The occurrence of acute kidney injury (AKI) in patients with end-stage liver disease constitutes one of the most challenging clinical scenarios in in-hospital and critical care medicine. Hepatorenal syndrome type 1 (HRS-1), which is a specific type of AKI that occurs in the context of advanced cirrhosis and portal hypertension, is associated with particularly high mortality. The pathogenesis of HRS-1 is largely viewed as a functional derangement that ultimately affects renal vasculature tone. However, new insights suggest that non-haemodynamic tubulo-toxic factors, such as endotoxins and bile acids, might mediate parenchymal renal injury in patients with cirrhosis, suggesting that concurrent mechanisms, including those traditionally associated with HRS-1 and non-traditional factors, might contribute to the development of AKI in patients with cirrhosis. Moreover, histological evidence of morphological abnormalities in the kidneys of patients with cirrhosis and renal dysfunction has prompted the functional nature of HRS-1 to be re-examined. From a clinical perspective, a diagnosis of HRS-1 guides utilization of vasoconstrictive therapy and decisions regarding renal replacement therapy. Patients with cirrhosis are at risk of AKI owing to a wide range of factors. However, the tools currently available to ascertain the diagnosis of HRS-1 and guide therapy are suboptimal. Short of liver transplantation, goal-directed haemodynamically targeted pharmacotherapy remains the cornerstone of treatment for this condition; improved understanding of the underlying pathogenic mechanisms might lead to better clinical outcomes. Here, we examine our current understanding of the pathophysiology of HRS-1 and existing challenges in its diagnosis and treatment.
Although various non-haemodynamic mechanisms of injury, such as endotoxin-mediated inflammation, bile acid-induced tubular toxicity and true tubular ischaemia, are now implicated in the pathogenesis of hepatorenal syndrome type 1 (HRS-1), renal vasoconstriction and reduced renal blood flow continue to be regarded as the quintessential mechanism of renal dysfunction.
The differential diagnosis of acute kidney injury (AKI) in patients with cirrhosis is broad, and ‘pure’ HRS-1 likely constitutes a minor subset of these cases; however, different pathogenic mechanisms can coexist and overlap of AKI aetiologies is conceivable.
Strictly functional HRS-1 may therefore exist alongside other haemodynamic and/or parenchymal forms of renal dysfunction in the same patient.
The current diagnostic International Club of Ascites criteria for HRS-1 provide a useful foundation to frame the diagnostic approach of AKI in patients with cirrhosis; however, one must remain cognizant of the limitations of those criteria and recognize that key aspects of the HRS-1 ‘phenotype’ are not routinely included and should be carefully considered during clinical evaluation.
The cornerstone of pharmacological therapy for HRS-1 is the use of vasoconstrictors with a goal-directed approach to target a substantial rise in mean arterial pressure by ~15 mmHg or to >85 mmHg.
As kidney function declines and the serum bilirubin increases during the course of HRS-1-associated AKI, the likelihood of successful reversal of HRS-1 with a vasoconstrictor decreases; early recognition of HRS-1 is therefore critical to initiating therapy at an early stage of AKI.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Current Treatment Options in Gastroenterology Open Access 15 September 2022
Characteristics of acute kidney injury and its impact on outcome in patients with acute-on-chronic liver failure
BMC Gastroenterology Open Access 11 May 2022
Low preoperative prealbumin predicts the prevalence of complications following liver transplantation
BMC Gastroenterology Open Access 22 May 2021
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Belcher, J. M. et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 60, 622–632 (2014).
Gines, A. et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 105, 229–236 (1993).
Salerno, F. et al. Diagnosis, treatment and survival of patients with hepatorenal syndrome: a survey on daily medical practice. J. Hepatol. 55, 1241–1248 (2011).
Weil, D. et al. Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis. Ann. Intensive Care 7, 33 (2017).
Butt, A. K. et al. Predicting hospital mortality in cirrhotic patients: comparison of Child-Pugh and Acute Physiology, Age and Chronic Health Evaluation (APACHE III) scoring systems. Am. J. Gastroenterol. 93, 2469–2475 (1998).
Flint, A. Clinical report on hydro-peritoneum, based on analysis of forty-six cases. Am. J. Med. Sci. 45, 306–339 (1863).
Schmidt, C. R. & Chesky, V. E. Clinical studies of liver function; the hepatorenal syndrome. Am. J. Surg. 75, 772–795 (1948).
Shear, L., Kleinerman, J. & Gabuzda, G. J. Renal failure in patients with cirrhosis of the liver. I. Clinical and pathologic characteristics. Am. J. Med. 39, 184–198 (1965).
Hecker, R. & Sherlock, S. Electrolyte and circulatory changes in terminal liver failure. Lancet 271, 1121–1125 (1956).
Papper, S., Belsky, J. L. & Bleifer, K. H. Renal failure in Laennec’s cirrhosis of the liver. I. Description of clinical and laboratory features. Ann. Intern. Med. 51, 759–773 (1959).
Epstein, M. et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am. J. Med. 49, 175–185 (1970).
Ring-Larsen, H. Renal blood flow in cirrhosis: relation to systemic and portal haemodynamics and liver function. Scand. J. Clin. Lab. Investig. 37, 635–642 (1977).
Koppel, M. H. et al. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functional nature of renal failure in advanced liver disease. N. Engl. J. Med. 280, 1367–1371 (1969).
Iwatsuki, S. et al. Recovery from “hepatorenal syndrome” after orthotopic liver transplantation. N. Engl. J. Med. 289, 1155–1159 (1973).
Shetty, S. et al. Acute kidney injury in patients with cirrhosis of liver: clinical profile and predictors of outcome. Indian J. Gastroenterol. 37, 248–254 (2018).
Xiong, J. et al. Evaluation of the criteria of hepatorenal syndrome type of acute kidney injury in patients with cirrhosis admitted to ICU. Scand. J. Gastroenterol. 53, 1590–1596 (2018).
Hamdy, H. S. et al. Urinary neutrophil gelatinase-associated lipocalin in cirrhotic patients with acute kidney injury. Ann. Hepatol. 17, 624–630 (2018).
Prakash, J., Mahapatra, A. K., Ghosh, B., Arora, P. & Jain, A. K. Clinical spectrum of renal disorders in patients with cirrhosis of liver. Ren. Fail. 33, 40–46 (2011).
Martin, P. Y., Gines, P. & Schrier, R. W. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N. Engl. J. Med. 339, 533–541 (1998).
Niederberger, M. et al. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 109, 1624–1630 (1995).
Chen, T. A. et al. Effect of intravenous albumin on endotoxin removal, cytokines, and nitric oxide production in patients with cirrhosis and spontaneous bacterial peritonitis. Scand. J. Gastroenterol. 44, 619–625 (2009).
Schrier, R. W. et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8, 1151–1157 (1988).
Wilkinson, S. P. & Williams, R. Renin-angiotensin-aldosterone system in cirrhosis. Gut 21, 545–554 (1980).
Bichet, D. G., Van Putten, V. J. & Schrier, R. W. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N. Engl. J. Med. 307, 1552–1557 (1982).
Ring-Larsen, H., Hesse, B., Henriksen, J. H. & Christensen, N. J. Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction, and renal release. Hepatology 2, 304–310 (1982).
Salo, J. et al. Renal and neurohormonal changes following simultaneous administration of systemic vasoconstrictors and dopamine or prostacyclin in cirrhotic patients with hepatorenal syndrome. J. Hepatol. 25, 916–923 (1996).
Fernandez-Seara, J. et al. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 97, 1304–1312 (1989).
Arroyo, V. et al. Pathophysiology of ascites and functional renal failure in cirrhosis. J. Hepatol. 6, 239–257 (1988).
Wong, F., Moore, K., Dingemanse, J. & Jalan, R. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology 47, 160–168 (2008).
Hocher, B. et al. Renal effects of the novel selective adenosine A1 receptor blocker SLV329 in experimental liver cirrhosis in rats. PLOS ONE 6, e17891 (2011).
Ortiz, M. C. et al. Microcomputed tomography of kidneys following chronic bile duct ligation. Kidney Int. 58, 1632–1640 (2000).
Kew, M. C. et al. Renal and intrarenal blood-flow in cirrhosis of the liver. Lancet 2, 504–510 (1971).
Baldus, W. P., Feichter, R. N., Summerskill, W. H., Hunt, J. C. & Wakim, K. G. The kidney in cirrhosis. II. Disorders of renal function. Ann. Intern. Med. 60, 366–377 (1964).
Jonassen, T. E. et al. Functional and structural changes in the thick ascending limb of Henle’s loop in rats with liver cirrhosis. Am. J. Physiol. 273, R568–R577 (1997).
Horbelt, M. et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 293, F688–F695 (2007).
Allegretti, A. S. et al. Prognosis of acute kidney injury and hepatorenal syndrome in patients with cirrhosis: a prospective cohort study. Int. J. Nephrol. 2015, 108139 (2015).
Chade, A. R. & Hall, J. E. Role of the renal microcirculation in progression of chronic kidney injury in obesity. Am. J. Nephrol. 44, 354–367 (2016).
Levy, M., Finestone, H. & Fechner, C. Action of renal vasodilators in dogs following acute biliary obstruction. J. Surg. Res. 36, 163–171 (1984).
Kahng, K. U., Monaco, D. O., Schnabel, F. R. & Wait, R. B. Renal vascular reactivity in the bile duct-ligated rat. Surgery 104, 250–256 (1988).
Chuang, C. L. et al. Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G752–G761 (2018).
Chuang, C. L. et al. Lipopolysaccharide enhanced renal vascular response to endothelin-1 through ETA overexpression in portal hypertensive rats. J. Gastroenterol. Hepatol. 30, 199–207 (2015).
Ortiz, M. C. et al. Vitamin E prevents renal dysfunction induced by experimental chronic bile duct ligation. Kidney Int. 64, 950–961 (2003).
Inan, M., Sayek, I., Tel, B. C. & Sahin-Erdemli, I. Role of endotoxin and nitric oxide in the pathogenesis of renal failure in obstructive jaundice. Br. J. Surg. 84, 943–947 (1997).
Kostreva, D. R., Castaner, A. & Kampine, J. P. Reflex effects of hepatic baroreceptors on renal and cardiac sympathetic nerve activity. Am. J. Physiol. 238, R390–R394 (1980).
Lang, F. et al. Hepatorenal reflex regulating kidney function. Hepatology 14, 590–594 (1991).
Ming, Z., Fan, Y. J., Yang, X. & Lautt, W. W. Contribution of hepatic adenosine A1 receptors to renal dysfunction associated with acute liver injury in rats. Hepatology 44, 813–822 (2006).
Ming, Z. & Lautt, W. W. Intrahepatic adenosine-mediated activation of hepatorenal reflex is via A1 receptors in rats. Can. J. Physiol. Pharmacol. 84, 1177–1184 (2006).
Ming, Z., Smyth, D. D. & Lautt, W. W. Decreases in portal flow trigger a hepatorenal reflex to inhibit renal sodium and water excretion in rats: role of adenosine. Hepatology 35, 167–175 (2002).
Lang, F. et al. Serotoninergic hepatorenal reflex regulating renal glomerular filtration rate. Pflugers Arch. 419, 111–113 (1991).
Jalan, R., Forrest, E. H., Redhead, D. N., Dillon, J. F. & Hayes, P. C. Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man? Gut 40, 664–670 (1997).
DiBona, G. F. & Sawin, L. L. Hepatorenal baroreflex in cirrhotic rats. Am. J. Physiol. 269, G29–G33 (1995).
Solis-Herruzo, J. A. et al. Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepatorenal syndrome. J. Hepatol. 5, 167–173 (1987).
Krag, A. & Gluud, L. L. Cross-talk between the liver, heart and kidney — another piece in the puzzle. J. Gastrointest. Liver Dis. 23, 119–121 (2014).
Krag, A., Bendtsen, F., Henriksen, J. H. & Moller, S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 59, 105–110 (2010).
Moller, S. & Henriksen, J. H. Review article: pathogenesis and pathophysiology of hepatorenal syndrome — is there scope for prevention? Aliment. Pharmacol. Ther. 20, 31–41 (2004). discussion 42–33.
Ruiz-del-Arbol, L. et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 42, 439–447 (2005).
Mandorfer, M. et al. Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 146, 1680–1690.e1 (2014).
Moller, S., Iversen, J. S., Henriksen, J. H. & Bendtsen, F. Reduced baroreflex sensitivity in alcoholic cirrhosis: relations to hemodynamics and humoral systems. Am. J. Physiol. Heart Circ. Physiol. 292, H2966–H2972 (2007).
Newton, J. L., Allen, J., Kerr, S. & Jones, D. E. Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis. Liver Int. 26, 197–202 (2006).
Mani, A. R. et al. Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G330–G338 (2009).
Busk, T. M. et al. Transjugular intrahepatic portosystemic shunt: impact on systemic hemodynamics and renal and cardiac function in patients with cirrhosis. Am. J. Physiol. Gastrointest. Liver Physiol. 314, G275–G286 (2018).
Kazory, A. & Ronco, C. Hepatorenal syndrome or hepatocardiorenal syndrome: revisiting basic concepts in view of emerging data. Cardiorenal Med. 9, 1–7 (2019).
Zardi, E. M., Zardi, D. M., Giorgi, C., Chin, D. & Dobrina, A. Portopulmonary hypertension and hepatorenal syndrome. Two faces same coin. Eur. J. Intern. Med. 43, 22–27 (2017).
Liberal, R., Grant, C. R., Baptista, R. & Macedo, G. Porto-pulmonary hypertension: a comprehensive review. Clin. Res. Hepatol. Gastroenterol. 39, 157–167 (2015).
Colle, I. O. et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 37, 401–409 (2003).
Lebrec, D., Capron, J. P., Dhumeaux, D. & Benhamou, J. P. Pulmonary hypertension complicating portal hypertension. Am. Rev. Respir. Dis. 120, 849–856 (1979).
Talwalkar, J. A., Swanson, K. L., Krowka, M. J., Andrews, J. C. & Kamath, P. S. Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment. Gastroenterology 141, 1673–1679 (2011).
Krowka, M. J., Swanson, K. L., Frantz, R. P., McGoon, M. D. & Wiesner, R. H. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 44, 1502–1510 (2006).
Savale, L. et al. Acute decompensated pulmonary hypertension. Eur. Respir. Rev. 26, pii: 170092 (2017).
Ruiz-del-Arbol, L. et al. Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 113, 579–586 (1997).
Moreau, R. et al. Comparison of the effect of terlipressin and albumin on arterial blood volume in patients with cirrhosis and tense ascites treated by paracentesis: a randomised pilot study. Gut 50, 90–94 (2002).
Appenrodt, B. et al. Prevention of paracentesis-induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study. Liver Int. 28, 1019–1025 (2008).
Gines, P. et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 93, 234–241 (1987).
Gines, A. et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 111, 1002–1010 (1996).
Patel, D. M. & Connor, M. J. Jr. Intra-abdominal hypertension and abdominal compartment syndrome: an underappreciated cause of acute kidney injury. Adv. Chronic Kidney Dis. 23, 160–166 (2016).
Doty, J. M. et al. Effects of increased renal parenchymal pressure on renal function. J. Trauma 48, 874–877 (2000).
Chang, Y. et al. Hepatorenal syndrome: insights into the mechanisms of intra-abdominal hypertension. Int. J. Clin. Exp. Pathol. 6, 2523–2528 (2013).
Cade, R. et al. Hepatorenal syndrome. Studies of the effect of vascular volume and intraperitoneal pressure on renal and hepatic function. Am. J. Med. 82, 427–438 (1987).
Savino, J. A., Cerabona, T., Agarwal, N. & Byrne, D. Manipulation of ascitic fluid pressure in cirrhotics to optimize hemodynamic and renal function. Ann. Surg. 208, 504–511 (1988).
Umgelter, A. et al. Renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites. Intensive Care Med. 35, 152–156 (2009).
de Cleva, R., Silva, F. P., Zilberstein, B. & Machado, D. J. Acute renal failure due to abdominal compartment syndrome: report on four cases and literature review. Rev. Hosp. Clin. Fac. Med. Sao Paulo 56, 123–130 (2001).
Huggins, J. T., Doelken, P., Walters, C. & Rockey, D. C. Point-of-care echocardiography improves assessment of volume status in cirrhosis and hepatorenal syndrome. Am. J. Med. Sci. 351, 550–553 (2016).
Acevedo, J. et al. Relative adrenal insufficiency in decompensated cirrhosis: relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology 58, 1757–1765 (2013).
Marik, P. E., Gayowski, T. & Starzl, T. E., Hepatic Cortisol Research and Adrenal Pathophysiology Study Group. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit. Care Med. 33, 1254–1259 (2005).
Fede, G. et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 55, 1282–1291 (2012).
Singh, R. R. et al. Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome). Dig. Liver Dis. 50, 1232–1237 (2018).
Mandal, A. K., Lansing, M. & Fahmy, A. Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study. Am. J. Kidney Dis. 2, 363–374 (1982).
Kanel, G. C. & Peters, R. L. Glomerular tubular reflux — a morphologic renal lesion associated with the hepatorenal syndrome. Hepatology 4, 242–246 (1984).
Hussain, S. M. & Sureshkumar, K. K. Refining the role of simultaneous liver kidney transplantation. J. Clin. Transl. Hepatol. 6, 289–295 (2018).
Sharma, P. et al. Short-term pretransplant renal replacement therapy and renal nonrecovery after liver transplantation alone. Clin. J. Am. Soc. Nephrol. 8, 1135–1142 (2013).
Nazar, A. et al. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 51, 219–226 (2010).
Poloni, J. A. T. et al. Utility of a urine sediment score in hyperbilirubinemia/hyperbilirubinuria. Clin. Nephrol. 92, 141–150 (2019).
Varga, Z. V. et al. Disruption of renal arginine metabolism promotes kidney injury in hepatorenal syndrome in mice. Hepatology 68, 1519–1533 (2018).
Holmes, T. W. Jr. The histologic lesion of cholemic nephrosis. J. Urol. 70, 677–685 (1953).
Betjes, M. G. & Bajema, I. The pathology of jaundice-related renal insufficiency: cholemic nephrosis revisited. J. Nephrol. 19, 229–233 (2006).
Uslu, A. et al. Human kidney histopathology in acute obstructive jaundice: a prospective study. Eur. J. Gastroenterol. Hepatol. 22, 1458–1465 (2010).
Mairiang, P., Bhudhisawasdi, V., Borirakchanyavat, V. & Sitprija, V. Acute renal failure in obstructive jaundice in cholangiocarcinoma. Arch. Intern. Med. 150, 2357–2360 (1990).
Uslu, A. et al. Renal failure in obstructive jaundice. Hepatogastroenterology 52, 52–54 (2005).
Tabatabaee, S. M., Elahi, R. & Savaj, S. Bile cast nephropathy due to cholestatic jaundice after using stanozolol in 2 amateur bodybuilders. Iran. J. Kidney Dis. 9, 331–334 (2015).
Aniort, J., Poyet, A., Kemeny, J. L., Philipponnet, C. & Heng, A. E. Bile cast nephropathy caused by obstructive cholestasis. Am. J. Kidney Dis. 69, 143–146 (2017).
Sequeira, A. & Gu, X. Bile cast nephropathy: an often forgotten diagnosis. Hemodial. Int. 19, 132–135 (2015).
Luciano, R. L., Castano, E., Moeckel, G. & Perazella, M. A. Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid. Am. J. Kidney Dis. 64, 473–476 (2014).
Kritmetapak, K., Sathidatekoonchorn, T. & Papanrueng, W. Bile cast nephropathy in a patient with cholangiocarcinoma—a case report. Clin. Case Rep. 6, 779–783 (2018).
Krones, E., Pollheimer, M. J., Rosenkranz, A. R. & Fickert, P. Cholemic nephropathy — historical notes and novel perspectives. Biochim. Biophys. Acta 1864, 1356–1366 (2018).
Nayak, S. L., Kumar, M., Bihari, C. & Rastogi, A. Bile cast nephropathy in patients with acute kidney injury due to hepatorenal syndrome: a postmortem kidney biopsy study. J. Clin. Transl. Hepatol. 5, 92–100 (2017).
van Slambrouck, C. M., Salem, F., Meehan, S. M. & Chang, A. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int. 84, 192–197 (2013).
Foshat, M. et al. Bile cast nephropathy in cirrhotic patients: effects of chronic hyperbilirubinemia. Am. J. Clin. Pathol. 147, 525–535 (2017).
Heyman, S. N., Darmon, D., Ackerman, Z., Rosenberger, C. & Rosen, S. Bile cast nephropathy. Kidney Int. 85, 479 (2014).
Rivera, M., Alghamdi, A. & Velez, J. C. Assessment of utility of urine sediment microscopy in hepatorenal acute kidney injury. J. Am. Soc. Nephrol. 29, F0004 (2018).
Kirkby, K. et al. Intravenous bilirubin provides incomplete protection against renal ischemia-reperfusion injury in vivo. Am. J. Physiol. Renal Physiol. 292, F888–F894 (2007).
Adin, C. A., Croker, B. P. & Agarwal, A. Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney. Am. J. Physiol. Renal Physiol. 288, F778–F784 (2005).
Barabas, K. et al. Hyperbilirubinemia’s protective effect against cisplatin nephrotoxicity in the Gunn rat. Anticancer Drugs 19, 495–502 (2008).
Oh, S. W. et al. Bilirubin attenuates the renal tubular injury by inhibition of oxidative stress and apoptosis. BMC Nephrol. 14, 105 (2013).
Fickert, P. et al. Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology 58, 2056–2069 (2013).
Kaler, B. et al. Are bile acids involved in the renal dysfunction of obstructive jaundice? An experimental study in bile duct ligated rats. Ren. Fail. 26, 507–516 (2004).
Ljubuncic, P., Tanne, Z. & Bomzon, A. Evidence of a systemic phenomenon for oxidative stress in cholestatic liver disease. Gut 47, 710–716 (2000).
Fulop, M. & Brazeau, P. Impaired renal function exaggerates hyperbilirubinemia in bile duct-ligated dogs. Am. J. Dig. Dis. 15, 1067–1072 (1970).
Adebayo, D., Morabito, V., Davenport, A. & Jalan, R. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int. 87, 509–515 (2015).
Garg, H. et al. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure. Dig. Liver Dis. 44, 166–171 (2012).
Hampel, H., Bynum, G. D., Zamora, E. & El-Serag, H. B. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am. J. Gastroenterol. 96, 2206–2210 (2001).
Wilkinson, S. P., Moodie, H., Stamatakis, J. D., Kakkar, V. V. & Williams, R. Endotoxaemia and renal failure in cirrhosis and obstructive jaundice. Br. Med. J. 2, 1415–1418 (1976).
Shah, N. et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int. 33, 398–409 (2013).
Arroyo, V. et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 23, 164–176 (1996).
Salerno, F., Gerbes, A., Gines, P., Wong, F. & Arroyo, V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 56, 1310–1318 (2007).
Angeli, P. et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J. Hepatol. 62, 968–974 (2015).
Wong, F. & Angeli, P. New diagnostic criteria and management of acute kidney injury. J. Hepatol. 66, 860–861 (2017).
Regner, K. R. & Singbartl, K. Kidney injury in liver disease. Crit. Care Clin. 32, 343–355 (2016).
Montano-Loza, A. J. et al. Inclusion of sarcopenia within MELD (MELD-Sarcopenia) and the prediction of mortality in patients with cirrhosis. Clin. Transl. Gastroenterol. 6, e102 (2015).
Sansoe, G. et al. Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis. Clin. Sci. 102, 91–98 (2002).
Daugherty, N. A., Hammond, K. B. & Osberg, I. M. Bilirubin interference with the kinetic Jaffe method for serum creatinine. Clin. Chem. 24, 392–393 (1978).
Gomaa, S. H., Shamseya, M. M. & Madkour, M. A. Clinical utility of urinary neutrophil gelatinase-associated lipocalin and serum cystatin C in a cohort of liver cirrhosis patients with renal dysfunction: a challenge in the diagnosis of hepatorenal syndrome. Eur. J. Gastroenterol. Hepatol. 31, 692–702 (2019).
Woitas, R. P. et al. Correlation of serum concentrations of cystatin C and creatinine to inulin clearance in liver cirrhosis. Clin. Chem. 46, 712–715 (2000).
Gerbes, 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 50, 106–110 (2002).
Demirtas, S., Bozbas, A., Akbay, A., Yavuz, Y. & Karaca, L. Diagnostic value of serum cystatin C for evaluation of hepatorenal syndrome. Clin. Chim. Acta 311, 81–89 (2001).
Ahn, H. S. et al. Cystatin C is a good predictor of hepatorenal syndrome and survival in patients with cirrhosis who have normal serum creatinine levels. Hepatogastroenterology 59, 1168–1173 (2012).
Amathieu, R. et al. Significance of oliguria in critically ill patients with chronic liver disease. Hepatology 66, 1592–1600 (2017).
Wilson, J. G. & Breyer, K. E. Critical care ultrasound: a review for practicing nephrologists. Adv. Chronic Kidney Dis. 23, 141–145 (2016).
Prekker, M. E., Scott, N. L., Hart, D., Sprenkle, M. D. & Leatherman, J. W. Point-of-care ultrasound to estimate central venous pressure: a comparison of three techniques. Crit. Care Med. 41, 833–841 (2013).
Velez, J. C. Q., Petkovich, B., Karakala, N. & Huggins, J. T. Point-of-care echocardiography unveils misclassification of acute kidney injury as hepatorenal syndrome. Am. J. Nephrol. 50, 204-211– (2019).
Alsaad, A. A. & Wadei, H. M. Fractional excretion of sodium in hepatorenal syndrome: clinical and pathological correlation. World J. Hepatol. 8, 1497–1501 (2016).
Patidar, K. R., Kang, L., Bajaj, J. S., Carl, D. & Sanyal, A. J. Fractional excretion of urea: a simple tool for the differential diagnosis of acute kidney injury in cirrhosis. Hepatology 68, 224–233 (2018).
Newell, G. C. Cirrhotic glomerulonephritis: incidence, morphology, clinical features, and pathogenesis. Am. J. Kidney Dis. 9, 183–190 (1987).
Wadei, H. M. et al. Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy. Am. J. Transpl. 8, 2618–2626 (2008).
Kohler, H., Wandel, E. & Brunck, B. Acanthocyturia — a characteristic marker for glomerular bleeding. Kidney Int. 40, 115–120 (1991).
Nguyen, M. T., Maynard, S. E. & Kimmel, P. L. Misapplications of commonly used kidney equations: renal physiology in practice. Clin. J. Am. Soc. Nephrol. 4, 528–534 (2009).
Perazella, M. A., Coca, S. G., Kanbay, M., Brewster, U. C. & Parikh, C. R. Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin. J. Am. Soc. Nephrol. 3, 1615–1619 (2008).
Perazella, M. A. et al. Urine microscopy is associated with severity and worsening of acute kidney injury in hospitalized patients. Clin. J. Am. Soc. Nephrol. 5, 402–408 (2010).
Chawla, L. S., Dommu, A., Berger, A., Shih, S. & Patel, S. S. Urinary sediment cast scoring index for acute kidney injury: a pilot study. Nephron Clin. Pract. 110, c145–c150 (2008).
Eknoyan, G. Letter: renal disorders in hepatic failure. Br. Med. J. 2, 670 (1974).
Elsom, K. Renal function in obstructive jaundice. Arch. Intern. Med. 60, 1028–1033 (1937).
Follo, A. et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 20, 1495–1501 (1994).
Watt, K., Uhanova, J. & Minuk, G. Y. Hepatorenal syndrome: diagnostic accuracy, clinical features, and outcome in a tertiary care center. Am. J. Gastroenterol. 97, 2046–2050 (2002).
Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007).
Davenport, A., Sheikh, M. F., Lamb, E., Agarwal, B. & Jalan, R. Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit? Kidney Int. 92, 1058–1070 (2017).
Velez, J. C. et al. Hepatorenal acute kidney injury and the importance of raising mean arterial pressure. Nephron 131, 191–201 (2015).
Puthumana, J. et al. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 15, 1003–1013.e3 (2017).
Fagundes, C. et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J. Hepatol. 57, 267–273 (2012).
Verna, E. C. et al. Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig. Dis. Sci. 57, 2362–2370 (2012).
Huelin, P. et al. Neutrophil gelatinase-associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study. Hepatology 70, 319–333 (2019).
Watany, M. M., Hagag, R. Y. & Okda, H. I. 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. Clin. Chem. Lab. Med. 56, 739–747 (2018).
Bichet, D. G., Groves, B. G. & Schrier, R. W. Effect of head-out water immersion on hepatorenal syndrome. Am. J. Kidney Dis. 3, 258–263 (1984).
Yersin, B., Burnier, M. & Magnenat, P. Improvement of renal failure with repeated head-out water immersions in patients with hepatorenal syndrome associated with alcoholic hepatitis. Am. J. Nephrol. 15, 260–265 (1995).
Ariyan, S., Sweeney, T. & Kerstein, M. D. The hepatorenal syndrome: recovery after portacaval shunt. Ann. Surg. 181, 847–849 (1975).
Pladson, T. R. & Parrish, R. M. Hepatorenal syndrome. Recovery after peritoneovenous shunt. Arch. Intern. Med. 137, 1248–1249 (1977).
Landini, S. et al. Spontaneous ascites filtration and reinfusion (SAFR) as ambulatory chronic treatment for hepatorenal syndrome. Trans. Am. Soc. Artif. Intern. Organs 31, 439–443 (1985).
Cobden, I., Shore, A., Wilkinson, R. & Record, C. O. Captopril in the hepatorenal syndrome. J. Clin. Gastroenterol. 7, 354–360 (1985).
Zipser, R. D., Kronborg, I., Rector, W., Reynolds, T. & Daskalopoulos, G. Therapeutic trial of thromboxane synthesis inhibition in the hepatorenal syndrome. Gastroenterology 87, 1228–1232 (1984).
Fevery, J. et al. Reversal of hepatorenal syndrome in four patients by peroral misoprostol (prostaglandin E1 analogue) and albumin administration. J. Hepatol. 11, 153–158 (1990).
Therapondos, G., Stanley, A. J. & Hayes, P. C. Systemic, portal and renal effects of terlipressin in patients with cirrhotic ascites: pilot study. J. Gastroenterol. Hepatol. 19, 73–77 (2004).
Lenz, K. et al. Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Effects on renal hemodynamics and atrial natriuretic factor. Gastroenterology 101, 1060–1067 (1991).
Ortega, R. et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 36, 941–948 (2002).
Salerno, F., Navickis, R. J. & Wilkes, M. M. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis. BMC Gastroenterol. 15, 167 (2015).
Angeli, P. et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 29, 1690–1697 (1999).
Skagen, C., Einstein, M., Lucey, M. R. & Said, A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J. Clin. Gastroenterol. 43, 680–685 (2009).
Wong, F., Pantea, L. & Sniderman, K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 40, 55–64 (2004).
Esrailian, E., Pantangco, E. R., Kyulo, N. L., Hu, K. Q. & Runyon, B. A. Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig. Dis. Sci. 52, 742–748 (2007).
Jamil, K., Pappas, S. C. & Devarakonda, K. R. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2. J. Exp. Pharmacol. 10, 1–7 (2018).
Bernadich, C., Bandi, J. C., Melin, P. & Bosch, J. Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension. Hepatology 27, 351–356 (1998).
Uriz, J. et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J. Hepatol. 33, 43–48 (2000).
Solanki, P. et al. Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J. Gastroenterol. Hepatol. 18, 152–156 (2003).
Mulkay, J. P. et al. Long-term terlipressin administration improves renal function in cirrhotic patients with type 1 hepatorenal syndrome: a pilot study. Acta Gastroenterol. Belg. 64, 15–19 (2001).
Moreau, R. et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 122, 923–930 (2002).
Saner, F. et al. Terlipressin and gelafundin: safe therapy of hepatorenal syndrome. Eur. J. Med. Res. 9, 78–82 (2004).
Munoz, L. E. et al. Reversal of hepatorenal syndrome in cirrhotic patients with terlipressin plus albumin. First experience in Mexico. Ann. Hepatol. 8, 207–211 (2009).
Narahara, Y. et al. The efficacy and safety of terlipressin and albumin in patients with type 1 hepatorenal syndrome: a multicenter, open-label, explorative study. J. Gastroenterol. 47, 313–320 (2012).
Gluud, L. L., Christensen, K., Christensen, E. & Krag, A. Terlipressin for hepatorenal syndrome. Cochrane Database Syst. Rev. CD005162, https://doi.org/10.1002/14651858.CD005162.pub3 (2012).
Martin-Llahi, M. et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 134, 1352–1359 (2008).
Neri, S. et al. Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Dig. Dis. Sci. 53, 830–835 (2008).
Cavallin, M. et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology 62, 567–574 (2015).
Sanyal, A. J. et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 134, 1360–1368 (2008).
Boyer, T. D. et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology 150, 1579–1589.e2 (2016).
Sanyal, A. J. 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. Aliment. Pharmacol. Ther. 45, 1390–1402 (2017).
BioSpace. Mallinckrodt announces positive top-line results from its pivotal phase 3 CONFRIM trial of terlipressin in patients with hepatorenal syndrome type 1 (HRS-1). BioSpace https://www.biospace.com/article/releases/mallinckrodt-announces-positive-top-line-results-from-its-pivotal-phase-3-confirm-trial-of-terlipressin-in-patients-with-hepatorenal-syndrome-type-1-hrs-1-/ (2019).
Duvoux, C. et al. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study. Hepatology 36, 374–380 (2002).
Sharma, P., Kumar, A., Shrama, B. C. & Sarin, S. K. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am. J. Gastroenterol. 103, 1689–1697 (2008).
Singh, V. et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J. Hepatol. 56, 1293–1298 (2012).
Alessandria, C. et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J. Hepatol. 47, 499–505 (2007).
Saif, R. U. et al. Noradrenaline versus terlipressin in the management of type 1 hepatorenal syndrome: a randomized controlled study. Indian J. Gastroenterol. 37, 424–429 (2018).
Ghosh, S. et al. Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study. Liver Int. 33, 1187–1193 (2013).
Badawy, S. S. I., Meckawy, N. M. & Ahmed, A. Norepinephrine versus terlipressin in patients with type 1 hepatorenal syndrome refractory to treatment with octreotide, midodrine, and albumin: a prospective randomized comparative study. Egypt J. Cardiothorac. Anesth. 7, 13–18 (2013).
Goyal, O., Sidhu, S. S., Sehgal, N. & Puri, S. Noradrenaline is as effective as terlipressin in hepatorenal syndrome type 1: a prospective, randomized trial. J. Assoc. Physicians India 64, 30–35 (2016).
Nassar Junior, A. P., Farias, A. Q., LA, D. A., Carrilho, F. J. & Malbouisson, L. M. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLOS ONE 9, e107466 (2014).
Arora, V. et al. Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure. Hepatology, https://doi.org/10.1002/hep.30208 (2018).
Tavakkoli, H., Yazdanpanah, K. & Mansourian, M. Noradrenalin versus the combination of midodrine and octreotide in patients with hepatorenal syndrome: randomized clinical trial. Int. J. Prevent. Med. 3, 764–769 (2012).
Pomier-Layrargues, G., Paquin, S. C., Hassoun, Z., Lafortune, M. & Tran, A. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology 38, 238–243 (2003).
Kiser, T. H. et al. Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: a retrospective study. Nephrol. Dial. Transpl. 20, 1813–1820 (2005).
Guevara, M. et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 27, 35–41 (1998).
Eisenman, A., Armali, Z., Enat, R., Bankir, L. & Baruch, Y. Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure. J. Intern. Med. 246, 183–190 (1999).
Gulberg, V., Bilzer, M. & Gerbes, A. L. Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. Hepatology 30, 870–875 (1999).
Hadengue, A. et al. Selective dopamine DA1 stimulation with fenoldopam in cirrhotic patients with ascites: a systemic, splanchnic and renal hemodynamic study. Hepatology 13, 111–116 (1991).
Velez, J. C. & Nietert, P. J. Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials. Am. J. Kidney Dis. 58, 928–938 (2011).
Maddukuri, G., Cai, C. X., Munigala, S., Mohammadi, F. & Zhang, Z. Targeting an early and substantial increase in mean arterial pressure is critical in the management of type 1 hepatorenal syndrome: a combined retrospective and pilot study. Dig. Dis. Sci. 59, 471–481 (2014).
Cai, C. X., Maddukuri, G., Jaipaul, N. & Zhang, Z. A treat-to-target concept to guide the medical management of hepatorenal syndrome. Dig. Dis. Sci. 60, 1474–1481 (2015).
Kelleher, S. P., Robinette, J. B. & Conger, J. D. Sympathetic nervous system in the loss of autoregulation in acute renal failure. Am. J. Physiol. 246, F379–F386 (1984).
Persson, P. B., Ehmke, H., Nafz, B. & Kirchheim, H. R. Sympathetic modulation of renal autoregulation by carotid occlusion in conscious dogs. Am. J. Physiol. 258, F364–F370 (1990).
Stadlbauer, V. et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology 134, 111–119 (2008).
Guevara, M. et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology 28, 416–422 (1998).
Brensing, K. A. et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 47, 288–295 (2000).
Anderson, C. L. et al. Effect of transjugular intrahepatic portosystemic shunt placement on renal function: a 7-year, single-center experience. J. Vasc. Interv. Radiol. 21, 1370–1376 (2010).
Song, T. et al. Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: a systematic review and meta-analysis. Dig. Liver Dis. 50, 323–330 (2018).
Flores, A., Nustas, R., Nguyen, H. L. & Rahimi, R. S. Severe cholestasis and bile acid nephropathy from anabolic steroids successfully treated with plasmapheresis. ACG Case Rep. J. 3, 133–135 (2016).
Lavayssiere, L. et al. Impact of molecular adsorbent recirculating system on renal recovery in type-1 hepatorenal syndrome patients with chronic liver failure. J. Gastroenterol. Hepatol. 28, 1019–1024 (2013).
Wong, F., Raina, N. & Richardson, R. Molecular adsorbent recirculating system is ineffective in the management of type 1 hepatorenal syndrome in patients with cirrhosis with ascites who have failed vasoconstrictor treatment. Gut 59, 381–386 (2010).
Wong, F., Leung, W., Al Beshir, M., Marquez, M. & Renner, E. L. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transplant. Soc. 21, 300–307 (2015).
Boyer, T. D. et al. Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1. Liver Transplant. 17, 1328–1332 (2011).
Heidemann, J., Bartels, C., Berssenbrugge, C., Schmidt, H. & Meister, T. Hepatorenal syndrome: outcome of response to therapy and predictors of survival. Gastroenterol. Res. Pract. 2015, 457613 (2015).
Capling, R. K. & Bastani, B. The clinical course of patients with type 1 hepatorenal syndrome maintained on hemodialysis. Ren. Fail. 26, 563–568 (2004).
Wong, L. P. et al. Survival of liver transplant candidates with acute renal failure receiving renal replacement therapy. Kidney Int. 68, 362–370 (2005).
Witzke, O. et al. Which patients benefit from hemodialysis therapy in hepatorenal syndrome? J. Gastroenterol. Hepatol. 19, 1369–1373 (2004).
Keller, F. et al. Risk factors and outcome of 107 patients with decompensated liver disease and acute renal failure (including 26 patients with hepatorenal syndrome): the role of hemodialysis. Ren. Fail. 17, 135–146 (1995).
Allegretti, A. S. et al. Prognosis of patients with cirrhosis and AKI who initiate RRT. Clin. J. Am. Soc. Nephrol. 13, 16–25 (2018).
Gupta, K. et al. Noradrenaline for reverting hepatorenal syndrome: a prospective, observational, single-center study. Clin. Exp. Gastroenterol. 11, 317–324 (2018).
Cavallin, M. et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study. Hepatology 63, 983–992 (2016).
Thanks to B. Siede from Medical Illustration at Ochsner Medical Center for her input on the figures.
J.C.V. has participated in Speaker Bureau and Advisory Board meetings for Mallinckrodt Pharmaceuticals, the manufacturer of terlipressin, and is a member of the Speaker Bureau of Otsuka Pharmaceuticals (in reference to products not discussed in this article). The other authors declare no competing interests.
Peer review information
Nature Reviews Nephrology thanks A. Rosenkranz, A. Tolwani, H. Wadei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Prerenal azotaemia
A reversible form of acute reduction in kidney function caused by hypoperfusion to the renal vessels triggered by volume depletion, impaired cardiac output or vasomotor derangement. Prerenal means ‘before the kidney’; azotaemia refers to an elevated blood urea nitrogen level.
- Acute tubular necrosis
New onset of injury to the kidney tubular cells.
- Splanchnic vasodilation
Relaxation of the arterial vascular bed supplying the abdominal viscera.
- Portosystemic shunting
Abnormal connection between the portal vascular system and the systemic circulation that bypasses the liver.
- Vascular rarefaction
Reduction in blood vessel density.
- Autonomic dysfunction
Hyperactive or hypoactive sympathetic nervous system.
- Transjugular intrahepatic portosystemic shunt
Artificial channel within the liver to create patent communication between the portal and the hepatic veins.
- Abdominal compartment syndrome
Rise in intra-abdominal pressure that impairs organ perfusion and function.
Necrosis of the renal tubuli.
State of reduced or abolished flow of bile from the liver into the gastrointestinal tract.
- Acute-on-chronic liver failure
New onset of damage to the liver superimposed over pre-existing chronic damage to the liver.
Loss of muscle mass.
Dilation of the pelvicalyceal system in the kidney that results from downstream obstruction of the urinary tract.
- Parenchymal echogenicity
Increased brightness of tissue with respect to a standard parameter as determined by ultrasonography.
Distinct type of dysmorphic erythrocytes (with protrusions) found in the urine of patients with haematuric glomerular diseases.
- Molecular adsorbent recirculating system
Extracorporeal support system that facilitates removal of albumin-bound toxins for patients with liver disease (‘liver dialysis’).
About this article
Cite this article
Velez, J.C.Q., Therapondos, G. & Juncos, L.A. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 16, 137–155 (2020). https://doi.org/10.1038/s41581-019-0218-4
This article is cited by
Characteristics of acute kidney injury and its impact on outcome in patients with acute-on-chronic liver failure
BMC Gastroenterology (2022)
Current Treatment Options in Gastroenterology (2022)
Low preoperative prealbumin predicts the prevalence of complications following liver transplantation
BMC Gastroenterology (2021)
Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications
Nature Reviews Cardiology (2021)
Current Treatment Options in Gastroenterology (2020)