Paradigmenwechsel im Verständnis der akuten Nierenschädigung bei chronischer Leberinsuffizienz: Von der Pathophysiologie zur Definition von Krankheitsentitäten

Zusammenfassung

Seit den ersten Beschreibungen von Patienten mit Aszites und fortgeschrittener Leberzirrhose durch Helvig und Schutz in den 1930er- und weiteren Obduktionsstudien von Hecker und Sherlock in den 1960er-Jahren wird das gleichzeitige Vorliegen einer Nierenfunktionsstörung als hepatorenales Syndrom (HRS) bezeichnet. Forschungsarbeiten der letzten Jahre liefern Hinweise, dass insbesondere systemische Entzündungsreaktionen einen kritischen Punkt in der Pathogenese der dekompensierten Leberzirrhose darstellen und maßgeblich an der Entstehung eines akut-auf-chronischen Leberversagens (ACLF) und einer Nierenfunktionsstörung beteiligt sind.

Das HRS ist nur ein Aspekt des Spektrums der Nierenschädigung in Zirrhosepatienten. Die fortgeschrittene chronische Lebererkrankung per se bzw. ihre Ätiologie, aber auch weitere begleitende komorbide systemische Erkrankungen bzw. deren Komplikationen wie Diabetes, Adipositas und Hypertonie können direkt zu parenchymatösen Veränderungen (z. B. Gallensäurenephropathie, ischämische Tubulusepithelzellnekrose, diabetische Nephropathie, Glomerulonephritiden assoziiert mit Hepatitis B und C usw.) führen. Diese Art der Nierenschädigung wird deskriptiv als Non-HRS-AKI bezeichnet.

In der vorliegenden Übersicht konzentrieren wir uns auf die neue Definition, Klassifikation und die zugrunde liegenden pathophysiologischen Mechanismen für das HRS, HRS-AKI und Non-HRS-AKI und untersuchen in dieser Hinsicht den diagnostischen und prognostischen Stellenwert neuerer Serum- und Urinmarker.

Abstract

The hepatorenal syndrome (HRS) is only a part of the wide spectrum of renal injury in patients with end-stage liver cirrhosis. Besides that, the advanced liver disease itself, or its underlying causes, as well as comorbidities, like diabetes mellitus, adiposity and arterial hypertension, can directly cause parenchymal renal insults (bile acid nephropathy, ischemic tubular injury, diabetic/hypertensive nephropathy, hepatitis B- and C-associated glomerulonephritis etc.). This kind of kidney injury is collectively described as non-hepatorenal syndrome AKI (non-HRS AKI. Beyond that, accumulating evidence highlights the role of systemic inflammation as an important common factor in the pathogenesis of decompensated liver cirrhosis, acute in chronic liver failure (ACLF) and renal dysfunction.

In this review, we discuss recent data about definition, classification and pathophysiology of HRS, HRS-AKI and Non-HRS-AKI and exploit in this regard the diagnostic and prognostic potential of respective newer serum and urine markers.

Schlüsselwörter

Leberinsuffizienz - Leberzirrhose - akute Nierenschädigung - chronische Niereninsuffizienz - hepatorenales Syndrom - HRS - HRS-AKI - Non-HRS-AKI - ACLF - Biomarker - Pathophysiologie

Key words

liver disease - liver cirrhosis - acute kidney injury - chronic kidney disease - hepatorenal syndrome - HRS - HRS-AKI - non-HRS-AKI - ACLF - biomarkers - pathophysiology

• Literatur

• 1 Francoz C, Durand F, Kahn JA. et al. Hepatorenal Syndrome. Clinical journal of the American Society of Nephrology: CJASN 2019; 14: 774-781 . doi:10.2215/CJN.12451018
• 2 Estes C, Anstee QM, Arias-Loste MT. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. Journal of hepatology 2018; 69: 896-904 . doi:10.1016/j.jhep.2018.05.036
• 3 Tacke F, Kroy DC, Barreiros AP. et al. Liver transplantation in Germany. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2016; 22: 1136-1142 . doi:10.1002/lt.24461
• 4 Tujios SR, Hynan LS, Vazquez MA. et al. Risk factors and outcomes of acute kidney injury in patients with acute liver failure. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2015; 13: 352-359 . doi:10.1016/j.cgh.2014.07.011
• 5 Moreau R, Jalan R, Gines P. et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144: 1426-1437, 1437 e1421–1429 . doi:10.1053/j.gastro.2013.02.042
• 6 Low G, Alexander GJ, Lomas DJ. Hepatorenal syndrome: aetiology, diagnosis, and treatment. Gastroenterology research and practice 2015; 2015: 207012 . doi:10.1155/2015/207012
• 7 Chancharoenthana W, Leelahavanichkul A. Acute kidney injury spectrum in patients with chronic liver disease: Where do we stand?. World journal of gastroenterology 2019; 25: 3684-3703 . doi:10.3748/wjg.v25.i28.3684
• 8 Wlodzimirow KA, Eslami S, Abu-Hanna A. et al. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver international: official journal of the International Association for the Study of the Liver 2013; 33: 40-52 . doi:10.1111/j.1478-3231.2012.02790.x
• 9 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood purification 2002; 20: 252-261 . doi:10.1159/000047017
• 10 Sarin SK, Choudhury A, Sharma MK. et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatology international 2019; 13: 353-390 . doi:10.1007/s12072-019-09946-3
• 11 Jalan R, Yurdaydin C, Bajaj JS. et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology 2014; 147: 4-10 . doi:10.1053/j.gastro.2014.05.005
• 12 Bajaj JS, O'Leary JG, Reddy KR. et al. Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology 2014; 60: 250-256 . doi:10.1002/hep.27077
• 13 Davenport A, Sheikh MF, Lamb E. et al. Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?. Kidney international 2017; 92: 1058-1070 . doi:10.1016/j.kint.2017.04.048
• 14 Arroyo V, Gines P, Gerbes AL. et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996; 23: 164-176 . doi:10.1002/hep.510230122
• 15 Salerno F, Gerbes A, Gines P. et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310-1318 . doi:10.1136/gut.2006.107789
• 16 Sort P, Navasa M, Arroyo V. et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. The New England journal of medicine 1999; 341: 403-409 . doi:10.1056/NEJM199908053410603
• 17 Follo A, Llovet JM, Navasa M. et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994; 20: 1495-1501
• 18 Fasolato S, Angeli P, Dallagnese L. et al. Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features. Hepatology 2007; 45: 223-229 . doi:10.1002/hep.21443
• 19 Terra C, Guevara M, Torre A. et al. Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score. Gastroenterology 2005; 129: 1944-1953 . doi:10.1053/j.gastro.2005.09.024
• 20 Gines A, Fernandez-Esparrach G, Monescillo A. et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 1996; 111: 1002-1010 . doi:10.1016/s0016-5085(96)70068-9
• 21 Angeli P, Fasolato S, Mazza E. et al. Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial. Gut 2010; 59: 98-104 . doi:10.1136/gut.2008.176495
• 22 Akriviadis E, Botla R, Briggs W. et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000; 119: 1637-1648 . doi:10.1053/gast.2000.20189
• 23 Leithead JA, Ferguson JW, Bates CM. et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut 2009; 58: 443-449 . doi:10.1136/gut.2008.154120
• 24 Schrier RW, Arroyo V, Bernardi M. et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8: 1151-1157
• 25 Ruiz-del-Arbol L, Monescillo A, Arocena C. et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005; 42: 439-447 . doi:10.1002/hep.20766
• 26 Krag A, Bendtsen F, Henriksen JH. et al. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 2010; 59: 105-110 . doi:10.1136/gut.2009.180570
• 27 Sanyal AJ, Boyer TD, Frederick RT. et al. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Alimentary pharmacology & therapeutics 2017; 45: 1390-1402 . doi:10.1111/apt.14052
• 28 Allegretti AS, Israelsen M, Krag A. et al. Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome. The Cochrane database of systematic reviews 2017; 6: CD005162 . doi:10.1002/14651858.CD005162.pub4
• 29 Sinclair M, Gow PJ, Grossmann M. et al. Review article: sarcopenia in cirrhosis--aetiology, implications and potential therapeutic interventions. Alimentary pharmacology & therapeutics 2016; 43: 765-777 . doi:10.1111/apt.13549
• 30 Piano S, Rosi S, Maresio G. et al. Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. Journal of hepatology 2013; 59: 482-489 . doi:10.1016/j.jhep.2013.03.039
• 31 Wong F, O'Leary JG, Reddy KR. et al. New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection. Gastroenterology 2013; 145: 1280-1288 e1281 . doi:10.1053/j.gastro.2013.08.051
• 32 Belcher JM, Garcia-Tsao G, Sanyal AJ. et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013; 57: 753-762 . doi:10.1002/hep.25735
• 33 Fagundes C, Barreto R, Guevara M. et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. Journal of hepatology 2013; 59: 474-481 . doi:10.1016/j.jhep.2013.04.036
• 34 Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013; 62: 131-137 . doi:10.1136/gutjnl-2011-301255
• 35 de Carvalho JR, Villela-Nogueira CA, Luiz RR. et al. Acute kidney injury network criteria as a predictor of hospital mortality in cirrhotic patients with ascites. Journal of clinical gastroenterology 2012; 46: e21-e26 . doi:10.1097/MCG.0b013e31822e8e12
• 36 Angeli P, Gines 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. Journal of hepatology 2015; 62: 968-974 . doi:10.1016/j.jhep.2014.12.029
• 37 Angeli P, Garcia-Tsao G, Nadim MK. et al. News in Pathophysiology, Definition and Classification of Hepatorenal Syndrome: a step beyond the International Club of Ascites (ICA) Consensus document. Journal of hepatology 2019;
• 38 [Anonym]. Summary of Recommendation Statements. Kidney international supplements 2012; 2: 8-12 . doi:10.1038/kisup.2012.7
• 39 Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. The New England journal of medicine 1998; 339: 533-541 . doi:10.1056/NEJM199808203390807
• 40 Sola E, Gines P. Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. Journal of hepatology 2010; 53: 1135-1145 . doi:10.1016/j.jhep.2010.08.001
• 41 Scurt FG, Kuczera T, Mertens PR. et al. The Cardiorenal Syndrome. Deutsche medizinische Wochenschrift 2019; 144: 910-916 . doi:10.1055/a-0768-5899
• 42 Kazory A, Koratala A, Ronco C. Customization of Peritoneal Dialysis in Cardiorenal Syndrome by Optimization of Sodium Extraction. Cardiorenal medicine 2019; 9: 117-124 . doi:10.1159/000495703
• 43 Fabrizi F, Dixit V, Messa P. et al. Terlipressin for hepatorenal syndrome: A meta-analysis of randomized trials. The International journal of artificial organs 2009; 32: 133-140
• 44 Salerno F, Navickis RJ, Wilkes MM. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis. BMC gastroenterology 2015; 15: 167 . doi:10.1186/s12876-015-0389-9
• 45 Fabrizi F, Dixit V, Martin P. Meta-analysis: terlipressin therapy for the hepatorenal syndrome. Alimentary pharmacology & therapeutics 2006; 24: 935-944 . doi:10.1111/j.1365-2036.2006.03086.x
• 46 Adebayo D, Morabito V, Davenport A. et al. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney international 2015; 87: 509-515 . doi:10.1038/ki.2014.338
• 47 Davenport A. AKI in a patient with cirrhosis and ascites. Clinical journal of the American Society of Nephrology: CJASN 2012; 7: 2041-2048 . doi:10.2215/CJN.03390412
• 48 Zardi EM, Abbate A, Zardi DM. et al. Cirrhotic cardiomyopathy. Journal of the American College of Cardiology 2010; 56: 539-549 . doi:10.1016/j.jacc.2009.12.075
• 49 Wiese S, Hove JD, Bendtsen F. et al. Cirrhotic cardiomyopathy: pathogenesis and clinical relevance. Nature reviews Gastroenterology & hepatology 2014; 11: 177-186 . doi:10.1038/nrgastro.2013.210
• 50 Cai H, Thomasset SC, P-Berry D. et al. Determination of anthocyanins in the urine of patients with colorectal liver metastases after administration of bilberry extract. Biomedical chromatography: BMC 2011; 25: 660-663 . doi:10.1002/bmc.1499
• 51 Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis – current status and future directions. Journal of hepatology 2014; 61: 912-924 . doi:10.1016/j.jhep.2014.05.047
• 52 Nazar A, Guevara M, Sitges M. et al. LEFT ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. Journal of hepatology 2013; 58: 51-57 . doi:10.1016/j.jhep.2012.08.027
• 53 Katsounas A, Canbay A. Intensive Care Therapy for Patients with Advanced Liver Diseases. Visceral medicine 2018; 34: 283-289 . doi:10.1159/000492088
• 54 Theocharidou E, Krag A, Bendtsen F. et al. Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis. Liver international: official journal of the International Association for the Study of the Liver 2012; 32: 1327-1332 . doi:10.1111/j.1478-3231.2011.02751.x
• 55 Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in patients with liver cirrhosis. World journal of gastroenterology 2013; 19: 445-456 . doi:10.3748/wjg.v19.i4.445
• 56 Acevedo J, Fernandez J, Prado V. et al. Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology 2013; 58: 1757-1765 . doi:10.1002/hep.26535
• 57 Bernardi M, Moreau R, Angeli P. et al. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. Journal of hepatology 2015; 63: 1272-1284 . doi:10.1016/j.jhep.2015.07.004
• 58 Trebicka J, Amoros A, Pitarch C. et al. Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis. Frontiers in immunology 2019; 10: 476 . doi:10.3389/fimmu.2019.00476
• 59 Claria J, Stauber RE, Coenraad MJ. et al. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology 2016; 64: 1249-1264 . doi:10.1002/hep.28740
• 60 Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. Journal of hepatology 2014; 60: 197-209 . doi:10.1016/j.jhep.2013.07.044
• 61 Gong T, Liu L, Jiang W. et al. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 2019;
• 62 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: 1227-1232 . doi:10.1002/hep.510270507
• 63 Du Plessis J, Vanheel H, Janssen CE. et al. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. Journal of hepatology 2013; 58: 1125-1132 . doi:10.1016/j.jhep.2013.01.038
• 64 Maiwall R, Chandel SS, Wani Z. et al. SIRS at Admission Is a Predictor of AKI Development and Mortality in Hospitalized Patients with Severe Alcoholic Hepatitis. Digestive diseases and sciences 2016; 61: 920-929 . doi:10.1007/s10620-015-3921-4
• 65 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 international: official journal of the International Association for the Study of the Liver 2013; 33: 398-409 . doi:10.1111/liv.12047
• 66 Shah N, Dhar D, El Zahraa Mohammed F. et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. Journal of hepatology 2012; 56: 1047-1053 . doi:10.1016/j.jhep.2011.11.024
• 67 Lindquist JA, Brandt S, Bernhardt A. et al. The role of cold shock domain proteins in inflammatory diseases. Journal of molecular medicine 2014; 92: 207-216 . doi:10.1007/s00109-014-1136-3
• 68 Fickert P, Krones E, Pollheimer MJ. et al. Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology 2013; 58: 2056-2069 . doi:10.1002/hep.26599
• 69 van Slambrouck CM, Salem F, Meehan SM. et al. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney international 2013; 84: 192-197 . doi:10.1038/ki.2013.78
• 70 Bairaktari E, Liamis G, Tsolas O. et al. Partially reversible renal tubular damage in patients with obstructive jaundice. Hepatology 2001; 33: 1365-1369 . doi:10.1053/jhep.2001.25089
• 71 Piano S, Schmidt HH, Ariza X. et al. Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2018; 16: 1792-1800 e1793 . doi:10.1016/j.cgh.2018.01.035
• 72 Davenport A, Argawal B, Wright G. et al. Can non-invasive measurements aid clinical assessment of volume in patients with cirrhosis?. World journal of hepatology 2013; 5: 433-438 . doi:10.4254/wjh.v5.i8.433
• 73 Ostermann M, Joannidis M. Acute kidney injury 2016: diagnosis and diagnostic workup. Critical care 2016; 20: 299 . doi:10.1186/s13054-016-1478-z
• 74 Francoz C, Prie D, Abdelrazek W. et al. Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2010; 16: 1169-1177 . doi:10.1002/lt.22128
• 75 Rosi S, Piano S, Frigo AC. et al. New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?. Liver international: official journal of the International Association for the Study of the Liver 2015; 35: 2108-2114 . doi:10.1111/liv.12852
• 76 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: 1514-1521 . doi:10.1002/hep.26704
• 77 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: 582-591 . doi:10.1002/hep.28891
• 78 Francoz C, Nadim MK, Durand F. Kidney biomarkers in cirrhosis. Journal of hepatology 2016; 65: 809-824 . doi:10.1016/j.jhep.2016.05.025
• 79 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: 1522-1531 . doi:10.1002/hep.26886
• 80 Mindikoglu AL, Dowling TC, Weir MR. et al. Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis. Hepatology 2014; 59: 1532-1542 . doi:10.1002/hep.26556
• 81 Markwardt D, Holdt L, Steib C. et al. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis. Hepatology 2017; 66: 1232-1241 . doi:10.1002/hep.29290
• 82 Maiwall R, Kumar A, Bhardwaj A. et al. Cystatin C predicts acute kidney injury and mortality in cirrhotics: A prospective cohort study. Liver international: official journal of the International Association for the Study of the Liver 2018; 38: 654-664 . doi:10.1111/liv.13600
• 83 Ariza X, Sola E, Elia C. et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PloS one 2015; 10: e0128145 . doi:10.1371/journal.pone.0128145
• 84 Durand F, Olson JC, Nadim MK. Renal dysfunction and cirrhosis. Current opinion in critical care 2017; 23: 457-462 . doi:10.1097/MCC.0000000000000457
• 85 Amathieu R, Al-Khafaji A, Sileanu FE. et al. Significance of oliguria in critically ill patients with chronic liver disease. Hepatology 2017; 66: 1592-1600 . doi:10.1002/hep.29303
• 86 Hinz M, Wree A, Jochum C. et al. High age and low sodium urine concentration are associated with poor survival in patients with hepatorenal syndrome. Annals of hepatology 2013; 12: 92-99
• 87 Diamond JR, Yoburn DC. Nonoliguric acute renal failure associated with a low fractional excretion of sodium. Annals of internal medicine 1982; 96: 597-600 . doi:10.7326/0003-4819-96-5-597
• 88 Patidar KR, Kang L, Bajaj JS. et al. Fractional excretion of urea: A simple tool for the differential diagnosis of acute kidney injury in cirrhosis. Hepatology 2018; 68: 224-233 . doi:10.1002/hep.29772
• 89 Belcher JM, Sanyal AJ, Peixoto AJ. et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 2014; 60: 622-632 . doi:10.1002/hep.26980
• 90 Trawale JM, Paradis V, Rautou PE. et al. The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study. Liver international: official journal of the International Association for the Study of the Liver 2010; 30: 725-732 . doi:10.1111/j.1478-3231.2009.02182.x
• 91 Ariza X, Graupera I, Coll M. et al. Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis. Journal of hepatology 2016; 65: 57-65 . doi:10.1016/j.jhep.2016.03.002
• 92 Ostermann M, Joannidis M. Biomarkers for AKI improve clinical practice: no. Intensive care medicine 2015; 41: 618-622 . doi:10.1007/s00134-014-3540-0
• 93 Marx D, Metzger J, Pejchinovski M. et al. Proteomics and Metabolomics for AKI Diagnosis. Seminars in nephrology 2018; 38: 63-87 . doi:10.1016/j.semnephrol.2017.09.007
• 94 Kerbert AJ, Verbeke L, Chiang FW. et al. Copeptin as an Indicator of Hemodynamic Derangement and Prognosis in Liver Cirrhosis. PloS one 2015; 10: e0138264 . doi:10.1371/journal.pone.0138264
• 95 Sola E, Kerbert AJ, Verspaget HW. et al. Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis. Journal of hepatology 2016; 65: 914-920 . doi:10.1016/j.jhep.2016.07.003
• 96 Kashani K, Al-Khafaji A, Ardiles T. et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Critical care 2013; 17: R25 . doi:10.1186/cc12503
• 97 Zhang CC, Hoffelt DAA, Merle U. Urinary cell cycle arrest biomarker [TIMP-2] [IGFBP7] in patients with hepatorenal syndrome. Biomarkers 2019; 24: 692-699 . doi:10.1080/1354750X.2019.1652347
• 98 Awdishu L, Tsunoda S, Pearlman M. et al. Identification of Maltase Glucoamylase as a Biomarker of Acute Kidney Injury in Patients with Cirrhosis. Critical care research and practice 2019; 2019: 5912804 . doi:10.1155/2019/5912804
• 99 Trionfini P, Benigni A, Remuzzi G. MicroRNAs in kidney physiology and disease. Nature reviews Nephrology 2015; 11: 23-33 . doi:10.1038/nrneph.2014.202
• 100 Amrouche L, Desbuissons G, Rabant M. et al. MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action. Journal of the American Society of Nephrology: JASN 2017; 28: 479-493 . doi:10.1681/ASN.2016010045
• 101 Watany MM, Hagag RY, Okda HI. Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: a pilot study. Clinical chemistry and laboratory medicine 2018; 56: 739-747 . doi:10.1515/cclm-2017-0483
• 102 Mindikoglu AL, Opekun AR, Putluri N. et al. Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis. Transl Res 2018; 195: 25-47 . doi:10.1016/j.trsl.2017.12.002