Renal function and MELD: Being direct is better
Authors: Stevan A. Gonzalez, James F. Trotter
Journal: Journal of Hepatology (2010)

Impaired liver regeneration of steatotic rats after portal vein ligation: A particular emphasis on 99mTc-DISIDA scintigraphy and adiponectin signalingJournal of HepatologyVol. 52Issue 4PreviewPortal vein ligation (PVL) is increasingly employed prior to major hepatectomy in order to enhance the volume of the future liver remnant (FLR) and to avoid post-hepatectomy liver failure. The efficacy of PVL on subjects with non-alcohol fatty liver disease (NAFLD) is largely unknown. Full-Text PDF Renal insufficiency is common in patients with end-stage liver disease (ESLD) and is strongly linked to survival in those awaiting liver transplantation. In liver patients, renal dysfunction is largely due to a circulatory disturbance characterized by a low systemic vascular resistance and decreased effective arterial volume leading to impaired renal excretion of solute-free water, dilutional hyponatremia and ultimately hepatorenal syndrome (HRS) [1Gines A. Escorsell A. Gines P. et al.Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar, 2Garcia-Tsao G. Parikh C.R. Viola A. Acute kidney injury in cirrhosis.Hepatology. 2008; 48: 2064-2077Crossref PubMed Scopus (487) Google Scholar, 3Gines P. Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management.Hepatology. 2008; 48: 1002-1010Crossref PubMed Scopus (225) Google Scholar]. Once a patient develops type I HRS, the median survival without treatment is as low as 2 weeks, while the median survival in type II HRS is approximately six months; both a significant decrease in survival compared to patients without HRS [1Gines A. Escorsell A. Gines P. et al.Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar, 4Alessandria C. Ozdogan O. Guevara M. et al.MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.Hepatology. 2005; 41: 1282-1289Crossref PubMed Scopus (316) Google Scholar, 5Arroyo V. Fernandez J. Gines P. Pathogenesis and treatment of hepatorenal syndrome.Semin Liver Dis. 2008; 28: 81-95Crossref PubMed Scopus (167) Google Scholar]. The diagnosis and severity of HRS is dependent on two biochemical markers, serum sodium and creatinine, both of which are independently associated with an increased risk of mortality in cirrhosis [6Kamath P.S. Wiesner R.H. Malinchoc M. et al.A model to predict survival in patients with end-stage liver disease.Hepatology. 2001; 33: 464-470Crossref PubMed Scopus (4092) Google Scholar, 7Malinchoc M. Kamath P.S. Gordon F.D. et al.A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.Hepatology. 2000; 31: 864-871Crossref PubMed Scopus (2315) Google Scholar, 8Wiesner R. Edwards E. Freeman R. et al.Model for end-stage liver disease (MELD) and allocation of donor livers.Gastroenterology. 2003; 124: 91-96Abstract Full Text Full Text PDF PubMed Scopus (2099) Google Scholar, 9Heuman D.M. Abou-Assi S.G. Habib A. et al.Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.Hepatology. 2004; 40: 802-810Crossref PubMed Scopus (458) Google Scholar, 10Ruf A.E. Kremers W.K. Chavez L.L. et al.Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.Liver Transpl. 2005; 11: 336-343Crossref PubMed Scopus (368) Google Scholar, 11Biggins S.W. Rodriguez H.J. Bacchetti P. et al.Serum sodium predicts mortality in patients listed for liver transplantation.Hepatology. 2005; 41: 32-39Crossref PubMed Scopus (339) Google Scholar, 12Biggins S.W. Kim W.R. Terrault N.A. et al.Evidence-based incorporation of serum sodium concentration into MELD.Gastroenterology. 2006; 130: 1652-1660Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 13Londono M.C. Cardenas A. Guevara M. et al.MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation.Gut. 2007; 56: 1283-1290Crossref PubMed Scopus (168) Google Scholar, 14Kim W.R. Biggins S.W. Kremers W.K. et al.Hyponatremia and mortality among patients on the liver-transplant waiting list.N Engl J Med. 2008; 359: 1018-1026Crossref PubMed Scopus (1088) Google Scholar]. Their importance is underscored by inclusion in the most widely utilized predictive survival function, the model for end-stage liver disease (MELD) score or Na-MELD, where the addition of serum sodium significantly improves [9Heuman D.M. Abou-Assi S.G. Habib A. et al.Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.Hepatology. 2004; 40: 802-810Crossref PubMed Scopus (458) Google Scholar, 10Ruf A.E. Kremers W.K. Chavez L.L. et al.Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.Liver Transpl. 2005; 11: 336-343Crossref PubMed Scopus (368) Google Scholar, 11Biggins S.W. Rodriguez H.J. Bacchetti P. et al.Serum sodium predicts mortality in patients listed for liver transplantation.Hepatology. 2005; 41: 32-39Crossref PubMed Scopus (339) Google Scholar, 12Biggins S.W. Kim W.R. Terrault N.A. et al.Evidence-based incorporation of serum sodium concentration into MELD.Gastroenterology. 2006; 130: 1652-1660Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 13Londono M.C. Cardenas A. Guevara M. et al.MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation.Gut. 2007; 56: 1283-1290Crossref PubMed Scopus (168) Google Scholar, 14Kim W.R. Biggins S.W. Kremers W.K. et al.Hyponatremia and mortality among patients on the liver-transplant waiting list.N Engl J Med. 2008; 359: 1018-1026Crossref PubMed Scopus (1088) Google Scholar] the performance of MELD. Whether sodium will be included into the MELD score (for prioritizing liver transplantation candidates) remains in question for two reasons. Serum sodium levels are easily manipulated with water ingestion and the administration of vaptans. In addition, hyponatremia may have a negative impact on post-transplant complications and survival, [15Dawwas M.F. Lewsey J.D. Neuberger J.M. et al.The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study.Liver Transpl. 2007; 13: 1115-1124Crossref PubMed Scopus (109) Google Scholar, 16Londono M.C. Guevara M. Rimola A. et al.Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation.Gastroenterology. 2006; 130: 1135-1143Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 17Hackworth W.A. Heuman D.M. Sanyal A.J. et al.Effect of hyponatraemia on outcomes following orthotopic liver transplantation.Liver Int. 2009; 29: 1071-1077Crossref PubMed Scopus (71) Google Scholar] although recent data have brought this into question [18Yun B.C. Kim W.R. Benson J.T. et al.Impact of pretransplant hyponatremia on outcome following liver transplantation.Hepatology. 2009; 49: 1610-1615Crossref PubMed Scopus (108) Google Scholar]. While serum sodium and creatinine are important predictors of mortality in cirrhosis, their relationship to the most sensitive gauge of renal function, measured glomerular filtration rate (GFR), is more complicated. To the degree that renal handling of sodium and water is altered in cirrhosis, serum sodium is determined by renal function. However, serum sodium only correlates roughly with GFR. With regard to serum creatinine, numerous studies have documented its incongruity with measured as well as estimated GFR. Specifically, creatinine typically overestimates renal function in patients listed for liver transplantation [19Papadakis M.A. Arieff A.I. Unpredictability of clinical evaluation of renal function in cirrhosis. Prospective study.Am J Med. 1987; 82: 945-952Abstract Full Text PDF PubMed Scopus (221) Google Scholar, 20Gonwa T.A. Jennings L. Mai M.L. et al.Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations.Liver Transpl. 2004; 10: 301-309Crossref PubMed Scopus (299) Google Scholar], particularly in those with the lowest GFR. This discrepancy may be due to lower serum creatinine levels in liver patients caused by decreased hepatic creatine production, poor nutrition, decreased muscle mass, and increased tubular secretion of creatinine [21Sherman D.S. Fish D.N. Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls.Am J Kidney Dis. 2003; 41: 269-278Abstract Full Text PDF PubMed Scopus (288) Google Scholar, 22Cholongitas E. Marelli L. Kerry A. et al.Different methods of creatinine measurement significantly affect MELD scores.Liver Transpl. 2007; 13: 523-529Crossref PubMed Scopus (142) Google Scholar]. Furthermore, in jaundiced patients, elevated bilirubin levels may interfere with commonly used assays leading to further variability in serum creatinine and MELD scores [22Cholongitas E. Marelli L. Kerry A. et al.Different methods of creatinine measurement significantly affect MELD scores.Liver Transpl. 2007; 13: 523-529Crossref PubMed Scopus (142) Google Scholar]. With this background Lim et al. have addressed the following issue: while renal disease and its serum markers, i.e., serum sodium and creatinine, are important predictors for survival in cirrhosis, their correlation with the gold-standard of renal function, measured GFR, is poor. Therefore, could the predictive capacity of the MELD score be improved by replacement of creatinine (and sodium) with measured GFR? This is a clever analysis which could only be conducted in very few places, because only a small number of liver transplant programs routinely measure GFR with iothalamate (or similar methodology) in their liver transplant candidates. Its rarity is likely due to the cumbersome nature of the test, requiring pre-test hydration and careful collection of timed samples over several hours after iothalamate administration. Consequently, GFR is usually measured only once during the evaluation phase of transplant candidacy and is poorly suited for critically ill or hospitalized patients. Lim et al. analyzed the effect of the measured GFR on the predictive capacity of MELD and we learn several key points from their study. First, there was an association between one-year mortality and measured renal function. While this is not a surprise to experienced clinicians, the strength of the association is remarkable. The one-year mortality rates for patients with a measured GFR of 30–60 ml/min and <30 ml/min were more than threefold and fivefold higher, respectively, compared to patients with normal renal function (GFR > 60 ml/min). In fact, GFR had a significant linear association with survival, independent of MELD score. Second, measured GFR was superior to serum creatinine as a predictor of mortality, in a model incorporating bilirubin, INR, and GFR (in the place of serum creatinine). Finally, the effect of serum sodium on the model loses significance when GFR is included. Thus, inclusion of sodium in the MELD score may not be necessary if measured GFR (or perhaps a yet-to-be-determined marker) is used to determine renal function. There are some qualifications to the findings in this study. The cohort is derived from the pre-MELD era. Consequently, the analyzed patients are likely to be less sick (median serum creatinine = 1.0 mg/dl and serum sodium 137 mEq/L) and have different demographics (only 20% with hepatitis C) than current liver transplant recipients. In addition, the total waiting list mortality (9.2%) over the course of this multi-year study was quite low, compared to current standards. These differences might limit the applicability of the authors' findings in our current cohort of liver transplant candidates. Finally, the improvement reported by the authors, while statistically significant, is relatively small between MELD (C-statistic = 0.780) and MELD with GFR (C-statistic = 0.792). Overall, the authors have broadened our understanding of the impact of renal function, and its markers, on the MELD score. Modification of the MELD score to include measured GFR may indeed improve the predictive accuracy of the model, yet challenges arise in its general applicability. Serum creatinine and serum sodium are easily accessible to all clinicians evaluating liver transplant candidates. In contrast, methods to assess GFR, including clearance of compounds such as iothalamate, require specialized laboratory resources not readily available at all liver transplant centers. However, these findings suggest that identification of more accurate laboratory tests for renal function might improve the predictive function of the MELD score. Perhaps the most likely candidate for this role is serum cystatin C. Unfortunately, there is relatively little data available assessing this marker in cirrhotic patients. Nevertheless, the available data suggests that, compared to serum creatinine, cystatin might provide a slightly more accurate estimate of renal function and therefore could improve the predictive capacity of the MELD [23Woitas R.P. Stoffel-Wagner B. Flommersfeld S. Poege U. Schiedermaier P. Klehr H.U. et al.Correlation of serum concentrations of cystatin C and creatinine to inulin clearance in liver cirrhosis.Clin Chem. 2000; 46: 712-725PubMed Google Scholar, 24Orlando R. Mussap M. Plebani M. Piccoli P. De Martin S. Floreani M. et al.Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis.Clin Chem. 2002; 48: 850-858PubMed Google Scholar, 25Gerbes A.L. Gülberg V. Bilzer M. Vogeser M. Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver.Gut. 2002; 50: 106-110Crossref PubMed Scopus (131) Google Scholar, 26Randers E. Ivarsen P. Erlandsen E.J. Hansen E.F. Aagaard N.K. Bendtsen F. et al.Plasma cystatin C as a marker of renal function in patients with liver cirrhosis.Scand J Clin Lab Invest. 2002; 62: 129-134Crossref PubMed Scopus (40) Google Scholar, 27Pöge U. Gerhardt T. Stoffel-Wagner B. Klehr H.U. Sauerbruch T. Woitas R.P. Calculation of glomerular filtration rate based on cystatin C in cirrhotic patients.Nephrol Dial Transpl. 2006; 21: 660-664Crossref PubMed Scopus (117) Google Scholar]. Whether this or any other marker could improve the function of MELD will require further careful analysis.