The evaluation of renal function and disease in patients with cirrhosis
Authors: Claire Francoz, Denis Glotz, Richard Moreau, François Durand
Journal: Journal of Hepatology (2010)

The MELD score has shown that, besides markers of liver function, serum creatinine has a strong prognostic value in cirrhosis. However, even though creatinine has a good prognostic value, it is an inaccurate marker of renal function in cirrhosis. Creatinine and creatinine-based equations tend to overestimate glomerular filtration rate (GFR), and creatinine clearance from timed urine collection also overestimates GFR. Hence, clearance of exogenous markers such as iohexol remains the only reliable method for assessing precisely GFR in cirrhosis. Whereas these investigations are limited by their costs and complexity, and they can hardly be repeated at short intervals, serum cystatin C could be an alternative, although it needs further validation. Accurate markers and/or specific equations are therefore still needed to assess GFR in cirrhotic patients. Pre-renal failure and hepatorenal syndrome (HRS) are the main causes of acute renal failure in cirrhosis. Both result from decreased renal blood flow and both can result in acute tubular necrosis. HRS is not always fully reversible with liver transplantation possibly due to underlying chronic kidney damage. A number of cirrhotic patients with acute renal failure may also have chronic kidney damage (“acute-on-chronic renal failure”); furthermore, cirrhotic patients frequently have co-morbidities such as diabetes that may result in chronic impairment in renal function. Since conventional urinary markers are biased in cirrhosis, a biopsy is the only way to document and quantify renal lesions; moreover, transvenous route should be preferred to percutaneous route. In candidates for transplantation, attention should therefore be focused on vascular lesions which may represent a risk factor for nephrotoxicities induced by calcineurin-inhibitors. The MELD score has shown that, besides markers of liver function, serum creatinine has a strong prognostic value in cirrhosis. However, even though creatinine has a good prognostic value, it is an inaccurate marker of renal function in cirrhosis. Creatinine and creatinine-based equations tend to overestimate glomerular filtration rate (GFR), and creatinine clearance from timed urine collection also overestimates GFR. Hence, clearance of exogenous markers such as iohexol remains the only reliable method for assessing precisely GFR in cirrhosis. Whereas these investigations are limited by their costs and complexity, and they can hardly be repeated at short intervals, serum cystatin C could be an alternative, although it needs further validation. Accurate markers and/or specific equations are therefore still needed to assess GFR in cirrhotic patients. Pre-renal failure and hepatorenal syndrome (HRS) are the main causes of acute renal failure in cirrhosis. Both result from decreased renal blood flow and both can result in acute tubular necrosis. HRS is not always fully reversible with liver transplantation possibly due to underlying chronic kidney damage. A number of cirrhotic patients with acute renal failure may also have chronic kidney damage (“acute-on-chronic renal failure”); furthermore, cirrhotic patients frequently have co-morbidities such as diabetes that may result in chronic impairment in renal function. Since conventional urinary markers are biased in cirrhosis, a biopsy is the only way to document and quantify renal lesions; moreover, transvenous route should be preferred to percutaneous route. In candidates for transplantation, attention should therefore be focused on vascular lesions which may represent a risk factor for nephrotoxicities induced by calcineurin-inhibitors. For more than 30 years, the Child–Pugh score has been the main prognostic tool for patients with cirrhosis [[1]M-LI Pugh.R.N.H. Dawson J.L. Pietroni M.C. Williams R. Transsection of the oesophagus for beeding oesophageal varices.Br J Surg. 1973; 60: 646-649Crossref PubMed Scopus (6867) Google Scholar]. The Child–Pugh score was based on 5 variables (i.e., ascites, encephalopathy, serum bilirubin, serum albumin and prothrombin time) which had been empirically selected because they were felt to have a determinant impact on the outcome. This score proved to be a robust prognostic tool in a number of situations [[2]Durand F. Valla D. Assessment of the prognosis of cirrhosis: Child–Pugh versus MELD.J Hepatol. 2005; 42: S100-107Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar]. However, it had some limitations, including the subjective interpretation of ascites and encephalopathy. In the early 2000s, the model for end-stage liver disease (MELD) score emerged as a simple, more objective, alternative to Child–Pugh score [3Malinchoc M. Kamath P.S. Gordon F.D. Peine C.J. Rank J. ter Borg P.C. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.Hepatology. 2000; 31: 864-871Crossref PubMed Scopus (2167) Google Scholar, 4Kamath P.S. Wiesner R.H. Malinchoc M. Kremers W. Therneau T.M. Kosberg C.L. et al.A model to predict survival in patients with end-stage liver disease.Hepatology. 2001; 33: 464-470Crossref PubMed Scopus (3837) Google Scholar, 5Wiesner R. Edwards E. Freeman R. Harper A. Kim R. Kamath P. 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 (2004) Google Scholar]. The 3 variables entered in the MELD score have been selected on the basis of statistical analysis, not empirically. The weight associated to each of the variables also derives from statistical analysis. Interestingly, besides serum bilirubin and international normalized ratio (INR) which are basic markers of liver function, the third component of the MELD score, serum creatinine, is essentially a marker of renal function. This finding highlights the prognostic significance of the interactions between liver function and renal function in cirrhosis. The value of creatinine weighs heavily on the MELD score [[5]Wiesner R. Edwards E. Freeman R. Harper A. Kim R. Kamath P. 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 (2004) Google Scholar]. As an example, an increase in serum creatinine from 1 to 1.5 mg/dl (88 to 132 μmol/L) in a patient with a bilirubin of 2.9 mg/dl (50 μmol/L) and an INR of 1 results in a 40% increase in the MELD score. The MELD score has been widely validated in different populations of cirrhotic patients [[6]Durand F. Valla D. Assessment of prognosis of cirrhosis.Semin Liver Dis. 2008; 28: 110-122Crossref PubMed Scopus (228) Google Scholar]. However, it has been suggested recently that creatinine weighs too heavily on the MELD score [[7]Sharma P. Schaubel D.E. Sima C.S. Merion R.M. Lok A.S. Re-weighting the model for end-stage liver disease score components.Gastroenterology. 2008; 135: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. In addition, it has been pointed out that patients with serum creatinine below 1 mg/dl are bounded to 1 mg/dl in order to avoid negative values after logarithmic transformation. A relatively large number of cirrhotic patients have baseline serum creatinine below 1 mg/dl and some of them have significant impairment in renal function. The assumption that mortality is constant for creatinine less than 1 mg/dl is likely to be false. As a result, a modified MELD score including loge (1 + creatinine [mg/dl]) without bounding and a lower weight for creatinine compared to the current MELD score has been proposed [[7]Sharma P. Schaubel D.E. Sima C.S. Merion R.M. Lok A.S. Re-weighting the model for end-stage liver disease score components.Gastroenterology. 2008; 135: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. This modified score seems to be slightly superior the current MELD score. However, even after these adjustments, creatinine still has a determinant prognostic value. Creatine is the simplest and the most widely used marker of renal function in the general population. However, it is a paradox that even if creatinine is a powerful prognostic marker in cirrhosis, it is an inaccurate marker of renal function in most cirrhotic patients. Indeed, in these patients, there are many biases and pitfalls in the interpretation of creatinine as well as creatinine-based estimates of renal function. Creatine is synthesized in the liver before being stored in muscles where it is phosphorylated as creatinine. The production of creatinine varies little from day to day. This small compound is freely filtered by the kidney but it can also be secreted by the proximal tubule. The ratio between creatinine secreted by the tubule to the amount of creatinine filtered by the glomerulus increases as glomerular filtration rate (GFR) decreases. In addition to muscle mass and protein intake, creatinine is influenced by age, gender and ethnicity. Several reasons make that in cirrhotic patients, serum creatinine may overestimate renal function. Impaired liver function results in decreased creatinine production. Protein-calorie malnutrition and muscle wasting which are common during cirrhosis [8Pirlich M. Schutz T. Spachos T. Ertl S. Weiss M.L. Lochs H. et al.Bioelectrical impedance analysis is a useful bedside technique to assess malnutrition in cirrhotic patients with and without ascites.Hepatology. 2000; 32: 1208-1215Crossref PubMed Scopus (163) Google Scholar, 9Figueiredo F.A. Dickson E.R. Pasha T.M. Porayko M.K. Therneau T.M. Malinchoc M. et al.Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease.Liver Transplant. 2000; 6: 575-581Crossref PubMed Scopus (124) Google Scholar] also contribute to decreased creatinine production. On average, baseline serum creatinine is lower in cirrhotic patients compared to the general population [10Cockcroft D.W. Gault M.H. Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41Crossref PubMed Scopus (13236) Google Scholar, 11Levey A.S. Bosch J.P. Lewis J.B. 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 Int Med. 1999; 130: 461-470Crossref PubMed Scopus (13136) Google Scholar]. Baseline serum creatinine within the normal range does not exclude a significant impairment in renal function [12Sherman 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 (273) Google Scholar, 13Papadakis 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 (207) Google Scholar, 14Caregaro L. Menon F. Angeli P. Amodio P. Merkel C. Bortoluzzi A. et al.Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.Arch Int Med. 1994; 154: 201-205Crossref PubMed Google Scholar, 15DeSanto N.G. Anastasio P. Loguercio C. Spitali L. Del Vecchio Blanco C. Corvinelli M. et al.Creatinine clearance: an inadequate marker of renal filtration in patients with early posthepatitic cirrhosis (Child A) without fluid retention and muscle wasting.Nephron. 1995; 70: 421-424Crossref PubMed Google Scholar]. Patients may present a twofold increase in baseline creatinine with levels remaining below 1 mg/dl (88 μmol/L), apparently within the normal range. Another bias comes from fluctuations of serum creatinine, especially in those with refractory ascites and/or those receiving diuretics. Wide variations may be observed, depending on large volume paracentesis and volume expansion. In such situations, the issue of which serum creatinine value is best correlated to the outcome is difficult to address. Significant inter-laboratory variations may be observed in the dosage of creatinine, mainly due to an interaction with bilirubin [16Spencer K. Analytical reviews in clinical biochemistry: the estimation of creatinine.Ann Clin Biochem. 1986; 23: 1-25PubMed Google Scholar, 17Badiou S. Dupuy A.M. Descomps B. Cristolead J.P. Comparison between the enzymatic vitros assay for creatinine determination and three other methods adapted on the Olympus analyzer.J Clin Lab Anal. 2003; 17: 235-240Crossref PubMed Scopus (38) Google Scholar]. Routine creatinine dosage is based on spectrophotometry. In patients with jaundice, bilirubin as a chromogen interferes with creatinine dosage, resulting in falsely low creatinine values. The higher is serum bilirubin, either conjugated or unconjugated, the higher is the interference. It has been shown that inter-laboratory variations may impact on MELD score [[18]Cholongitas E. Marelli L. Kerry A. Senzolo M. Goodier D.W. Nair D. et al.Different methods of creatinine measurement significantly affect MELD scores.Liver Transplant. 2007; 13: 523-529Crossref PubMed Scopus (139) Google Scholar]. For example, when four different methods of creatinine dosage are applied in patients with serum bilirubin between 200 and 400 μmol/L, a difference in MELD score ⩾2 points may be observed in about 60% [[18]Cholongitas E. Marelli L. Kerry A. Senzolo M. Goodier D.W. Nair D. et al.Different methods of creatinine measurement significantly affect MELD scores.Liver Transplant. 2007; 13: 523-529Crossref PubMed Scopus (139) Google Scholar]. Several techniques such as deproteinization, the use of bilirubin oxidase or kinetic alkaline picrate methods may help overcome this interference [19Boot S. LaRoche N. Legg E.F. Elimination of bilirubin interference in creatinine assays by routine techniques: comparisons with a high performance liquid chromatography method.Ann Clin Biochem. 1994; 31: 262-266PubMed Google Scholar, 20Lolekha P.H. Jaruthunyaluck S. Srisawasdi P. Deproteinization of serum: another best approach to eliminate all forms of bilirubin interference on serum creatinine by the kinetic Jaffe reaction.J Clin Lab Anal. 2001; 15: 116-121Crossref PubMed Scopus (35) Google Scholar]. However, the dosage of serum creatinine has not been standardized. On an individual basis, serum creatinine should be interpreted with caution in cirrhotic patients due to frequent overestimation of renal function. Overestimation is especially high in patients with advanced liver disease, high bilirubin and refractory ascites. Therefore, creatinine alone is insufficient for identifying either acute or chronic renal disease in these patients. In theory, creatinine clearance from timed urine collections might be a reliable method for assessing renal function. However, several studies have shown that, in cirrhotic patients, creatinine clearance, when compared to inulin clearance as the reference standard, overestimates true GFR by a mean of about 13 ml/min/1.73 m3[15DeSanto N.G. Anastasio P. Loguercio C. Spitali L. Del Vecchio Blanco C. Corvinelli M. et al.Creatinine clearance: an inadequate marker of renal filtration in patients with early posthepatitic cirrhosis (Child A) without fluid retention and muscle wasting.Nephron. 1995; 70: 421-424Crossref PubMed Google Scholar, 21Orlando 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, 22Roy L. Legault L. Pomier-Layrargues G. Glomerular filtration rate measurement in cirrhotic patients with renal failure.Clin Nephrol. 1998; 50: 342-346PubMed Google Scholar, 23Proulx N.L. Akbari A. Garg A.X. Rostom A. Jaffey J. Clark H.D. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis.Nephrol Dial Transplant. 2005; 20: 1617-1622Crossref PubMed Scopus (99) Google Scholar]. Overestimation is highest in patients with low GFR [[23]Proulx N.L. Akbari A. Garg A.X. Rostom A. Jaffey J. Clark H.D. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis.Nephrol Dial Transplant. 2005; 20: 1617-1622Crossref PubMed Scopus (99) Google Scholar]. The reasons for the discordance between creatinine clearance and true GFR could be related, at least in part, to the increased proportion of creatinine secreted by the tubule compared to creatinine filtered by the glomerulus during cirrhosis, especially in those with low GFR [[22]Roy L. Legault L. Pomier-Layrargues G. Glomerular filtration rate measurement in cirrhotic patients with renal failure.Clin Nephrol. 1998; 50: 342-346PubMed Google Scholar]. From a practical view point, non specific factors including incomplete urine collection and errors in the timing of collection may play a more difficult to identify role in the inaccuracy of creatinine clearance. Creatinine clearance based on timed urine collections, even if well conducted, is not the guarantee of an accurate assessment of renal function in cirrhotic patients. Overestimation may lead to inappropriate classification and/or therapeutic adjustments in about 50% patients [[23]Proulx N.L. Akbari A. Garg A.X. Rostom A. Jaffey J. Clark H.D. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis.Nephrol Dial Transplant. 2005; 20: 1617-1622Crossref PubMed Scopus (99) Google Scholar]. There is no evidence that creatinine clearance is preferable to serum creatinine. The creatinine-based Cockcroft and MDRD equations are widely used in the general population to estimate GFR [10Cockcroft D.W. Gault M.H. Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41Crossref PubMed Scopus (13236) Google Scholar, 11Levey A.S. Bosch J.P. Lewis J.B. 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 Int Med. 1999; 130: 461-470Crossref PubMed Scopus (13136) Google Scholar]. MDRD is considered the gold standard in nephrology [[24]Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function-measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2345) Google Scholar]. However, as these equations are based on serum creatinine, it is not surprising that they are also inaccurate in cirrhotic patients. Several studies have shown that both Cockcroft and MDRD tend to overestimate true GFR [12Sherman 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 (273) Google Scholar, 14Caregaro L. Menon F. Angeli P. Amodio P. Merkel C. Bortoluzzi A. et al.Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.Arch Int Med. 1994; 154: 201-205Crossref PubMed Google Scholar, 22Roy L. Legault L. Pomier-Layrargues G. Glomerular filtration rate measurement in cirrhotic patients with renal failure.Clin Nephrol. 1998; 50: 342-346PubMed Google Scholar, 25Orlando R. Floreani M. Padrini R. Palatini P. Evaluation of measured and calculated creatinine clearances as glomerular filtration markers in different stages of liver cirrhosis.Clin Nephrol. 1999; 51: 341-347PubMed Google Scholar]. The largest series has shown that only 66% of estimates were within 30% of the measured GFR [[26]Gonwa T.A. Jennings L. Mai M.L. Stark P.C. Levey A.S. Klintmalm G.B. Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations.Liver Transplant. 2004; 10: 301-309Crossref PubMed Scopus (293) Google Scholar]. In cirrhotic patients, MDRD which does not take into account body weight seems to be less inaccurate than Cockcroft [[26]Gonwa T.A. Jennings L. Mai M.L. Stark P.C. Levey A.S. Klintmalm G.B. Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations.Liver Transplant. 2004; 10: 301-309Crossref PubMed Scopus (293) Google Scholar]. Indeed, body weight may be markedly biased in patients with oedema and/or ascites. However, the accuracy of MDRD, even if slightly superior to that of Cockcroft, remains limited [[12]Sherman 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 (273) Google Scholar]. The inaccuracy of Cockcroft and MDRD in cirrhotic patients may be related to several factors. As discussed above, creatinine is an inaccurate marker of renal function in this population. In particular, normal serum creatinine does not exclude a marked decrease in GFR. Secondly, Cockcroft and MDRD equations include serum creatinine adjusted for several variables which were shown to have a significant impact on GFR in the general population (i.e., age, body weight and gender for Cockcroft; age, gender and ethnicity for simplified MDRD). The factors associated with each of these variables are not necessarily well suited for cirrhotic patients. Different adjustments could be needed. Finally, Cockcroft and MDRD are not adjusted for some variables which are likely to have a determinant impact on the estimation of GFR in cirrhotic patients. For example, body weight is difficult to interpret without taking into account ascites and oedema. Recently, a new creatinine-based equation termed CKD-EPI (for Chronic Kidney Disease Epidemiology Collaboration), adjusted for gender and ethnicity has been proposed as a more accurate formula compared to Cockcroft and MDRD [[27]Levey A.S. Stevens L.A. Schmid C.H. Zhang Y.L. Castro 3rd, A.F. Feldman H.I. et al.A new equation to estimate glomerular filtration rate.Ann Int Med. 2009; 150: 604-612Crossref PubMed Scopus (16605) Google Scholar]. This formula has not been tested in cirrhotic patients yet. However, as it is also based on serum creatinine, it can be anticipated that CKD-EPI is not markedly superior to other creatinine-based equations in cirrhosis. Creatinine-based equations should not be recommended to estimate renal function in cirrhotic patients. Indeed, these formulas may give falsely reassuring values since they tend to overestimate GFR. More data are needed to create and validate more specific equations with an acceptable accuracy in cirrhosis. To date, no such equations have been proposed. Direct measurement of GFR using exogenous markers remains the reference to assess renal function in cirrhotic patients. Direct measurement of GFR is mandatory to precisely assess renal function and adequately classify patients into the different categories of impaired renal function (Table 1) [[28]K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266.Google Scholar].Table 1Proposed definitions for staging chronic kidney diseases [28]K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266.Google Scholar.StageDescriptionGFR (ml/min/1.73 m2)1Kidney damage⁎Kidney damage is defined as pathologic abnormalities or markers of damage including abnormalities in blood or urine tests or imaging studies. with normal or increased GFR⩾902Kidney damage with mild decreased GFR60–893Moderate decreased GFR30–594Severe decreased GFR15–295Kidney failure<15 or dialysis Kidney damage is defined as pathologic abnormalities or markers of damage including abnormalities in blood or urine tests or imaging studies. Open table in a new tab Inulin clearance has been considered the “gold standard”. Inulin is freely filtered by the glomerulus and not secreted, reabsorbed, synthesized or metabolized by the kidney. Consequently, for a stable concentration of inulin in the plasma, the amount of filtered inulin by the glomerulus is equal to the amount excreted in the urine [[29]Gaspari F. Perico N. Remuzzi G. Measurement of glomerular filtration rate.Kidney Int Suppl. 1997; 63: S151-154PubMed Google Scholar]. However, this technique requires a continuous intravenous infusion and timed urine collections over a period of several hours. This technique is time consuming, costly and potentially invasive if bladder catheterization has to be done for urine collection. Other techniques using markers such as synthetic inulin-like polyfructosans, radiolabeled compounds (51Cr-EDTA, 99mTc-DPTA and 125I-iothalamate) or non-radioactive agents (iohexol or iothalamate) have been proposed [24Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function-measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2345) Google Scholar, 30Gaspari F. Perico N. Ruggenenti P. Mosconi L. Amuchastegui C.S. Guerini E. et al.Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate.J Am Soc Nephrol. 1995; 6: 257-263PubMed Google Scholar]. The main advantage of these markers is a single-injection with measurement of GFR based on the total area under the curve of the plasma concentration of the marker. Time collection of urine samples is not needed. The use of radiolabeled compounds is limited by exposure to radiation and costs. Contrast agents seem to be safer even though rare allergic events have been reported. None of these alternative techniques have been specifically validated in cirrhosis. However, since markers are exogenous and only eliminated by the kidney, it can be assumed that their accuracy is similar to that of inulin clearance. Measurements using iohexol or iothalamate can be recommended. However, these techniques which are technically demanding and costly can hardly be repeated at close intervals. Recently, it has been shown that serum cystatin C, another endogenous marker, could represent an interesting alternative to serum creatinine [[24]Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function-measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2345) Google Scholar]. Cystatin C is a low molecular weight protein produced at a constant rate by all nucleated cells and eliminated almost exclusively by glomerular filtration [[31]Herget-Rosenthal S. Trabold S. Pietruck F. Holtmann M. Philipp T. Kribben A. Cystatin C: efficacy as screening test for reduced glomerular filtration rate.Am J Nephrol. 2000; 20: 97-102Crossref PubMed Scopus (132) Google Scholar]. After filtration, cystatin C is reabsorbed and catabolized by the tubular epithelial cells. Consequently, urinary clearance cannot be measured [24Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function-measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2345) Google Scholar, 32Laterza O.F. Price C.P. Scott M.G. Cystatin C: an improved estimator of glomerular filtration rate?.Clin Chem. 2002; 48: 699-707PubMed Google Scholar]. In contrast to creatinine, serum cystatin C is independent of gender, age and muscle mass. The dosage is not influenced by serum bilirubin, inflammation or malignancy [33Gerbes A.L. Gulberg 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 (130) Google Scholar, 34Cholongitas E. Shusang V. Marelli L. Nair D. Thomas M. Patch D. et al.Review article: renal function assessment in cirrhosis – difficulties and alternative measurements.Aliment Pharmacol Ther. 2007; 26: 969-978Crossref PubMed Scopus (124) Google Scholar]. A recent meta-analysis has shown that, in non-cirrhotic patients, cystatin C is better correlated with GFR than creatinine [[35]Dharnidharka V.R. Kwon C. Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis.Am J Kidney Dis. 2002; 40: 221-226Abstract Full Text Full Text PDF PubMed Scopus (1331) Google Scholar]. Interestingly, it has been shown that the sensitivity of cystatin C for the diagnosis of impaired renal function, with a cut-off value of 1.25 mg/dl, is similar in cirrhotic patients and in non-cirrhotic patients [[21]Orlando 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]. Several small studies have suggested that, after kidney or liver transplantation, serum cystatin C could be useful to monitor renal function [36Le Bricon T. Thervet E. Froissart M. Benlakehal M. Bousquet B. Legendre C. et al.Plasma cystatin C is superior to 24-h creatinine clearance and plasma creatinine for estimation of glomerular filtration rate 3 months after kidney transplantation.Clin Chem. 2000; 46: 1206-1207PubMed Google Scholar, 37Hermida J. Romero R. Tutor J.C. Serum cystatin C-immunoglobulin high-molecular-weight complexes in kidney and liver transplant patients.Kidney Int. 2001; 60: 1561-1564Crossref PubMed Scopus (13) Google Scholar, 38Schuck O. Gottfriedova H. Maly J. Jabor A. Stollova M. Bruzkova I. et al.Glomerular filtration rate assessment in individuals after orthotopic liver transplantation based on serum cystatin C levels.Liver Transplant. 2002; 8: 594-599Crossref PubMed Scopus (54) Google Scholar, 39Gerhardt T. Poge U. Stoffel-Wagner B. Ahrendt M. Wolff M. Spen