Renal Dysfunction in Patients with Liver Cirrhosis

Abstract

Liver cirrhosis is a major health problem that can affect people of different ages. It induces pivotal hemodynamic and metabolic systemic disturbances along with other organs dysfunction. Renal dysfunction in cirrhotic patients is not uncommon, and subtle renal impairment is an early and very frequent finding. Liver cirrhosis can afflict kidney functions through different mechanisms. Renal vasoconstriction is usually the initial response of splanchnic vasodilation and decreased effective renal plasma flow. This induces a reduction of intraglomerular pressure leading to stimulation of renin-angiotensin system to maintain the glomerular filtration rate. Other causes of renal dysfunction include electrolytes and acid-base disturbances, systemic inflammation, bile cast nephropathy, and intra-abdominal hypertension. Loss of renal reserve is usually the earliest manifestation of kidney dysfunction in cirrhotic patients. This makes the kidney supersensitive to any subsequent hemodynamic or metabolic abnormalities. Proper assessment of kidney function is one of the major challenges in cirrhotic patients. The use of serum creatinine and creatinine-based equations is inaccurate and can overestimate kidney function. Hepato-renal syndrome (HRS) is a life-threatening disorder. In the last decade, there was significant progress in understanding the mechanism of this mysterious disorder. In this article, we are focusing on different mechanisms of kidney dysfunction in cirrhotic patients and the major diagnostic and therapeutic challenges.

Keywords

liver cirrhosis - kidney function - HRS

Publication History

Received: 03 December 2021

Accepted: 19 January 2022

Article published online:
13 June 2022

• References

• 1 Singbartl K. Renal Physiology in Liver Disease. Hepatic Critical Care; Springer: 2018: 53-58
• 2 Matloff RG, Arnon R. The Kidney in Pediatric Liver Disease. Curr Gastroenterol Rep 2015; 17 (09) 36 DOI: 10.1007/s11894-015-0457-x.
• 3 Iwakiri Y. The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007; 41 (Suppl. 03) S288-S294 DOI: 10.1097/MCG.0b013e3181468b4c.
• 4 Hu LS, George J, Wang JH. Current concepts on the role of nitric oxide in portal hypertension. World J Gastroenterol 2013; 19 (11) 1707-1717 DOI: 10.3748/wjg.v19.i11.1707.
• 5 Laffi G, Foschi M, Masini E. et al. Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation. Hepatology 1995; 22 (06) 1666-1673
• 6 Lee FY, Albillos A, Colombato LA, Groszmann RJ. The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats. Hepatology 1992; 16 (04) 1043-1048 DOI: 10.1002/hep.1840160430.
• 7 Adebayo D, Morabito V, Davenport A, Jalan R. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int 2015; 87 (03) 509-515 DOI: 10.1038/ki.2014.338.
• 8 Solà E, Ginès P. Challenges and Management of Liver Cirrhosis: Pathophysiology of Renal Dysfunction in Cirrhosis. Dig Dis 2015; 33 (04) 534-538 DOI: 10.1159/000375344.
• 9 Liamis G, Filippatos TD, Liontos A, Elisaf MS. Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise. Hepatol Int 2016; 10 (05) 762-772 DOI: 10.1007/s12072-016-9746-1.
• 10 Liamis G, Filippatos TD, Elisaf MS. Correction of hypovolemia with crystalloid fluids: Individualizing infusion therapy. Postgrad Med 2015; 127 (04) 405-412 DOI: 10.1080/00325481.2015.1029421.
• 11 Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol 2008; 19 (06) 1076-1078 DOI: 10.1681/asn.2007091042.
• 12 Angeli P, Wong F, Watson H, Ginès P. CAPPS Investigators. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006; 44 (06) 1535-1542 DOI: 10.1002/hep.21412.
• 13 Kim WR, Biggins SW, Kremers WK. et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008; 359 (10) 1018-1026 DOI: 10.1056/NEJMoa0801209.
• 14 Sersté T, Gustot T, Rautou PE. et al. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol 2012; 57 (02) 274-280 DOI: 10.1016/j.jhep.2012.03.018.
• 15 Casey TH, Summerskill WH, Orvis AL. BODY AND SERUM POTASSIUM IN LIVER DISEASE. I. RELATIONSHIP TO HEPATIC FUNCTION AND ASSOCIATED FACTORS. Gastroenterology 1965; 48: 198-207
• 16 Casey TH, Summerskill WH, Bickford RG, Rosevear JW. BODY AND SERUM POTASSIUM IN LIVER DISEASE. II. RELATIONSHIPS TO ARTERIAL AMMONIA, BLOOD PH, AND HEPATIC COMA. Gastroenterology 1965; 48: 208-215
• 17 Han KH. Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism. Electrolyte Blood Press 2011; 9 (02) 45-49 DOI: 10.5049/ebp.2011.9.2.45.
• 18 Krapf R, Beeler I, Hertner D, Hulter HN. Chronic respiratory alkalosis. The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med 1991; 324 (20) 1394-1401 DOI: 10.1056/nejm199105163242003.
• 19 Baertl JM, Sancetta SM, Gabuzda GJ. Relation of acute potassium depletion to renal ammonium metabolism in patients with cirrhosis. J Clin Invest 1963; 42 (05) 696-706 DOI: 10.1172/jci104761.
• 20 Bonavia A, Singbartl K. Kidney Injury and Electrolyte Abnormalities in Liver Failure. Semin Respir Crit Care Med 2018; 39 (05) 556-565 DOI: 10.1055/s-0038-1673616.
• 21 Bourgeois N, Devaere S, Adler M, Cremer M. [Use of diuretics in the treatment of ascites in patients with cirrhosis]. Acta Gastroenterol Belg 1990; 53 (02) 256-260
• 22 Ahya SN, José Soler M, Levitsky J, Batlle D. Acid-base and potassium disorders in liver disease. Semin Nephrol 2006; 26 (06) 466-470 DOI: 10.1016/j.semnephrol.2006.11.001.
• 23 Vatsalya V, Gala KS, Mishra M. et al. Lower Serum Magnesium Concentrations are associated With Specific Heavy Drinking Markers, Pro-Inflammatory Response and Early-Stage Alcohol-associated Liver Injury§. Alcohol Alcohol 2020; 55 (02) 164-170 DOI: 10.1093/alcalc/agaa001.
• 24 Scheiner B, Lindner G, Reiberger T. et al. Acid-base disorders in liver disease. J Hepatol 2017; 67 (05) 1062-1073 DOI: 10.1016/j.jhep.2017.06.023.
• 25 Karetzky MS, Mithoefer JC. The cause of hyperventilation and arterial hypoxia in patients with cirrhosis of the liver. Am J Med Sci 1967; 254 (06) 797-804 DOI: 10.1097/00000441-196712000-00004.
• 26 Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363 (9419): 1461-1468 DOI: 10.1016/s0140-6736(04)16107-2.
• 27 Regner KR, Singbartl K. Kidney Injury in Liver Disease. Crit Care Clin 2016; 32 (03) 343-355 DOI: 10.1016/j.ccc.2016.03.005.
• 28 Rehman HU. A woman with ketoacidosis but not diabetes. BMJ 2012; 344: e1535 DOI: 10.1136/bmj.e1535.
• 29 Komatsuda A, Wakui H, Ohtani H. et al. Tubulointerstitial nephritis and renal tubular acidosis of different types are rare but important complications of primary biliary cirrhosis. Nephrol Dial Transplant 2010; 25 (11) 3575-3579 DOI: 10.1093/ndt/gfq232.
• 30 van Slambrouck CM, Salem F, Meehan SM, Chang A. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int 2013; 84 (01) 192-197 DOI: 10.1038/ki.2013.78.
• 31 El Chediak A, Janom K, Koubar SH. Bile cast nephropathy: when the kidneys turn yellow. Renal Replacement Therapy 2020; 6 (01) 15
• 32 Cade R, Wagemaker H, Vogel S. et al. Hepatorenal syndrome. Studies of the effect of vascular volume and intraperitoneal pressure on renal and hepatic function. Am J Med 1987; 82 (03) 427-438 DOI: 10.1016/0002-9343(87)90442-6.
• 33 Umgelter A, Reindl W, Wagner KS. et al. Effects of plasma expansion with albumin and paracentesis on haemodynamics and kidney function in critically ill cirrhotic patients with tense ascites and hepatorenal syndrome: a prospective uncontrolled trial. Crit Care 2008; 12 (01) R4 DOI: 10.1186/cc6765.
• 34 Arora V, Vijayaraghavan R, Maiwall R. et al. Paracentesis-Induced Circulatory Dysfunction With Modest-Volume Paracentesis Is Partly Ameliorated by Albumin Infusion in Acute-on-Chronic Liver Failure. Hepatology 2020; 72 (03) 1043-1055 DOI: 10.1002/hep.31071.
• 35 Aithal GP, Palaniyappan N, China L. et al. Guidelines on the management of ascites in cirrhosis. Gut 2021; 70 (01) 9-29 DOI: 10.1136/gutjnl-2020-321790.
• 36 Anderson SS, McCreary JB, Alvarez KS, Brown LS, Agrawal D. Standardizing the Use of Albumin in Large Volume Paracentesis. J Pharm Pract 2020; 33 (04) 420-424 DOI: 10.1177/0897190018816252.
• 37 Shah N, Mohamed FE, Jover-Cobos M. et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int 2013; 33 (03) 398-409 DOI: 10.1111/liv.12047.
• 38 Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol 2009; 51 (03) 475-482 DOI: 10.1016/j.jhep.2009.04.017.
• 39 Navasa M, Follo A, Filella X. et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology 1998; 27 (05) 1227-1232 DOI: 10.1002/hep.510270507.
• 40 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61 (06) 1385-1396 DOI: 10.1016/j.jhep.2014.08.010.
• 41 Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for liver cirrhosis: Ascites and related complications. Clin Mol Hepatol 2018; 24 (03) 230-277 DOI: 10.3350/cmh.2018.1005.
• 42 Piano S, Romano A, Di Pascoli M, Angeli P. Why and how to measure renal function in patients with liver disease. Liver Int 2017; 37 (Suppl. 01) 116-122 DOI: 10.1111/liv.13305.
• 43 Romano TG, Schmidtbauer I, Silva FM, Pompilio CE, D'Albuquerque LA, Macedo E. Role of MELD score and serum creatinine as prognostic tools for the development of acute kidney injury after liver transplantation. PLoS One 2013; 8 (05) e64089 DOI: 10.1371/journal.pone.0064089.
• 44 Yoo JJ, Kim SG, Kim YS. et al. Estimation of renal function in patients with liver cirrhosis: Impact of muscle mass and sex. J Hepatol 2019; 70 (05) 847-854 DOI: 10.1016/j.jhep.2018.12.030.
• 45 Proulx NL, Akbari A, Garg AX, Rostom A, Jaffey J, Clark HD. 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 (08) 1617-1622 DOI: 10.1093/ndt/gfh839.
• 46 Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal function and disease in patients with cirrhosis. J Hepatol 2010; 52 (04) 605-613 DOI: 10.1016/j.jhep.2009.11.025.
• 47 Orlando 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 (06) 341-347
• 48 Takabatake T, Ohta H, Ishida Y, Hara H, Ushiogi Y, Hattori N. Low serum creatinine levels in severe hepatic disease. Arch Intern Med 1988; 148 (06) 1313-1315
• 49 Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003; 41 (02) 269-278 DOI: 10.1053/ajkd.2003.50035.
• 50 Slack AJ, Wendon J. The liver and kidney in critically ill patients. Blood Purif 2009; 28 (02) 124-134 DOI: 10.1159/000227281.
• 51 Cullaro G, Park M, Lai JC. “Normal” Creatinine Levels Predict Persistent Kidney Injury and Waitlist Mortality in Outpatients With Cirrhosis. Hepatology 2018; 68 (05) 1953-1960 DOI: 10.1002/hep.30058.
• 52 Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet 2003; 362 (9398): 1819-1827 DOI: 10.1016/s0140-6736(03)14903-3.
• 53 Mezey E. Liver disease and protein needs. Annu Rev Nutr 1982; 2: 21-50 DOI: 10.1146/annurev.nu.02.070182.000321.
• 54 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 (02) 582-591 DOI: 10.1002/hep.28891.
• 55 Ahn HS, Kim YS, Kim SG. et al. Cystatin C is a good predictor of hepatorenal syndrome and survival in patients with cirrhosis who have normal serum creatinine levels. Hepatogastroenterology 2012; 59 (116) 1168-1173 DOI: 10.5754/hge11616.
• 56 Levey AS, Coresh J, Greene T. et al; Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145 (04) 247-254 DOI: 10.7326/0003-4819-145-4-200608150-00004.
• 57 Carrier P, Debette-Gratien M, Essig M, Loustaud-Ratti V. Beyond serum creatinine: which tools to evaluate renal function in cirrhotic patients?. Hepatol Res 2018; 48 (10) 771-779 DOI: 10.1111/hepr.13224.
• 58 Koratala A, Kazory A. Pregnancy Outcomes in “Recovered” Acute Kidney Injury: Underscoring Renal Functional Reserve. Nephron 2017; 136 (03) 243-244 DOI: 10.1159/000459637.
• 59 Koratala A, Alquadan KF. Diminishing Kidney Reserve and the “Pseudo”normal Creatinine. Hepatology 2018; 68 (05) 2045 DOI: 10.1002/hep.30159.
• 60 Angeli P, Ginès P, Wong F. et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015; 62 (04) 968-974 DOI: 10.1016/j.jhep.2014.12.029.
• 61 Wadei HM, Geiger XJ, Cortese C. et al. Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy. Am J Transplant 2008; 8 (12) 2618-2626 DOI: 10.1111/j.1600-6143.2008.02426.x.
• 62 Arroyo V, Ginès P, Gerbes AL. et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996; 23 (01) 164-176 DOI: 10.1002/hep.510230122.
• 63 Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document. J Hepatol 2019; 71 (04) 811-822 DOI: 10.1016/j.jhep.2019.07.002.
• 64 Belcher JM, Sanyal AJ, Peixoto AJ. et al; TRIBE-AKI Consortium. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 2014; 60 (02) 622-632 DOI: 10.1002/hep.26980.
• 65 Fagundes C, Pépin MN, Guevara M. et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012; 57 (02) 267-273 DOI: 10.1016/j.jhep.2012.03.015.
• 66 Ariza X, Solà E, Elia C. et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS One 2015; 10 (06) e0128145 DOI: 10.1371/journal.pone.0128145.
• 67 Huelin P, Solà E, Elia C. et al. Neutrophil Gelatinase-Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study. Hepatology 2019; 70 (01) 319-333 DOI: 10.1002/hep.30592.
• 68 Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56 (09) 1310-1318 DOI: 10.1136/gut.2006.107789.
• 69 KDIGO AKI Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2 (01) 1-138
• 70 Angeli P, Ginès P, Wong F. et al; International Club of Ascites. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut 2015; 64 (04) 531-537
• 71 Wong F, Jepsen P, Watson H, Vilstrup H. Un-precipitated acute kidney injury is uncommon among stable patients with cirrhosis and ascites. Liver Int 2018; 38 (10) 1785-1792 DOI: 10.1111/liv.13738.
• 72 Fernández J, Navasa M, Planas R. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007; 133 (03) 818-824 DOI: 10.1053/j.gastro.2007.06.065.
• 73 Salerno F, Navickis RJ, Wilkes MM. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol 2013; 11 (02) 123-30.e1 DOI: 10.1016/j.cgh.2012.11.007.
• 74 China L, Freemantle N, Forrest E. et al; ATTIRE Trial Investigators. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis. N Engl J Med 2021; 384 (09) 808-817 DOI: 10.1056/NEJMoa2022166.
• 75 Ojeda-Yuren AS, Cerda-Reyes E, Herrero-Maceda MR, Castro-Narro G, Piano S. An Integrated Review of the Hepatorenal Syndrome. Ann Hepatol 2021; 22: 100236 DOI: 10.1016/j.aohep.2020.07.008.
• 76 European Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69 (02) 406-460 DOI: 10.1016/j.jhep.2018.03.024.
• 77 Wong F, Pappas SC, Curry MP. et al; CONFIRM Study Investigators. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med 2021; 384 (09) 818-828 DOI: 10.1056/NEJMoa2008290.
• 78 Cavallin M, Piano S, Romano A. et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study. Hepatology 2016; 63 (03) 983-992 DOI: 10.1002/hep.28396.
• 79 Abdel-Razik A, Mousa N, Abdelsalam M. et al. Endothelin-1/Nitric Oxide Ratio as a Predictive Factor of Response to Therapy With Terlipressin and Albumin in Patients With Type-1 Hepatorenal Syndrome. Front Pharmacol 2020; 11: 9 DOI: 10.3389/fphar.2020.00009.
• 80 Copelan A, Kapoor B, Sands M. Transjugular intrahepatic portosystemic shunt: indications, contraindications, and patient work-up. Semin Intervent Radiol 2014; 31 (03) 235-242 DOI: 10.1055/s-0034-1382790.
• 81 Rajakumar A, Appuswamy E, Kaliamoorthy I, Rela M. Renal Dysfunction in Cirrhosis: Critical Care Management. Indian J Crit Care Med 2021; 25 (02) 207-214 DOI: 10.5005/jp-journals-10071-23721.
• 82 Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation 1995; 59 (03) 361-365