1.30 (1.19-1.42)
1.28 (1.17-1.39)
1.31 (1.20-1.43)
Solid cancer without metastasis
*
*
2.07 (1.81-2.35)
2.11 (1.85-2.41)
2.12 (1.86-2.42)
Solid cancer with metastasis
*
*
1.83 (1.20-2.79)
2.03 (1.33-3.10)
1.92 (1.26-2.94)
Acute or chronic leukaemia
*
*
1.89 (0.85-4.23)
1.95 (0.87-4.37)
2.01 (0.90-4.48)
Lymphoma
*
*
3.32 (2.61-4.23)
3.15 (2.48-4.01)
2.94 (2.31-3.74)
Positive HIVAb
*
*
*
2.35 (1.43-3.85)
2.19 (1.33-3.59)
Positive HbsAg
*
*
*
0.78 (0.46-1.32)
0.77 (0.46-1.30)
Positive HCVAb
*
*
*
1.34 (1.04-1.72)
1.35 (1.05-1.73)
Albuminaemia less than 3.5 g/dl
*
*
*
1.60 (1.48-1.72)
1.45 (1.34-1.57)
Haematocrit (for each unit % more)
*
*
*
0.99 (0.99-1.00)
1.00 (0.99-1.00)
Glomerular filtration rate (per each ml/m)
*
*
*
1.00 (1.00-1.01)
1.01 (1.00-1.02)
Initial temporary vascular access
*
*
*
*
2.12 (1.95-2.31)
Values expressed as HR (95% confidence interval); the variables/values that resulted significant in the models are in bold.
*Variable not included in the model
western provinces (Tucuman, Salta, and Jujuy), all of the
north-eastern provinces (Formosa, Chaco, Corrientes, and
Misiones), three of the central provinces (La Pampa, Buenos
Aires, and Cordoba), and all of the Cuyo provinces
(Mendoza, San Juan, and San Luis) have percentages greater
than 40%. All other provinces have lower percentages, with
the lowest observed in the southern provinces of Patagonia
(Chubut, Santa Cruz, and Tierra del Fuego) and the city of
Buenos Aires.
Some 42% of the Argentinean total corresponds to the
incident population on HD between 2004 and 2008.
However, it is heartening to know that the percentage of
patients with no income declared decreased over time from
61% of incident patients in 2004, to 52% in 2005, 46% in
2006, 35% in 2007, and finally 22% in 2008.
“Lack of income” was demonstrated to be a predictive factor
for low survival after one year in patients on HD, although
the HR obtained, in spite of its significance (P=.000),
appears to be quite low, and we would have expected to
observe a value higher than 1.22-1.26. As an explanation for
this “relatively low” HR value, we could hypothesise that the
lack of economic resources is a reliable reflection of a
Nefrologia 2012;32(1):79-88
lifestyle in which the basic needs are not met, and that
probably the HR was not higher because, once attended by
the health system, the patient moves from being very
vulnerable to less vulnerable. Care is provided as soon as
he/she starts haemodialysis: social workers are sent to the
home, the poor living conditions are recognised, a better
household and more food are acquired through the county,
provincial, or national government aid systems, and some
sort of economic subsidy is provided. That is to say, after
starting renal replacement therapy, the patient is often the
recipient of several actions that are not considered in our
study, and that eventually change the status of the patient
from one of very high risk to one of moderate risk in the “no
income” population.
Another finding from our study was the fact that the “no
income” population had a significantly lower rate of access
to kidney transplants than the other group during the first
year on HD: 0.25% vs 1.18%. Both values are low, but the
value for poor patients is much lower. The causes of this
phenomenon are still unknown, but hypothetically, poor
patients must go through much more bureaucratic processes
(with a greater loss of time) in order to be included on the
kidney waiting list.
85
1.00
1.00
0.95
0.95
With income
No income
0.90
Cumulative survival
Cumulative survival
originals
0.85
0.80
With income
No income
0.90
0.85
0.80
0.75
0.75
0
3
6
9
12
0
3
6
9
12
Figure 2. Left: Cox predictive curves for Model 3 using the dichotomous variable of with or without income. Right: predictive curves
for model 5, also for the dichotomous covariate of with or without income
The quality of health care provided to renal patients, in
particular renal replacement therapy, whether through
dialysis or transplant, has been the subject of a large number
of medical publications. Many authors have dealt with the
subject, examining all of the different factors that influence
the survival of these patients. However, very few studies
have made the attempt to include and evaluate the incidence
of socioeconomic factors (for the patient and family
members) in the treatment results. In a literature review we
observed that some of these studies have certain local and
methodological factors that impede the possibility of
generalising these results across other populations. The
various methods used to measure poverty and low
socioeconomic status, for instance, and the different
responses of health systems to high dependency patients,
such as those with renal failure, makes comparisons difficult.
In the USA, a strong relationship was shown between a low
socioeconomic status and a high mortality rate,12,13,14 whereas
other researchers in the same country could not find these
results.8 Abraham et al in southern India examined 558 CD
patients, finding that mortality was higher at lower
socioeconomic levels (especially among diabetics), as well
as a lower level of access to kidney transplants; but the
extremely poor access to treatment, the fact that these
patients receive treatment at different institutions, and the
young age of the prevalent patients does not allow us to
make comparisons.6 The study by Caskey et al showed that
low-income patients are referred for treatment late in the
progression of the disease, have a lower probability of
undergoing peritoneal dialysis, undergoing a kidney
transplant, and reaching target haemoglobin and
phosphorous values after one year of treatment, and have a
86
higher mortality rate under the age of 65 years. This lower
survival rate remained significant even after adjusting for
age, sex, and the underlying cause of the renal failure, but
was corrected when adjusting for comorbidities. The authors
inferred that these factors should be responsible for the
difference. However, in this study, social deprivation was
based solely on the characteristics of the area or
neighbourhood where the patient was living, which is a
completely indirect method with a high margin of error.7 Our
study, which was based on the entire incident population in
Argentina during a given period and used a survey taken
upon starting HD, with the final result of survival after one
year, has certain aspects that have not been explored
previously. Our results reinforce the idea that, in addition to
the absence of income, an unstable household and low level
of education are both statistically significant independent
risk factors.
Our study did have some limitations: 1) Absence of races
and ethnicities. Since colonial times, Argentina has been
the site of substantial racial mixing, which was enhanced
by the three large waves of immigrants that arrived here
between 1880 and 1950. As such, it is difficult to
establish patterns of race and ethnicity. The selfrecognised indigenous population was only 1.56% of the
total population in 2004-2005.15 There are no official data
for people of African heritage (Afro-Argentine), but this
ethnicity is thought to make up only 0.03% of the total
population. 2) The study is not reproducible in societies
where the level of poverty and indigence is very low. It is,
however, in other Latin American countries where access
to renal replacement therapy is also universal and where
Nefrologia 2012;32(1):79-88
Tucuman
Misiones
Entre
Rios
City of Buenos Aires
Ne
uq
ue
n
Cordoba
Rio Negro
Relative
frequencies (%)
Tierra del Fuego
Equal to or more than 50
45-49
40-44
35-39
30-34
Less than 30
Figure 3. Percentage of incident patients on CHD in 20022004 that declared no income (patients and house members).
Distribution by Argentine province
the patterns of poverty are similar to Argentina: in
particular, Uruguay, Chile, and Brazil.16
It is quite probable that the indigent and poor people of
Argentina have a very late contact with the health system,
which could be due to a lack of information, the need to deal
with their basic needs at all times, the lack of time to spend
in long lines at public hospitals, or the lack of health centres
and public hospitals close to their place of residence. For
some or all of these reasons, these patients do not have
access to a healthy life. The vulnerability of this population
is extreme. This is not just an issue of renal health, or even
public health: this is a social problem that has its roots in the
highest circles of social health policy, and will not be solved
or even improved until it is approached from this
perspective. It will improve when the social, cultural,
economic, and health status of the population improves, and
when the level of inequality is reduced.
High poverty indices were once the exclusive domain of
developing countries, but in the economic crisis of the last few
Nefrologia 2012;32(1):79-88
originals
years, large portions of the population in developed countries
have begun to enter these conditions or are about to. As such,
these countries may do well to anticipate these changes by
developing containment policies directed at the population
with renal failure and a low socioeconomic level.
In conclusion, “lack of income” was shown to be a
predictive factor for low survival after one year on HD,
after adjusting for age, sex, diabetes, comorbidities,
albuminaemia, glomerular filtration rate, haematocrit, and
the initial type of vascular access. We propose the
consideration of this variable or another similar measure
that represents low or absent income in the incident HD
patient, adjusted for other factors, in order to adequately
predict short-term survival.
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Análisis Demográficos, vol. 31. Ministerio de Economía y Producción
de la República Argentina-Secretaría de Política Económica, 2005.
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D, et al. Registro Argentino de Diálisis Crónica 2008. Informe 2010. Nefrología Argentina 9, Suplemento 1 (parte 2). P.71-127. 2011. Available at http://www.san.org.ar/docs/registros/dc/2008/REGISTRO_ARGENTINO_DC_2008_VERSION_COMPLETA.pdf (Accesed July 9, 2011).
4. Barómetro de la Deuda Social Argentina. Universidad Católica Argentina, Número 6. Año 2010. Available at http://www.uca.edu.ar/index.php/site/index/es/universidad/investigacion/programa-observatorio-de-la-deuda-social-argentina/publicaciones/informes/nro-6—-201
0/ (Accesed July 9, 2011).
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6. Abraham G, Jayaseelan T, Matthew M, Padma P, Saravanan AK, Lesley N, et al. Resource settings have a major influence on the outcome of maintenance hemodialysis patients in South India. Hemodial
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7. Caskey FJ, Roderick P, Steenkamp R, Nitsch D, Thomas K, Ansell D,
et al. Social deprivation and survival on renal replacement therapy
in England and Wales. Kidney Int 2006;70(12):2134-40.
8. Eisenstein EL, Sun JL, Anstrom KJ, Stafford JA, Szczech LA, Muhlbaier LH, et al. Do income level and race influence survival in patients receiving hemodialysis? Am J Med 2009;122(2):170-80.
9. SINTRA. Formulario 02-DRI. Available at: http://sintra.incucai.gov.ar/
(Accesed November 16, 2011).
10. Levey AS, Bosch JP, Breyer-Lewis J, Greene T, Rogers N, Roth A. A more
accurate meted to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-70.
11. Lorenzo V, Boronat M. La enfermedad renal asociada con diabetes en Islas Canarias: un problema de salud pública, de elevado
sufrimiento humano y alto coste económico. Nefrologia
2010;30(4):381-4.
12. Port F, Wolfe R, Levin N. Income and survival in chronic dialysis
patients. ASAIO Trans 1990;36:M154-M157.
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outcomes for patients with chronic kidney disease. Semin
Nephrol 2001;21:377-85.
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et al. Social adaptability index: application and outcomes in a
dialysis population. Nephrol Dial Transplant 2011;26(8):266774.
15. Instituto Nacional de Estadística y Censos (INDEC). Encuesta
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Sent for review: 3 Ago. 2011 | Accepted: 1 Nov. 2011
88
Nefrologia 2012;32(1):79-88
originals
Effect of Intranasal DDAVP in Prevention
of Hypotension during Hemodialysis
Seyed S. Beladi-Mousavi1, Marzieh Beladi-Mousavi2, Fatemeh Hayati1, Mehdi Talebzadeh1
1
2
Department of Internal Medicine, Faculty of Medicine. Jundishapur University of Medical Sciences. Ahvaz (Iran)
Department of Chemistry, Islamic Azad University, Omidiyeh Branch, Omidiyeh (Iran)
Nefrologia 2012;32(1):89-93
ABSTRACT
Efecto de la DDVAP intranasal en la prevención de la
hipotensión durante la hemodiálisis
Introduction: The
development
of
intradialytic
hypotension during hemodialysis (HD) in which fluid
removal is the primary goal, contributes to the excessive
morbidity that is associated with the dialysis procedure.
Materials and Methods: In a double blinded clinical
trial, we compared the possible effect of intranasal
DDAVP with intranasal distilled water as a placebo in
prevention of intradialytic hypotension (IDH) in patients
with known symptomatic IDH. In the first month of the
study, nasal spray of distill water were administrated 30
minutes before all HD session (Placebo Group, Group 1)
and then after a 30-day washout period we were used
intranasal DDAVP 30 minutes before HD session
(Vasopressin Group, Group 2). Blood pressure was
measured just before HD, two hours later and after
termination of HD. A hypotensive episode was defined as
a decline of systolic blood pressure of more than 10mm
Hg. Results: In overall Seventeen patients (nine men,
eight women; mean age, 47.5 years) with known
symptomatic IDH were enrolled in the study. The kind of
dialysis membranes, mean of blood flow rate, dialyzate
flow rate and ultrafiltration rate were the same in both
groups. Each group has 204 HD session (17 * 12).
Hypotensive episode occurred 18 times (8.82%) in
vasopressin group compared with 125 times (61.27%) in
placebo group and there was a significant association
between them (p=0.0001). In addition mean arterial
blood pressure in vasopressin group was 80.77 and in
placebo group was 73.92 and also there was a significant
association (p=0.0001). The mean Kt/v in group 1 and 2
were 1.29 and 1.28 without any differences between
them (p=0.896). Conclusion: These results indicate that
Compared with placebo, Vasopressin is significantly
associated with a decreased incidence of intradialytic
hypotension episodes during hemodialysis.
Introducción: La aparición de hipotensión intradialítica
durante la hemodiálisis (HD) en la que el objetivo principal es
la eliminación de fluidos, contribuye a una morbilidad excesiva
que se asocia con la diálisis. Materiales y métodos: Mediante
un ensayo clínico doble ciego, comparamos los posibles
efectos de la DDAVP intranasal con los del agua destilada
intranasal como placebo en la prevención de la hipotensión
intradialítica (HID) en pacientes con HID sintomática
diagnosticada. Durante el primer mes del estudio, la
pulverización nasal de agua destilada se realizaba 30 minutos
antes de todas las sesiones de HD (grupo de placebo, grupo 1)
y luego, tras un periodo de reposo de 30 días, utilizamos
DDVAP intranasal 30 minutos antes de las sesiones de HD
(grupo vasopresina, grupo 2). La presión arterial se medía
justo antes de la HD, dos horas después y una vez finalizada la
HD. Se definió como episodio de hipotensión la caída de la
presión arterial sistólica del más de 10 mmHg. Resultados: Se
incluyó en el estudio un total de 17 pacientes (nueve hombres
y ocho mujeres de 47,5 años de edad media) con HID
sintomática diagnosticada. En ambos grupos, el tipo de
membranas de diálisis, la media del flujo sanguíneo, la tasa del
flujo dializado y la tasa de ultrafiltración eran los mismos.
Ambos grupos se sometieron a 204 sesiones de HD (17 x 12).
Los episodios de hipotensión sucedieron en 18 ocasiones
(8,82%) en el grupo de vasopresina en comparación con las
125 ocasiones (61,27%) del grupo de placebo y hubo una
relación significativa entre ellos (p=0,0001). Además, la presión
arterial media en el grupo de vasopresina era de 80.77 y en el
grupo de placebo era de 73,92 e igualmente se observó una
asociación significativa (p=0,0001). La media Kt/v en el grupo 1
y el 2 fue de 1,29 y 1,28 sin diferencias entre ellos (p=0,896).
Conclusión: Estos resultados indican que, en comparación con
el placebo, la vasopresina está relacionada de forma
significativa con una menor incidencia de los episodios de
hipotensión intradialítica durante la hemodiálisis.
Keywords:
DDAVP.
Ultrafiltration
Intradialytic Hypotension.
Palabras clave: DDAVP. Ultrafiltración. Hemodiálisis.
Hipotensión intradialítica.
Hemodialysis.
Correspondence: Seyed S. Beladi-Mousavi
Department of Internal Medicine, Faculty of Medicine, Jundishapur
University of Medical Sciences, Ahvaz, Iran
[email protected]
[email protected]
RESUMEN
INTRODUCTION
Although considerable technical improvements have gained
since the introduction of hemodialysis in the early 1950’s
89
originals
Seyed S. Beladi-Mousavi et al. DDAVP in Prevention of Hypotension during HD
and life expectancy of patients with End stage renal disease
(ESRD) has improved, there are some complications with
different underlying mechanisms that commonly occur
during hemodialysis (HD) including intradialytic
hypotension (IDH), cramps, itching, nausea and vomiting,
chest and back pain, headache, and fever and chills.1-4
IDH is an important side effect of HD and continues to be a
leading problem, especially in the elderly and
cardiovascularly compromised patients and it has a negative
impact on health-related quality of life.5-7 In some patients,
the development of IDH necessitates decrease of the blood
flow rate in HD apparatus and in some times, even
discontinuation of HD and therefore it is an important cause
of under dialysis. On the other hand, in the patients that they
are need to ultrafiltration during HD, the development of
hypotention episodes contribute to discontinuation of
ultrafiltration and in some times, even necessitate
intravenous fluid replacement before they are able to leave
the dialysis unit and therefore, this problem can cause
volume overload and some other significant complication.7
Unfortunately the incidence of this problem is very high
especially among patients that they are received
ultrafiltration during dialysis. It is occurred in significant
percent of ESRD patients during or immediately following
HD and its incidence ranges from 15 to 50 percent of
dialysis sessions.7,8
Although a number of Studies have been evaluated to
decrease the incidence of IDH, however because of small
number of comparative studies and conflicting results, there
are no generally accepted guidelines for prevention of
hypotension during hemodialysis.9-14
The aim of this study is evaluating the possible effect of
intranasal DDAVP for prevention of IDH episodes during
hemodialysis.
MATERIAL AND METHODS
In a cross sectional clinical trial from May 2010 to
September 2010, the present double blinded study was
performed on ESRD patients who underwent hemodialysis
treatments at Imam hospital, Ahvaz, Iran.
The ESRD was defined as permanent and irreversible loss of
renal function due to any causes with creatinine clearance of
less than 10-15ml/min per 1.73m2 requiring renal
replacement therapy.
A standardized questionnaire was used to collect general
information such as age, gender, the record of previous
diseases and drugs, vital signs, causes of ESRD, date of
onset of HD and length of time receiving HD services.
90
HD patients with known symptomatic episode of IDH in at
least 30% of HD session in the 30 days preceding enrollment
were included and those with the following characteristics
were excluded from the study.
Patients who had used antihypertensive drugs in recent two
weeks, those that they didn’t need to ultrafiltration during
HD, Patients who had used other preventive measure for
prevention of hypotention during HD such as cold dialysate,
midodrine and others, those with a history of MI in 6 weeks
ago, anemic patients with hemoglobin level less than 10
gr/dl, and Patients who were suffered from gastrointestinal
bleeding during HD. The study was explained to the subjects
and all participants provided written informed consent. The
study has approved by the Research Center of Ahvaz
Joundishapur University of Medical Sciences.
After selection of patients, in the first month of the study, all
participants were received nasal spray of distill water (two
puffs) 30 minutes before all HD session (Placebo group,
Group 1) and then after a 30-day washout period we were
used intranasal DDAVP (two puffs) 30 minutes before all
HD session (Vasopressin group, Group, 2).
Blood pressure was measured and recorded by a trained
neurse, just before the needles for dialysis access were
placed, 2 hour after starting and at the end of each HD
session. Mean arterial blood pressure (MABP) was also
calculated as the diastolic pressure plus one-third of the
pulse pressure. For measurement of blood pressure, the
patients were seated for at least 5 minutes and arm supported
at heart level. We were used a manual aneroid
sphygmomanometer with an appropriate cuff size so that the
cuff bladder encircles at least 80% of the arm. An
intradialytic hypotensive episode was defined as a fall in
systolic blood pressure of at least 10 mm Hg two hour after
starting and or after termination of HD compared to pre
dialysis.
Statistical analysis: For data analysis, we were used the
statistical package for social sciences (SPSS) version 15
software. Chi-square tests or Fishers exact test were
performed to evaluate the distribution of variables. Statistical
significance was assessed at a probability level of < 0.05 in
all analysis.
Hemodialysis Methods
Hemodialysis was performed for 9-12h, three times a week,
using Fresenius machines, semi-synthetic (cellulose
diacetate), or synthetic (polysulfone) dialyzer membranes,
and bicarbonate- buffered dialysate (sodium 135mmol/l,
potassium 2mmol/l, calcium 1.5mmol/l, magnesium 0.5
mmol/l and bicarbonate 35mmol/l). Blood flow rate was
maintained from 250 to 400 mL/min, and the dialysate flow
Nefrologia 2012;32(1):89-93
rate at 500ml/min. Dialysate temperature was 36.58C
throughout the study period. Dry weight and rate of
ultrafiltration was determined individually by the patient’s
attending nephrologist on clinical grounds.
KT/V
KT/V was also calculated for the first and the end HD
session in two groups. For evaluation of KT/V, blood
sampling for blood urea nitrogen (BUN) was done
immediately before HD session and for postdialysis BUN,
our practice was to slow the blood pump to 100ml/min and
then obtain the blood sample 15 seconds later.
RESULTS
One hundred twenty eight ESRD patients were on HD in
Imam Hospital, Ahvaz, Iran. From them, one hundred eleven
patients were not assessable because they had no
hypotensive episodes and or because they had other
exclusion criteria; therefore the study was performed on
seventeen HD patients (nine men, eight women) with mean
age of 47.5 years (range of 22 yr to 65 yr). The cause of
ESRD in the patients on the study was diabetes mellitus in
eight patients (four men and four women) and others were
non diabetic (Hypertension, 5; Unknown, 3 and ADPKD, 1).
In overall 408 HD performed in the period of the study; 204
times (17 X 12) in the placebo group (Group 1) and 204
times (17 X 12) in the vasopressin group (Group 2).
The kind of hemodialysis machines, dialyzer membranes,
dialysate were the same in the both groups. The mean rate of
blood flow rate, dialysate flow rate and ultrafiltration rate
among vasopressin and placebo group in each HD session
were 300ml/mim and 290ml/min, 500ml/min and 500ml/min
and 2.3 liters and 2.2 liters respectively without a significant
difference between them.
Hypotensive episode during HD occurred 18 times (8.82%)
in vasopressin group compared with 125 times (61.27%) in
placebo group and therefore the rate of IDH was significantly
lower in vasopressin group (p=0.001). The mean of systolic
and diastolic blood pressure after termination of HD session
were 111.854 and 65.228 in vasopressin group and 102.671
and 59.550 in placebo group and there were a significant
association between them (p=0.025 in mean of systolic and
p=0.033 in mean of diastolic blood pressure).
In addition, the mean of arterial blood pressure after
termination of HD session in vasopressin group was 80.77
and in placebo group was 73.92 and also there was a
significant difference between them (p=0.0001). The mean
of Kt/v in group 1 and 2 were 1.297±0.217 and 1.290± 0.252
without any association between them (p=0.896).
Nefrologia 2012;32(1):89-93
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DISCUSSION
The pathogenesis of hemodialysis hypotension is thought to
be multifactorial, but generally results from inadequate
cardiovascular compensatory mechanisms and impairs
autonomic response to the aggressive reduction of
circulating blood volume during ultrafiltration.15,16 In addition
there are very strong arguments for an important role of
several vasoactive substances such as adenosine
(cardiodepressive and endogenous vasodilator) and nitric
oxide (endogenous vasodilator) which may be synthesized or
released during dialysis in pathogenesis of IDH.17,18
Although vasopressin is widely recognized for its role in the
regulation of sodium balance and plasma osmolality, it is
also a well-recognized vasoconstrictor and the role of
vasopressin insufficiency as an important cause of IDH has
also demonstrated in recent years by several observations.19-23
In the first time, the possible role of vasopressin
insufficiency as a cause of hemodynamic instability during
HD, showed by Friess et al in 1994. They measured plasma
AVP level in 23 patients with recurrent dialysis
hypotension and showed that AVP concentration only
increased in six patients with nausea and hypotension and in
the remaining 17 patients without nausea AVP level did not
increased.19
In the setting of hypotension as an example in patients with
septic shock, the release of vasopressin is usually increased
and in together with other vasoconstrictors cause systemic
vascular resistance and elevates blood pressure.23 It is
therefore hypothesized that the inappropriately low
vasopressin concentrations due to decreased endogenous
AVP synthesis and or secretion may explain recurrent
dialysis hypotension in the previous study.
Sato et al and Cignareli et al in two separate study in
nondialysis diabetic patients with severe diabetic
neuropathy demonstrated that AVP concentrations do not
appropriately increase in the setting of orthostatic
hypotension.24,25 Therefore the results of two studies are
supported the important effect of vasopressin in maintenance
of blood pressure. In addition because of diabetes mellitus is
the most common co morbidities associated with ESRD, the
results of these studies also suggested that vasopressin
insufficiency may be a part of the underlying mechanism of
IDH in diabetic patients.
Mira Rho et al also demonstrated vasopressin insufficiency
as a possible mechanism of IDH in ESRD patients and
supported the findings of Friess et al.20 They performed an
observational pilot study on 20 chronic hemodialysis
patients and observed that AVP concentration did not
increase as would normally be expected in patients with
symptomatic IDH in response to severe hypotension and
therefore they have suggested that intravenous vasopressin
91
originals
and perhaps intranasal vasopressin administration may
improve hemodynamic stability in patients with
symptomatic IDH.
Although in our study we were not measured concentration
of AVP in HD patients with IDH, however the data from this
clinical trial are also supported the findings of the studies of
Friess et al and Mira Rho et al. According to the our study,
the use of two puffs of intranasal DDAVP 30 minutes before
HD session was significantly associated with a decreased
incidence of hypotensive episodes among patients that they
are received ultrafiltration during dialysis.
hypotension episodes among patients that they are received
ultrafiltration hemodialysis. Although the results of our study
are interesting but the small number of patients enrolled in
the study is a limit factor and therefore further research with
larger number of patients is needed to determine the effect of
vasopressin administration for prevention of hypotension
during HD.
Acknowledgements
Other than our study, there are few clinical trials that they
have evaluated the possible effect of vasopressin in
prevention of IDH episodes during hemodialysis. As an
example, in a study Van der Zee et al measured plasma
vasopressin concentration during HD and found that plasma
vasopressin levels did not increase during ultrafiltration
dialysis. Then they examined 22 ESRD patients in a
randomized, double-blinded and placebo-controlled trial and
showed that blood pressure was more stable in the patients
receiving constant infusion of a non-pressor dose of
vasopressin during hemodialysis and the incidence of
symptomatic hypotensive episode was significantly lower in
comparison to the placebo group. Finally, they concluded
that administration of vasopressin improves cardiovascular
stability and facilitates fluid removal during hemodialysis.21
This paper is issued from thesis of Dr. Mehdi Talebzadeh and financial
support was provided by Ahvaz Joundishapur University of Medical
Sciences. We would like to express our appreciation to the division
head and the staff and of course ESRD patients in HD center of Imam
Hospital in the province of Khuzestan, Ahvaz, Iran, for their help.
Jills et al have also showed efficacy of vasopressin in
prevention of hypotension during hemodialysis. In this
double-blind crossover study, they were used intranasal
lysine vasopressin in 6 patients with refractory
hemodialysis-induced hypotension and have reported that
Systolic, diastolic, and mean arterial blood pressures were
more stable with use of vasopressin.22
1. Skroeder NR, Jacobson SH, Lins LE, Kjellstrand CM. Acute symptoms
during and between hemodialysis: the relative role of speed, duration, and biocompatibility of dialysis. Artif Organs 1994;18:880.
2. Van der Sande FM, Kooman JP, Leunissen KM. Intradialytic hypotension—new concepts on an old problem. Nephrol Dial Transplant
2000;15:1746.
3. Milinkovic M, Zidverc-Trajkovic J, Sternic N, Trbojevic-Stankovic J,
Maric I, Milic M, et al. Hemodialysis headache. Clin Nephrol
2009;71:158.
4. Zager PG, Nikolic J, Brown RH, Campbell MA, Hunt WC, Peterson
D, et al. “U” curve association of blood pressure and mortality in
hemodialysis patients. Kidney Int 1998;4:561-9.
5. Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int 2004;66:1212-20.
6. Dasselaar JJ, Huisman RM, de Jong PE, Franssen CF. Measurement
of relative blood volume changes during haemodialysis: merits and
limitations. Nephrol Dial Transplant 2005;20(10):2043-9.
7. Kooman J, Basci A, Pizzarelli F, Canaud B, Haage P, Fouque D, et al.
EBPG guideline on haemodynamic instability. Nephrol Dial Transplant 2007;22 Suppl 2:ii22-44.
8. Dheenan S, Henrich WL. Preventing dialysis hypotension: a comparison of usual protective maneuvers. Kidney Int 2001;59(3):117581.
9. Daugirdas JT. Preventing and managing hypotension. Semin Dial
1994;7:276-83.
10. Knoll GA, Grabowski JA, Dervin GF, O’Rourke K. A randomized,
CONCLUSION
Intradialytic hypotension (IDH) continues to be a leading
problem in patients with ESRD and it has an important
negative effect on health-related quality of life.
Unfortunately, because of small number of comparative
studies, there are no generally accepted guidelines for
prevention of this problem. Some studies have showed that
AVP concentration do not increase as would normally be
expected in patients with symptomatic IDH. Therefore it is
hypothesized that the inappropriately low vasopressin
concentrations is a significant part of the underlying
mechanism of IDH and perhaps intravenous vasopressin and
or intranasal vasopressin administration may prevent
hypotension during HD. According to the present clinical
trial, the use of two puffs of intranasal DDAVP 30 minutes
before HD session Compared with placebo is significantly
associated with a decreased incidence of intradialytic
92
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Daugirdas JT. Pathophysiology of dialysis hypotension: an update.
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Leunissen KM, Kooman JP, van Kuijk W, van der Sande F, Luik AJ, van
Hooff JP. Preventing haemodynamic instability in patients at risk for intra-dialytic hypotension. Nephrol Dial Transplant 1996;11 Suppl 2:11-5.
Armengol NE CAA, Bono Illa M, Calls Ginesta J, Gaya Bertran J, Rivera Fillat DR. Vasoactive hormones in uraemic patients with chronic hypotension. Nephrol Dial Transplant 1997;12:321-4.
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19. Friess U, Rascher W, Ritz E, Gross P. Failure of arginine-vasopressin and other pressor hormones to increase in severe recurrent
dialysis hypotension. Nephrol Dial Transplant 1995;10:1421-7.
20. Rho M, Perazella MA, Parikh CR, Peixoto AJ, Brewster UC.
Serum Vasopressin Response in Patients with Intradialytic
Hypotension: A Pilot Study. Clin J Am Soc Nephrol
2008;3(3):729-35.
21. Van der Zee S, Thompson A, Zimmerman R, Lin J, Huan Y, Braskett M,
et al. Vasopressin administration facilitates fluid removal during hemodialysis. Kidney Int 2007;71:318-24.
22. Lindberg JS, Copley JB, Melton K, Wade CE, Abrams J, Goode D. Lysine Vasopressin in the Treatment of Refractory Hemodialysis-Induced
Hypotension. Am J Nephrol 1990;10:269-75.
23. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin
relevant to management of septic shock. Chest 2001;120:989-1002.
24. Sato K, Kimura T, Ota K, Shoji M, Ohta M, Yamamoto T, et al. Changes in plasma vasopressin levels and cardiovascular function due to
postural changes in diabetic neuropathy. Tohoku J Exp Med
1995;177:49-60.
25. Cignarelli M, De Pergola G, Paternostro A, Corso M, Cospite MR, Centaro GM, et al. Arginine-vasopressin response to supine-erect posture
change: an index for evaluation of the integrity of the afferent component of baroregulatory system in diabetic neuropathy. Diabete Metab
1986;12:28-33.
Sent for review:11 May. 2011 | Accepted: 1 Nov. 2011
Nefrologia 2012;32(1):89-93
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Echocardiographic impact of hydration status in
dialysis patients
Isabel Juan-García1, María J. Puchades1, Rafael Sanjuán2, Isidro Torregrosa1, Miguel Á. Solís1,
Miguel González1, Marisa Blasco2, Antonio Martínez1, Alfonso Miguel1
1
2
Servicio de Nefrología. Hospital Clínico Universitario de Valencia. Spain
Servicio de Medicina Intensiva. Hospital Clínico Universitario de Valencia. Spain
Nefrologia 2012;32(1):94-102
ABSTRACT
Introduction: Cardiovascular disease is the main cause of death
in Chronic Kidney Disease patients. Left ventricular hypertrophy
is the most common manifestation and it is linked to arterial
hypertension and overhydration. The goal of this paper is to
stratify dialyzed patients according to hydration status and to
make an evaluation about the possible echocardiography
alterations of the different groups. Methods: a transversal study
was carried out with 117 patients: 65 were on hemodialysis and
52 on peritoneal dialysis. We performed the following tests:
multifrequency bioimpedance with the BCM-Body Composition
Freesenius’ Monitor system, transthoracic echocardiography,
and blood tests. If ECW/TBW (extracellular water vs total body
water) normalization ratio for age and gender was > 2.5% SD,
the patient was considered overhydrated. Results: HD patients
are significantly overhydrated before HD (67.1%) compared to
DP patients (46.1%), and almost half of the overhydrated
population presents arterial hypertension. However, after an
HD session, a better control of the hydration status is reached
(26.1%). DP patients frequently present high arterial pressure
and/or are under antihypertensive treatment (DP 76.9% vs HD
49.2%). Left ventricular hypertrophy is much more common in
HD overhydrated patients, eccentric LVH being more prevalent.
Overhydrated patients present significantly high values of LAVI,
ILVM, OH/ECW. Conclusions: Bioimpedance technique allows for
the detection of a large number of overhydrated patients.
Echocardiographic alterations in dialyzed patients show a high
correlation between the hydration stage by ECW/TBW
normalized ratio for age and gender and the LAVI and ILVM.
Keywords: Bioimpedance spectroscopy. Left arterial volumen
index. Left ventricular hypertrophy. Volume status.
Correspondence: Isabel Juan García
Hospital Clínico Universitario de Valencia.
Avda. Blasco Ibáñez 17. Valencia. Spain.
[email protected]
94
Repercusión ecocardiográfica del estado de hidratación
en los pacientes en diálisis
RESUMEN
Introducción: La enfermedad cardiovascular es la principal
causa de muerte en los pacientes con enfermedad renal crónica. La hipertrofia ventricular izquierda (HVI) es la manifestación más frecuente y está relacionada con la hipertensión
arterial y la hiperhidratación. El objetivo del presente trabajo
es estratificar a los pacientes en diálisis según el estado de hidratación y valorar las posibles alteraciones ecocardiográficas
en los distintos grupos. Métodos: Realizamos un estudio
transversal de 117 pacientes, 65 en hemodiálisis (HD) y 52 en
diálisis peritoneal (DP). Las exploraciones realizadas fueron:
bioimpedancia multifrecuencia con el sistema BCM-Body
Composition Monitor de Freesenius, ecocardiografía transtorácica y analítica de sangre. Definimos hiperhidratación cuando el cociente volumen extracelular-volumen corporal total
(ECW/TBW) normalizado para edad y sexo es > 2,5% de la
desviación estándar. Resultados: Los pacientes en HD están
pre-HD (67,1%) más hiperhidratados de forma significativa
que los de DP (46,1%), presentando casi la mitad de la población hiperhidratada hipertensión arterial; tras la sesión de HD
se consigue un mejor control del estado de hidratación
(26,1%). Los pacientes en DP presentan con más frecuencia
cifras de tensión arterial alta y/o llevan tratamiento antihipertensivo (DP 76,9 vs. HD 49,2%). La HVI es más frecuente en
los pacientes en HD e hiperhidratados, siendo la más prevalente la HVI excéntrica. Los pacientes hiperhidratados presentan cifras superiores, de forma significativa, del IVAI (volumen
de aurícula izquierda indexada por superficie corporal, la
IMVI (masa ventricular izquierda indexada) y el cociente sobrehidratación-agua extracelular. Conclusiones: La bioimpedancia es una técnica que nos permite detectar un gran número de pacientes hiperhidratados. Al estudiar las
alteraciones ecocardiográficas en los pacientes en diálisis encontramos una alta correlación entre el estado de hidratación
por ECW/TBW normalizado para edad y sexo, y el IVAI e IMVI.
Palabras clave: Bioimpedancia espectroscópica. Volumen
de aurícula izquierda indexada. Hipertrofia de ventrículo
izquierdo. Estado de hidratación.
INTRODUCTION
Cardiovascular disease is the main cause of death in patients
with chronic kidney disease (CKD).1 This is usually due to
Isabel Juan-García et al. Echocardiographic impact of hydration status in dialysis patients
the presence of traditional risk factors, such as diabetes
mellitus, hypertension (AHT), dyslipidaemia and advanced
age,2 and to the actual kidney disease (overhydration,
uraemic cardiomyopathy and vascular damage, i.e.
atherosclerosis, vascular calcification and arterial stiffness).
The main manifestations of cardiovascular disease in these
patients are arterial vascular disease and cardiomyopathy.3
The high prevalence of cardiomyopathy is due to AHT and
atherosclerosis, which create excess pressure and lead to the
development of concentric left ventricular hypertrophy
(LVH). Anaemia, fluid overload and arteriovenous fistulae
create volume overload, which leads to left ventricular
dilation with eccentric LVH.4,5,6
There are various methods for assessing hydration status.
Assessment of the inferior vena cava and biochemical
parameters, such as B-type natriuretic peptide, are useful
methods for assessing intravascular hydration status,7 while
bioimpedance spectroscopy (BIS) assesses body and
extracellular hydration states.8 The latter technique is simple,
inexpensive, reproducible, non-invasive and easy to apply,
and is based on the human body’s resistance to alternating
electrical currents. It assesses not only hydration status but
also intracellular and extracellular water, the extracellular
and intracellular ratio, the total water volume, as well as
nutritional parameters.
The aim of this study was to stratify patients on dialysis
according to hydration status, and to assess possible
echocardiographic abnormalities in the various groups
according to dialysis technique.
METHOD
Patients
We performed a cross-sectional observational study on 117
clinically stable patients on the dialysis programme of the
University Clinical Hospital of Valencia between 2008 and 2010.
The study included 65 patients (41 males) from the Haemodialysis
Unit and 52 patients (28 males) from the Peritoneal Dialysis Unit.
Those patients who had arrhythmia, severe valvular heart disease,
amputation of any limb, pacemakers or metal prostheses that
would interfere with bioimpedance were excluded. All patients
signed the informed consent and the hospital ethics committee
approved the study protocol.
Measurements
Examinations of patients on haemodialysis (HD) were
performed during the middle of the week, while patients on
peritoneal dialysis were examined before the first
replacement of the morning with an empty peritoneum.
Nefrologia 2012;32(1):94-102
originals
To assess hydration status, we used multifrequency
bioimpedance with the Fresenius BCM-Body Composition
Monitor, which measures 50 different frequencies from
5kHz to 1MHz. This technique has been validated by
dilution techniques that are considered the gold standard,9
dual X-ray absorptiometry and plethysmography,10 among
others.11,12 For the measurement, we used two pairs of
electrodes: one at a distal position, an injector and a sensor,
placed dorsally on the hand (third metacarpophalangeal and
carpal joints, respectively) and another on the foot (third
metatarsophalangeal and tibiotarsal joints). The reference
was the right hemisoma; in HD, the reference was the
hemisoma free of vascular accesses. Prior to the procedure,
patients were accurately measured and weighed.
Examination was performed in the HD group before and
after the session. In both HD and peritoneal dialysis (PD),
the patient was placed in supine decubitus for 15-20 minutes
before the examination in order to help distribute excess
fluid and avoid the presence of oedema that could distort
results. After the HD session, we also waited the same
amount of time to allow balancing among the various
compartments (intravascular-extravascular-cellular).
Among the various parameters obtained by BIS, we chose
the extracellular water-total body water ratio (ECW/TBW) to
assess hydration status and the overhydration-extracellular
water ratio (OH/ECW) for the mortality risk.
Patients were classified by hydration status by means of
ECW/TBW normalised for age and gender using the method
described by Lindley et al, i.e. the difference between the
theoretical ratio under normal conditions and that obtained
by bioimpedance. If the difference is >2.5%, the patient is
hyperhydrated (HHD), if between >2.5% and <2.5% the
patient is normohydrated (NHD), and dehydrated if <2.5%.13
The OH/ECW is a ratio that currently is defined as a
significant and independent predictor of mortality in patients
on dialysis when it is greater than 15%.14
We defined AHT in those patients who had blood pressure
(BP) readings >140/80mm Hg and/or were taking
antihypertensive drugs.
On the examination day, a blood test was performed to
determine haemoglobin (mg/dl), calcium (mg/l), phosphorus
(mg/l), parathormone (pg/ml), total proteins (g/dl) and
albumin (g/dl) in each patient.
We performed transthoracic echocardiography with a
multifrequency transducer and a tissue Doppler program
(Aloka) before the HD session, and after emptying the
peritoneal cavity in PD. Readings and measurements were
made following the recommendations of the American
Society of Echocardiography (ASE).11,15 Left ventricular
mass (LVM) was calculated using the modified ASE
95
originals
formula,16,17 which is the most widely used method since it
has shown values closely associated with autopsy findings:
LVM=0.8x [1.04x (LVTDD + TDTS + TDTPW) 3+
(LVTDD)3] +0.6 (LVTDD: LV telediastolic diameter;
TDTS: telediastolic thickness of the septum; TDTPW:
telediastolic thickness of the posterior wall). LVM was
indexed by body surface (ILVM). Based on the studies of
Devereux et al, the cut-off point for the diagnosis of LVH
using the ILVM was ≥125g/m2, with no difference by
gender (Figure 1).16
r > 0.45
ILVM (g/m2)
< 125
ILVM (g/m2)
> 125
Remodeling
Concentric hypertrophy
Normal
Eccentric LVH
To classify the type of LVH, we calculated the relative
thickness (RT) with the formula: RT=2xPW/LVTDD; we
considered a normal RT when <0.45.16
The assessment of the left atrium was performed by
measuring the left atrium volume by the indexed Simpson’s
disc summation method, where the volume of the left atrium
is the individual summation of all discs in the series. We
used this method for its speed and for correlating well with
any method for determining left atrial volume.18,19
r < 0.45
ILVM: indexed left ventricular mass
Figure 1. Patterns of left ventricular hypertrophy
Data were processed using the SPSS 15 program. Results are
expressed as mean, standard deviation for data with normal
distribution; and as median, interquartile range (IQR) and
confidence interval (CI) for data that did not have normal
distribution. We performed the comparison of means with
the Mann-Whitney and Student’s-t test according to the
distribution of the variables. Linear regression was
performed with Pearson’s p. To compare means between the
two groups, we performed ANOVA for one factor with
Bonferroni and Dunnett’s C post-hoc tests, according to the
homogeneity of variances. Values of P<.05 were considered
statistically significant. We performed a multivariate
analysis, using eccentric LVH as the dependent variable and
the other study variables as independent variables.
RESULTS
We examined 117 patients, 65 patients in the HD group and
52 in the PD group. The relevant demographic and clinical
characteristics and cardiovascular risk factors are shown in
Table 1. It is noteworthy that patients who were on HD had
been longer on the technique and had lower residual renal
function (RRF) than patients on PD. As for laboratory tests,
it is noteworthy that patients on HD had higher readings of
total proteins and albumin in blood.
The presence of AHT was greater in PD patients, although HD
had poorer control of readings. The use of antihypertensive drugs
and their combination was greater in patients on PD patients
(59.6% vs 30.8%). The most frequently used drugs in both
groups were calcium antagonists and angiotensin-converting
enzyme inhibitors (ACEI)/angiotensin II receptor antagonists
(ARAII). Diuretics were used more frequently in PD.
96
We initially examined the relationship in each dialysis group
between the hydration status and BP, by means of
normalised ECW/TBW ratios. Patients on HD before and
after performing the session presented hydration states and
BP readings that are shown in Figure 2 and Figure 3. The
distribution of patients on PD is shown in Figure 4.
In the HD group, 37.5% presented systolic blood pressure
(SBP) readings >140mm Hg, with 25% being HHD and
12.5% NHD. Some 62.5% were normotensive, with 42.1%
being HHD and 18.8% NHD. In the PD group, 24.9% had
SBP >140mm Hg, 11.5% were HHD and 11.5% were NHD.
Some 74.9% were normotensive, with 34.6% being HHD and
32.6% NHD. We observed a decline in the number of HHD
patients in the HD group after the session (67.1% pre-HD
compared to 26.1% post-HD), as well as a decline in blood
pressure readings (SBP>140mm Hg - 37.5% to 32.6%).
If we consider the presence of hypertension (>140/80mm Hg
or drug treatment) and the hydration status in each dialysis
group, we observe AHT in 45.45% of the HD group, of
which 30.3% were HHD. After the HD session, we observed
a decrease in AHT patients (post-HD 43.4%) and a decrease
in the number of HHD patients (68.1% vs 27.3%). In PD
patients, 69.2% had HTA, of which 28.8% were HHD.
Therefore, if we consider the readings for BP and drug
treatment, we find greater AHT in PD patients and greater
HHD states in PD patients than in readings after HD.
The presence of HHD according to ECW/TBW was more
frequent in HD than in PD before the dialysis session
(67.1% pre-HD compared to 46.1% PD), but after the HD
Nefrologia 2012;32(1):94-102
originals
Table 1. Characteristics of patients on peritoneal haemodialysis and dialysis
HD Group
PD Group
(n=65)
(n=52)
60 ±13,8
59 ±17,8
NS
41/24
28/24
NS
51.8 (3-259)
33.5 (3-93)
0.04
RRF (% pac)
43.1
65.38
NS
Diuresis (cc)
1000 (421.5-749.6)
1625 (482-981.6)
NS
Hypertension (%)
46.2
69.2
0.04
BP>140/80mm Hg (%)
37.5
24.9
NS
Antihypertensive treatment (%)
30.8
59.6
0.003
Diuretics (%)
15,2
21,2
NS
ß-blockers (%)
12,1
17,3
NS
Calcium antagonists (%)
18,2
32,7
NS
ACEI/ARAII (%)
18,2
46,2
0,007
α-blockers (%)
18,2
19,2
NS
Drug combination (%)
18.2
48.1
NS
Calcium (mg/l)
9.2±0.64
9.5±0.63
P<.05
Phosphorus (mg/l)
4.9±1.48
4.7±1.37
NS
283.83 (20.8-1.485)
214.8 (18-763.7)
NS
6.8±0.54
6.2±0.59
P<.001
Albumin (g/dl)
3.9±0.31
3.5±0.37
P<.001
Haemoglobin (mg/dl)
12.24±1.7
11.8±1.68
NS
Age (years)
Gender (M/F)
Time on technique (months)
PTH (pg/ml)
SD
ARA II: angiotensin II receptor antagonists; PD: peritoneal dialysis; SD: standard deviation; HD: haemodialysis; ACEI: angiotensin-converting enzyme
inhibitors; RRF: residual renal function; NS: not significant; PTH: parathormone; BP: blood pressure.
session a better control of the hydration status is achieved
(post-HD 26.1%).
When analysing each dialysis group according to hydration
status, the subgroup of HHD patients in both techniques had
been longer on the technique (HHD HD 60.9 months vs
NHD HD 36.5 months; HHD PD 36.3 months vs NHD PD
34.8 months), with only those on HD showing a significant
difference. The presence of RRF was similar in both
techniques, although it was lower in the HHD group (RRF
HHD HD 34.9% vs NHD HD 55%; HHD PD 37.5% vs
NHD PD 42.9%).
According to the data obtained using BCM, patients on HD
had significantly greater overhydration (OH) and
extracellular/intracellular (E/I) water than those on PD
(Table 2).
The second phase of the study consisted of assessing each
dialysis group, according to the hydration status as
Nefrologia 2012;32(1):94-102
measured by ECW/TBW, the echocardiographic
characteristics and the correlation among the data obtained
by bioimpedance (Table 3).
Left atrial volume indexed to body surface (LAVI) and
indexed left ventricular mass (ILVM) were significantly
greater in patients in the HD group and in the HHD
subgroup of both techniques. The OH/ECW ratio was
significantly greater in HD patients than in PD patients
(>15%, 14.06% in HD vs 3.8% in PD), as well as in HHD
patients in each type of dialysis.
If we assess the geometry of the left ventricle in our study
population, we observe the presence of LVH in 27.6% of the
HD group and 13.4% in PD; the most prevalent in both
groups being the eccentric one. According to the hydration
status, the presence of LVH was greater in the HHD group
(HD 27.9% vs PD 20.8%) than in the NHD group (25% vs
9.5%), with eccentric LVH being the most prevalent (Tables
4 and 5). In the univariate study of eccentric LVH with all
97
originals
220
220
12.5%
251%
200
BP (mm Hg)
BP (mm Hg)
160
140
120
18.7%
1.5%
100
42.1%
140
120
4.9%
44.2%
18%
80
-4
-2
0
2
4
6
8
60
-6
10
Pre HD ECW/TBW (%)
24.5%
11.5%
11.5%
200
180
160
140
120
100
7.6%
34.6%
32.6%
80
60
-6
-4
-2
0
2
-2
0
2
4
6
8
10
ECW/TBW: extracellular water-total body water ratio; HD:
haemodialysis; BP: blood pressure.
Figure 2. Distribution of patients on haemodialysis before the
session according to blood pressure readings and the difference
of the ECW/TBW ratio.
220
-4
Post HD ECW/TBW (%)
ECW/TBW: extracellular water-total body water ratio; HD:
haemodialysis; BP: blood pressure.
BP (mm Hg)
160
100
80
4
6
8
10
PD ECW/TBW (%)
PD: peritoneal dialysis; ECW/TBW: extracellular water-total body
water ratio; BP: blood pressure.
Figure 4. Distribution of patients on peritoneal dialysis
according to blood pressure readings and the difference of the
ECW/TBW ratio
variations, the only one of significance was eccentric LVH
with hydration status (normalised ECW/TBW) with a
significance of P=.03 (CI 1.1-11.5).
DISCUSSION
Bioimpedance is a technique that allows us to detect a large
number of HHD patients. It is an easily applicable method
and may be considered the gold standard in determining
98
8.1%
180
180
60
24.5%
200
Figure 3. Distribution of patients on haemodialysis after the
session according to blood pressure readings and the difference
of the ECW/TBW ratio.
hydration states. Various methods have been used to assess
hydration status, but they are unreliable since numerous
factors may interfere. The assessment of the hydration status
by means of the BP may be distorted by antihypertensive
therapy, AHT not dependent on volume, and the presence of
heart disease;20 the inferior vena cava shows the intravascular
volume by diastolic dysfunction;21 and RRF and the presence
of heart diseases,22 among others, may interfere with
biochemical markers, such as BNP and pro-BNP.
We found in the literature that various parameters have been
used to define hydration status by bioimpedance: OH/ECW,
ECW/TBW, E/I and OH. Lopot et al determined the optimal
dry weight in HD patients using the deviation between
ECW/TBW obtained by bioimpedance and that obtained in a
control group, according to age and sex. This is based on
changes produced in the cell mass (with increasing age, the
cell mass and therefore the intracellular water decreases) and
the hydration status (with increasing age and/or female
gender, the intracellular water decreases).23 Lindley et al
determined the dry weight in PD using the difference
between ECW/TBW obtained by BIS compared to
ECW/TBW of a control group according to patient age and
gender (defining HHD as those who had +2.5% standard
deviation).13
We assessed the hydration status of our patients based on
these principles.9,24 In the HD group, we found significantly
more HHD patients before HD (67.1%) than in the PD group
(46.1%), and almost half had AHT. After the HD session,
better control of hydration status is achieved (26.1%).
Devolder I et al assessed hydration status by means of
OH/ECW (overhydrated OH/ECW>15%),23 Plum et al by
Nefrologia 2012;32(1):94-102
originals
Table 2. Assessment of the heart and the overhydration-extracellular water ratio according to the state of hydration in
each dialysis group
LAVI (ml/m )
2
ILVM (g/m2)
HD Group
HDHHD
HDNHD
HD Group
PDHHD
PDNHD
35.6±13.2
37.5±12.9
31.2±11.6
28.5±10.3
31.6±10.9
25.6±10
(32.3-38.9)α
(33.5-41.6)β
(25.7-36.6)
(25.5-31.6)
(26.5-36.8)
(20.8-30.4)
108.8±30.3
116.5±28.4
94±26.1
96.7±25.1
105.5±26.4
85.1±20.7
(101.2-116.4)α
(107.5-125.4)β
(81.7-106.2)γ
(104.2-89.28)
(93.1-117.9)
(75.1-95.1)
14.06
100
0
3.8
100
0
OH/ECW
(> 15%)
ECW/TBW
48.7±3.05
50.2±2.3
46.2±1.5
47±4.6
50.7±3.1
44.6±2.8
(48.03-49.5)α
(49.5-50.9)β
(45.4-46.9)γ
(45.7-48.3)
(49.4-52.1)
(43.4-45.9)
(a) P<.05 between HD and PD; (b) P<.05 between HDHHD and PDHHD; (g) P<.05 between HDNHD and PDNHD.
PD: peritoneal dialysis; ECW/TBW: extracellular water-total body water ratio; HD: haemodialysis; HHD: hyperhydrated; ILVM: indexed left ventricular mass;
LAVI: left atrial volume indexed to body surface; NHD: normohydrated; OH/ECW: overhydration/extracellular water ratio.
Table 3. Parameters obtained by bioimpedance in peritoneal haemodialysis and dialysis groups
HD Group
PD Group
P
Pre-HD
Post-HD
OH (l)
1.13±1.36 (0.7-1.4)
–0.27±1.39 (–0.63-0.08)
0.28±1.3 (–0.09-0.66)
0.000
0.001
TBW (l)
32.9±7.7 (31-34.8)
31.7±7.5 (29.8-33.6)
32.7±6 (31-34.4)
0.000
0.86
ECW (l)
16±3.9 (15.11-16.9)
14.6±3.3 (13.7-15.4)
15.2±2.5 (14.5-15.9)
0.000
0.2
ICW (l)
16.8±4.3 (15.8-17.9)
17.1±4.4 (15.9-18.2)
17.4±4.1 (16.2-18.5)
0.059
0.48
E/I
0.96±0.11 (0.93-0.99)
0.86±0.1 (0.83-0.89)
0.9±0.17 (0.85-0.95)
0.000
0.03
32.6±9.8
33.4±9.7
33.2±11.9
0.08
0.7
(30.1-35)
(31-35.9)
(29.8-36.5)
28.9±9.2 (26.6-31.2)
27±8.6 (24.8-29.2)
26.7±10.2 (23.9-29.6)
0.09
0.2
Muscle mass (kg)
Fat mass (kg)
Pre-Post-HD-P
PD: peritoneal dialysis; ECW: extracellular water; E/I: ECW/ICW ratio; HD: haemodialysis; ICW: intracellular water; OH: overhydration water; TBW: total body
water.
ECW/TBW25 and Passauer et al by OH (litres of
overhydration >1.1 I).11 They found that hydration status was
harder to control in patients on PD than in post-HD patients,
which is consistent with our data.
Table 4. Left ventricular geometry according to dialysis
type
HD Group (%)
DP Group (%)
Normal
46.15
61.5
Concentric remodelling
26.1
25
Eccentric hypertrophy
21.5
9.6
6.1
3.8
PD: peritoneal dialysis; HD: haemodialysis.
Nefrologia 2012;32(1):94-102
The bodily distribution of excess fluid in patients on dialysis
varies according to the type of technique. Therefore, the
impact of hydration status on BP and at the cardiac level
must vary. In the literature, excess fluid in patients on PD is
found peripherally in the subcutaneous tissue, while in HD
patients it is located in the bloodstream.25 In HD, there is an
increase in body weight in the interdialytic period (48
hours), due to the consumption of liquids and food, and a
decrease during the session (4 hours) by the ultrafiltration of
the accumulated water volume and by the convective and
diffusive transport of sodium. Abrupt changes occur at the
intravascular level, very slowly from the interstitial space by
means of refilling. Interdialytic weight gain is greater in
patients who do not have RRF. The PD technique is usually
performed continuously, and the balance between the various
compartments is produced constantly. Ultrafiltration is
produced from the interstitial space.
99
originals
Table 5. Left ventricular geometry according to hydration state
HHDHD (%)
NHDHD (%)
DHDHD (%)
HHDPD (%)
NHDPD(%)
DHDPD(%)
Normal
46.5
45
----
54.1
66.6
71.5
Concentric remodelling
25.5
30
----
25
23.8
28.5
9.3
0
----
8.3
0
0
Eccentric hypertrophy
18.6
25
----
12.5
9.5
0
DHD: dehydrated; PD: peritoneal dialysis; HD: haemodialysis; HHD: hyperhydrated; NHD: normohydrated.
We must remember that bioimpedance assesses the intraextracellular hydration status, and not hydration at the
intravascular level. The increased state of HHD in HD before the
session is due to weight gain in the interdialytic period, which is
located at the extracellular and intravascular level, resulting in a
greater E/I ratio. After the HD session, the hydration status is
reduced by the ultrafiltration of the intravascular space, and it
takes some time for the various compartments to reach a
balance. In PD, we observed a significantly lower E/I ratio than
in HD (E/I pre-HD 0.96 vs PD 0.9) due to a lower extracellular
water (ECW pre-HD 16 1 vs PD 15.2 1) because ultrafiltration
in this technique is performed constantly. Therefore, when we
perform bioimpedance in patients on HD, especially after the
session, balance has not yet been reached among the various
compartments. Probably because of this, hydration parameters in
PD compared to post-HD may be distorted.
dry weight, continuous changes in the peritoneal membrane,
etc.) Patients in HD had greater hydration states before the
dialysis session, but decreased after the session, with
subsequent increases up to the next session, reflecting these
changes in the blood pressure. Patients on HD usually had less
antihypertensive treatment because during the HD session a
reduction in intravascular volume is produced and this must
be adapted. If the patient is undergoing antihypertensive
treatment, the compensation and/or vascular adaptation
mechanisms are blocked and present continuous vasodilation,
which results in hypotension, poor tolerance, and an inability
to reach the target dry weight. At the same time, vascular
refilling is produced from the interstitial liquid at different
speeds, depending on the patient’s characteristics (elderly,
diabetic, and patients with ventricular dysfunction or
pulmonary hypertension present very slow refilling).
In the literature, the prevalence of AHT in patients on HD is
around 60% in the interdialytic period,26 while for PD it is
greater (80%).27 Our prevalence of AHT was lower. The
presence of high BP readings and/or antihypertensive treatment
was greater in PD patients (PD 76.9% vs HD 49.2%), but they
had better blood pressure control (BP<140mm Hg, 37.5% HD
vs 24.9% PD), probably due to the greater use of
antihypertensive drugs. The most widely used drugs in both
groups were calcium antagonists and ACEI/ARAII.
The prevalence of LVH is 75% among patients on dialysis,30,31,32
and develops in initial stages of CKD. Numerous studies have
shown its increase in parallel with the reduction of GFR.33 AHT
and hyperhydration have an impact on the heart with the
development of LVH, among other risk factors. We found
studies, such as the Wang AY et al study, where RRF had
considerable influence and 70% of patients with no RRF
presented ventricular modelling disorders.34 The development
of LVH varies according to the type of overload. Fluid or
volume overload is related to the onset of eccentric LVH, while
pressure overload and AHT is related to concentric LVH. We
found a correlation between eccentric LVH and the hydration
state. Foley et al suggest that regression of LVH does not occur
after starting dialysis and that it is irreversible, due to high
patient mortality.35,36 However, last year we found published
studies that demonstrated that LVH regression is possible after
years of dialysis. Several therapeutic strategies may work:
control of anaemia, control of hydration status, use of
antihypertensive drugs in normotensive and hypertensive
patients, daily or night-time use of HD, prevention and
treatment of hyperphosphataemia, vitamin D administration,
and multifactorial intervention.37,38,39 We found regression not
only in patients on HD, but also in patients on PD.40,41
Diuretics are used more in PD due to the greater prevalence
of RRF, and this allows us to increase the diuresis volume
and adjust hydration status. The increased presence of RRF in
PD is due to PD being a continuous technique, with constant
ultrafiltration that precludes abrupt changes in volume, which
helps protect the kidney. Moreover, patients on HD usually
have poorer renal function due to the greater use of
nephrotoxic agents (aminoglycosides, contrast media, non
steroidal anti-inflammatory drugs), the bioincompatibility of
filter membranes and/or increased frequency of hypotension
episodes.28,29 We found an inverse correlation between time on
dialysis and presence of RRF in our patients, due to the
continuous development of kidney disease over time, which
results in a reduced RRF, although in most studies the mean
time on the technique is lower than ours.
The greater frequency of AHT in PD patients may be due to
the greater hydration status (less accuracy in the adjustment of
100
In our study, the prevalence of LVH was less (53.5% in HD
vs 38.4% in PD). The lower presence of cardiac disorders
may be due to acceptable control of hydration status and BP,
a high presence of RRF, as well as good control over
Nefrologia 2012;32(1):94-102
haemoglobin readings, calcium-phosphorus metabolism, and
the use of ACEI and ARA II. The difference found between
both dialysis techniques may be explained by the greater
percentage of patients with no RRF in HD,31 the lower use of
ACEI/ARAII, and greater extracellular water ratio. LAVI
shows the average of increased filling pressures,42 the
functional situation of the heart and overload, and thus, the
hydration status. Patients on HD have a significantly greater
LAVI than those on PD, and HHD patients have greater
intravascular volume and therefore greater cardiac overload,
leading to increased LVH.
Lastly, we analysed two emerging markers for the
stratification and monitoring of cardiovascular risk in
patients with CKD, LAVI and OH/ECW.8,14,17,42 Wizemann et
al14 defined the OH/ECW ratio >15 as a cardiovascular risk
factor, based on the study performed by Wabel et al in which
NHD patients presented an OH/ECW of 6.8%-15%.20 LAVI
is a chronic marker of diastolic function that shows the
average of increased filling pressures,42 and is considered
the best index for assessing filling pressures and the
functional situation of the heart, since it is linked to the
severity and duration of diastolic dysfunction of the left
ventricle.18,19 In our study, both indices are significantly
higher in patients on HD, as well as in HHD patients in both
groups. Therefore, being HDD according to the normalised
ECW/TBW ratio >2.5% is a high cardiovascular risk.
4.
5.
6.
7.
8.
9.
10.
11.
We can conclude that bioimpedance detects a greater number
of HDD patients on both dialysis techniques. When studying
echocardiographic disorders in dialysis patients, we found a
high correlation between hydration status and LAVI and
ILVM. Additional prospective studies are warranted to assess
the hydration states of the dialysis population and to determine
whether there is regression in cardiac remodelling with the
control of the hydration status by means of bioimpedance.
12.
13.
14.
15.
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c
20.
c
originals
Sent for Review: 23 Feb. 2011 | Accepted: 1 Nov. 2011
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Nefrologia 2012;32(1):94-102
short originals
Vascular accesses in haemodialysis:
a challenge to be met
Gloria Antón-Pérez1, Patricia Pérez-Borges1, Francisco Alonso-Almán2, Nicanor Vega-Díaz1
1
2
Servicio de Nefrología. Hospital Universitario de Gran Canaria Dr. Negrín. Las Palmas de Gran Canaria (Spain)
Unidad Satélite de Hemodiálisis. Centro Satélite de Hemodiálisis RTS-Baxter. Las Palmas de Gran Canaria (Spain)
Nefrologia 2012;32(1):103-7
doi10.3265/Nefrologia.pre2011.Oct.11027
Accesos vasculares en hemodiálisis: un reto por conseguir
ABSTRACT
Background: Chronic kidney disease is a leading problem in public
health due to its high incidence, prevalence and high morbidity and
mortality, especially for those who require renal replacement
therapy (RRT). As has already been described by other authors, the
vascular access is one of the factors determining morbidity and
mortality of patients in haemodialysis as well as their complications,
which incur a high cost. Objectives: To know the real situation of
our clinical practice, compare it with data from other studies, and to
measure the degree of compliance by these patients with the
recommendations of haemodialysis (HD) Clinical Practice Guidelines
regarding vascular access . Also, to assess survival according to the
type of vascular access used, adjusting for comorbidity factors.
Patients and Methods: We studied the vascular access of our
prevalent patients on haemodialysis by October 2009 (n=299, 62%
men). Of these, 64% underwent HD through an autologous
arteriovenous fistula (AVF), 3% were carrying synthetic grafts,
and 33% had a central venous catheter (CVC). These percentages
do not comply with the recommendations of the S.E.N. and KDOQI
clinical guidelines. In order to know the real situation of our clinical
practice, we compared our data with other studies, and measured
the degree of compliance with the recommendations of the
guidelines. The incident patients on HD were studied from January
2004 to October 2009 (n=422). We analysed basal nephropathy,
associated diseases, and the type of vascular access at the start of
HD. Results: A total of 30% had an AVF, 1% had synthetic grafts,
and 69% had CVC. The calculated relative risk (RR) of death
associated with the use of CVC at the start of HD was 3.68 (95% CI:
2.93-6.35) adjusted for other factors of comorbidity (age, diabetes
mellitus, ischaemic heart disease, peripheral arterial disease).
Conclusions: The high mortality associated at the beginning of HD
with CVC (RR: 3.68), independently of other factors, make the
decrease in the use of this vascular access an objective of first order.
Presently, we have not been able to meet the objectives from the
different Clinical Guidelines with respect to the prevalence and
incidence of the vascular accesses for HD.
Keywords: Central venous catheter. Arteriovenous fistula.
Haemodialysis. Vascular access
Correspondence: Gloria Antón-Pérez
Hospital Universitario de Gran Canaria Dr. Negrín.
Las Palmas de Gran Canaria. Spain.
[email protected]
RESUMEN
Introducción: La enfermedad renal crónica representa un problema de salud pública por su elevada incidencia, su prevalencia, su
alta morbimortalidad, sobre todo en aquellos que precisan de tratamiento renal sustitutivo. Uno de los factores que determinan la
morbimortalidad de los pacientes en hemodiálisis (HD) es el acceso vascular del que disponen, y las complicaciones asociadas a los
problemas de acceso vascular suponen una importante carga en
nuestro trabajo diario, así como un elevado coste. Objetivos: Conocer la situación real de nuestra práctica clínica, compararla con
otros estudios y medir el grado de cumplimiento de las recomendaciones de las Guías de Práctica Clínica en HD en lo relativo al acceso vascular de pacientes incidentes y prevalentes. Estudiar la supervivencia de los pacientes incidentes en función de su acceso
vascular, ajustada a otros factores comórbidos. Pacientes y métodos: Se estudiaron los pacientes incidentes en HD desde enero de
2004 a octubre de 2009 (n = 422). Se analizaron: acceso vascular al
inicio de HD, nefropatía de base, servicios de procedencia y enfermedades asociadas. Estudiamos el acceso vascular de nuestros pacientes prevalentes a fecha de octubre de 2009 (n = 299). Comparamos la supervivencia de los pacientes incidentes en función de
su acceso vascular, ajustándolo a otros factores comórbidos. Resultados: El 67% de los pacientes prevalentes (62% hombres) portaban acceso vascular definitivo, y el 33%, un catéter venoso central
(CVC). Del total de 422 pacientes incidentes, 42% provenían de la
consulta por enfermedad renal crónica avanzada. El 54% eran diabéticos, el 92% hipertensos, el 28% presentaban cardiopatía isquémica filiada y un 13% arteriopatía periférica. Un 30% de los pacientes iniciaron HD a través de fístula arteriovenosa, un 1%
portaban injerto sintético de PTFE (politetrafluoretileno) y un 69%
CVC. El riesgo relativo de muerte asociado al uso de CVC al inicio
de HD fue de 3,68 (intervalo de confianza: 95%, 2,93-6,35), ajustándolo a otros factores de comorbilidad (edad, diabetes mellitus,
cardiopatía isquémica, arteriopatía periférica). Conclusiones: La
alta mortalidad asociada al inicio de HD con CVC (riesgo relativo:
3,68), independientemente de otros factores, hacen de la reducción del uso de este acceso vascular un objetivo de primer orden.
En nuestro medio no hemos podido conseguir los objetivos reseñados en las diferentes Guías en lo referente a la prevalencia e incidencia de los accesos vasculares para HD.
Palabras clave: Catéter venoso central. Fístula arteriovenosa.
Hemodiálisis. Acceso vascular
INTRODUCTION
Chronic kidney disease (CKD) is a public health problem
due to its elevated incidence, prevalence, morbidity and
mortality rates, and because it is considered as an
103
Gloria Antón-Pérez et al. Vascular accesses in haemodialysis
short originals
independent cardiovascular risk factor, especially in patients
that require renal replacement therapy (RRT).
According to the registry maintained by the Spanish Society
of Nephrology (S.E.N.), 36 388 patients underwent RRT in
Spain in 2007, over 46% of them on haemodialysis (HD).
The incidence of patients on RRT is 125 patients per million
population (pmp), a value that increases to 400pmp in the
elderly age group (>70 years).1 One of the factors that
determines the morbidity and mortality rates in HD patients
is the type of vascular access used.
The recognised clinical practice guidelines, the European
Best Practice Guidelines (EBPG),2 the Kidney Disease
Outcomes Quality Initiative (KDOQI),3 and the guidelines
from the S.E.N.,4 which are currently under review, establish
as quality indicators in HD that the percentage of incident
patients with a permanent vascular access point
(arteriovenous fistula [AVF]) must be 50% (KDOQI) vs 80%
(S.E.N.). Also, the percentage of prevalent patients with AVF
in HD units must reach 80% (S.E.N), and the number of
prevalent patients with a tunnelled central venous catheter
(CVC) must be less than 10% (S.E.N. and KDOQI).
Several different studies have analysed the conditions in
which HD patients are treated, including vascular accesses.
The DOPPS study,5,6 in its various phases, describes a
progressive increase in the use of CVC in incident patients
on HD. By 2007, based on a representative sample of
Spanish patients participating in this study, there was a
greater relative risk (RR) of death (RR: 1.2) associated with
CVC than with AVF.7 The ANSWER study8 in 2006 also
reported high percentages of CVC use in incident HD
patients (41%), similar to those described in 2006 by the
Spanish Group for CKD9 in a sample of 1504 incident
patients on RRT from 35 Spanish hospitals. More recently, in
2009, Gruss et al published a prospective study including
260 incident patients on HD and reported up to 47% of
patients with CVC. They also observed high mortality rates
(hazard ratio [HR]: 1.86) associated with this type of
vascular access, which increased with the duration of use.10
The aim of our study was to evaluate the current situation in our
clinical practice as regards the use of CVC in HD units, and the
high mortality associated with this technique, comparing it to
the published results from our field of medicine.
MATERIAL AND METHOD
We examined the vascular accesses in 299 prevalent patients
on HD (62% males) at our unit of the Dr. Negrín University
Hospital, Gran Canaria (HUGCDN) in October 2009, as well
as the vascular accesses for the 422 incident patients on HD
(66% males) between January 2004 and October 2009. We
analysed the underlying nephropathy and associated diseases
in each case. We also compared the results with the
objectives set out by the clinical guidelines and with the
results published in the mentioned studies. In the sample of
incident patients, we did not include those with acute renal
failure without previous CKD that started emergency HD
and then recovered renal function. We analysed where the
incident patients were referred from and how this affected
the vascular access point at the start of HD, as well as the
percentage of deaths in incident patients. We also calculated
the RR of death associated with the use of CVC at the start
of HD, and adjusted values for other factors of comorbidity.
We used SPSS software, version 17, for statistical analyses.
We performed a descriptive analysis of the continuous and
non-continuous variables. In order to compare for
differences between the means of continuous variables, we
used Student’s t-tests. We compared survival curves for
incident patients on HD with CVC or AVF using KaplanMeier analyses and log-rank tests. We used a Cox regression
analysis to evaluate whether other factors were influencing
mortality in incident HD patients.
RESULTS
Prevalent patients
Of the total 299 prevalent patients in October 2009, 67%
were undergoing dialysis through a permanent vascular
access, and 33% through a CVC (Table 1).
Incident patients
Of the 422 patients that started RRT on HD, 93% were
incident RRT patients, 6% came from peritoneal dialysis
(PD), and 1% were patients with non-functioning kidney
transplants. The mean age of this patient group was 62 years.
Table 1. Vascular accesses used in prevalent patients. Comparison with guideline recommendations
Vascular access
S.E.N. recommendatioNs (%)
KDOQI recommendations (%)
DOPPS (%)
Dr. Negrín hospital (%)
64
AV fistula
>80
>40
81
Synthetic graft
<10
-------
10
3
CVC
<10
<10
8
33
Vascular accesses in prevalent patients at our haemodialysis unit (%) compared to the recommendations established in the guidelines.
AV: arteriovenous; CVC: central venous catheter
104
Nefrologia 2012;32(1):103-7
When we analysed our sample by year, the annual incidence
rate was fairly homogeneous, ranging between 62 patients in
2007 and 82 in 2008. In this group, 53.8% were diabetic,
91.7% had arterial hypertension, 28.2% had ischaemic heart
disease of a known origin, and 12.6% had peripheral arterial
disease, based on the data from the Canary Islands Renal
Patient Registry.11
As regards where the patients came from, 42% were derived
from advanced chronic kidney disease (ACKD) visits, 15%
from other nephrological visits, 1% were transplant
recipients with graft loss/dysfunction, 6% were from PD,
15% were from hospital emergency departments, and 21%
were from other hospital departments. The patients started
HD with a permanent vascular access in 31% of cases
(AVF/PTFE [polytetrafluoroethylene] graft); and 77% of
them (24% of the total) came from ACKD visits. Patients
started HD with a CVC in 69% of cases, 74% of which were
derived from other nephrological visits or other departments
(Table 2). We compared the vascular accesses in incident
patients from our unit with the recommendations from the
guidelines and results from previously published studies
(Table 3).
We compared survival curves between the group of incident
HD patients with CVC and the group with AVF (Figure 1).
The RR of death was 3.68 times greater in patients that
started HD using a CVC (95% confidence interval [CI]:
2.93-6.35). Using the Cox regression analysis (Table 4), we
examined which other factors may influence the mortality of
our patients, and found a significant association with age
(HR: 1.02) and the presence of diabetes mellitus (HR: 1.5),
with an HR value associated with starting HD with a CVC of
2.85. We found no significant differences between the mean
age of incident patients starting HD with a CVC and those
starting with an AVF (62.7 years vs 61.2 years, respectively).
When comparing our results from October 2009 with those
already analysed from our department in December 2005
and November 2007, we found no significant differences in
the use of AVF and/or CVC in prevalent patients, although
the use of CVC has progressively increased by 27%, 29%,
and 33%, respectively, and the use of AVF has increased by
72%, 71%, and 67%.
short originals
DISCUSSION
There is a wealth of evidence in the literature regarding the
mortality of patients on HD with a series of potentially
modifiable factors, such as planning the entrance into HD,
where patients are referred from, adequate control of
phosphorous-calcium metabolism, anaemia and nutrition,
and of course, the type of vascular access used.5-8,10,12
The studies published in our field have produced varying
results in the level of compliance with the recommendations
set forth by the clinical practice guidelines in terms of the
type of vascular access to be used in HD, but they certainly
are far from perfect.5-10 Are these recommendations realistic?
Many authors have analysed the possible causes of the
disparities observed:13
- The current real profile of an incident HD patient:
elderly, with multiple comorbidities.
- The characteristics of the various reference centres, the
existence of ACKD visits, the formation of multidisciplinary teams (nephrologists, vascular surgeons, and
interventional radiologists).
- The equipment for monitoring vascular accesses in HD
units.
- Protocols for early action, given the complications in
permanent vascular accesses.
In our daily clinical practice, despite the fact that 42% of our
patients are referred from ACKD visits, which would imply
the ability to choose the correct technique, scheduled
entrance, and a better control of other factors (anaemia,
nutrition, etc.) and other preparations,12 up to 18% of these
patients start HD with a CVC. In this group of patients, we
registered at least one case of attempting a permanent
vascular access (AVF) that failed. The incident population
on HD in our sample had a mean age similar to that reported
in other studies (62 years), although the incidence of diabetic
nephropathy in our study was much higher (42% vs
21.5%),10,11 as is also shown in the most recent registries of
patients on RRT published by the S.E.N. in 2009.14
One could interpret that these comorbidities are causing the
elevated use of CVC on HD, but other authors have shown
Table 2. - Vascular accesses in incident patients according to departments of origin
Vascular access
AV fistula
Synthetic graft
CVC
ACKD (%)
23
1
18
NEPH (%)
3
0
12
Other (%)
4
0
39
Type of vascular access (%) according to the origin of incident patients on HD at our unit between January 2004 and October 2009.
AV: arteriovenous; CVC: central venous catheter; ACKD: advanced chronic kidney disease visits; NEPH: Other nephrological visits.
Nefrologia 2012;32(1):103-7
105
short originals
Table 3. Vascular accesses in incident patients. Comparison with guideline recommendations and previous studies
Vascular access
S.E.N. recommendations (%) KDOQI recommendations (%) DOPPS (%) ANSWER (%) Spanish Group CKD (%) HUGCDN(%)
AV fistula
80
50
71
54
40
30
Synthetic graft
<10
-------
5
--------
1
1
CVC
<10
>10
24
30
43
69
Comparison of the level of compliance with S.E.N. and KDOQI guideline recommendations regarding vascular accesses in incident patients on HD (%)
for the different studies cited and our own findings.
AV: arteriovenous; CVC: central venous catheter; HUGCDN: Dr. Negrín University Hospital, Gran Canaria
that, even in the non-diabetic population with no associated
cardiovascular comorbidities and with nephrological
monitoring previous to HD, the percentage of incident
patients starting with a CVC is high (31.4%).15 Also, the
difference in the mortality rates from patients with a CVC
and those with an AVF is dependent on time, and is
maintained even after adjusting for other comorbidity
factors.10
In our study, we showed that elderly and diabetic patients die
at a greater rate, but the factor most highly associated with
mortality was starting HD with a CVC.
A decrease in the use of this type of vascular access should
be a primary objective, necessitating the formation of multidisciplinary teams (nephrologists, vascular surgeons, and
interventional radiologists) and coordination for the
monitoring of patients with advanced chronic kidney
disease. Additionally, HD units should be equipped with the
means to adequately monitor the permanent vascular
accesses used and to guarantee emergency treatment of
these, avoiding the need for CVC.
However, in our clinical experience, although we should
optimise the monitoring of vascular accesses and use
protocols for early action in the case of complications, we do
have the impression that there is a sub-group of patients with
CVC following several failed attempts at establishing a
permanent access point, probably due to their precarious
vascular system. This all leads us to reflect on the indication
for this technique to be used in select populations: is the
survival of these patients (diabetics, elderly, with
compromised vascular system analysed using a venous map)
greater when following a conservative treatment for CKD?
CONCLUSIONS
Throughout the years encompassed by our study, we have
not been able to achieve the objectives set out by the
different guidelines in terms of the prevalence and incidence
1.0
Cumulative survival
0.8
Table 4. Factors related to mortality. Cox regression.
0.6
0.2
0.0
0.00
20.00
40.00
Time
60.00
AVHD1_R
CATHETER
AVF
CATHETER-censored
AVF-censored
Kaplan-Meier survival curves. Survival of patients with an
arteriovenous fistula vs those with a central venous catheter
Figure 1. Survival curves
106
P
OR (95% CI)
Age upon starting HD
0.014
1.020 (1.004-1.037)
Male
0.292
1.225 (0.840-1.786)
DM
0.050
1.504 (0.999-2.264)
AHT
0.439
0.705 (0.291-1.709)
IC
0.445
1.153 (0.800-1.663)
PAP
0.620
1.126 (0.705-1.7961)
VAHD
0.000
2.825 (1.744-4.576)
0.4
DM: Diabetes Mellitus. AHT: Arterial hypertension. IHD: ischaemic
heart disease. PAD: peripheral arterial disease. VAHD: vascular access
at the start of HD (CVC).
Nefrologia 2012;32(1):103-7
short originals
of vascular accesses for HD. The high mortality associated
with a start of HD using a CVC (RR: 3.68), independently of
other factors, makes the decrease in the use of this type of
vascular access a primary objective, taking into account the
resources used and potential costs. Probably, the high
prevalence of diabetic nephropathy in our field negatively
influences the achievement of these objectives.
could improve these results, as appears to be the case in
isolated experiences.
The implementation in our hospitals of monographic ACKD
visits and the creation of multi-disciplinary teams
(nephrologists, vascular surgeons, and vascular radiologists)
Acknowledgements:
We would like to thank Dr José Carlos Rodríguez Pérez for his efforts in
reviewing and correcting this manuscript.
Authors declare no potential conflicts of interest.
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et al., and on behalf of all Investigators from the ANSWER study.
Baseline characteristics of an incident haemodialysis population in
Spain: results from ANSWER—a multicentre, prospective, observa-
tional cohort study. Nephrol Dial Transplant 2009;24(2):578-88.
9. Marrón B, Ortiz A, de Sequera P, Martín-Reyes G, de Arriba G, Lamas JM, Martínez Ocaña JC, Arrieta J, Martínez F; Spanish Group
for CKD. Impact of end-stage renal disease care in planned dialysis
start and type of renal replacement therapy--a Spanish multicentre
experience. Nephrol Dial Transplant. 2006 Jul;21 (Suppl 2):ii51-5.
10. Gruss E, Portolés J, Tato A, Hernández T, López-Sánchez P, Velayos
P, et al. Repercusiones clínicas y económicas del uso de catéteres
tunelizados de Hemodiálisis en un Area Sanitaria. Nefrología
2009;29:123-9.
11. RERCAN. Registro de las enfermedades renales de Canarias. Sociedad Canaria de Nefrología (Informe de la Sociedad), 2008.
12. Marrón B, Martínez Ocaña JC, Salgueira M, Barril G, Lamas JM,
Martín M, et al. Analysis of patient flow into dialysis: role of education in choice of dialysis modality. Perit Dial Int 2005;25(Suppl.
3):S56-59.
13. Roca Tey R. El Acceso Vascular para Hemodiálisis. La asignatura pendiente. Nefrología 2010;30:280-7.
14. Registro Español de Enfermos Renales 2009. Congreso Nacional de
Nefrología, Granada, 2010. [Available at: www. senefro.org].
15. Arcos E, Comas J, Deulofeu R y la Comisión de seguimiento del Registre de Malalts Renals de Catalunya. Datos del Registre de Malalts Renals de Catalunya. Grupos de trabajo: accesos vasculares.
[Available at: www.senefro.org].
Send for review: 27 Jun. 2011 | Accepted: 22 Oct. 2011
Nefrologia 2012;32(1):103-7
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short reviews
Changes in body composition parameters in patients
on haemodialysis and peritoneal dialysis
M. Cristina Di-Gioia, Paloma Gallar, Isabel Rodríguez, Nuria Laso, Ramiro Callejas,
Olimpia Ortega, Juan C. Herrero, Ana Vigil
Servicio de Nefrología. Hospital Severo Ochoa. Leganés, Madrid (Spain)
Nefrologia 2012;32(1):108-13
ABSTRACT
Cambios en los parámetros de composición corporal en
pacientes en hemodiálisis y diálisis peritoneal
RESUMEN
Introduction: Proper hydration is one of the major aims in
haemodialysis (HD) and peritoneal dialysis (PD). Bioimpedance
spectroscopy appears to be a promising method for the
evaluation and follow up of the hydration status in dialysis
patients (P). Objectives: We compared body composition
between stable patients on HD and PD after six months. Patients
and method: An observational study with 62 P on HD and 19 P on
PD was performed. Clinical, biochemical and bioimpedance
parameters were analysed. Results: In the comparative study, PD
P were younger (50±10 vs 57±14 years, P=.031). The Charlson
Comorbidity Index (4.8±3 vs 7.5±3, P<.001), time on dialysis
(16.9±18.01 vs 51.88±68.79 months, P=.020) and C-Reactive
Protein [3 (3-9.3) vs 5.25 (1-76.4)] were lower. Total protein levels
(7.46±0.44 vs 7.04±0.55 g/dl, P=.005) and transferrin levels (205±41
vs 185±29 mg/dl, P=.024) were higher. BIS: Intracellular water
(19.67±3.61 vs 16.51±3.36 litres, P=.010), lean tissue mass (LTM)
(37.20±8.65 vs 32.57±8.72 kg, P=.029), total cellular mass (TCM)
(20.53±5.65 vs 17.56±5.91 kg, P=.033), and bioelectrical impedance
phase angle (Phi 50) (5.81±0.86 vs 4.74±0.98, P=.000) were higher
than in HD P. Overhydration: 22% in HD y 10% in PD, in
conditions referred to in methods. Six months later, PD
P increased in weight (73.75±12.27 vs 75.22±11.87 kg, P=.027),
total fat (FAT) (26.88±10 vs 30.02±10 kg, P=.011) and relative fat
(Rel FAT) (35.75±9.87 vs 39.34±9.12, P=.010); and decreased in ICW
(18.56±3.45 vs 17.65±3.69 l, P=.009), LTM (36.95±8.88 vs 34±9.70
kg, P=.008) and relative LTM (Rel LTM) (50.85±12.33 vs
45.40±11.95%, P=.012). In the multivariate analysis, weight
variation (∆) was related to ∆ FAT (P<.001). We found a correlation
between fat increase and lean tissue mass decrease. Six months
later, in HD P, we observed a reduction in ECW (15.11±2.45 vs
14.00±2.45, P=.001), without changes in other parameters.
Conclusions: Bioelectrical impedance analysis facilitates the
assessment of changes in body composition so as to correct dry
weight and to introduce changes in treatment schedule.
Introducción: La normohidratación es uno de los mayores objetivos en hemodiálisis (HD) y diálisis peritoneal (DP). La bioimpedancia por espectroscopia (BIS) se postula como el método más prometedor para la evaluación y seguimiento del estado de hidratación
en pacientes en diálisis. Objetivo: Comparar la composición corporal de pacientes prevalentes en HD y DP en un intervalo de seis meses. Pacientes y métodos: Estudio observacional de 62 pacientes
en HD y 19 en DP comparando los parámetros clínicos, bioquímicos
y de bioimpedancia. Resultados: En el estudio comparativo, los pacientes en DP fueron más jóvenes (50 ± 10 vs. 57 ± 14 años, p =
0,031). El índice de comorbilidad de Charlson (4,8 ± 3 vs. 7,5 ± 3, p
< 0,001), tiempo en diálisis (16,9 ± 18,01 vs. 51,88 ± 68,79 meses, p
= 0,020) y proteína C reactiva [3 (3-9,3) vs. 5,25 (1-76,4)] fueron menores. Los niveles de proteínas totales (7,46 ± 0,44 vs. 7,04 ± 0,55
g/dl, p = 0,005) y transferrina (205 ± 41 vs. 185 ± 29 mg/dl, p = 0,024)
fueron más elevados. BIS: agua intracelular (AIC) (19,67 ± 3,61 vs.
16,51 ± 3,36 litros, p = 0,010), masa muscular total (MM) (37,20 ±
8,65 vs. 32,57 ± 8,72 kg, p = 0,029), masa celular total (MCT) (20,53
± 5,65 vs. 17,56 ± 5,91 kg, p = 0,033) y ángulo de fase (Phi 50) (5,81
± 0,86 vs. 4,74 ± 0,98, p = 0,000) fueron más elevados que en HD.
Sobrehidratados 22% en HD y 10% en DP, en las condiciones referidas en métodos. A los seis meses en DP observamos aumento de
peso (73,75 ± 12,27 vs. 75,22 ± 11,87 kg, p = 0,027), grasa total (MG)
(26,88 ± 10 vs. 30,02 ± 10 kg, p = 0,011) y relativa (MG %) (35,75 ±
9,87 vs. 39,34 ± 9,12%, p = 0,010); disminución de AIC (18,56 ± 3,45
vs. 17,65 ± 3,69 l, p = 0,009), MM (36,95 ± 8,88 vs. 34 ± 9,70 kg, p =
0,008) y MM relativa (MM %) (50,85 ± 12,33 vs. 45,40 ± 11,95%, p =
0,012). En el análisis multivariante, la variación (∆) de peso guarda
relación con el ∆ de grasa (p < 0,001). Encontramos correlación entre el incremento de grasa y el decremento de masa muscular (p =
0,01). A los seis meses en HD no se observaron cambios en estos parámetros, salvo una reducción en el agua extracelular (15,11 ± 2,45
vs. 14,00 ± 2,45, p = 0,001). Conclusiones: BIS permite valorar los
cambios en la composición corporal y ayuda a establecer el peso
seco e introducir cambios en las pautas de tratamiento.
Keywords: Body composition. Overhydration. Haemodialysis.
Peritoneal dialysis. Bioimpedance spectroscopy
Palabras clave: Composición corporal. Sobrehidratación.
Hemodiálisis. Diálisis peritoneal. Bioimpedancia por espectroscopia.
Correspondence: M. Cristina Di Gioia
Hospital Severo Ochoa. Leganés, Madrid. (Spain).
[email protected]
[email protected]
108
INTRODUCTION
Achieving a normal hydration state is one of the primary
objectives in haemodialysis (HD) and peritoneal dialysis
M. Cristina Di Gioia et al. Body composition in HD and PD
(PD) treatments. The concept of dry weight is essential to
integrated dialysis therapy.1 The abnormal state of
overhydration has been related to arterial hypertension, signs
and symptoms of pulmonary and peripheral oedema, heart
failure, left ventricular hypertrophy, and other adverse
cardiovascular effects.2 The increase in left ventricular mass
is correlated with worse cardiovascular evolution in PD
patients,3 and it has also been described that hydration state is
an important independent predictor for mortality in chronic
HD patients.4 It appears essential that dialysis providers have
a good strategy for maintaining the euvolemic state of their
patients. However, the evaluation of normovolemia is
difficult, since there is no method that has been established
for use in daily clinical practice. The clinical evaluation of
dry weight is the most commonly used method, but this leads
to frequent conditions of sub-clinical over-hydration and subhydration, which can cause increased morbidity rates.5
Among the various tests that can be used to measure dry
weight, chest x-ray aids in the clinical management of
patients, but does not comply with the aims of being rapid
and non-invasive; the diameter of the inferior vena cava and
its respiratory variations are good measures of preload,6 but
they are also influenced by cardiovascular factors such as
diastolic dysfunction, pulmonary hypertension, and chronic
obstructive pulmonary disease.7 Biochemical markers such as
ANP (atrial natriuretic peptide) have a prognostic value and
may indirectly reflect overhydration due to its effect on left
ventricular mass,5 but these levels appear to depend more on
the primary situation of the ventricle. It is difficult to
establish the proper concentration in dialysis patients, and
values frequently remain elevated in patients considered to be
properly hydrated.8
The standard methods for measuring body water such
as deuterium and sodium bromide for extracellular
water are laborious and are not commonly used in
clinical practice. 9
The new bioelectrical impedance analysis techniques are
being used for the evaluation and follow-up of hydration
state. In a study evaluating the detection limits for different
methods used for determining hydration states in dialysis
patients, bioimpedance spectroscopy has demonstrated high
sensitivity, emerging as the most promising method for a
practical treatment of dialysis patients.7 This technique uses
the variation in the electrical frequency applied and
distinguishes between extracellular water and total body
water. The variation in frequency applying currents that
range between 5kHz and 1000kHz facilitates the
determination of extracellular water (ECW) and total body
water (TBW); intracellular water (ICW) is extrapolated by
analysing at different frequencies.8,10
It has been well established that the changes produced over
time in body weight among peritoneal dialysis patients are
due to changes both in body water content and lean tissue/fat
Nefrologia 2012;32(1):108-13
short reviews
mass. Multifrequency bioelectrical impedance analysis
offers the possibility of evaluating body composition and
hydration state.11
The body composition monitor (BCM, Fresenius Medical
Care) has been validated for use in clinical practice to
determine hydration state.10 As measured by BCM, a relative
overhydration greater than 15% has been shown to be
associated with increased cardiovascular mortality in
haemodialysis patients.4
Recently, overhydration has also been correlated with
inflammation, malnutrition, and atherosclerosis in PD
patients.12
The objective of our study is to compare the body
composition of prevalent HD and PD patients in a crosssectional analysis, and to evaluate the changes in these
values by performing two studies 6 months apart in both
techniques, HD and PD, in a dialysis unit with special
attention to maintaining dry weight.
METHODS
Patients
We performed a cross-sectional study of prevalent
patients on HD (n=62) and PD (n=19) monitored at the
same centre for a period that included two
measurements of bioelectrical impedance with an
interval of 6 months. The number of patients at the start
of the study was 65 on HD and 19 on PD. After 6
months, there were 49 on HD and 14 on PD. All
patients were older than 18 years. We excluded those
patients with contraindications for bioelectrical
impedance: an implanted electronic device, any type of
metallic implants, amputation, pregnancy, and lactating
women. All patients signed an informed consent that
was approved by the ethics committee.
Of the 62 patients on HD, 21 used online
haemodiafiltration and 41 were on conventional HD. Of the
19 patients on PD, 10 were on automated PD (APD) and 9
were on continuous ambulatory PD (CAPD); icodextrin
was administered in 49% of patients on both techniques,
and 23 patients (27%) were diabetic.
Measurements
In the initial cross-sectional study, we compared the
following clinical parameters for the two techniques: age,
sex, Charlson comorbidity index,13 time on dialysis, weight,
body mass index (BMI), and systolic and diastolic blood
pressure (BP).
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short reviews
Laboratory analyses: we measured C-reactive protein (CRP)
using immunoturbidimetry, and creatinine, total protein,
albumin, transferrin, and haemoglobin were measured using
certified methods in the biochemistry department of the
Severo Ochoa Hospital. The erythropoietin resistance index
was defined as the weekly doses of erythropoietin (U/kg
predialysis/dose) divided by haemoglobin (Hb) g/dl.
had higher values of total protein (TP) (7.46±0.44g/dl vs
7.04±0.55g/dl, P=.005) and transferrin (205±41mg/dl vs
185±29mg/dl, P=.024) than HD patients. Patients on PD had
a residual renal function (RRF) of 5.33±3.89ml/min, diuresis
at 1115±758ml/day, and ultrafiltration at 887±445ml/day.
The ultrafiltration volume per session of HD patients on the
day of bioelectrical impedance analysis was 2372±921ml.
We performed the predialysis bioelectrical impedance
analysis immediately before the second session of the week,
and in PD patients, coinciding with the peritoneal
equilibration test and with the peritoneum full. We used a
body mass composition analysis device using bioimpedance
spectroscopy (BCM, Fresenius Medical Care). The
parameters for bioelectrical impedance were: TBW in litres
(l), ECW in l, ICW in l, ECW/ICW, lean tissue mass (LTM)
in kg, LTM% in percentage, lean tissue mass index in kg/m2,
total fat (FAT) in kg, FAT% in percentage, phase angle (Phi
50), total cellular mass (TCM) in kg, and overhydration
(OH) in l. The state of OH was calculated by standardising
OH to ECW and considering OH to be present if >15%.4
As regards the bioelectrical impedance analysis parameters,
PD patients had values of ICW (19.67±3.61 vs 16.51±3.36
litres, P=.010), LTM (37.20±8.65kg vs 32.57±8.72kg,
P=.029), TCM (20.53±5.65kg vs 17.56±5.91kg, P=.033) and
phase angle (5.81±0.86 vs 4.74±0.98, P=.000) greater than
HD patients. Under the conditions the study was being
carried out in, a total of 14 HD patients and 2 PD patients
were overhydrated (22% and 10%, respectively).
The clinical, biochemical, and bioelectrical impedance
values were analysed after six months for both dialysis
techniques.
Statistical Analysis
We performed all statistical analyses using SPSS statistical
software version 12 (Chicago, Illinois, SL, USA). Normally
distributed variables were expressed as a mean and standard
deviation, and non-normal variables as a median and range
(maximum and minimum). We compared the means between
groups using Student’s t-tests or Mann-Whitney U-tests
and/or chi-square tests according to the nature of the
variable. Categorical variables were expressed as number
and percentage. We set the value of statistical significance at
P<.05. For the univariate analysis, we used Pearson’s or
Spearman’s correlation coefficients, according to the nature
of the variable. The multivariate analysis involved linear
correlation, considering the increase in weight as the
dependent variable, and individually introducing variables
that were statistically significant in the univariate analysis.
RESULTS
We analysed the data from a total of 65 patients on HD and
19 on PD. The demographic, clinical, biochemical, and
bioelectrical impedance values from the initial analysis are
summarised in Table 1. The patients on PD were younger
(50±10 years vs 57±14 years, P=.031), with a lower
Charlson comorbidity index (4,8±3 vs 7,5±3, P<.001), less
time on dialysis (16.9±18.01 months vs 51.88±68.79
months, P=.020), lower CRP [3 (3-9.3) vs 5.25 (1-76.4)] and
110
Diabetic patients had a higher mean systolic BP (P=.012)
and lower phase angle (P=.008), with no difference in the
rest of the parameters used to measure body composition.
In patients on PD after 6 months (table 2), we observed a
significant increase in weight (73.75±12.27kg vs
75.22±11.87kg, P=.027), with an increase in total fat
(26.88±10kg vs 30.02±10kg, P=.011) and relative fat
(35.75±9.87% vs 39.34±9.12%, P=.010), and decreased
ICW (18.56±3.45l vs 17.65±3.69l, P=.009), total LTM
(36.95±8.88kg vs 34±9.70kg, P=.008) and relative LTM
(50.85±12.33% vs 45.40±11.95%, P=.012). There was a
global correlation between the variation (∆) in weight and ∆
in fat, but not with ∆ in extracellular weight. In the
multivariate analysis, the ∆ in weight was correlated with ∆
in fat (P<.001). There was also a correlation between the
increase in fat and a decrease in LTM (P=.01). In the
multivariate analysis that held the decrease in LTM as the
dependent variable and a progressive introduction of age,
sex, dialysis technique, and BMI, only age had an influence
on the decrease in LTM (P=.012).
Upon analysing the data according to the technique of PD
used, we observed a tendency towards lower increase in fat
when on APD (1.58±3.05 vs 3.5±3.05), despite a higher
glucose load (206±58 vs 62.98±75.5, P=.006).
In patients on HD, only ECW was significantly reduced
(P=.001); all other parameters measured using bioelectrical
impedance did not vary in the measurements taken over the
6-month interval (Table 3).
DISCUSSION
This study demonstrates the differences in body composition
between patients on HD and those on PD. In the initial
study, the differences in the nutritional parameters evaluated
(TP, transferrin) and bioelectrical impedance (ICW, LTM,
Nefrologia 2012;32(1):108-13
short reviews
Table 1. Clinical, biochemical, and bioelectrical impedance parameters from the initial analysis
HD (n=65)
PD (n=19)
P (value)
57±14
50±10
0.031
Age
Sex: % women
34%
39%
0.681
Charlson C I
7.5±3
4.8±3
0.001
Time on dialysis (months)
51.88±68.79
16.9±18.01
0.020
Weight (kg)
68.38±14.26
73.93±14.46
0.108
BMI
25.95±5.88
26.96±4.62
0.401
135±22
127±18
0.164
Systolic BP (mmHg)
Diastolic BP (mmHg)
75±13
80.87±8.20
0.011
5.25 (0.6-76.4)
3.00 (3-9.30)
0.113
Creatinine (mg/dl)
8.38±2.21
8.35±1.97
0.954
7.04±0.55
7.46±0.44
0.005
CRP (mg/l)
Hb (g/l)
11±1.45
12.20±1.23
0.414
3.76±0.37
3.68±0.39
0.424
Transferrin (mg/dl)
185±29
205±41
0.024
ERI (u/kg/patients/Hb)
22±21
8±5
0.010
Albumin (g/dl)
TBW (l)
31.80±5.71
34.17±6.4
0.101
ECW (l)
15.31±2.81
15.47±3.11
0.819
ICW (l)
16.51±3.36
19.67±3.61
0.010
ECW/ICW
0.94±0.14
0.83±0.10
0.001
LTM (kg)
35.26±8.72
37.20±8.65
0.029
Relative LTM (%)
49.33±16.16
51.17±11.63
0.621
FAT (kg)
25.19±11.45
26.98±9.82
0.500
Relative FAT (%)
35.52±11.98
35.81±8.86
0.914
TCM (kg)
17.56±5.91
20.53±5.65
0.033
Phi 50
4.74±0.98
5.81±0.86
0.000
Overhydration (OH) (l)
1.15±1.58
–0.69±1.70
Overhydration/ECW >0.15%
14 (22%)
2 (10%)
Data are expressed as a mean±standard deviation or range, median (interquartile range or percentage).
ECW: extracellular water; ICW: intracellular water; TBW: total body water; PD: peritoneal dialysis; HD: haemodialyis; Charlson C I: Charlson comorbidity
index; BMI: body mass index; ERI: erythropoietin resistance index; TCM: total cellular mass; FAT: fat mass; relative FAT: relative percentage of fat mass;
LTM: lean total mass; relative LTM: relative percentage of lean total mass; CRP: c-reactive protein; Phi 50: phase angle; OH: overhydration; BP: blood
pressure.
TCM, and phase angle) can be attributed to the younger age,
less time on dialysis, and better nutritional state in the group
on PD. Despite this, a significant weight gain is evident over
the six-month observation period among patients on PD,
which is not produced in patients on HD. The weight gain is
primarily in the form of fat mass. These data could indicate
on the one hand that the glucose input from PD could be
responsible for the fat increase in these patients, and that it is
more difficult to control extracellular volume in PD than in
HD, as a consequence of the progressive reduction in RRF.
Patients on HD experienced a decrease in ECW with no
variations in the other parameters measured over the sixmonth period.
Nefrologia 2012;32(1):108-13
LTM decreases in patients on PD, probably secondary to the
more sedentary lifestyle associated to dialysis, which could
contribute to the increase in fat content in PD patients, and
also probably indicates the need for a physical exercise
regimen. We were surprised that the decrease in LTM was
not significant in HD patients, which we believe could be
due to the short time span between the two measurements.
We will continue with more prolonged follow-up times.
In our study, 22% of the HD patients and 10% of the PD
patients were overhydrated, according to the criteria
established by other publications.4 We did not perform postdialysis bioelectrical impedance analysis, since it requires at
least 30 minutes to carry out the procedure and the patients
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short reviews
Table 2. Evolution after 6 months in the 14 patients on peritoneal dialysis
Initial
6 months
P
ECW (l)
15.57±2.64
15.96±2.66
0.180
ICW (l)
18.56±3.45
17.65±3.69
0.009
ECW/ICW
0.84±0.10
0.91±0.10
0.003
LTM (kg)
36.95±8.88
34±9.70
0.008
Relative LTM (%)
50.85±12.33
45.40±11.95
0.006
26.88±10
30.02±10
0.011
FAT (kg)
Relative FAT (%)
35.75±9.87
39.34±9.12
0.012
LTMI (kg/m2)
13.31±2.58
12.19±2.80
0.008
Weight (kg)
73.75±12.27
75.22±11.87
0.027
RRF (ml/min)
6.06±3.58
5.75±4.44
0.608
Diuresis ml/24h
2500±1115
2200±1030
0.742
887±445
871±432
0.828
Ultrafiltration cc/d
Data expressed as mean±standard deviation or percentage.
ECW: extracellular water; ICW: intracellular water; RRF: residual renal function; LTMI: lean total mass index; FAT: fat mass; relative FAT: relative percentage of
fat mass; LTM: lean total mass; relative LTM: relative percentage of lean total mass.
would not consent. Even so, in the case of HD, we evaluated
the level of overhydration in the patients’ maximum state of
overhydration (pre-HD), and we doubt that the two situations
would be comparable.
When pre and post-HD measurements were available, and
overhydration was calculated over the mean at centres that took
similar care to reach dry weight in each dialysis session, 10% of
patients were overhydrated,11 similar to our patients on PD.
Our results indicate that our patients on PD gain weight
above all due to fat increase. Additionally, a slight increase
in ECW, probably due to a slight decrease in diuresis,
contributes to the weight gain observed, although these
changes were not statistically significant.
In our patients on PD, the prevalence of overhydration
(10%) was lower than reported from other centres.15,16
As has been shown, BP control is harder on automated PD
than CAPD due to a worse negative sodium balance on APD
resulting from a sodium sieving coefficient in the peritoneal
membrane.17,18 The use of icodextrin can favour improved
control of the volume situation and reduce left ventricular
mass.19 In our experience,20 there is no difference in
controlling BP or residual renal function between the two
types of PD, probably due to the insistence in restricting salt
from the diet and ample use of icodextrin.
The tendency in our patients on APD was for a lower
increase in fat, despite a greater glucose load than in CAPD,
Table 3. Evolution after 6 months in the 49 patients on haemodialysis
ECW (l)
ICW (l)
ECW/ICW
LTM (kg)
Relative LTM (%)
FAT (kg)
Relative FAT (%)
LTMI (kg/m2)
Weight (kg)
Initial
15.11±2.45
15.75±3.07
0.97±0.136
31.04±8.22
49.14±16.99
23.94±10.99
35.05±12.79
11.82±2.60
65.63±12.89
6 months
14.61±2.45
15.69±3.46
0.49±0.135
30.86±9.10
48.81±17.32
24.26±11.27
35.82±12.74
11.75±3.00
64.71 ±13.70
P
0.001
0.797
0.112
0.112
0.782
0.820
0.725
0.470
0.076
Data expressed as mean±standard deviation or percentage.
ECW: extracellular water; ICW: intracellular water; LTMI: lean total mass index; FAT: fat mass; relative FAT: relative percentage of fat mass; LTM: lean total
mass; relative LTM: relative percentage of lean total mass.
112
Nefrologia 2012;32(1):108-13
perhaps due to the reduced time the glucose spends in the
peritoneal cavity and thus lower total absorption.
The high prevalence of arterial hypertension and volume
overload in HD centres and the difficulty for establishing dry
weight in dialysis patients21 situates bioelectrical impedance
as another tool for evaluating the changes suffered in body
composition that can orient the physician to establish dry
weight in HD patients and to introduce changes in the liquids
provided to PD patients.
Authors declare no potential conflicts of interest.
REFERENCES
1. Charra B. “Dry weight” in dialysis: the history of a concept. Nephrol Dial Transplant 1998;7:1882-5.
2. Wizemann V, Schilling M. Dilemma of assessing volume state- the
use and limitations of a clinical score. Nephrol Dial Transplant
1995;10:2114-7.
3. Wang X, Axelsson J, Lindholm B, Wang T. Volume status and blood
pressure in continous ambulatory peritoneal dialysis patients. Blood
Purif 2005;23:373-8.
4. Wizemann V, Wabel P, Charnney P, Zaluska V, Moissl U, Rode C, et
al. The mortality risk of overhydration in haemodialysis patients.
Nephrol Dial Transplant 2009;24:1574-9.
5. Kooman J, van der Sande F, Leunissen K. Wet or dry in dialysis- Can
new tecnologies help? Semin Dial 2009;22(1):9-12.
6. Cherlex E, Leunissen K, Janssen J. Echografy of the inferior vena cava
is a simple and reliable tool for estimation of “dry weight” in haemodialysis patients. Nephrol Dial Transplant 1989;4:563-8.
7. Kraemer M, Rode C, Wizemann V. Detection limit of methods to assess fluid status changes in dialysis patients. Kidney Int
2006;69:1609-20.
8. Jaeger J, Metha R. Assessement of dry weight in hemodialysis. An
overwiew. J Am Soc Nephrol 1999;10:392-403.
9. Leunissen K, Kouw P, Kooman J, Cheriex EC, deVries PM, Donker
AJ, et al. New techniques to determine fluid status in hemodialysis
patients. Kidney Int Suppl 1993;41:S50-6.
short reviews
10. Chamney P, Kramer M, Rode C, Kleinekofort W, Wizemann V. A new
technique for establishing dry weight in hemodialysis patients via
whole body bioimpedance. Kidney Int 2002;61:2250-8.
11. Devolder I, Verleysen A, Vijt D, Vanholder R, Van Biesen W. Body
composition, hydration, and related parameters in hemodialysis versus peritoneal dialysis patients. Perit Dial Int 2010;30:208-14.
12. Demirci MS, Demirci C, Ozdogan O, Kircelli F, Akcicek F, Basci A, et
al. Relations between malnutrition-inflamation-atherosclerosis and
volume status. The usefulness of bioimpedance analysis in peritoneal dialysis patients. Nephrol Dial Transplant 2011;26(5):1708-16.
13. Charlson M, Pompei P, Ales k, MacKenzie CR. A new method of
classifiying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-83.
14. Wabel P, Moissl U, Chamney P, Jirka T, Machek P, Ponce P, et al. Towards improved cardiovascular management: the necessity of combining blood pressure and fluid overload. Nephrol Dial Transplant
2008;23:2965-71.
15. Lindley E, Devine Y, Hall L, Cullen M, Cuthbert S, Woodrow G, et al.
A ward bases peocedure for assessment of fluid status in peritoneal
dialysis using bioimpedance spectroscopy. Perit Dial Int 2005;25
Suppl 3:S46-8.
16. Plum J, Schoenicke G, Kleophas W, Kulas W, Steffens F, Azem A, et
al. Comparison of body fluid distribution between chronic haemodialysis and peritoneal dialysis patients as assessed by biophysical
and biochemical methods. Nephrol Dial transplant 2001;16:237885.
17. Rodríguez Carmona A, Pérez Fontán M. Sodium removal in patients
undergoing CAPD and Automated Peritoneal Dialysis. Perit Dial Int
2002;22:705-13.
18. Ortega O, Gallar P, Carreño A, Gutiérrez M, Rodríguez I, Oliet A, et
al. Peritoneal sodium mass removal in continuous ambulatory peritoneal dialysis and automated peritoneal dialysis: influence on blood pressure control. Am J Nephrol 2001;21:189-93.
19. Konings CJ, Kooman J, Schonck M, Gladziwa U, Wirtz J, van den
Wall Bake AW, et al. Effect of icodextrin on volume status, blood
pressure and echocardiographic parameters: A randomozed study.
Kidney Int 2003;63:1556-63.
20. Gallar P, Ortega O, Rodríguez I, Mon C, Ortiz M, Herrero JC, et al.
Control de la tensión arterial y balance peritoneal de sodio en DPCA
y DPA. VI Reunión Anual de Diálisis Peritoneal. Vitoria, 2008. Libro
de resúmenes.
21. Passauer J, Petrov H, Schleser A, Leitch J. Evaluation of clinical dry
weight assessment in haemodialysis patients using bioimpedance
spectroscopy: a cross-sectional study. Nephrol Dial Transplant
2010;25:545-51.
Sent for review: 8 Jun. 2011 | Accepted: 22 Oct. 2011
Nefrologia 2012;32(1):108-13
113
letters to the editor
A) COMMENTS ON PUBLISHED ARTICLES
The role of interleukin
6 in the pathogenesis
of hyponatremia
associated with
Guillain-Barré
syndrome
Nefrologia 2012;32(1):114
doi: 10.3265/Nefrologia.pre2011.Oct.11115
To the Editor,
We read with great interest the
contribution by Monzón et al.1 They
reported a significant case of a man who
had Guillain-Barré syndrome (GBS) with
syndrome of inappropriate antidiuretic
hormone (SIADH) and speculated that
increased sensitivity to vasopressin in the
renal tubule and a long-lasting hypoosmolarity or antidiuretic substances
might cause GBS-related SIADH.
However, we would like to add a possible
pathomechanism in the development of
hyponatremia associated with GBS.
Furthermore, Mastorakos et al.6 reported
that plasma antidiuretic hormone levels
were elevated after IL-6 injection in
cancer patients, suggesting that IL-6
activated the magnocellular ADHsecreting neurons and that it might be
involved in SIADH. Activation of the
subfornical organ and the organum
vasculosum of the lamina terminalis by
IL-6 could eventually lead to thirst and
increased vasopressin secretion by
neurons from the supraoptic nucleus and
The
paraventricular
nucleus.4
combination of antidiuresis and increased
water intake may result in hyponatremia.
Therefore, there is a possibility that
IL-6 may play a central role in the
pathogenesis
of
hyponatremia
associated with GBS. However, further
studies are necessary to elucidate if IL6 crosses the blood-brain barrier
(BBB), or whether lipopolysaccharides
cross the BBB and then increase IL-6
locally in the brain in the future.
According to a previous study by
Maimone et al.,2 interleukin (IL)-6, a
multifunctional cytokine, might be
implicated in the immunopathogenesis
of GBS. In their study, serum IL-6
levels were increased in six (26%) of
23 GBS patients, and detectable levels
of IL-6 were also found in the
cerebrospinal fluid in 13 (57%).2
Using enzyme-linked immunospot
assays, Press et al.3 found elevated
numbers of IL-6-secreting blood
mononuclear cells during the acute
phase in patients with GBS.
Quite recently and importantly, Swart
et al.4 depicted the cascade-like fashion
of events initiated by an inflammatory
stimulus (lipopolysaccharides), with
tumor necrosis factor-α secreted first,
IL-1β second, and IL-6 last, suggesting
possible pathways connecting IL-6 to
vasopressin release. These proinflammatory cytokines are secreted
into the systemic circulation to initiate
the acute phase response which is
involved in the innate immune system.5
114
The authors declare they have no
potential conflicts of interest related to
the contents of this article.
1. Monzón Vázquez T, Florit E, Marqués
Vidas M, Rodríguez Cubillo B, Delgado
Conde P, Barrientos Guzmán A.
Syndrome of inappropriate antidiuretic
hormone hypersecretion associated with
Guillain-Barré syndrome. Nefrologia
2011;31:498-9.
2. Maimone D, Annunziata P, Simone IL,
Livrea P, Guazzi GC. Interleukin-6 levels in
the cerebrospinal fluid and serum of
patients with Guillain-Barré syndrome
and chronic inflammatory demyelinating
polyradiculoneuropathy. J Neuroimmunol
1993;47:55-61.
3. Press R, Ozenci V, Kouwenhoven M, Link
H. Non-T(H)1 cytokines are augmented
systematically early in Guillain-Barré
syndrome. Neurology 2002;58:476-8.
4. Swart RM, Hoorn EJ, Betjes MG, Zietse R.
Hyponatremia and inflammation: the
emerging role of interleukin-6 in
osmoregulation.
Nephron
Physiol
2011;118:45-51.
5. Gabay C, Kushner I. Acute-phase proteins
and other systemic responses to
inflammation.
N
Engl
J
Med
1999;340:448-54.
6. Mastorakos G, Weber JS, Magiakou MA,
Gunn H, Chrousos GP. Hypothalamicpituitary-adrenal axis activation and
stimulation of systemic vasopressin
secretion by recombinant interleukin-6 in
humans: potential implications for the
syndrome of inappropriate vasopressin
secretion. J Clin Endocrinol Metab
1994;79:934-9.
Se Jin Park1, Ki Soo Pai1, Ji Hong Kim2, Jae II Shin2
Department of Pediatrics. Ajou University
School of Medicine, Ajou University. Suwon
(Korea).
2
Department of Pediatrics. Yonsei University
College of Medicine, Severance Children’s
Hospital. Seoul (Korea).
Correspondence: Jae II Shin
Department of Pediatrics. Yonsei University
College of Medicine. Severance Children’s
Hospital, 250 Seongsan-ro, Seodaemun-gu,
120-752, Seoul, Korea.
[email protected]
1
Acyclovir and
valacyclovir
neurotoxicity in
patients with renal
failure
Nefrologia 2012;32(1):114-5
To the Editor,
It was with great interest that we read
the article by Quiñones et al1 in which
they mention how toxicity secondary
to starting new treatments in patients
with renal failure can give rise to false
diagnoses.
One of the patients cited by the authors
suffered from neurotoxicity due to
acyclovir. Acyclovir and its ester,
valacyclovir, are widely used in treating
infection with the varicella zoster virus,
Nefrologia 2012;32(1):114-32
and its Summary of Product
Characteristics lists neurotoxicity as an
extremely rare event. However, we have
observed 3 episodes similar to that
described by Quiñones et al in patients
on haemodialysis receiving acyclovirvalacyclovir for metameric herpes
zoster.
Case 1. Female patient aged 61 years
treated with oral acyclovir at 800mg/12
hours. After the third dose, she
experienced a psychotic reaction with
visual hallucinations and dysarthria.
Antiviral treatment was suspended and
the psychiatric symptoms resolved
completely in 3 days.
Case 2. Male patient aged 66 years
undergoing treatment with oral
valacyclovir (500mg/12 hours). After
the second dose, he presented
dysarthria and reduced consciousness.
In light of a possible case of
herpesviral encephalitis, treatment was
changed to IV acyclovir at 400mg/day,
with no noticeable response. The level
of consciousness improved after each
haemodialysis session, and then
decreased again. When we suspected
neurotoxicity caused by the antiviral
agent, we reduced the acyclovir dose to
200mg/day
and
started
daily
haemodialysis sessions; the patient
improved progressively and had
recovered completely by the ninth day.
Case 3. Female patient aged 83 years
who was treated with valacyclovir at
1g/12 hours as prescribed by her
general practitioner. Dysarthria began
following the third dose. Valacyclovir
was suspended and the patient
underwent daily haemodialysis during
3 days, the speech disorder resolving
completely.
This last patient received a high dose
of valacyclovir, but in the other two
patients, acyclovir and valacyclovir
doses were adjusted according to the
stage of renal failure. A correlation
between toxicity and plasma drug
levels is under debate. Some authors
state that there is a higher risk of
toxicity when levels exceed 20
Nefrologia 2012;32(1):114-32
micromoles per litre,2 but others claim
not to have witnessed symptoms in
patients with levels greater than 30
micromoles, and it is therefore
impossible to establish a safe
therapeutic range.3 Furthermore, the
early onset of the neurological
symptoms was remarkable in our three
cases: in all of the patients, symptoms
appeared on the second day of
treatment after the second or third oral
dose, which would suggest that the
cause was drug idiosyncrasy rather
than drug accumulation.
Haemodialysis was effective in
reducing the levels of acyclovir and its
metabolites.4 This is the most effective
treatment for this type of neurotoxicity,
and it is an important tool for the
differential diagnosis of acyclovir
neurotoxicity and viral encephalitis.2,5
The appearance of neurological or
psychiatric changes in these patients
should be taken into account in order to
prevent misdiagnosis, as occurred in
our own case 2 and in the case
described by Quiñones et al.
observational study. Nephrol Dial
transplant 2003;18:1135-41.
5. Peces R, de la Torre M, Alcázar R.
Acyclovir-associated encephalopathy in
haemodialysis patients. Nephrol Dial
Transplant 1996;11:752.
Gloria Ruiz-Roso, Antonio Gomis,
Milagros Fernández-Lucas,
Martha Díaz-Domínguez,
José L. Teruel-Briones, Carlos Quereda
Servicio de Nefrología. Hospital Universitario
Ramón y Cajal. Madrid. Spain.
Correspondence: Gloria Ruiz Roso
Ramón y Cajal, Madrid. Spain.
[email protected]
Estimating glomerular
filtration rate in order
to adjust drug doses:
confusion abounds
Nefrologia 2012;32(1):115-7
To the Editor,
Two recent events led to our writing
this letter.
1. Quiñones Ortiz L, Suárez Laurés A, Pobes
Martínez A, de la Torre M, Torres Lacalle
A, Forascepi Roza R. Alerta ante
medicación inesperada en hemodiálisis.
Nefrologia 2011;31:611-2.
2. Gómez Campderá F, Verde E, Vozmediano
MC, Valderrábano F. More about acyclovir
neurotoxicity in patients on haemodialysis.
Nephron 1998;78:228-9.
3. Haefeli WE, Schoenenberger RA, Weiss P,
Ritz RF. Acyclovir-induced neurotoxicity:
Concentration-side effect relationship in
acyclovir
overdose.
Am
J
Med
1993;94:212-5.
4. Helldén A, Odar-Cederlöf I, Diener P,
Barkholt L, Medin C, Svensson JO, et al.
High serum concentrations of the
acyclovir
main
metabolite
9carboxymethoxymethylguanine in renal
failure patients with acyclovir-related
neuropsychiatric
side
effects:
an
One. For 2 or 3 years now, our local
biochemistry laboratories calculate the
estimated glomerular filtration rate
(eGFR) by means of the MDRD-IDMS
formula (formerly MDRD) and the
isolated creatinine value, as per National
Kidney Foundation recommendations.1
Yet in October 2011, we still observe the
following:
- The constant used by some
biochemistry laboratories for the
MDRD-IDMS formula is 186, when
it should be 175 since the calculation
for the serum creatinine value is
standardised by IDMS.
- Some laboratories deliver MDRDIDMS results in ml/min instead of
ml/min/1.73m2. Although it is
dependent on an individual’s body
surface area, this could lead one to
115
assume that the measurement is
absolute, which could have
consequences when adjusting doses.
Two. While the new formula for
measuring glomerular filtration rate
(GFR),2 CKD-EPI, seems to improve on
the current MDRD-IDMS formula in
both accuracy and precision, it is likely
to make things even more confusing
when it comes to choosing an equation
to adjust a drug dose.
Furthermore, an article recently published
in this journal comparing the MDRDIDMS and CKD-EPI formulas in a
Spanish population3 contained what
appears to be an erratum in Table 1,
which describes the formulas used to
calculate CKD-EPI: for males with
creatinine levels >80 micromoles/litre, it
states to divide by 0.7, and we believe
that it should be by 0.9.
In light of all of the above, we would
like to make the following observation:
From the 1980s until quite recently,
GFR was estimated using the formula
published by Cockcroft and Gault (CG)
in 1976.4 The result of this equation (an
estimation of creatinine clearance) was
used to evaluate renal function and
adjust the doses of any drugs that so
required. We would like to stress that the
value obtained by this formula is
absolute. This means that it accounts for
the individual’s size (since it includes
weight among its variables) and gives a
result in ml/min (if the body surface area
differs greatly from the mean, using
ideal rather than true weight is
recommended.)
In 1999, 23 years after the CG formula
was published, Levey published a new
formula for estimating GFR: the
MDRD.5 Shortly afterwards, in 2002,
the KDOQI proposed using this
formula for early detection and
classification of chronic kidney disease
so that patients in earlier stages would
have better access to nephrology care.1
The result given by this formula is
dependent on body surface area
(ml/min/1.73m2), as is also the case
with the recently improved MDRDIMDS and CKD-EPI formulas.6,2 Since
the result is dependent on a surface area
of 1.73m2, we only need the variables
age, sex, serum creatinine and race.
This formula was recommended by
such societies as the Spanish Society of
Clinical Biochemistry and Molecular
Pathology (SEQC) and the Spanish
Society of Nephrology (S.E.N).7
Nevertheless, although generalised use
of the MDRD method seems appropriate
for categorising individuals in different
stages of chronic kidney disease, it
causes some problems in adjusting drug
doses, especially if the value given by
the laboratories is interpreted as an
absolute value.
If we consider only the relative results
(ml/min/1.73m2) given by MDRD,
Table 1. Recommended dabigatran dose adjustments according to the
glomerular filtration rate estimated by different equations
Formula used
to estimate GFR
Results
Units
Cockcroft-Gault
31.3
ml/min
MDRD-4v
28.6
ml/min/1.73m
Recommendation
as SmPC
Indicated
2
Contraindicated
MDRD-4v adjusted
for body surface area
35.1
ml/min
Indicated
CKD-EPI
26.3
ml/min/1.73m2
Contraindicated
White male 85 years of age, 180cm height, 90kg, with a serum creatinine level of 2.2mg/dL.
Estimated body surface area 2.1m . GFR=Glomerular filtration rate
2
116
MDRD-IMDS or CKD-EPI –those
results
given
by
biochemical
laboratories– individuals with a body
surface area >1.73m2 will have a higher
absolute eGFR value. This could lead to
underdosing the patient. If the patient’s
body surface area is less than 1.73m2, the
absolute eGFR will be lower, which
could lead to overdosing the patient
(Tables 1 and 2).
On the other hand, the required dose of a
certain drug may vary considerably
depending on the equation used to
estimate GFR, and this may have clinical
repercussions.8 With this in mind, most
published drug adjustment guidelines
recommend a dose and/or drug interval
according to the Cockcroft-Gault
formula; very few guidelines make use
of MDRD.9 In two recent examples,
regulatory authorities based their
recommendations on the CG formula:
- The Spanish Agency for Medicines
and Health Products (AEMPS)
followed the European Medicines
Agency
recommendation
and
modified the SmPC for Pradaxa®
(dabigatran)
and
issued
an
informative note on 27 October 2011
reminding doctors of the importance
of checking renal function before
and after treatment with this new
drug. They informed that before
starting dabigatran treatment, renal
function must be assessed in all
patients by calculating creatinine
clearance (CrCl) in order to exclude
patients with severe renal failure
(CrCl<30ml/min).10
- The Food and Drug Administration
(FDA)’s safety update of 1
September 2011 stated that the
SmPC had been changed and issued
a reminder that “Reclast should not
be used (is contraindicated) in
patients with creatinine clearance
less than 35ml/min”.11
The FDA guidelines for the industry
simply cite the CG and MDRD equations
as being the most commonly used.
However, experts do not agree on which
of the formulas should be used for
adjusting doses in patients with renal
Nefrologia 2012;32(1):114-32
Table 2. Recommended daptomycin dose adjustments according to the
glomerular filtration rate estimated by different equations
Formula used
to estimate GFR
Cockcroft-Gault
MDRD-4v
Results
Units
Recommendation
as SmPC
21.6
ml/min
/48h
33
ml/min/1.73m2
/24h
MDRD-4v adjusted
for body surface area
27.5
CKD-EPI
31.5
ml/min
ml/min/1.73m
11.
/48h
2
/24h
12.
White female 85 years of age, 150cm height, 50kg, with a serum creatinine level of 1.5mg/dl.
Estimated body surface area 1.4m2. GFR=Glomerular filtration rate
failure. Some advocate using the equation
recommended by the pharmaceutical
manufacturer, particularly in the case of
elderly patients,12 while others13,14 state
that the MDRD and CG equations are
completely interchangeable.
In summary, and as a general rule, using
the equation recommended by the
pharmaceutical manufacturer (mainly
CG) seems reasonable. If there is no
specific recommendation, the most
reliable method of estimating GFR in the
target population should be should.
Regardless of which equation is used,
we must remember that dose
adjustments must be made using
absolute GFR values, especially for
patients whose body surface area differs
greatly from 1.73m2.
4.
5.
6.
7.
1. National Kidney Foundation. K/DOQI clinical
practice guidelines for chronic kidney
disease: evaluation, classification, and
stratification. Am J Kidney Dis 2002;39(2
Suppl 1):S1-266.
2. Levey AS, Stevens LA, Schmid CH, Zhang
YL, Castro III AF, Feldman HI, et al., for the
CKD-EPI
(Chronic
Kidney
Disease
Epidemiology Collaboration). A new
equation to estimate glomerular filtration
rate. Ann Intern Med 2009;150(9):604-12.
3. Montañés R, Bover J, Oliver A, Ballarín JA,
Gracia S. Valoración de la nueva ecuación
Nefrologia 2012;32(1):114-32
8.
9.
10.
CKD-EPI para la estimación del filtrado
glomerular. Nefrologia 2010;30(2):185-94.
Cockcroft DW, Gault MH. Prediction of
creatinine clearance from serum creatinine.
Nephron 1976;16(1):31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers
N, Roth D. A more accurate method to
estimate glomerular filtration rate from serum
creatinine: a new prediction equation.
Modification of Diet in Renal Disease Study
Group. Ann Intern Med 1999;130(6):461-70.
Levey AS, Coresh J, Greene T, Marsh J,
Stevens LA, Kusek JW, et al. Expressing the
Modification of Diet in Renal Disease Study
equation for estimating glomerular filtration
rate with standardized serum creatinine
values. Clin Chem 2007;53(4):766-72.
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.
Denetclaw TH, Oshima N, Dowling TC.
Dofetilide dose calculation errors in elderly
associated with use of the modification of diet
in renal disease equation. The Ann
Pharmacother 2011;45:e44.
Dowling TC, Matzke GR, Murphy JE, Burckart
GJ. Evaluation of renal drug dosing:
prescribing information and clinical
pharmacist approaches. Pharmacotherapy
2010;30(8):776-786.
Nota informativa de la AEMPS, del 27 de
octubre de 2011, sobre dabigatrán
(Pradaxa®) y riesgo de hemorragia:
nuevas recomendaciones de vigilancia de
la
función
renal.
Available
at:
http://www.aemps.gob.es/informa/notasI
nformativas/medicamentosUsoHumano/seguri
13.
14.
dad/2011/NI-MUH_21-2011.htm. [Accessed:
Oct/31/2011].
Comunicado de la FDA, del 1 de
septiembre de 2011, sobre la seguridad
de
los
medicamentos:
Nueva
contraindicación y advertencia actualizada
sobre el deterioro renal causado por
Reclast (ácido zoledrónico). Available at:
http://www.fda.gov/Drugs/DrugSafety/ucm27
0199.htm#ref. [Accessed: Oct/31/2011].
Corsonello A, Pedone C, Lattanzio F, Semeraro
R, D’Andria F, Gigante M, et al. Agreement
between equations estimating glomerular
filtration rate in elderly nursing home residents
and in hospitalised patients: implications for
drug dosing. Age and Ageing 2011;40:583-9.
Stevens LA, Nolin TD, Richardson MM, Feldman HI, Lewis JB, Rodby R, et al., on behalf
of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Comparison
of drug dosing recommendations based on
measured GFR and kidney function estimating equations. Am J Kidney Dis
2009;54:33-42.
Jones G. Estimating renal function for drug
dosing decisions. Clin Biochem Rev
2011;32:81-8.
Javier Peral-Aguirregoitia1,
Unax Lertxundi-Etxebarria2,
Ramon Saracho-Rotaeche3,
Sira Iturrizaga-Correcher4,
M. José Martínez-Bengoechea5
1
Servicio de Farmacia Hospitalaria.
Hospital Galdakao-Usansolo. Galdakao,
Vizcaya. Spain.
2
Farmacéutico especialista en Farmacia
Hospitalaria. Jefe de Servicio de Farmacia.
Hospital Psiquiátrico de Álava. Vitoria-Gasteiz,
Álava. Spain.
3
Servicio de Nefrología. Hospital Santiago
Apóstol. Vitoria-Gasteiz, Álava. Spain.
4
Laboratorio de Análisis Clínicos. Hospital
Txagorritxu. Vitoria-Gasteiz, Álava. Spain.
5
Farmacéutica especialista en Farmacia Hospitalaria.
Jefa de Servicio de Farmacia. Hospital
Galdakao-Usansolo. Galdakao, Vizcaya. Spain.
Correspondence: Javier Peral Aguirregoitia
Servicio de Farmacia Hospitalaria.
Hospital Galdakao-Usansolo.
Barrio Labeaga s/n, 48960 Galdakao, Vizcaya.
Spain.
[email protected]
[email protected]
117
B) BRIEF PAPERS ON RESEARCH AND CLINICAL EXPERIENCES
Is peripheral and/or
catheter blood
necessary for
performing
haemoculture in
haemodialysis patients
whose central venous
catheter presents
bacteraemia?
Nefrologia 2012;32(1):118-20
To the Editor,
The profile of today’s patients in
haemodialysis (HD) programmes has
changed. HD patients are now older and
have more co-morbidities. The factors
responsible
for
their
poorer
cardiovascular and immunological
health are mainly the increase in
diabetes, followed by increased survival
rates of patients within the programme.
As a result, their blood vessels (arteries
and veins) are in worse condition for
creating an internal arteriovenous fistula
(IAVF), the number of punctures and
the risk of infection are higher, and the
patients have poorer HD clearance. This
leads to increased use of central venous
catheters (CVC) and a higher
probability of catheter dysfunction,
which is accompanied by a higher risk
of bacteraemia.1-4 The high percentage
of patients who start HD treatment
using catheters is well-known. One
multi-centre study evaluated the onset
of renal replacement therapy in 1504
patients from 35 different Spanish
hospitals in 2003, and found that nearly
half (46%) began with unscheduled
dialysis sessions, and therefore used a
CVC. Of these patients, 82% decided to
continue with HD.5-6 In the region of the
Canary Islands, the 2009 Dialysis and
Transplant report by the S.E.N.7
reported an incidence rate of 129
patients per million population (pmp) on
renal replacement therapy, with 85%
undergoing HD. A total of 226 patients,
118
with a mean age of 66 years, underwent
dialysis at our peripheral hospital in
2010; 43% were diabetic, 28% had a
tunnelled CVC, and the length of stay
was very little for patients with nontunnelled CVC. Despite the outsourcing
efforts, we found that there are very
long delays in achieving a permanent
access site. This is due to delays in both
the surgical procedure to create the
access and in the arteriovenous fistula
maturation time in the population
described above. Furthermore, many of
these patients refuse surgery repeatedly,
and a large percentage do not have the
option of a permanent surgical access.
Furthermore, this patient population has
a high rate of CVC-related bacteraemia.8
In Chapter 1 (procedures prior to
creation of a vascular access) of the
S.E.N. guidelines for vascular access in
haemodialysis (November 2004), we
find the following recommendations
for preserving the venous network:9
1) Warn the patient about its
importance. 2) Provide the patient
with a card or recommend wearing a
wrist
band.
3)
Recommend
venipuncture in the back of the hand.
4) Use low-plasma laboratory
techniques (capillary or dry samples).
5) Make other professionals aware of
these problems. 6) Avoid implanting
the CVC in the shoulder girdle, and
especially in the subclavian vein. 7)
Femoral
vein
catheters
are
recommended for patients who
experience flare-ups in the course of
their chronic kidney disease. 8)
Stimulate muscular and vascular
development
through
isometric
physical exercises or venous dilation
techniques. 9) Carefully monitor the
venous network of peritoneal dialysis
and kidney recipients as well. In
kidney recipients, patients and
professionals must be made aware of
the importance of i) rescuing a
thrombosed IAVF and ii) repairing
rather than closing elbow IAVF in the
absence of congestive heart failure.
Haemodialysis unit personnel are
aware that bacteraemia due to CVC is
the most common complication in
vascular accesses. The incidence rate
of bacteraemia varies, but it is higher
for non-tunnelled catheters (3.8-6.5 per
1000 catheters/day) than for tunnelled
catheters.
(1.6-5.5
per
1000
catheters/day).10-13 In our peripheral
unit, the bacteraemia incidence rate for
tunnelled CVC was 1.63 per 1000
catheters/day.
Non-hospitalised
HD
patients
(outpatients) and those with a CVC
may develop bacteraemia after
beginning dialysis, which suggests a
systemic influx of bacteria and/or
endotoxins from the intraluminal
wall of the catheter. We must
consider how to take blood samples
for
blood
culture
without
interrupting dialysis, unless this is
necessary due to haemodynamic
instability or another major clinical
complication.
The definitive diagnosis of bacteraemia
due to CVC requires that 1 the
following criteria are met:
- Positive blood cultures that find the
same microorganism in the catheter
and in a peripheral vein, with a
bacterial colony count 5 times
higher in the catheter or a difference
in bacterial growth of more than
120 minutes.
- Cultures of the same microorganism
from both the tip of the catheter and
from at least one peripheral blood
culture.
- Cultures of the same microorganism
from two different peripheral blood
cultures where there is no other
source of infection.
At least 2 blood cultures taken between
10 and 15 minutes apart.
According to section 6.10.2 on
infections,9 chapter 6 (central venous
catheters) of the S.E.N. guidelines for
vascular accesses in haemodialysis
Nefrologia 2012;32(1):114-32
(November 2004), when fever is
present in a patient with a CVC,
samples must be drawn of peripheral
blood and from both lumens of the
catheter, and samples must be extracted
simultaneously and cultured using
quantitative techniques if possible.
Evidence B.
which may be needed for creating a
permanent vascular access. At
times, venipuncture is a labourious
task which does not guarantee an
aseptic field, in addition to causing
added pain and suffering in a
patient already subjected to a
number of traumatic procedures.
There is no controversy regarding the
universal criteria for obtaining blood
cultures in patients with CVC and
bacteraemia. There is abundant
literature on CVC implanted for other
reasons, such as for administering
drugs, parenteral nutrition and
haemodynamic monitoring, as well as
CVC in HD patients. However, it does
not specify whether patients who have
CVC for HD developed bacteraemia
after
beginning
haemodialysis
treatment.14-15
Although culture blood samples
obtained by venipuncture have been
held up as the gold standard for
diagnosing bacteraemia, we must
consider the extracorporeal system an
extension of the circulatory system. It
is not likely that there would be
significant differences between the
blood sample obtained by venipuncture
and that extracted from the arterial
line of the extracorporeal circuit.19
In this context, complying with criteria
for obtaining blood cultures is difficult
due to the following reasons:
- Blood from the catheter: when
dialysis
is
interrupted,
disconnecting both lines to obtain
blood cultures may even have an
iatrogenic effect, given the risk of
infection from handling the
catheter16 in a clinical situation that
is already complicated. Such a step
also entails the possibility of
clotting the entire extracorporeal
system and wasting precious time,
since we do not know if the patient
will be able to continue with
dialysis treatment or how long the
patient will have to wait for the
next session following catheter
removal. On the other hand,
extracting blood samples from both
CVC lumens gives rise to false
positives in more than 60% of
cases. These are related to
colonisation of the CVC by
microorganisms from the skin.17-18
- Peripheral
blood:
obtaining
peripheral blood in the population
described above is very difficult in
as much as 40% of all patients,
especially if they are under heparin,
with the risk of developing
haematomas and damage to veins,
Nefrologia 2012;32(1):114-32
In order to correctly perform
haemodialysis through a catheter,
maximum flow rates are required to
overcome the deficit due to
recirculation (where possible, blood
flow rates of more than 300ml/min).
Under these conditions, it is likely that
large volumes of blood have circulated
through the catheter in both directions
(arterial and venous) and –when
bacteraemia is present– the sample
obtained from the catheter will not
maintain the quantitative colony
differential (with respect to peripheral
blood) that is necessary to determine
whether the bacteraemia arose in the
CVC. However, this is not the case
when obtaining samples from CVC
implanted for other purposes or
tunnelled/non-tunnelled CVC for HD
during interdialysis periods.
In conclusion, a universal protocol for
obtaining blood cultures from the
patients described here may do more
harm than good, and we believe that
the S.E.N. expert committee should
review this matter to determine
whether or not they should establish an
exception.
1. Wasse H, Kutner N, Zhang R, Huang Y.
Association of initial hemodialysis vascular
access with patient-reported health status
and quality of life. Clin J Am Soc Nephrol
2007;2:708-14.
2. Wasse H, Speckman R, Frankenfiel D, Rocco
M,McClellan. Predictors of central venous
catheter use at the initiation of
Hemodialysis. Semin Dial 2008;21(4):34651.
3. Mermel LA. What is the predominant
source of intravascular catheter infections?
Clin Infect Dis 2011;52(2):211-2.
4. Matajira T, Félez I, Lacambra I, Azuara
M, Álvarez Lipe R, Iñigo P. Endocarditis
bacteriana por SAMR en paciente
portador de catéter venoso central para
hemodiálisis: uso de daptomicina.
NefroPlus 2010;3(2):41-5.
5. Gil Cunquero JM, Marrón B. La realidad y la
percepción de las infecciones en diálisis.
Nefrologia 2010;1(Supl Ext 1):56-62.
6. Marrón B, Ortiz A, de Sequera P, MartínReyes G, de Arriba G, Lamas JM, et al.;
Spanish Group for CKD. Impact of endstage renal disease care in planned dialysis
start and type of renal replacement therapya Spanish multicentre experience. Nephrol
Dial Transplant 2006;21 (Suppl 2):ii51-5.
7. Informe de Diálisis y Trasplante 2009
(Registro Español de Enfermos Renales).
Congreso de Granada, 2010.
8. Lee T, Barker J, Allon M. Tunneled catheters
in hemodialysis patients: reasons and
subsequent outcomes. Am J Kidney Dis
2005;46(3):501.
9. Guías
de
Acceso
Vascular
en
Hemodiálisis. Sociedad Española de
Nefrología. Noviembre de 2004.
10. Weijmer MC, Vervloet MG, Piet M, ter
Wee. Compared to tunnelled cuffed
hemodialysis catheters, temporary
untunnelled catheters are associated
with more complications already 2
weeks of use. Nephrol Dial Transplant
2004;19:670-7.
11. Oliver MJ. Acute dialysis catheters. Semin
Dial 2001;14(6):432-5.
12. Kairaitis LK, Gottlieb T. Outcome and
complications of temporary hemodialysis
catheters. Nephrol Dial Transplant
1999;14:1710-4.
13. Robinson D, Suhocki P, Schwab SJ.
Treatment of infected tunneled venous
access hemodialysis wih guidewire
exchange. Kidney Int 1998;53:1792-4.
119
14. Yébenes JC, Capdevila JA. Infección
relacionada con catéteres intravasculares.
Med Clin (Barc) 2002;119(13):500-7.
15. León C, Ariza J. Documento de consenso:
Guías para el tratamiento de las
infecciones relacionadas con catéteres
intravasculares de corta permanencia en
adultos: conferencia de consenso SEIMCSEMICYUC. Enferm Infecc Microbiol Clin
2004;22(2):92-101.
16. Albalate M, Pérez García R, De Sequera P,
Alcázar R, Puerta M, Ortega M, et al.
¿ Hemos olvidado lo más importante para
prevenir las bacteriemias en pacientes
portadores de catéteres para hemodiálisis?
Nefrologia 2010;30(5):573-7.
17. Gaur AH, Fynn PM, Heine DJ, Giannini
MA, Shenep JL, Hayden RT. Diagnosis of
catheter-related bloodstream infections
among pediatric oncology patients
lacking a peripheral culture, using
differential time to detection. Pediatr
Infect Dis J 2005;24:445.
18. Guembe M, Rodríguez-Créixems M,
Sánchez-Carrillo C, Pérez-Parra A,
Martín-Rabadán P, Bouza E. How many
lumens should be cultured in the
conservative diagnosis of catheterrelated bloodstream infections? Clin
Infect Dis 2010; 50:1575.
19. García CP, Payá GE, Olivares CR, Cotera
FA, Rodríguez TJ, Sanz RM. Documento
de consenso: Diagnóstico de las
infecciones asociadas a catéteres
vasculares centrales. Rev Chilena Infectol
2003;20(1):41-50.
Juan F. Betancor-Jiménez1, Francisco
Alonso-Almán1, Yanet Parodis-López1,
Beatriz Quintana-Viñau1,
Sonia González-Martínez1,
Cristina García-Laverick1,
Patricia Pérez-Borges2,
José C. Rodríguez-Pérez2
1
Centro de hemodiálisis RTS-GranCanaria.
2
Hospital Universitario de Gran Canaria Dr.
Negrín. Las Palmas de Gran Canaria. Spain.
Correspondence: José C. Rodríguez Pérez
Hospital Universitario de Gran Canaria Dr. Negrín.
[email protected]
120
Serial ultrasound of the
vascular access
Nefrologia 2012;32(1):120-2
To the Editor,
Current advances in nephrology and
similar advances in other areas of
medical knowledge mean that
nephrologists
must
develop
technical skills that are not provided
by traditional training in nephrology.
We present a case that illustrates
that fact.
The patient in question is an 83 year old
male in a conventional haemodialysis
(HD) programme with chronic kidney
disease secondary to diabetic nephropathy.
He had a history of type 2 diabetes
mellitus with various diabetes-related
complications, arterial hypertension
and atypical chest pain with no
evidence of ischaemic heart disease.
The patient started HD via a tunnelled
catheter in February 2010, with good
haemodynamic
tolerance
and
adaptation. A left humeral-cephalic
arteriovenous fistula (AVF) was
created one month later. Following a
30-day maturation period, we began
venipuncture in the AVF and observed
suboptimal
maturation,
difficult
anatomical interpretation, venous
collapse, ´frequent extravasations and
impossibility of reaching a blood flow
(Qb) greater than 250ml/min.
Given these findings, we examined the
vascular access (VA) with a portable
vascular ultrasound machine (EcoAVP)
in the HD room (Figure 1) and
observed no stenosis in the
arteriovenous fistula and a dual venous
system with a collateral vessel
branching off 3cm from the arterial
anastomosis with a thickness similar to
that of the two veins (diameter: 0.39cm
vs 0.36cm; area: 0.12 vs 0.14cm2). We
found 2 stenoses in the proximal part
of the cephalic vein.
The fistulography (Figure 2) confirmed the
ultrasound findings, a haemodynamically
A: cephalic vein; B: collateral vessel to cephalic vein
Figure 1. First B-mode ultrasound image
of the vascular access in which we see
two veins of similar size
significant (80%) stenosis at 10cm from the
arteriovenous fistula and another smaller
one in the proximal third of the cephalic
vein. Percutaneous angioplasty was
performed on the 2 stenoses with good
angiographic results. The identified
collateral vessel was not treated in any way.
One month later, the AVF had
progressed well, allowing for
cannulation with no extravasations and
an acceptable Qb rate. A second image
from the EcoAVP (Figure 3) confirmed
the increase in the diameter and the
cross-sectional area of the main vein
(diameter: 0.5cm, area: 0.24cm2) with a
decrease in the size of the collateral
vessel (diameter: 0.35, area: 0.08cm2).
One year later, the AVF was
functioning properly, with a Qb of
350ml/min and a normal venous
pressure of 140mmHg.
Table 1 shows the changes in some
clinical parameters and ultrasound
images taken after the treatment with
percutaneous angioplasty.
The use of an EcoAVP is not common in
daily practice. However, it is very useful for
approaching, monitoring, and diagnosing
AVF complications.1 Ultrasound provides
both morphological and functional
information in a fast, reliable and noninvasive way, which helps us determine
whether percutaneous or surgical treatment
is necessary.2 The EcoAVP enables us to
combine B-mode imaging, which estimates
Nefrologia 2012;32(1):114-32
diagnosis and treatment of VA
complications may reduce the number
and duration of hospital stays
associated with such problems, reduce
the use of venous catheters, shorten
waiting times for having an AVF,
reduce costs derived from diagnostic
and therapeutic procedures, and
optimise prevention of complications
in general.10
Figure 3. Second B-mode ultrasound of
the arteriovenous fistula showing an
increase in cephalic vein size and decrease
in the width of the collateral vessel
interventions,4,5,6,7 and estimated venous
elastography as a tool that may predict
AVF success (limited evidence at
present).5
Figure 2. Fistulography image taken after
percutaneous angioplasty to both
stenoses
vein volume, the presence of haematomas,
parietal calcifications, intraluminal thrombi,
collateral vessels and stenosis, with the
Colour Doppler mode, which estimates
blood flow, peak systolic velocity, the
presence of turbulences, and the shape of
pulse waves with the corresponding
resistance indices.3 Ultrasound results must
always be interpreted in conjunction with
clinical findings.3
A broader view of the nephrologists’
participation in decision-making would
include using ultrasound for arterial
and venous mapping, which has been
proven to increase success in surgical
Nefrologia 2012;32(1):114-32
At present, guidelines do not set strict
criteria for periodical ultrasound
assessments of VA or recommend a
time to initiate ultrasound monitoring.
In some studies, the complications
involved in VA failure, which can be
detected with a EcoAVP, are present in
AVF that still function normally.8 On
the other hand, early dysfunction and
primary failure in radiocephalic AVF
and the frequent delayed maturation in
diabetic patients leads us to
recommend using a EcoAVP as a
monitoring device for all patients on
dialysis.4 Considering the increased
mean age of patients in dialysis units
and data on the high number of
complications at any level and any type
of VA in elderly patients,4,9 we can state
that
training
in
ultrasound
examinations should be included in the
nephrological curriculum. Active
participation of nephrologists in the
Despite a certain amount of
dependence on specialties such as
vascular surgery or interventional
radiology in this field, the nephrologist
is ultimately responsible for ensuring
that the VA works correctly. This
responsibility requires strict monitoring
and
early
treatment
of
VA
complications in a multidisciplinary
area
that
encounters
frequent
administrative
obstacles.
Proper
training in ultrasound examinations
will enable professionals to make
better treatment decisions in situations
in which success depends upon swift
action.
1. Tordoir J, Canaud B, Haage P, Konner K,
Basci A, Kooman J, et al. EBPG on
Vascular Access. Nephrol Dial Transplant
2007;22 (Suppl 2):ii88-117.
2. Chandra AP, Dimascio D, Gruenewald S,
Nankivell B, Allen RD, Swinnen J. Colour
duplex ultrasound accurately identifies
focal
stenoses
in
dysfunctional
autogenousarteriovenous
fistulae.
Nephrology (Carlton) 2010;15(3):300-6.
3. Kerr SF, Krishan S, Lapham RC, Weston MJ.
Duplex sonography in the planning and
Table 1. Changes in certain study parameters following percutaneous
transluminal angioplasty of the arteriovenous fistula
Diameter of
Diameter of
Area of
cephalic vein collateral vein cephalic vein
Area of
collateral vein
Blood flow
Pre-PTA
39mm
36mm
0.12cm2
0.14cm2
≤250ml/min.
Post-PTA
50mm
35mm
0.24cm
0.08cm
>
_350 ml/min.
2
2
PTA: percutaneous transluminal angioplasty
121
4.
5.
6.
7.
8.
9.
10.
evaluation of arteriovenous fistulae for
haemodialysis. Clin Radiol 2010;65(9):
744-9.
FerringM, Henderson J, Wilmink A, Smith S.
Vascular ultrasound for the pre-operative
evaluation prior to arteriovenous fistula
formation for haemodialysis: review of the
evidence.
Nephrol
Dial
Transplant
2008;23:1809-15.
Biswas R, Patel P, Park DW, Cichonski TJ,
Richards MS, Rubin JM, et al. Venous
elastography: Validation of a novel highresolution
ultrasound
method
for
measuring vein compliance using finite
element
analysis.
Semin
Dial
2010;23(1):105-9.
Ives CL, Akoh JA, George J, VaughanHuxley E, Lawson H. Pre-operative vessel
mapping and early post-operative
surveillance
duplex
scanning
of
arteriovenous fistulae. J Vasc Access
2009;10(1):37-42.
Davidson I, Chan D, Dolmatch B, Hasan M,
Nichols D, Saxena R, et al. Duplex
ultrasound evaluation for dialysis access
selection and maintenance: a practical
guide. J Vasc Access 2008;9(1):1-9.
Pietura R, Janczarek M, Zaluska W, Szymanska
A, Janicka L, Skublewska-Bednarek A, et al.
Colour Doppler ultrasound assessment of
well-functioning mature arteriovenous fistulas
for haemodialysis access. Eur J Radiol
2005;55(1):113-9.
Martín Navarro J, Petkov V, Ríos F, Gutiérrez
Sánchez MJ, Alcázar de la Ossa JM. Acceso
vascular para HD: elección en mayores de
75 años. Nefrologia 2011;31 (supl 2):80.
Asif A, Merrill D, Briones P, Roth D, Beathard
GA.
Hemodialysis
Vascular
Access:
Percutaneous Interventions by Nephrologists.
Semin Dial 2004;17(6):528-34.
Juan A. Martín-Navarro,
M. José Gutiérrez-Sánchez,
Vladimir Petkov-Stoyanov
Unidad de Hemodiálisis. Hospital del Tajo.
Aranjuez, Madrid. Spain.
Correspondence: Vladimir Petkov Stoyanov
Unidad de Hemodiálisis. Hospital del Tajo.
Avda. Amazonas Central s/n,
28300 Aranjuez, Madrid. Spain.
[email protected]
[email protected]
122
Economic impact of
estimating renal
function in patients
with systemic lupus
erythematosus
Nefrologia 2012;32(1):122-3
To the Editor,
Kidney injury is one of the most
important morbidity and mortality
factors in patients with systemic lupus
erythematosus (SLE).1,2 Glomerular
filtration rate (GFR) is the best indicator
of renal function, and it is important in
the diagnosis, determining the stage,
gauging treatment response and dosing
medications.3
The National Kidney Foundation (NKF)
recommends estimating GFR using
creatinine-based equations.4,5 On the
other hand, the European Consensus of
Lupus Glomerulonephritis suggests that
renal function in SLE patients should be
measured either by serum creatinine
levels or by estimating renal function
using serum creatinine-based equations,
but where GFR is higher than
60ml/min/1.73m2, creatinine clearance
should be used (CrCl).6 In a recent
publication, we reported on the high
frequency of inappropriate sample
collection from SLE patients when
CrCl is used.7
We took a survey of Mexican
rheumatologists to better understand
the use of NKF-recommended
equations in evaluating renal function
in SLE patients.
We used the google.com survey tool to
send questionnaires to members of the
Mexican College of Rheumatology in
September 2010. We evaluated their
demographic data, including sex, years
practicing medicine, number of SLE
patients evaluated per week and the
rheumatologist’s method for evaluating
renal function in patients with SLE.
We received responses from 45
rheumatologists
throughout
the
country; the mean age of those
responding was 40 years, with a mean
of 9.5 years practicing medicine. Of
those responding, 75.6% were male
and 51.2% saw more than 10 SLE
patients per week.
Almost half of the rheumatologists
(46.7%) use CrCl in all of their patients
in order to estimate GFR; 17.8% use it
in two-thirds of their patients, and only
13.3% do not use it at all. Only 28.9%
of those responding used equations for
estimating GFR (MDRD, CKD-EPI,
Cockcroft-Gault, others).
According to INEGI (Mexican National
Institute of Statistics and Geography),
nearly 112 million people lived in Mexico
in 2010. As per the Peláez-Ballestas et al
study, the SLE prevalence in Mexico is
0.06%.8 We evaluated the mean cost of
CrCl (serum and urinary creatinine in 24
hours) and the mean cost of measuring
only serum creatinine (in order to
determine GFR by means of equations) in
three laboratories in central Mexico. The
difference in cost between taking a single
GFR measurement by one method or the
other is more than 500 000 dollars if the
rheumatologist uses CKD-EPI or MDRD
instead of 24 hour CrCl (Table 1).
Despite the evidence suggesting a high
frequency of inappropriate sample
collecting and the recommendation made
Table 1. Costs associated with a single estimate of GFR in Mexico
Equations
DCr
Saving $
Saving USD
Costs
$ 47
$ 160
Population (Mexico)
112.337.000
112.337.000
Population total LES
Cost total
67.402
$ 3.167.894
67.402
$ 10.784.320
$ 7.616.426
USD 647.396
$: Mexican pesos; CKD-EPI: the Chronic Kidney Disease Epidemiology Collaboration equation;
CrCl: creatinine clearance. USD: dollars.
Nefrologia 2012;32(1):114-32
by the NKF, Mexican rheumatologists
continue to use CrCl to estimate GFR.
The importance of disseminating studies
in other diseases, in addition to the NKF
guidelines, is firstly due to the fact that
the methods mentioned above do not
require 24 hour urine collection and that
health care systems would save thousands
of dollars if this practice were generalised
(worldwide); considering that a number
of controlled international clinical trials
use CrCl to estimate GFR.9,10
These findings show that although the
guidelines suggest the use of more exact,
less expensive methods, Mexican
rheumatologists continue to use methods
that are both more expensive and less
reflective of true GFR. We must promote
studies among doctors showing the
benefits for patients in terms of both
economic
sustainability
and
reproducibility. If our results among
Mexican rheumatologists were similar on
a global level, the savings incurred by
using better estimation methods could
amount to millions of dollars.
1. Cervera R, Khamashta MA, Font J, Sebastiani
GD, Gil A, Lavilla P, et al. Morbidity and
mortality in systemic lupus erythematosus
during a 10-year period: a comparison of
early and late manifestations in a cohort of
1,000 patients. Medicine (Baltimore)
2003;82(5):299-308.
2. Stoll T, Seifert B, Isenberg DA. SLICC/ACR
Damage Index is valid, and renal and
pulmonary organ scores are predictors of
severe outcome in patients with systemic
lupus erythematosus. Br J Rheumatol
1996;35(3):248-54.
3. Soares AA, Eyff TF, Campani RB, Ritter L,
Camargo JL, Silveiro SP. Glomerular filtration
rate measurement and prediction equations.
Clin Chem Lab Med 2009;47(9):1023-32.
4. K/DOQI clinical practice guidelines for chronic
kidney disease: evaluation, classification, and
stratification. Am J Kidney Dis 2002;39(2
Suppl 1):S1-266.
5. Levey AS, Coresh J, Balk E, Kausz AT, Levin A,
Steffes MW, et al. National Kidney Foundation
Nefrologia 2012;32(1):114-32
6.
7.
8.
9.
10.
practice guidelines for chronic kidney disease:
evaluation, classification, and stratification.
Ann Intern Med 2003;139(2):137-47.
Gordon C, Jayne D, Pusey C, Adu D, Amoura
Z, Aringer M, et al. European consensus
statement on the terminology used in the
management of lupus glomerulonephritis.
Lupus 2009;18(3):257-63.
Martínez-Martínez MU, Borjas-García JA,
Magaña-Aquino M, Cuevas-Orta E,
Llamazares-Azuara L, Abud-Mendoza C.
Renal function assessment in patients with
systemic lupus erythematosus. Rheumatol Int.
2011 May 21. [Epub ahead of print].
Peláez-Ballestas I, Sanin LH, Moreno-Montoya
J, Alvarez-Nemegyei J, Burgos-Vargas R, GarzaElizondo M, et al. Epidemiology of the
rheumatic diseases in Mexico. A study of 5
regions based on the COPCORD methodology.
J Rheumatol Suppl 2011;86:3-8.
Mak A, Mok CC, Chu WP, To CH, Wong SN,
Au TC. Renal damage in systemic lupus
erythematosus: a comparative analysis of
different age groups. Lupus 2007;16(1):28-34.
Mak SK, Lo KY, Lo MW, Chan SF, Tong GM,
Wong PN, et al. Efficacy of enteric-coated
mycophenolate sodium in patients with
active lupus nephritis. Nephrology (Carlton)
2008;13(4):331-6.
Marco U. Martínez-Martínez,
Carlos Abud-Mendoza
Unidad Regional de Reumatología
y Osteoporosis. Hospital Central Dr. Ignacio
Morones Prieto. San Luis Potosí (México).
Correspondence: Carlos Abud-Mendoza
Unidad Regional de Reumatología y Osteoporosis.
Hospital Central Dr. Ignacio Morones Prieto, Av. V.
Carranza 2395, 78240 San Luis Potosí, Mexico.
[email protected]
[email protected]
chronic kidney disease (CKD) in
women than in men, regardless of
age.1,2 The study by Labrador et al
assesses the prevalence of occult renal
disease (defined as an estimated
glomerular filtration rate (eGFR)
below 60ml/min and serum creatinine
within the normal range), and the
authors found this condition in 43.5%
of the women in a group with a mean
age of 77 years.3
We therefore propose studying sex as a
factor involved in GFR in a cohort of
elderly patients with both normal and
altered serum creatinine (sCr) levels.
We will also analyse the effect of this
factor in patients considered as carriers
of occult renal disease.
Between January and April 2006, we
conducted a cross-sectional study in a
population with a mean age of 83 years
(range: 69-97 years) that was recruited
when patients came in for scheduled
check-ups with the Geriatric Medicine
and General Nephrology Departments
at the General Hospital of Segovia. In
this group, 38 patients had sCr within
the normal range: Group 1, sCr
≤1.1mg/dl (range 0.7-1.1): 6 males and
32 females; 42 had altered sCr. Group
2, sCr >1.1mg/dl (range 1.2-3): 19
males and 23 females.3% of the total
had diabetes mellitus, and 81.3% had
arterial hypertension. GFR was
estimated using the abbreviated
MDRD method4 and the CockcroftGault formula.5
Table 1 shows the mean GFR given by
the formulae, broken down by group
and sex.
Out of the patient total, 56 (70%) had a
GFR (MDRD) <60ml/min. Of the
patients with a GFR<60ml/min according
to MDRD, 18 had sCr within the normal
range (100% female), while 38 had a
baseline sCr>1.1mg/dl (15 males [39.5%]
and 23 females [60.5%], P=.001.
To the Editor,
In epidemiological studies we
generally find a higher prevalence of
The 18 patients with a normal sCr and
GFR by MDRD <60ml/min (occult
renal disease) had a mean age of
81.33±6 years.
Chronic kidney disease
in the elderly: the
impact of patients’ sex
Nefrologia 2012;32(1):123-4
123
Table 1. Mean estimated baseline glomerular filtration rates in the study group
broken down by sex
Group
Group
Group
Group
1
1
2
2
(MDRD (ml/min)
(Cockcroft-Gault) (ml/min)
(MDRD (ml/min)
(Cockcroft-Gault) (ml/min)
Male
78.01 (7)
58.78 (11)
43.60 (15)
31.86 (16)
Female
60.85 (8)
45.63 (9)
37.30 (8)
29.69 (6)
P
0.000
0.007
NS
NS
Group 1: sCr <
_1.1mg/dl (6 males, 32 females). Group 2: sCr>1.1mg/dl (19 males, 23 females).
NS: not significant.
In our study, we also found that eGFR
(estimated using the two methods listed
here) in women with sCr within the
normal range was significantly lower
than in men. However, these
differences are not as pronounced in
the patient group with altered sCr
(Group 2). Our data therefore confirm
a higher prevalence rate of CKD in
women if they are evaluated by eGFR;
this statement is especially true for the
subjects in Group 1.
The differences in GFR between the
sexes and study groups may lie within
the mathematical formulae used to
estimate GFR. The mathematical
formulae used in our study are based
on sCr, which involves the patient’s
muscle mass and nutritional state.
Therefore, these significant differences
in GFR between the sexes among
patients with a normal sCr are more
likely to show women’s smaller muscle
mass rather than their true GFR. It is
also important to note that the MDRD
formula was designed in patients with
altered renal function and not validated
in a healthy population: applying the
MDRD formula to estimate GFR in
individuals with a normal sCr may
underestimate true GFR by up to 50%.6
On the other hand, when we use the
MDRD formula in patients with altered
renal function, the differences between
males and females are less pronounced.
This means that the resulting eGFR
may successfully show the presence of
kidney disease rather than the patient’s
nutritional state and/or muscle mass.
In conclusion, sex is a factor to
consider when checking for chronic
kidney disease in the elderly. The
systematic use of formulae based on
creatinine levels can lead to healthy
elderly women being considered
carriers of occult renal disease.
2. Chadban SJ, Briganti EM, Kerr PG, Dunstan
DW, Welborn TA, Zimmet PZ, et al.
Prevalence of kidney damage in Australian
adults: The AusDiab kidney study. J Am Soc
Nephrol 2003;14: S131-38.
3. Labrador PJ, Mengotti T, Jiménez M, Macías
M, Vicente F, Labrador J, et al. Insuficiencia
renal oculta en Atención Primaria. ¿Un
problema exclusivo de mujeres? Nefrologia
2007;27:716-20.
4. Levey AS, Greene T, Kusek JW, Beck GJ.
Simplified equation to predict glomerular
filtration rate from serum creatinine. J Am
Soc Nephrol 2000;11:828.
5. Cockroft DW, Gault MH. Prediction of
creatinine clearance from serum creatinine.
Nephron 1976;16:31-41.
6. Heras M, Fernández-Reyes MJ, Guerrero MT.
Sobre la estimación de la función renal en el
anciano: implicaciones del uso sistemático de
la fórmula Modification of Diet in Renal
Disease para el ajuste farmacológico. Rev Esp
Geriatr
Gerontol
2010;45(1):50-1.
1. Zhang QL, Rothenbacher D. Prevalence of
chronic kidney disease in population-based
studies: systematic review. BMC Public Health
2008;8:117.
Manuel Heras1, Pedro García-Cosmes2,
M. José Fernández-Reyes1,
M. Teresa Guerrero3, Rosa Sánchez1
1
Servicio de Nefrología. Hospital General de
Segovia. Spain.
2
de Salamanca. Spain.
3
Servicio de Geriatría. Hospital General de
Segovia. Spain.
Correspondence: Manuel Heras
Hospital General de Segovia.
40002 Segovia. Spain.
[email protected]
[email protected]
laparoscopic surgery for an adrenal
myelolipoma associated with primary
hyperaldosteronism. Myelolipomas
are rare tumours; they are benign,
grow slowly, and vary in size. They
are made up of adipose and
haematopoietic tissue. These tumours
are typically non-functional and if
they reach a large size, they can cause
pain, pressure on adjacent organs and
acute intratumoural or retroperitoneal
bleeding.
The patient was a male aged 54 years,
obese and a smoker, with long-standing
hypertension (HT) and chronic kidney
disease (CKD) secondary to malignant
nephroangiosclerosis
that
was
diagnosed by kidney biopsy in 2000.
He started peritoneal dialysis in 2006
and underwent a deceased donor
transplant in 2008. Previous x-ray
studies already showed a right adrenal
mass compatible with a myelolipoma;
in 2005, it measured 5*5.4cm in
C) BRIEF CASE REPORTS
Adrenal myelolipoma
associated with
primary
hyperaldosteronism
Nefrologia 2012;32(1):124-5
To the Editor,
We present the case of a kidney
recipient who recently underwent
124
Nefrologia 2012;32(1):114-32
diameter. When we were monitoring
the patient’s CKD in our department,
the patient also presented persistent
hypokalaemia due to hyperreninemic
hyperaldosteronism secondary to the
underlying disease (malignant HT),
which ruled out the possibility of a
functional adrenal mass. However, as
part of the pre-transplant study in
2008, the patient underwent a CTguided needle biopsy of the adrenal
mass, and the results from the
histological study suggested a
myelolipoma, thus confirming the
initial diagnosis. As the tumour was
benign, it did not contraindicate
kidney transplantation.
During the two-year outpatient
monitoring period following the
transplant, the patient presented
refractory HT requiring six different
hypotensive drugs to achieve rather
poor blood pressure control. His
renal function deteriorated slowly
over this time, and he presented
proteinuria and microhaematuria.
The
persistent
hypokalaemia
reappeared and doctors ordered a
new hormonal study. This time, the
study found high plasma aldosterone
(1098pg/ml) and suppressed plasma
renin activity (0.13ng/ml/h). The
patient was then diagnosed with
primary hyperaldosteronism and the
CT and MRI scans were repeated; the
adrenal mass had reached 12*5cm in
diameter along the cranio-caudal
plane and 10cm in diameter along the
transversal plane. It contained mainly
fatty tissue with dense soft tissue
areas. The patient was referred to the
General Surgery Department, and in
March 2010, underwent laparoscopic
right adrenalectomy with excellent
and prompt recovery.
The histological study showed an
adrenal myelolipoma with hyperplasia
of the adrenal cortex (zona
glomerulosa) secondary to the
pressure exerted by the large size of
the myelolipoma. This explained the
patient’s primary hyperaldosteronism,
even though the tumour was benign
and non-functional.
Nefrologia 2012;32(1):114-32
We could reduce the hypotensive
drugs by half in the post-operative
phase. The patient now has excellent
control over his hypertension with
the aid of two hypotensive drugs and
blood potassium levels are normal,
which suggests that the renal
hyperplasia was not bilateral and
was clearly associated with the
myelolipoma.
We found cases of myelolipomas
associated with arterial HT in the
literature, but the tumours have
never been shown to be functional.
Arterial HT was rather explained
by renovascular causes, due to
pressure exerted by the tumour, or
associated with obesity or endocrine
conditions such as Cushing’s
syndrome or Conn’s syndrome. This
case is exceptional as primary
hyperaldosteronism was caused by a
myelolipoma, which could possibly
be explained by the pressure exerted
on the adrenal gland by the large
tumour.
1. Villar del Moral JM, Rodríguez González
JM, Moreno Llorente P, Martos Martínez
JM, de la Quintana Barrasate A, Expósito
Rodriguez A, et al. Adrenal surgery in
Spain: final results of a national survey. Cir
Esp 2011;89(10):663-9.
2. Brogna A, Scalisi G, Ferrara R, Bucceri
AM. Giant secreting adrenal myelolipoma
in a man: a case report. J Med Case
Reports 2011;5:298.
3. Wani NA, Kosar T, Rawa IA, Qayun A.
Giant adrenal myelolipoma: Incidentaloma
with a rare incidental association. Urol
Ann 2010;2(3):130-3.
4. Lu HS, Gan MF, Chen HS, Huang SQ.
Adrenal myelolipoma within myxoid
cortical adenoma associated with Conn´s
syndrome. J Zhejiang Univ Sci B
2008;9(6):500-5.
5. Dluhy RG, Maher MM, Wu Ch-L. A 59Year-Old Woman with an Incidentally
Discovered Adrenal Nodule. N Engl J Med
2005;352:1025-32.
Vanesa Camarero-Temiño,
Verónica Mercado-Ortiz,
Badawi Hijazi-Prieto, Pedro Abaigar-Luquin
Sección de Nefrología.
Complejo Hospitalario Universitario de
Burgos. Spain.
Correspondence: Vanesa Camarero Temiño
Complejo Hospitalario Universitario
de Burgos, Avda. del Cid 96, 09005 Burgos.
Spain.
[email protected]
Reactive
haemophagocytic
syndrome associated
with parvovirus B19
in a kidney-pancreas
transplant patient
Nefrologia 2012;32(1):125-6
To the Editor,
Reactive haemophagocytic syndrome or
secondary haemophagocytic lymphohistiocytosis (HLH) is a disorder of the
mononuclear phagocyte system characterised by generalised, ineffective and uncontrolled histiocytic proliferation that
leads to cell damage and multiple organ
dysfunction with haemophagocytosis.
The first description of secondary forms
of this disease was by Risdall et al,1 who
in 1979 described a syndrome characterised by a proliferation of histiocytes
with haemophagocytic activity, associated
with a viral infection. This syndrome was
later described in association with infections of all types and with non-infectious
diseases such as rheumatoid arthritis, lupus, leukaemia, lymphomas, myelodysplastic syndromes and carcinomas.
Its pathogenesis is still unclear, although
there are several hypotheses. The
development of this syndrome is likely to
be due to an immunological disorder that
results in uncontrolled T-lymphocyte
activation,2 causing hypercytokinaemia,
and consequently, excessive macrophage
activation.
125
It is diagnosed according to the criteria in
HLH-20043 and the treatment focuses on
the infectious process, as well as on the
use
of
gamma
globulin
and
immunosuppression.4
We describe the case of a patient aged 42
years with a history of type 1 diabetes, diabetic nephropathy, and chronic renal
failure who underwent a kidney-pancreas
transplant (October 2010). The patient’s
maintenance immunosuppressants are
deltisone B, everolimus, and tacrolimus
(FK) in addition to prophylaxis with valgancyclovir
and
trimethoprim/
sulfamethoxazole (TMS). The patient experienced fever, vomiting and odynophagia for 2 weeks, and was treated with oral
antibiotics. Fever, asthenia and dehydration persisted, so the patient was hospitalised. Laboratory analyses revealed
pancytopoenia and renal and pancreatic
dysfunction; the patient received subcutaneous insulin but not haemodialysis.
Blood and urine cultures were performed, as well as a PCR (polymerase
chain reaction) test for cytomegalovirus
(CMV), and empirical treatment with
ceftriaxone and ciprofloxacin was administered. Twenty-four hours after admission, the haemodynamic state had deteriorated severely and the patient was
moved to intensive care, where all immunosuppressants except for corticosteroids were discontinued. Antibiotic
coverage was increased through vancomycin, imipenem, fluconazole and
ganciclovir. Seven days after admission,
the patient was still feverish with positive
cultures for common microbes and fungi
and a negative PCR for CMV. We ordered PCR for parvovirus B19 due to the
persistent pancytopoenia. The physical
examination showed cutaneous and mucosal pallor, asthenia, adynamia and
splenomegaly. The laboratory results
were as follows: Hb: 8.6mg/dl, leukocytes: 900mm3, triglycerides: 317mg/dl;
ferritin >1500mcg/l. In light of suspected haemophagocytic syndrome (5 criteria met), we performed a bone marrow
biopsy, which revealed histiocytes with
haemophagocytosis. The patient was
treated with high doses of gamma globulin (400mg/kg) during 5 days. In the end,
PCR was positive for parvovirus B19.
126
All of the patient’s low values improved
(haematocrit 28%; Hb 9.4g/dl; leukocytes
1900mm3; platelets 203 000mm3) and
immunosuppressant treatment was
resumed. Pancreatic function remained
weak, and the nephrology department
found the renal function to be so severely
affected that the patient needed
haemodialysis. A kidney biopsy puncture
was performed which yielded insufficient
material.
At 30 days of hospitalisation, the patient
was once again feverish with a headache;
lumbar puncture revealed normal
cerebrospinal fluid, acid-alcohol resistant
bacilli (AARB) negative; PCR for CMV,
herpes simplex virus, Epstein-Barr virus,
cryptococcal antigenaemia all negative;
adenosine deaminase at the upper cut-off
level; cerebral MRI showed no lesions.
The thoracic radiography showed
bilateral interstitial and alveolar
infiltrates, which was confirmed by
thoracic CT as bilateral radiodense
infiltrates; fibrobronchoscopy with
bronchoalveolar lavage was performed;
negative for AARB and positive for
pneumocystitis carinii (PCP) when TMS
treatment began. Due to the persistent
fever and the lack of culture isolation in a
case with pulmonary lesions, empirical
treatment with isoniazid, rifampicin,
ethambutol and liposomal amphotericin
was administered. Another kidney biopsy
puncture was performed, but graft
bleeding ensued and the patient had to go
to the surgical ward. Doctors decided to
extirpate both grafts, and observed
mesenteric adenopathies and abundant
purulent matter. This matter tested
AARB (+) under direct examination, and
therefore antibiotic and antifungal
treatments were suspended, with the
patient continuing tuberculosis treatment.
Final culture was positive for
tuberculosis. Patient’s fever subsided and
overall condition improved; he returned
to his home city and is monitored by his
local haemodialysis centre.
Haemophagocytic syndrome that
reacts to associated infections is a
severe and potentially fatal condition.
Immunosuppressed patients who
present
with
a
fever
and
haematological
abnormalities
(cytopoenias) should be screened for
haemophagocytosis as early diagnosis
enables proper treatment and a
favourable prognosis.
1. Risdall RJ, McKenna RW, Nesbit MF, Krivit
W, Balfour HH Jr, Simmons RL, et al. Virusassociated hemophagocytic syndrome: A
benign histyocitic proliferation distinct
from malignant histiocytosis. Cancer
1979;44:993-02.
2. Alexei A. Groma and Elizabeth D.
MellinsbMacrophage activation syndrome:
advances
towards
understanding
pathogenesis. Curr Opin Rheumatol
2010;22:561-6.
3. Henter JI, Horne A, Aricó M, Egeler RM,
Filipovich AH, Imashuku S, et al. HLH2004: Diagnostic and therapeutic
guidelines
for
hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer
2007;48(2):124-31.
4. Ardalan MR, Shoja MM, Tubbs RS, Esmaili
H, Keyvani H. Postrenal Transplant
Hemophagocytic Lymphohistiocytosis and
Thrombotic Microangiopathy American
Journal of Transplantation 2008; 8:
1340–1344Associated with Parvovirus B19
Infection. Am J Transplant 2008;8:1340-4.
Maico Tavera1, Jorgelina Petroni2,
Luis León3, Elena Minue3, Domingo Casadei3
1
Trasplante Renal. Instituto de Nefrología Sa
Buenos Aires. Capital Federal, Buenos Aires
(Argentina).
2
Trasplante Renal y Pancreático.
Instituto de Nefrología Sa Buenos Aires.
Capital Federal, Buenos Aires (Argentina).
3
Trasplante Renal. Instituto de Nefrología Sa
Buenos Aires. Capital Federal, Buenos Aires
(Argentina).
Correspondence: Luis León
Trasplante Renal.
Instituto de Nefrología Sa Buenos Aires,
cabello 3889, 1425 Capital Federal, Buenos
Aires, Argentina.
[email protected]
Nefrologia 2012;32(1):114-32
Emphysematous cystitis
resolved with medical
treatment. A case
report and literature
review
To the Editor,
Emphysematous cystitis is a rare infectious complication mainly seen in diabetic patients.
Here, we present the first case of this
disease examined by our Department. A
69 years old male patient with insulindependent diabetes and poor metabolic
control was admitted due to an acute fever accompanied by nausea, vomiting
and pneumaturia. The patient also had
arterial hypertension, stent revascularisation for coronary heart disease, and
had been diabetic for 20 years. He presented diabetic retinopathy, neuropathy
and nephropathy. He had been monitored for obstructive uropathy secondary
to adenoma of the prostate.
He was conscious and alert during the
physical examination: arterial blood pressure 110/60; heart rate 80bpm; axillary
temperature 38ºC; jugular veins flat. The
rest of the examination was uneventful.
Laboratory testing delivered the following results: haemoglobin: 12g/dl; leukocytes: 6500; glycaemia: 738mg/dl;
blood urea nitrogen: 68mg/dl; creatininaemia: 1.4mg/dl; [Na+] = 127mmol;
[K+] = 5.4mmol; [Cl-] = 88mmol;
[HCO3-] = 27mmol.
The urine test revealed leukocyturia,
red blood cells >100 per field and abundant bacteria. The urine culture showed
extended-spectrum beta lactamase-producing Escherichia coli.
The CT urography (a specific CT technique) showed air within the bladder lumen near its ventral face.
The patient received hydration, insulin
therapy and treatment with ertapenem.
Nefrologia 2012;32(1):114-32
Figure 1. CT
intravesical air
Urography
showing
Progress was excellent, with no septic
shock and easy-to-manage hyperosmolar syndrome.
Emphysematous cystitis was discovered
by Eisenlohr1 at the end of the 19th century and Bailey2 described this illness. It
may present asymptomatically until the
onset of severe sepsis, or it may pass
through stages with pneumaturia and
acute abdomen. For the case in question,
the key symptom was pneumaturia and
the presence of air in the bladder as
shown by the CT (Figure 1).
In the series described by Thomas et al.3,
the most common bacterial strain was E.
coli, followed by Klebsiella. The mean
age was 66 years, most affected individuals were women (64%) and most were
diabetic (67%). The patient treated in our
Department was similar in age to those in
the other study, and also suffered diabetes
with poor metabolic control. It has been
postulated that air is produced by the fermentation of glucose in urine.4
Treatment is usually medical, as in our
case, and the mortality rate is close to
7%. In isolated cases, treatment has
been combined with surgery or a hyperbaric chamber.
2. Bailey H. Cystitis emphysematosa; 19
cases with intraluminal and interstitial
collections of gas. Am J Roentgenol
Radium Ther Nucl Med 1961;86:850-62.
3. Thomas AA, Lane BR, Thomas AZ,
Remer EM, Campbell SC, Shoskes DA.
Emphysematous cystitis: a review of 135
cases. BJU Int 2007;100(1):17-20.
4. González-Martín V, Rodrigo E, Arias
M, Lastra P. Cistitis enfisematosa en
un trasplantado renal. Nefrologia
2008;28(1):110-1.
Héctor Parra-Riffo, Juan Lemus-Peñaloza,
Paula Maira
Unidad de Nefrología.
Hospital FACH. Santiago de Chile (Chile).
Correspondence: Héctor Parra Riffo
Unidad de Nefrología, Hospital FACH,
Av. Las Condes 8631, Santiago de Chile,
7560171 Santiago de Chile, Chile.
[email protected]
Rhabdomyolysis and
acute renal failure
following hard physical
activity in a patient
treated with
rosuvastatin
Nefrologia 2012;32(1):127-8
To the Editor,
Muscular problems constitute one of
the most important adverse effects of
statin drugs, and they range from myalgias to myositis/rhabdomyolysis.1,2 The
incidence rates of myalgia and rhabdomyolysis due to statins are 5-10%
and 0.01% respectively.1 However, this
is the drug type that is most frequently
involved in rhabdomyolysis.3
Risk factors for developing rhabdomyolysis due to statins include, but are not limited to, high doses, intense physical exercise and interactions with other drugs.2,4
1. Eisenlohr W. Das Interstielle vagina, darm
und harnblasenemphysem zurückgefürt
auf gasentwickelnde bakterien. Beitr
Path Anat Allg Path 1888;3:101.
We describe a patient treated with rosuvastatin who developed rhabdomyolysis and acute renal failure following intense physical activity.
127
Male patient diagnosed with dyslipidaemia and arterial hypertension 3
months prior to the event. He began treatment with rosuvastatin (10mg/day),
olmesartan and torasemide; creatinine
level was 1.1mg/dl.
One week before being admitted, he
was hired to install antennas, which
required considerable physical effort.
About three days before admission, he
experienced muscle soreness in the lower limbs and took 2 ibuprofen
600mg tablets. The pain did not subside and he experienced nausea and vomiting, so he came to the hospital.
Physical examination findings were
normal. Diagnostic tests provided the
following
results;
haemoglobin
14.6g/dl; urea 141 mg/dl; creatinine
9.33mg/dl; uric acid 12.2mg/dl; total
calcium 7.7mg/dl; phosphate 4mg/dl;
sodium 137mEq/l; potassium 6mEq/l;
chlorine
103mEq/l;
bicarbonate
24mEq/l; albumin 4g/dl; creatine kinase (CK) 6243U/l (nv: 38-174); lactate-dehydrogenase 768U/l (nv: 140300); triglycerides 253mg/dl; CRP
42.5mg/l; coagulation, platelets, and
other basic biochemical parameters
were within normal values. Normal
thyrotropin. Urine: d 1030, proteinuria 30-70mg/dl; sediment 80/90 leukocytes/field,
5-10
red
blood
cells/field; sodium 59mEq/l; urine
culture negative. Serology for hepatitis B, C and HIV was negative. Thoracic radiography: normal; electrocardiogram: sinus rhythm, right bundle
branch block. Ultrasound showed normal kidneys. Medication was suspended and we prescribed hydration/electrolyte replacement. The patient
maintained good urine production and
creatinine levels and other biochemical parameters improved. After 11
days, the patient was discharged with
a creatinine level of 1.29mg/dl and
normal CK; the decision was made later to prescribe atorvastatin 20mg
every other day.
Rosuvastatin is a synthetic HMG-CoA
reductase inhibitor with pharmacological characteristics that, in theory, imply
a lower risk of myotoxicity: 1) it has a
128
low liposolubility, which makes it less
able to penetrate muscle tissue;1 2) it is
potent, and generally speaking, low doses of potent statins are less myotoxic
than high doses of less potent drugs;1
and 3) it is eliminated through biliary
(90%) and renal (10%) excretion. Metabolism by cytochrome P450 is minimal, and performed by the CYP2C9
and CYP2C19 subfamilies and not by
CYP3A4. This means that there is less
possibility of it interacting with other
drugs.1,5 However, cases of rhabdomyolysis and kidney failure associated
with rosuvastatin have been reported.6,7
Renal failure appears in approximately
40% of cases of rhabdomyolysis due to
statins, which gives a poorer prognosis.3
In the case of this patient, the renal failure, which could also have been affected by the ibuprofen and the olmesartan, resolved favourably.
The patient had been taking rosuvastatin with no incidents until he engaged in hard physical labour. Statin-related rhabdomyolysis is related to: 1)
depletion of intermediary metabolites
in the pathway of mevalonate, such as
geranylgeranyl pyrophosphate and
farnesyl pyrophosphate, causing
myocyte apoptosis and 2) mitochondrial dysfunction.8 Decreases in Q10
coenzyme and changes in membrane
stability due to lower cholesterol levels may also be contributing factors.2
Hard physical activity has an additional myotoxic effect by increasing
oxygen consumption and provoking
mitochondrial overload.8
The course of action to take with patients who develop statin-related rhabdomyolysis and need hypolipidaemic
agents afterwards is a matter of debate.
Some recommend atorvastatin every
other day, or fluvastatin or rosuvastatin
on alternate days or administered once
weekly.1,2
To conclude, patients receiving statin
drugs must be aware that hard physical labour, whether exercise or occupational, may trigger muscular complications.
1. Jacobson TA. Toward «pain-free» statin
prescribing: clinical algorithm for
diagnosis and management of myalgia.
Mayo Clin Proc 2008;83:687-700.
2. Joy TR, Hegele RA. Narrative review:
statin-related myopathy. Ann Intern Med
2009;150:858-68.
3. Oshima Y. Characteristics of drugassociated rhabdomyolysis: analysis of
8,610 cases reported to the U.S. Food and
Drug Administration. Intern Med
2011;50:845-53.
4. Sirvent AE, Cabezuelo JB, Enríquez R,
Amorós F, González C, Reyes A.
[Rhabdomyolysis and anuric kidney failure
induced by the treatment with a
gemfibrozil-cerivastatin
combination].
Nefrologia 2001;21:497-500.
5. Calza L. Long-term use of rosuvastatin: a
critical risk benefit appraisal and
comparison
with
other
antihyperlipidemics. Drug Healthc Patient
Saf 2009;1:25-33.
6. Buyukhatipoglu H, Sezen Y, Guntekin U,
Kirhan I, Dag OF. Acute renal failure with
the combined use of rosuvastatin and
fenofibrate. Ren Fail 2010;32:633-5.
7. Pérez Díaz I, Sánchez Argaiz M, Sánchez
Gómez E. Possible rosuvastatin-induced
fatal
rhabdomyolysis.
Farm
Hosp
2011;35:340-1.
8. Meador BM, Huey KA. Statin-associated
myopathy and its exacerbation with
exercise. Muscle Nerve 2010;42:469-79.
Diana Martínez-López1, Ricardo Enríquez2,
Ana E. Sirvent2, M. Dolores Redondo-Pachón2,
Isabel Millán2, Francisco Amorós2
1
Servicio de Medicina Intensiva.
Hospital General de Elche. Elche, Alicante.
Spain.
2
Hospital General de Elche. Elche, Alicante.
Spain.
Correspondence: Ricardo Enríquez
Hospital General de Elche. Camino de la
Almazara, 03203 Elche, Alicante. Spain.
[email protected]
Nefrologia 2012;32(1):114-32
Intestinal pseudoobstruction secondary
to persistent
constipation due to
lanthanum carbonate
To the Editor,
Hyperphosphataemia is a complication
of chronic kidney disease (CKD)
which is often accompanied by
hypocalcaemia and low serum vitamin
D levels. Without treatment, these
deficiencies generally lead to severe
secondary
hyperparathyroidism.
Restricting dietary phosphate is key to
treating this condition, but this
approach alone is not sufficient to
control hyperphosphataemia. As a
result, oral phosphate binders are used
by more than 90% of patients with
CKD.1
Lanthanum carbonate is a non-calcium,
metal-containing phosphate binder
used in hyperphosphataemia treatment.
This trivalent cation forms ionic bonds
with phosphate. Precipitation of
insoluble complexes then takes place in
the intestinal lumen. Due to the very
low degree of absorption by the
gastrointestinal tract (<0.0013%), an
abdominal radiography will show
radiopaque images of lanthanum
carbonate, which may slow intestinal
transit as a side effect.2 Recent studies
have shown that this may cause or
worsen diverticular colitis, which
would increase serum lanthanum
levels. In conclusion, caution must be
exercised when using this drug in
patients with diverticula.3
We present the clinical case of a 55 year
old patient with CKD treated with
periodic haemodialysis, secondary
hyperparathyroidism
and
severe
hyperphosphataemia, mainly due to poor
dietary compliance. Therefore, we
prescribed a non-calcium phosphate
binder, lanthanum carbonate (Fosrenol®),
since the patient also presented significant
peripheral vascular disease of ischaemic
Nefrologia 2012;32(1):114-32
origin and the aim was to reduce the risk
of vascular calcifications. The patient
came to the Emergency Department on
two occasions due to abdominal pain and
constipation, and was admitted to the
General Surgery Department the second
time for suspected diverticulitis. The
abdominal CT revealed uncomplicated
sigmoid diverticulitis.
One month after being discharged from
the hospital, the patient returned with
abdominal pain, constipation, nausea and
vomiting, and was then admitted by our
Nephrology Department. Examination
showed peristaltic activity and diffuse
abdominal pain. Laboratory test results
were uneventful (absence of leukocytosis;
amylase and lipase within normal ranges).
In both the preliminary and current
radiographies, as shown in Figure 1, we
can observe abundant deposits of
lanthanum carbonate in the colon and
dilated intestinal loops consistent with the
ingestion of lanthanum carbonate 3g/daily
for 3 months. The diagnosis was intestinal
pseudo-obstruction secondary to persistent
constipation due to lanthanum carbonate.
That drug was suspended; with
administration of two cleansing enemas
and the addition of an oral osmotic
laxative (Duphalac®) the clinical
symptoms resolved completely.
Plain film abdominal radiography showing
abundant radiopaque lanthanum carbonate
remains in the colon and dilated intestinal
loops.
Figure 1. Intestinal pseudo-obstruction
due to lanthanum carbonate
Hyperphosphataemia is closely related
to developing a risk of cardiovascular
disease with tissue ischaemia and
calciphylaxis in CKD, and with an
increase in fibroblast growth factor 23
and secondary hyperparathyroidism.
However, when faced with preventing
such complications, we must be
mindful of the fact that treating
hyperphosphataemia with lanthanum
carbonate presents a risk of
developing abdominal symptoms such
as those described here. We
recommend
closely
monitoring
tolerance-based doses in order to
prevent related complications.4
1. Tonelli M, Pannu N, Manns B. Oral
phosphate binders in patients with kidney
failure. N Engl J Med 2010; 362:1312-24.
2. Turkmen K, Solak Y, Anil M, Polat H,
Tonbul HZ. An unusual hurdle to renal
transplantation: speckled abdominal
opacities
induced
by
lanthanum
carbonate. Intern Med J 2010;40(12):
e1-2.
3. Kato A, Takita T, Furuhashi M.
Accumulation of lanthanum carbonate in
the digestive tracts. Clin Exp Nephrol
2010;14(1):100-1.
4. Cronin RE, Quarles LD, Berns JS, Sheridan
AM. Treatment of hyperphosphatemia in
chronic kidney disease. Last literature
review version 19.1: January 2011 | This
topic last updated: February 9, 2011.
[Available at: www.uptodate.com].
Vanesa Camarero-Temiño,
Verónica Mercado-Valdivia,
Badawi Hijazi-Prieto, Pedro Abaigar-Luquin
Sección de Nefrología. Complejo Hospitalario
Universitario de Burgos. Spain.
Correspondence: Vanesa Camarero Temiño
Complejo Hospitalario Universitario de Burgos.
Avda del Cid, 96, 09005 Burgos. Spain.
[email protected]
[email protected]
129
Acute renal failure due
to gabapentin.
A case report and
literature review
Nefrologia 2012;32(1):130-1
To the Editor,
Gabapentin is an anticonvulsive that is
widely used for a number of indications at
present: diabetic neuropathy, neuropathic
pain of other causes, epilepsy, etc. Some of
its most common side effects include the
following: ataxia, nystagmus, drowsiness,
headaches, diplopia, fatigue and myoclonic
twitches.1 All of these effects appear quite
often in patients with chronic kidney disease,
especially if they are undergoing dialysis and
their doses are not adjusted to their
glomerular filtration rates.2 We describe a
new case of rhabdomyolysis and acute renal
failure due to gabapentin in order to raise
awareness of the importance of monitoring
creatine kinase (Ck) and renal function, and
of being on the alert for side effects every
time this drug is used.1,3
The patient, aged 49 years, was taken to
the Emergency Department due to
delirium, deteriorating condition and
myalgias evolving over 48 hours. The
patient had visited the Emergency
Department two days before due to
lumbosacral pain, was diagnosed with
mechanical low back pain, and began
treatment with 600mg gabapentin every
8 hours.
Relevant medical history included smoking
1 packet/day, active use of multiple
substances (alcohol, heroin, cocaine, etc.)
and a recent hospital admission. Arterial
hypertension treated with eprosartan and
bisoprolol. Anxiety-depression syndrome.
No relevant nephrological or urological
history. Ten days prior to being admitted, he
underwent laboratory testing at the clinic.
Tests showed normal renal function
(creatinine 0.9mg/dl, urea 30mg/dl and no
pathological findings in urinary sediment.
His normal treatment consisted of paroxetine,
mianserin, disulfiram, eprosartan, bisoprolol,
and, during the last 48 hours, gabapentin.
130
The physical examination showed
acceptable general condition, no fever,
and low blood pressure (90/60mmHg).
The patient was conscious, disoriented
and drowsy, with myoclonic twitches.
Eupnoea at rest. Normal breath sounds;
no oedema in lower limbs, with
mucous membrane dehydration. The
neurological examination found no
focal dystonia or neck stiffness, and the
significant finding was that the patient
trembled when at rest.
Due to the patient history mentioned
above, we screened urine for toxins, and
it was positive for cocaine, heroin and
morphine. We also ran a full blood and
urine analysis which provided the
following relevant results:
- Blood: glucose: 146mg/dl; GOT:
246IU/l; GPT: 231IU/l; bilirubin:
0.8mg/dl; LDH: 2520U/l; C-reactive
protein: 258; Ck: 14911U/l; creatinine:
13.5mg/dl; urea: 273mg/dl; Na:
136mmol/l; Ki: 6.8mmol/l; Ca:
6.1mg/dl; Pi: 16mg/dl; pH 7.2;
bicarbonate: 12mmol/l.
- Urine: specific gravity 1020; pH 5;
proteins 30mg/dl; glucose negative;
ketone bodies: present; leukocytes 70;
erythrocytes
200/µl
(after
catheterisation).
Given these findings and oligoanuria,
doctors requested a kidney ultrasound
that showed kidneys of normal size,
shape and ecogenicity and no ureteral
dilation. Medical treatment for
hyperkalaemia and metabolic acidosis
was initiated as well as plasma
volume expansion. As oliguria, severe
metabolic acidosis and delirium
persisted
with
only
minimal
improvements after administration of
0.5mg flumazenil, we decided to place
a femoral catheter and perform an
emergency dialysis session. In order
to avoid imbalance syndrome, we
used a low cut-off dialyser with a flow
of 200ml/min during 2 hours 30
minutes and neutral-pH Balance
solution. Under this treatment, the
patient improved partially from a
clinical standpoint; diuresis resumed
at 60ml/hour and the metabolic
acidosis resolved.
As the patient had a history of multiple drug
use in addition to the delirium and the
abnormal laboratory results described here,
we performed a differential diagnosis to rule
out other causes of delirium, such as
Wernicke encephalopathy, neuroleptic
malignant syndrome and sepsis. The
biochemical study was expanded to measure
thyroid hormones, vitamin B12 and folic
acid; results were normal. Serological
analyses for hepatitis B and C and HIV were
negative. Cultures from blood and urine
samples were negative. A cerebral MRI
found non-specific demyelinating lesions in
pale nuclei and the pyramidal tract that were
not compatible with Wernicke-Korsakoff
syndrome. Neuroleptic malignant syndrome
was effectively ruled out by the absence of
high fever and rigidity, in addition to the
clinical response following the first dialysis
session. We gathered information from
family members, who confirmed that the
patient had ingested at least 6 gabapentin
tablets in the 24 hours prior to admission,
along with the drugs cited above.
After discontinuing gabapentin and
providing hydration and an additional
dialysis session in the following 12 hours,
the patient’s encephalopathy improved
progressively. The electrocardiogram taken
at 72 hours showed no pathological findings,
renal function became normal (creatinine:
1mg/dl; urea: 55mg/dl in 48 hours and
0.9mg/dl in 36 hours) and Ck values
decreased progressively (7327 at 48 hours
and 555 at 96 hours).
Gabapentin toxicity and side effects are
well-known among nephrologists and
fully described in the literature as
myoclonic
twitches,
myopathy,
neurotoxicity, etc., particularly in
dialysis patients.2,4
Rhabdomyolysis with associated acute
renal failure is an uncommon side
effect, but it has been described in
earlier cases.1,3
The aetiology of rhabdomyolysis varies
greatly. Its most frequent causes include
trauma, intense physical exercise,
infections, and drugs such as statins,
fibrates, neuroleptics, colchicine and
proton pump inhibitors.5,6 It is also
Nefrologia 2012;32(1):114-32
associated with cocaine use, but unlike
the
case
described
here,
rhabdomyolysis tends to be associated
with hypertension and malignant
nephrosclerosis. While our patient did
use cocaine, this is unlikely to be the
root of the problem7 given that the
patient was originally hypotensive and
experienced early renal function
recovery.
While gabapentin levels were not
measured, the rapid resolution of the
delirium and recovery of renal function
after only two sessions of low cut-off
haemodialysis seem to indicate that
gabapentin caused the symptoms. In
fact, gabapentin is eliminated through
renal excretion only, and since it does
not bind to proteins, a single dialysis
session will eliminate nearly 35% of
the total.8,9 In our case, this would
explain the rapid improvement in
symptoms. As in the other 2 cases of
gabapentin-induced acute renal failure
and rhabdomyolysis, the patients
involved had multiple illnesses and
were affected by multiple medications
or other factors that might lead to
rhabdomyolysis and renal failure.
Another similarity was the rapid
resolution of the condition and the
improvement in Ck values after
discontinuing the drug.
In summary, we can conclude that
although it happens infrequently,
gabapentin may cause myotoxicity,
rhabdomyolysis and renal failure even
in patients whose renal function was
previously normal. This is why we
must take special care with its dosage,
with concomitant medications and the
patient’s co-morbidities, and why, after
prescribing gabapentin, we must be
watchful for any signs of muscle
toxicity or kidney failure and quickly
discontinue the drug if necessary.
1. Bilgir O, Calan M, Bilgir F, Kebapçilar L,
Yüksel A, Yildiz Y, et al. GabapentinNefrologia 2012;32(1):114-32
2.
3.
4.
5.
6.
7.
8.
9.
10.
induced rhabdomyolysis in a patient with
diabetic
neuropathy.
Intern
Med
2009;48(12):1085-7.
Bassilios N, Launay-Vacher V, Khoury N,
Rondeau E, Deray G, Sraer JD. Gabapentin
neurotoxicity in a chronic haemodialysis patient.
Nephrol Dial Transplant 2001;16(10):2112-3.
Tuccori M, Lombardo G, Lapi F, Vannacci
A, Blandizzi C, Del Tacca M. Gabapentininduced
severe
myopathy.
Ann
Pharmacother 2007;41(7):1301-5.
Lipson J, Lavoie S, Zimmerman D.
Gabapentin-induced myopathyin 2 patients
on short daily hemodialysis. Am J Kidney Dis
2005;45(6):e100-4.
Guis S, Mattei JP, Cozzone PJ, Bendahan D.
Pathophysiology and clinical presentations
of rhabdomyolysis. Joint Bone Spine
2005;72: 382-91.
Marinella MA. Rhabdomyolysis associated
with haloperidol withoutevidence of NMS.
Ann Pharmacother 1997;31:927-8.
Horowitz BZ, Panacek EA, Jouriles NJ.
Severe rhabdomyolysis with renal failure
after intranasal cocaine use. J Emerg Med
1997;15(6):833-7.
Bluma RA, Pharm D, Thomas J, Schultz RW,
Keller E, Reetze P, et al. Pharmacocinetics
of gabapentin in subjects with various
degrees of renal function. Clin Pharmacol
Ther 1994;56:154-9.
Wong MO, Eldon MA, Keane WF, Türck
D, Bockbrader HN, Underwood BA, et al.
Disposition of gabapentin in anuric
subjects on hemodialysis. J Clin Pharmacol
1995;35(6):622-6.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz
I, Roberts EA, et al. A method for estimatingthe
probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239-45.
Eduardo Torregrosa-de Juan,
Pau Olagüe-Díaz, Pilar Royo-Maicas,
Enrique Fernández-Nájera,
Rafael García-Maset
Hospital de Manises. Manises, Valencia.
Spain.
Correspondence: Eduardo Torregrosa de Juan
Hospital de Manises, Av. Generalitat
Valenciana, 50, 46940 Manises. Valencia.
Spain.
[email protected]
[email protected]
Haemorrhagic fever
with renal failure
syndrome: a case report
Nefrologia 2012;32(1):131-2
To the Editor,
Haemorrhagic fever with renal syndrome
(HFRS) is a clinical condition secondary to
infection with a hantavirus (Hantaan, Seoul, No Name, Andes virus, Puumala and
Dobrava); the latter two varieties are endemic in rural areas of Eastern Europe, and
of the two, infection with the Puumula virus has a better long-term prognosis.1
Rodents are the natural carriers of hantavirus, which is transmitted to humans when
they come into direct contact with rodent
secretions (urine, faeces and saliva).
The natural evolution of the disease entails
4 successive phases following an incubation period of about 3 weeks. The first phase is characterised by fever, followed by a
phase with shock and oliguria; patients
who survive this phase enter a phase with
polyuria, which in turn is followed by a
convalescence period of variable duration.
Thrombocytopoenia is common and may
produce haemorrhages at any location.
Renal symptoms include proteinuria,
haematuria and decreased glomerular
filtration rate. Direct vascular endothelial lesions and tubulo-interstitial nephritis mediated by cytokines have been
proposed as the underlying physiopathological cause.2
Diagnosis is based on a strong clinical
suspicion, and confirmed by specific
serological methods.3 Kidney biopsy is
not necessary.4 A renal ultrasound can
show the increase in kidney size and in
resistance indices. Perirenal fluid collection is also a common finding (in
addition to pleural or pericardial effusion or ascites). No vaccine or specific
treatment exists; supportive therapy is of
vital importance. One double-blind study
showed decreased mortality given early
treatment with ribavirin.5
131
Below, we describe our hospital’s experience with a case of HFRS secondary to
infection with the Puumala virus.
morphologically normal kidneys with no
ureteral dilation, with perirenal and pelvic
free liquid. (Figure 1)
The patient was a male aged 18 years with
no relevant prior history who came to the
Emergency Department due to fever, muscle aches and a frontal headache evolving
over 3 days with no improvement following his doctor’s prescription of amoxicillin-clavulanic acid and paracetamol. Two
weeks before, he had been hiking in a rural area of Slovenia.
The patient was admitted for observation,
which is why he was initially given empirical antibiotic treatment with ceftriaxone
and levofloxacin after the samples were
extracted. The day after admission, he suffered a conjunctival haemorrhage (Figure
2), tendency toward oliguria, the appearance of oedemas, and decreased renal function; his creatinine level was 2.7mg/dl. As
a hantavirus infection was suspected, we
opted for antiviral treatment with ribavirin
(500mg/i.v. every 8 hours). The same day,
8 hours later, he suffered an episode of
dyspnoea and tachypnoea with desaturation (89%) and hypoxia (pO2: 63), and the
decision was made to send him to the Intensive Care Unit. On the fourth day after
admission, the patient presented epistaxis
that subsided with anterior nasal packing.
The oliguria became more pronounced,
oedemas increased and the renal function
worsened with creatinine levels of
5.6mg/dl. We then decided to start haemodialysis by means of a temporary catheter
in the right femoral vein. After 4 session of
haemodialysis, we observed improvements in urinary volume and renal function. The immunological study (antinuclear antibodies, anti-neutrophil cytoplasmic
antobodies, anti-DNA, anti-GBM antibodies, complementary components, immunoglobulins, protein electrophoresis, cryoglobulin, circulating immune complexes)
and serology study for hepatitis B and C,
HIV, Epstein-Barr virus, cytomegalovirus,
leptospira, parvovirus B19 and toxoplasms
were negative or normal. On day 7, the laboratory reported IgG (+) 1/512 for Puu-
The physical examination found a fever of
39.2ºC, normal blood pressure, no adenopathy, and diffuse pain upon abdominal
palpation. The Emergency Department laboratory blood test found 10 010 leukocytes/mm3 with no eosinophilia; thrombocytopoenia of 32 000/mm3 with no platelet
additives; haemoglobin: 18; haematocrit:
48%; creatinine: 1.35mg/dl; urea:
47mg/dl; lactate dehydrogenase (LDH):
324U/l. All other blood tests were normal.
Microhaematuria was present.
Thoracic and abdominal radiographies
were normal. The abdominal ultrasound
and the abdominal and pelvic CT showed
Figure 1. Abdominal and pelvic computed
tomography
132
Figure 2. Conjunctival haemorrhage
appearing the day after patient was
admitted
mala virus, and antibiotic treatment was
consequently discontinued.
On day 13, the patient was discharged after completing the antiviral treatment, showing recovered renal function and a creatinine level of 1.25. At follow-up 5 weeks
later, his renal function was completely
normal (creatinine: 0.69, estimated glomerular filtration rate >60).
1. Miettinen MH, Mäkelä SM, Ala-Houhala IO,
Huhtala HS, Kööbi T, Vaheri AI, et al. Tenyear prognosis of Puumala hantavirusinduced acute intersticial nephritis. Kidney
int 2006;69:2043-8.
2. Mäkelä S, Mustonen J, Ala-Houhala I,
Hurme M, Koivisto AM, Vaheri A, et al.
Urinary excretion of inerleukin-6 correlates
whith proteinuria in acute Puumala
hantavirus - induced nephritis. Am J Kidney
Dis 2004;43:809-16.
3. Vapalahti O, Mustonen J, Lundkvist A,
Henttonen H, Plyusnin A, Vaheri A.
Hantavirus infections in Europe. Lancet
Infect Dis 2003;3:653-61.
4. Kim S, Sung SH, An HR, Jun YH, Yu M, Ryu
DR, et al. A case report of crescentic
glomerulonephritis
associated
with
hantavirus
infection.
Nephrol
Dial
Transplant 2010;25(8):2790-2.
5. Huggins JW, Hsiang CM, Cosgrriff M,
Guang MY, Smith JI, Wu ZO, et al.
Prospective, double-blind, concurrent,
placebo-controlled
clinic
trial
of
intravenous
ribavirin
therapy
of
hemorrhagic fever with renal syndrome. J
Infect Dis 1991;164:1119-27.
Rodrigo Avellaneda-Campos
Hospital Universitario Donostia.
San Sebastián, Gipuzkoa. Spain.
Correspondence:
Rodrigo Avellaneda Campos
Hospital Universitario Donostia.
San Sebastián, Gipuzkoa. Spain.
[email protected]
Nefrologia 2012;32(1):114-32

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