EDUARDO VILAR - esteatosis hepática en los pacientes renales

EDUARDO VILAR - esteatosis hepática en los pacientes renales

¿Qué importancia debemos darle a la esteatosis
hepática en los pacientes renales?
Eduardo Vilar, M.D, Ph.D.
Centro de Investigación Avanzada CQS salud
Madrid, España
Prof. Manuel Romero Gómez
UG MQ Enfermedades Digestivas
Hospital Universitario de Valme
Universidad de Sevilla, Sevilla.
Goals
  Epidemiological association between NAFLD and CKD
Does NAFLD affect the risk of CKD independent of major confounders?
  Molecular aspects in the pathogenesis of CKD and NAFLD
What is the link?
  Is NAFLD severity associated with severity of CKD and CVD?
Relevance of simple steatosis / NASH / Fibrosis
  Methods for diagnosing steatosis - NASH - advanced fibrosis
BURDEN DISEASE
NAFLD is the main cause of liver disease across western countries
Prevalence: 6-33%, up to 50% in 2030
Incidence: 2 new cases/100 people/year
Xu et al. J Hepatol 2012; Chalasani et al Gastroenterology 2012;
Ekstedt, Hepatology 2006;Musso et al, Ann Med, 2011
NAFLD AND CKD - CVD
WHY THE LINKING?
TOBACCO*EXPOSURE*
RACE*
AGE*
CKD
CVD
>65*=*Prev:*25%*
T2DM
OVERWEIGHT*AND*OBESITY*
VISCERAL*AND*SUBCUTANEOUS*
FAT**
INSULIN*RESISTANCE*
NAFLD
MetS
HTA
PHYSICAL*INACTIVITY*
GENETIC*
BACKGROUND*
*
*********
Estadios insuficiencia renal crónica
Tasa*de*filtrado*glomerular!
Estadio*I*
≥*90*mL/min/1.73*m2*
Estadio*II*
60V89*mL/min/1.73*m2*
Estadio*III*
30V59*mL/min/1.73*m2*
Estadio*IV*
15V29*mL/min/1.73*m2*
Estadio*V*
<15*mL/min/1.73*m2*ó*diálisis*
MDRD o Cockcroft-Gault
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
CKD is more prevalent and incident in NAFLD patients!
Cross-sectional studies / Prevalence*
Musso, et al Plos One 2014.*
Prospective studies / Incidence*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
CKD is strongly associated to NAFLD!
202 T1DM pts
1760 T2DM pts followed for 78 months
Proteinuria and/or estimated GFR < 60 ml/min Proteinuria and/or estimated GFR < 60 ml/min
Non*NAFLD*
NAFLD*
Adjusted HR: 1.6 (95% CI: 1.2-2.5)
Targher, et al J Am Soc Nephrol 2008.*
Targher, et al Diabetologia 2010.*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
NAFLD is associated to CKD!
*NAFLD*was*defined*by*CAP*values*≥238*dB/m*
Fibrosis:*>*7kPa*
N=62*
Mikolasevic*et*al.*Kidney*Blood*Pres*Res*2013.*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
Severity of NAFLD is strongly associated to CKD in cross-sectional studies!
Prevalence of CKD (NASH vs SS)*
OR: 2.53 (95% CI: 3.1 – 8.6)*
Musso, et al Plos One 2014.*
CKD (No advanced fibrosis vs advanced fibrosis*
OR: 5.20 (95% CI: 3.1 – 8.6)*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
Severity of NAFLD is strongly associated to severity of CKD in prospective studies!
Incidence of CKD – stage 3B (NASH vs SS)*
HR: 2.5 (95% CI: 1.2 – 5.1)*
Musso, et al Plos One 2014.*
Incidence of CKD – stage 4 (NASH vs SS)*
OR:3.5 (95% CI: 1.1 – 3.4)*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
Severity of NAFLD is strongly associated to severity of CKD in prospective studies!
Incidence of CKD – stage 5 (NASH vs SS)* Inc CKD – stage 5 (no advanced vs advanced fibrosis)*
HR: 3.9 (95% CI: 1.1 – 13.6)*
Musso, et al Plos One 2014.*
OR:7.5 (95% CI: 2.9 – 18.9)*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
Severity of CKD is strongly associated to severity of NAFLD in prospective studies!
Incidence of advanced fibrosis – CKD stage 4*
Incidence of advanced fibrosis – CKD stage 5*
Musso, et al Plos One 2014.*
NAFLD AND CKD
EPIDEMIOLOGICAL ASPECTS
Severity of NAFLF is strongly associated to severity of CKD in prospective studies!
Targher, et al J Hepatol 2011.*
Epidemiological studies relating NAFLD to increased cardiovascular risk
Increased incidence of CVD mortality HR= 1.20 - 8
Author
Patients
Diagnosis
Follow time
Ruttmann, et al
163,944
GGT
12 years
Wannamethee, et al
7613
GGT
11.5 years
Lee, et al
28,838
GGT
11.9 years
Fraser, et al
Meta-analysis 10 studies
-
GGT
7-13 years
Fraser, et al
2961
ALT/GGT
4,6 years
Shindhelm, et al
1439
ALT
10 years
Dunn, et al (NHANES III)
7574
ALT
8,7 years
Yun, et al
37,085
ALT
5 years
Targher, et al (Vapolicella study)
2103
US
6,5 years
Hamaguchi, et al
1637
US
5,8 years
Haring, et al
4160
GGT/US
7,3 years
Adams, et al
420
US/biopsy
7,6 years
Ekstedt, et al
129
Liver biopsy
13,7 years
Soderberg, et al
118
Liber biopsy
24 years
Schwimmer, et al
817 Childs
autopsy
Cross
sectional
1.66
1.42
1.20
1.34
1.17 (only GGT)
1.88
8.15
2.26
1.87
4.12
6.22 (only men)
1.34
1.38
1.69
1.80
V1**********0******1******2*****3*****4*****5*****6*****7******8**
HR/RR**
Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With
Cardiovascular Disease Among Type 2 Diabetic Patients
Valpolicella*Heart*Diabetes*Study*based*on*US*diagnosis*
Non*NAFLD*
NAFLD*
NAFLD*increases*the*risk*of*incident*nonfatal*CVD*events*in*1.87*folds**
It is independent of the risk conferred by traditional risk factors and
components of the metabolic syndrome*
*
Targher!Yet!al.,!Diabetes!Care!2007!
Targher*Y*et*al.,*Diabetes*Care*2005*
NAFLD AND INCREASES CVD AND CKD RISK
Why is the connection?
 Early carotid changes (intima-media thickness)
 Increased levels of biomarkers of inflammation and procoagulants
  Endothelial dysfunction
Epicardial and pericardial fat
 Early myocardial dysfunction
 Cardiac steatosis (a coexistent entity)
“NAFLD no just a biomarker but an early mediator of atherosclerosis
and endothelial dysfunction”
NAFLD AND EARLY ATHEROSCLEROSIS
What is the evidence?
Arterial stiffness is associated to steatosis severity
OR after adjusting for age, sex, and parameters of metabolic syndrome
Lee, et al. Dig Dis and Sci 2012.
NAFLD AND EARLY ATHEROSCLEROSIS
What is the evidence?
Carotid-artery intima medial thickness and its relationship with NAFLD severity
Inflammatory and procoagulants biomarkers in NAFLD
HS C-reactive protein
Targher G, et al. NEJM 2010.
PAI-1
Adiponectin
Fibrinogen
NAFLD AND CVD
What is the evidence?
NAFLD could contribute to CVD via atherosclerotic pathways
The inflamed liver and the atherosclerosis
Relationship between lipid ratios and histology severity
Alkhouri, et al. Dig Dis Sci 2010
LINK BETWEEN NAFLD AND CKD
Crosstalk between fat, the kidney, and liver through at least two serum proteins
“Fetuin-A and Adiponectin”.
Fetuin-A.
 64-kDa glycoprotein produced exclusively by the liver
- Inhibitor of ectopic calcium deposition
- Promoter of insulin resistance
- FA inhibits the insulin receptor tyrosine kinase in skeletal muscle and
hepatocytes resulting in insulin resistance
 Fetuin-A and Adiponectin may work in concert to regulate insulin resistance
 Both appear to act through the energy sensor 5’-AMP activated protein kinase (AMPK)
Joachim, et al. J Am Soc Nephrol 2010.*
Associafon*of*PNPLA3*GVallele*and*CKD**
N=61!
PNPLA3=CC!
PNPLA3=CG/GG!
p!
NASH*
33%*
64%*
p=0.039*
CKD*
0%*
29%*
P=0.005*
microALB*
0%*
26%*
P=0.009*
79+11*
66+8*
P=0.001*
eGFR*
Musso*G*et*al.*Hepatology*2015;(In*Press)*
Dongiovanni*P,*Anstee*Q,*Valenf*L.*2013,*Current*Pharmaceufcal*Design**
NAFLD.!DIAGNOSIS!AND!MANAGEMENT!
Met S - IR
Hyperechogenicity
Raised ALT/GGT
Increased risk of
VS
Simple!steatosis!
NASH!
  CLD and complications
  CVD
  CKD
Therefore
We need to use Noninvasive
methods to differentiate
F0=F1!
VS
Simple steatosis vs. NASH
F2=F4!
Non advanced vs. advanced fibrosis
Diagnosfc*method*of*Steatosis*
Ecograla*>>*CAP*
Steatotest*>>*FLI*>>*HSI*>>*LAP*
*>>*MRs*
Diagnostic method of Steatosis
Abdominal Ultrasound
Ventajas y desventajas
  Útil si infiltración grasa > 25%
 Sensibilidad 60-94%
 Especificidad 84-95%
 No discrimina entre:
- Esteatosis simple vs. NASH
- Entre distintos estadios de fibrosis
 Alta variabilidad intra-interobservador
Schwenzer, et al. J Hepatolo 2009.*
 Operador dependiente
CAP: Controlled Attenuation Parameter (CAP), a noninvasive
method for the detection of hepatic steatosis based on
transient elastography
Parámetro físico desarrollado asumiendo que la grasa hepática afecta a la
propagación de ondas del FibroScan®.
VENTAJAS:
!  Método no invasivo
!  Fácil de realizar
! Resultados operador independientes
!  Simultáneo y no ralentiza el FibroScan®
!  Ofrece resultados inmediatos
! Sensible a bajos grados de esteatosis
DESVENTAJAS:
! Preliminar: falta acumular más evidencias
! Inversión inicial elevada: FibroScan®
! Necesita personal entrenado
Medición del CAP
Adquisición*con*la*
sonda*M*del**
FibroScan®*
El!valor!CAP!aumenta!cuanta!más!
esteatosis!haya!en!el!tejido!hepáSco.!!
Señal!Ultrasónica!
Elastograma!
Medición!válida!
de!dureza!
SÍ!
Grado!de!esteatosis!
AUROC!
>*5%*
0,79*
>*33%*
0,76*
>*66%*
0,70*
07/2011*
NO!
Sin!resultado!
CAP!!
(dB/m)!
E!
(kPa)!
Myers et al, Liver Int 2012 27*
CAP -- Resultados
Diagnosfc*methods*of*steatohepaffs*(NASH)*
OWL=liver!>>*NASHVtest*>>*NASH=MRi!(DeMILI)!
NAS Score = 5
Positive NASH
NASHMRi = 0.688
AUROC
OWL!
CK=18!
AFABP!
FGF=21!
NASH=
test!
NASH
=MRi!
0,87
0,70
0,69
0,62
0,77
0,89
Barr J et al. J Proteome Res 2012;11:2521-32
Shen et al, J Hepatol 2012;56:1363-1370
Gallego-Durán et al. AEEH 2013
Diagnósfco*de*NASH:*Fibroscan*
V  Mide*la*velocidad*de*propagación*de*las*ondas*elásfcas*en*el*
hígado*evaluando*el*grado*de*fibrosis*hepáfca.*
V*****Inconveniente:*Influenciado*por*el*IMC,*espacio*intercostal*
estrecho.*
*Castera*et*al,*Gastroenterology*2012*
Pera*S*et*al.*Liver*Int*2014*
Máster*en*Hepatología*
Diagnósfco*de*Fibrosis*avanzada*
NAFLDVfibrosis*score*
Fibroscan*®*
FibroVMRi*(DeMILI®)*
Fibrosis*assessment*
NAFLDVFibrosis*Score®*
hrp://nafldscore.com/*
(n=321)!>F3! AUROC!
Test!
Curva!ROC!
NAFLD*Fib*Score*
0,82*
Fibroscan*
0.85*
NFS*
0.73*
FS+NFS*
0.84*
FP!
FN!
0%* 7.3%*
ZONA!
gris!
41%*
*Castera*et*al,*Gastroenterology*2012*
Pera*S*et*al.*Liver*Int*2014*
Angulo*et*al*Hepatology*2007**
Máster*en*Hepatología*
Diagnósfco*de*fibrosis:*Fibroscan*
Máster*en*Hepatología*
FibroVMRi*(DEMILI®)*
CONCLUSIONES
  NAFLD es un factor de riesgo independiente de CKD.
  La severidad de NAFLD and CKD están directamente relacionadas.
 Pacientes deben estar bajo programas de screening anuales con eGFR
y microalbuminuria.
  La ecografía abdominal es útil para la detección de NAFLD, sin
embargo, existen otras técnicas no invasivas útiles.
  La discriminación de steatosis vs. NASH continua siendo un reto en
práctica clínica.
  El fibroscan es una herramienta útil para la determinación de fibrosis
avanzada.