Serum creatinine in cirrhotic patients: a cornerstone

Serum creatinine in cirrhotic patients: a cornerstone

Paul Carrier1,2, Marilyne Debette-Gratien1,2, Véronique Loustaud-Ratti1,2

1Fédération d’Hépatologie, Service d’Hépato-Gastroentérologie, Limoges’ Teaching Hospital, Limoges, France; 2Unité INSERM 1248, Faculté de Médecine et de Pharmacie, Limoges, Rue du Docteur Marcland, France

Correspondence to: Paul Carrier. Fédération d’Hépatologie, Service d’Hépato-Gastroentérologie, Centre Hospitalier Universitaire Dupuytren Limoges, Avenue Martin Luther King, Limoges, France. Email:;

Provenance: This is an invited Editorial commissioned by Editor-in-Chief Xingshun Qi (Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China).

Comment on: Cullaro G, Park M, Lai JC. "Normal" Creatinine Levels Predict Persistent Kidney Injury and Waitlist Mortality in Outpatients With Cirrhosis. Hepatology 2018;68:1953-60.

Received: 16 October 2018; Accepted: 25 October 2018; Published: 15 November 2018.

doi: 10.21037/amj.2018.10.07

In a recent issue of Hepatology, Cullaro et al. highlighted, in a population of cirrhotic patients listed for liver transplant, the association between patient’ s basal serum creatinine level, including “normal range values” and the occurrence of acute kidney injury (AKI), the persistent kidney injury after AKI, and the death/delisting risk (1). In this retrospective single center study involving 385 patients, they showed thanks to a competing risk analysis, that each 1mg/dL increase of basal serum creatinine was associated with a 62% higher risk of mortality. If these results confirm the crucial prognosis impact of an impaired renal function in cirrhotic patients, they also encourage us to stay alert to changes in creatinine values within the normal range. This paper leads to key reflections on creatinine role in cirrhosis management.

Serum creatinine, as well as creatinine-based equations (MDRD4 and MDRD6 formulas) which are supposed to reflect the glomerular filtration rate (GFR), are clearly insufficient. However, in the absence of other simple tool, creatinine still remains essential for the diagnosis of impaired renal function in this population. An increase of serum creatinine in cirrhosis may be the consequence of multiple causes: alteration of kidney perfusion due to splanchnic vasodilation associated to portal hypertension which leads to hepatorenal syndrome (HRS), specific kidney damages associated to cirrhosis specific etiologies (2), but also all nonspecific etiologies encountered in other populations (sepsis, medications, hypovolemia…). Therefore, serum creatinine must be regularly measured in this population in clinical practice (3).

Creatinine is included in multiple cirrhosis prognostic criteria: it has a significant weighting in specific liver transplantation scores such as the MELD score (Mayo model for end-stage liver disease) (4). The MELD score is probably the most accurate for graft selection in the majority of countries. Renal insufficiency is also a major problem after liver transplantation, particularly in case of previous renal disease, with an overall incidence of 15% to 25% of stage ≥4 CKD (chronic kidney disease), 5 years after liver transplantation; it is predictive of mortality and increases health care costs (5). Post-liver transplantation renal insufficiency is influenced by renal function, particularly acute kidney injury occurring before liver transplantation (6). Simultaneous liver and kidney transplantation in the case of preexisting renal disease meets specific criteria to select the good patients (7-10). They are based on renal function, and eventually on kidney sample, essentially in case of multifactorial renal insufficiency. They help selecting the most severe patients, but remain drastic and do not clearly help to assess the complete reversibility of HRS, the main renal complication of end-staged cirrhosis.

An accurate evaluation of renal function is crucial but remains a great challenge in cirrhotic patients, if we aim to improve patient prognosis after liver transplantation and to select patients for simultaneous liver-kidney transplantation.

Specific limits of creatinine must be underlined and well-known (11). It clearly overestimates renal function in cirrhotic patients and particularly severe ones (12). There are several explanations such as a less creatine—the precursor of creatine—specific hepatic secretion. A hypermetabolic state might play an important role too, due to pro-inflammatory cytokines, endotoxinemia, and sympathetic hyperactivity. Furthermore, a sarcopenia is more frequent in cirrhotic patients and is associated with a decrease in creatinine production (13). An increased tubular creatinine secretion was supposed in cirrhotic patients, but these data remain debatable. Moreover, there is a possible interference with bilirubin dosage—which acts as a chromogen in spectrophotometry, giving an overestimation of renal function (2,14). This specific problem seems to be no more relevant in the majority of laboratories nowadays (15). New tools are necessary to assess renal function. Specific equations, which are easily available such as recent royal free hospital equation (RFH), were recently proposed (16). Among markers tested, Cystatin C is the most often used. Cystatin C is more accurate than creatinine-based equations to assess renal function before liver transplantation (17). Nevertheless, other studies are necessary to assess its potential help of cystatin to select patients on the waiting list for liver transplantation. Other strategies aiming to assess severity of renal function impairment, and to predict mortality are necessary: functional tests, renal functional reserve and furosemide stress test, may be interesting in the goal to assess reversibility of renal function, but are not classically used in cirrhotic patients. Renal functional reserve is highlighted by Koratala et al. in their response to Cullaro’s article in Hepatology (18). Furosemide stress test remains potentially dangerous in cirrhotic patients. Reference tools for GFR measurement are exogenous kidney markers, which have an exclusive renal elimination, free filtration in the glomerulus and neither secretion nor reabsorption by the tubules (inulin, 51Cr-EDTA, iohexol) but they are time-consuming, expensive, heavy to implement and only used in sparse clinical trials. Equations requiring few plasma samples are acutely needed (11).

Finally, it is interesting to note that in Cullaro et al.’s paper, one of the differences between each group of serum creatinine values (<0.70, 0.70–0.97, and >0.97 mg/dL) proposed by the authors, is the more frequent presence of ascites in the group with a high basal serum creatinine value, and this group is the most susceptible to develop complications, including chronic hepatorenal syndrome often linked to refractory ascites and AKI. AKI impacts mortality and post-transplantation chronic kidney damage (6). According to KDIGO classification, applied in liver cirrhosis, AKI is defined by a rapid serum creatinine variation (19) and no more by creatinine absolute levels. Contrary to serum creatinine variations during time, imputed serum creatinine doesn’t play any role in acute kidney injury diagnosis however (20). Thus limitations linked to serum creatinine dosage cannot be applied in AKI. Also, Finally, an early diagnosis by repeated dosages of creatinine level is necessary for a specific early management.

In summary, Cullaro’s study, again asserts the absolute necessity of serum creatinine thorough follow-up in cirrhotic patients’ daily care. Basal creatinine helps to screen the early occurrence of acute kidney injury, but also predicts the severity of the patients even if its value remains in the “normal range”. Prospective studies are necessary to confirm these interesting data and basal serum creatinine may help to modify priority scores to access liver transplantation or to discuss simultaneous liver-kidney transplantation.




Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Cullaro G, Park M, Lai JC. "Normal" Creatinine Levels Predict Persistent Kidney Injury and Waitlist Mortality in Outpatients With Cirrhosis. Hepatology 2018;68:1953-60. [Crossref] [PubMed]
  2. Francoz C, Glotz D, Moreau R, et al. The evaluation of renal function and disease in patients with cirrhosis. J Hepatol 2010;52:605-13. [Crossref] [PubMed]
  3. European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406-60. [Crossref] [PubMed]
  4. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-71. [Crossref] [PubMed]
  5. Durand F, Francoz C, Asrani SK, et al. Acute Kidney Injury After Liver Transplantation. Transplantation 2018;102:1636-49. [Crossref] [PubMed]
  6. Maurel P, Loustaud-Ratti V, Carrier P, et al. PS-044 - Effect of longitudinal exposure to tacrolimus on chronic kidney disease occurrence at one year post liver transplantation. J Hepatol 2018;68:S26. [Crossref]
  7. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol 2016;64:433-85. [Crossref] [PubMed]
  8. Nadim MK, Sung RS, Davis CL, et al. Simultaneous liver-kidney transplantation summit: current state and future directions. Am J Transplant 2012;12:2901-8. [Crossref] [PubMed]
  9. Cullaro G, Hirose R, Lai JC. Changes in Simultaneous Liver Kidney Transplant Allocation Policy May Impact Post Liver Transplant Outcomes. Transplantation 2018. [Epub ahead of print]. [Crossref] [PubMed]
  10. Eason JD, Gonwa TA, Davis CL, et al. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant 2008;8:2243-51. [Crossref] [PubMed]
  11. Carrier P, Debette-Gratien M, Essig M, et al. Beyond serum creatinine: which tools to evaluate renal function in cirrhotic patients? Hepatol Res 2018;48:771-9. [Crossref] [PubMed]
  12. Francoz C, Nadim MK, Baron A, et al. Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations. Hepatology 2014;59:1514-21. [Crossref] [PubMed]
  13. Plauth M, Schütz ET. Cachexia in liver cirrhosis. Int J Cardiol 2002;85:83-7. [Crossref] [PubMed]
  14. Badiou S, Dupuy AM, Descomps B, et al. Comparison between the enzymatic vitros assay for creatinine determination and three other methods adapted on the Olympus analyzer. J Clin Lab Anal 2003;17:235-40. [Crossref] [PubMed]
  15. Srisawasdi P, Chaichanajarernkul U, Teerakanjana N, et al. Exogenous interferences with Jaffe creatinine assays: addition of sodium dodecyl sulfate to reagent eliminates bilirubin and total protein interference with Jaffe methods. J Clin Lab Anal 2010;24:123-33. [Crossref] [PubMed]
  16. Kalafateli M, Wickham F, Burniston M, et al. Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate. Hepatology 2017;65:582-91. [Crossref] [PubMed]
  17. De Souza V, Hadj-Aissa A, Dolomanova O, et al. Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis. Hepatology 2014;59:1522-31. [Crossref] [PubMed]
  18. Koratala A, Alquadan KF. Diminishing Kidney Reserve and the "Pseudo"normal Creatinine. Hepatology 2018;68:2045. [Crossref] [PubMed]
  19. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179-84. [PubMed]
  20. Platt JF, Marn CS, Baliga PK, et al. Renal dysfunction in hepatic disease: early identification with renal duplex Doppler US in patients who undergo liver transplantation. Radiology 1992;183:801-6. [Crossref] [PubMed]
doi: 10.21037/amj.2018.10.07
Cite this article as: Carrier P, Debette-Gratien M, Loustaud-Ratti V. Serum creatinine in cirrhotic patients: a cornerstone. AME Med J 2018;3:109.