Kidney injury in deeply jaundiced patients became known as cholemic nephropathy. This umbrella term covers impaired renal function in cholestatic patients with characteristic histomorphological changes including intratubular cast formation and tubular epithelial cell injury. Cholemic nephropathy represents a widely underestimated but important cause of kidney dysfunction in patients with cholestasis and advanced liver disease. However, the nomenclature is inconsistent since there are numerous synonyms used; the underlying mechanisms of cholemic nephropathy are not entirely clear, and widely accepted diagnostic criteria are still missing. Consequently, the current article aims to summarize the present knowledge on the clinical and morphological characteristics, available preclinical models, derived potential pathomechanisms, and future diagnostic and therapeutic strategies in cholemic nephropathy. Furthermore, we provide a potential research agenda for this evolving field.

Keywords:
Acute kidney injury, Cholemic nephropathy, Hepatorenal syndrome
1.
Nair S, Verma S, Thuluvath PJ: Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35:1179-1185.
2.
Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, Kremers W, Lake J, Howard T, Merion RM, Wolfe RA, Krom R; United Network for Organ Sharing Liver Disease Severity Score Committee: Model for End-Stage Liver Disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96.
3.
Moreau R, Lebrec D: Acute renal failure in patients with cirrhosis: perspectives in the age of MELD. Hepatology 2003;37:233-243.
4.
Garcia-Tsao G, Parikh CR, Viola A: Acute kidney injury in cirrhosis. Hepatology 2008;48:2064-2077.
5.
Arroyo V, Fernandez J, Ginès P: Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis 2008;28:81-95.
6.
Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Schölmerich J: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164-176.
7.
Ginès P, Schrier RW: Renal failure in cirrhosis. N Engl J Med 2009;361:1279-1290.
8.
Jouët P, Meyrier A, Mal F, Callard P, Guettier C, Stordeur D, Trinchet JC, Beaugrand M: Transjugular renal biopsy in the treatment of patients with cirrhosis and renal abnormalities. Hepatology 1996;24:1143-1147.
9.
Trawalé JM, Paradis V, Rautou PE, Francoz C, Escolano S, Sallée M, Durand F, Valla D, Lebrec D, Moreau R: The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study. Liver Int 2010;30:725-732.
10.
Francoz C, Glotz D, Moreau R, Durand F: The evaluation of renal function and disease in patients with cirrhosis. J Hepatol 2010;52:605-613.
11.
Cholongitas E, Shusang V, Marelli L, Nair D, Thomas M, Patch D, Burns A, Sweny P, Burroughs AK: Review article: renal function assessment in cirrhosis - difficulties and alternative measurements. Aliment Pharmacol Ther 2007;26:969-978.
12.
Sherman DS, Fish DN, Teitelbaum I: Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:269-278.
13.
Randers E, Erlandsen EJ: Serum cystatin C as an endogenous marker of the renal function - a review. Clin Chem Lab Med 1999;37:389-395.
14.
Zahran A, Qureshi M, Shoker A: Comparison between creatinine and cystatin C-based GFR equations in renal transplantation. Nephrol Dial Transplant 2007;22:2659-2668.
15.
Grubb A, Nyman U, Björk J, Lindström V, Rippe B, Sterner G, Christensson A: Simple cystatin C-based prediction equations for glomerular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the Schwartz and the Counahan-Barratt prediction equations for children. Clin Chem 2005;51:1420-1431.
16.
Gerbes AL, Gülberg V, Bilzer M, Vogeser M: Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver. Gut 2002;50:106-110.
17.
Xirouchakis E, Marelli L, Cholongitas E, Manousou P, Calvaruso V, Pleguezuelo M, Guerrini GP, Maimone S, Kerry A, Hajjawi M, Nair D, Thomas M, Patch D, Burroughs AK: Comparison of cystatin C and creatinine-based glomerular filtration rate formulas with 51Cr-EDTA clearance in patients with cirrhosis. Clin J Am Soc Nephrol 2011;6:84-92.
18.
Woitas RP, Stoffel-Wagner B, Flommersfeld S, Poege U, Schiedermaier P, Klehr HU, Spengler U, Bidlingmaier F, Sauerbruch T: Correlation of serum concentrations of cystatin C and creatinine to inulin clearance in liver cirrhosis. Clin Chem 2000;46:712-715.
19.
Orlando R, Mussap M, Plebani M, Piccoli P, De Martin S, Floreani M, Padrini R, Palatini P: Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem 2002;48:850-858.
20.
Ustundag Y, Samsar U, Acikgoz S, Cabuk M, Kiran S, Kulah E, Aydemir S: Analysis of glomerular filtration rate, serum cystatin C levels, and renal resistive index values in cirrhosis patients. Clin Chem Lab Med 2007;45:890-894.
21.
De Souza V, Hadj-Aissa A, Dolomanova O, Rabilloud M, Rognant N, Lemoine S, Radenne S, Dumortier J, Chapuis-Cellier C, Beyerle F, Bon C, Iwaz J, Selistre L, Dubourg L: Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis. Hepatology 2014;59:1522-1531.
22.
Mindikoglu AL, Dowling TC, Weir MR, Seliger SL, Christenson RH, Magder LS: Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis. Hepatology 2014;59:1532-1542.
23.
Slack AJ, McPhail MJ, Ostermann M, Bruce M, Sherwood R, Musto R, Dew T, Auzinger G, Bernal W, O'Grady J, Heneghan MA, Moore K, Wendon JA: Predicting the development of acute kidney injury in liver cirrhosis - an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers. Aliment Pharmacol Ther 2013;37:989-997.
24.
Wagner D, Kniepeiss D, Stiegler P, Zitta S, Bradatsch A, Robatscher M, Müller H, Meinitzer A, Fahrleitner-Pammer A, Wirnsberger G, Iberer F, Tscheliessnigg K, Reibnegger G, Rosenkranz AR: The assessment of GFR after orthotopic liver transplantation using cystatin C and creatinine-based equations. Transpl Int 2012;25:527-536.
25.
Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, Froissart M, Kusek JW, Zhang YL, Coresh J, Levey AS: Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75:652-660.
26.
Walker JG: Renal failure in jaundice. Proc R Soc Med 1962;55:570.
27.
Dawson JL: the incidence of postoperative renal failure in obstructive jaundice. Br J Surg 1965;52:663-665.
28.
Dawson JL: Acute post-operative renal failure in obstructive jaundice. Ann R Coll Surg Engl 1968;42:163-181.
29.
Betjes MG, Bajema I: The pathology of jaundice-related renal insufficiency: cholemic nephrosis revisited. J Nephrol 2006;19:229-233.
30.
Pasero G, Tamagnini G: Cholemic tubulo-nephrosis; functional symptomatology of the kidney in icteric syndromes (in Italian). Omnia Ther Suppl 1958;36:1-35.
31.
Sant SM, Purandare NM: Cholemic nephrosis - an autopsy and experimental study. J Postgrad Med 1965;11:79-89.
32.
Luciano RL, Castano E, Moeckel G, Perazella MA: Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid. Am J Kidney Dis 2014;64:473-476.
33.
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;84:192-197.
34.
Armstrong CP, Dixon JM, Taylor TV, Davies GC: Surgical experience of deeply jaundiced patients with bile duct obstruction. Br J Surg 1984;71:234-238.
35.
Neuhaus TJ, Stallmach T, Leumann E, Altorfer J, Braegger CP: Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease - a newly recognized entity? Eur J Pediatr 1997;156:723-726.
36.
Popović-Rolović M, Kostić M, Sindjić M, Jovanović O, Peco-Antić A, Kruscić D: Progressive tubulointerstitial nephritis and chronic cholestatic liver disease. Pediatr Nephrol 1993;7:396-400.
37.
Montini G, Carasi C, Zancan L, Dall'Amico R, Murer L, Zacchello G, Sorino P: Chronic cholestatic liver disease with associated tubulointerstitial nephropathy in early childhood. Pediatrics 1997;100:E10.
38.
Tekin N, Durmuş-Aydoğdu S, Dinleyici EC, Bör O, Bildirici K, Akşit A: Clinical and pathological aspects of ARC (arthrogryposis, renal dysfunction and cholestasis) syndrome in two siblings. Turk J Pediatr 2005;47:67-70.
39.
Papadia F, Pollice L, Natale B, Bellantuono R, Conti P, Carnevale F: Biliary malformation with renal tubular insufficiency in two male infants: third family report. Clin Genet 1996;49:267-270.
40.
Mikati MA, Barakat AY, Sulh HB, Der Kaloustian VM: Renal tubular insufficiency, cholestatic jaundice, and multiple congenital anomalies - a new multisystem syndrome. Helv Paediatr Acta 1984;39:463-471.
41.
Gentilini P, La Villa G: Liver-kidney pathophysiological interrelationships in liver diseases. Dig Liver Dis 2008;40:909-919.
42.
Harris HW Jr, Carpenter TO, Shanley P, Rosen S, Levey RH, Harmon WE: Progressive tubulointerstitial renal disease in infancy with associated hepatic abnormalities. Am J Med 1986;81:169-176.
43.
Proesmans W, van Damme B, Desmet V, Eeckels R: Fatal tubulo-intestitial nephropathy with chronic cholestatic liver disease. Acta Paediatr Belg 1976;29:231-238.
44.
Henrot B, Vermylen C, Caus D, Cosyns JP, Gosseye S, Verellen G, Cornu G: Progressive tubulointerstitial nephropathy with hepatic involvement in an infant. Eur J Pediatr 1990;149:365-367.
45.
Holmes TW: The histologic lesion of cholemic nephrosis. J Urol 1953;70:677-685.
46.
Haessler H, Rous P, Broun GO: The renal elimination of bilirubin. J Exp Med 1922;35:533-552.
47.
Kaler B, Karram T, Morgan WA, Bach PH, Yousef IM, Bomzon A: Are bile acids involved in the renal dysfunction of obstructive jaundice? An experimental study in bile duct ligated rats. Ren Fail 2004;26:507-616.
48.
Hatipoglu S, Yildiz H, Bulbuloglu E, Coskuner I, Kurutas EB, Hatipoglu F, Ciralik H, Berhuni MS: Protective effects of intravenous anesthetics on kidney tissue in obstructive jaundice. World J Gastroenterol 2014;20:3320-3326.
49.
Levy M, Finestone H: Renal response to four hours of biliary obstruction in the dog. Am J Physiol 1983;244:F516-F525.
50.
Topuzlu C, Stahl WM: Effect of bile infusion on the dog kidney. N Engl J Med 1966;274:760-763.
51.
Gollan JL, Billing BH, Huang SN: Ultrastructural changes in the isolated rat kidney induced by conjugated bilirubin and bile acids. Br J Exp Pathol 1976;57:571-581.
52.
Rivera-Huizar S, Rincón-Sánchez AR, Covarrubias-Pinedo A, Islas-Carbajal MC, Gabriel-Ortíz G, Pedraza-Chaverrí J, Alvarez-Rodríguez A, Meza-García E, Armendáriz-Borunda J: Renal dysfunction as a consequence of acute liver damage by bile duct ligation in cirrhotic rats. Exp Toxicol Pathol 2006;58:185-195.
53.
Bomzon A, Holt S, Moore K: Bile acids, oxidative stress, and renal function in biliary obstruction. Semin Nephrol 1997;17:549-562.
54.
Kramer HJ, Schwarting K, Bäcker A, Meyer-Lehnert H: Renal endothelin system in obstructive jaundice: its role in impaired renal function of bile-duct ligated rats. Clin Sci (Lond) 1997;92:579-585.
55.
Panozzo MP, Basso D, Balint L, Biasin MR, Bonvicini P, Metus P, Infantolino D, Plebani M: Altered lipid peroxidation/glutathione ratio in experimental extrahepatic cholestasis. Clin Exp Pharmacol Physiol 1995;22:266-271.
56.
Panozzo MP, Basso D, Balint L, Zaninotto M, Bonvicini P, Plebani M: Renal functional alterations in extrahepatic cholestasis: can oxidative stress be involved? Eur Surg Res 1995;27:332-339.
57.
Parks RW, Rowlands BJ: Renal dysfunction and endotoxaemia in obstructive jaundice. Natl Med J India 1995;8:249-251.
58.
Clements WD, Parks R, Erwin P, Halliday MI, Barr J, Rowlands BJ: Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 1996;39:587-593.
59.
Hampel H, Bynum GD, Zamora E, El-Serag HB: Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 2001;96:2206-2210.
60.
Terg R, Gadano A, Cartier M, Casciato P, Lucero R, Muñoz A, Romero G, Levi D, Terg G, Miguez C, Abecasis R: Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study. Liver Int 2009;29:415-419.
61.
Kramer HJ, Schwarting K, Bäcker A: Impaired renal function in obstructive jaundice: enhanced glomerular thromboxane synthesis and effects of thromboxane receptor blockade in bile duct-ligated rats. Clin Sci (Lond) 1995;88:39-45.
62.
Kramer HJ: Impaired renal function in obstructive jaundice: roles of the thromboxane and endothelin systems. Nephron 1997;77:1-12.
63.
Green J, Better OS: Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol 1995;5:1853-1871.
64.
Nath KA: Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int 2006;70:432-443.
65.
Fickert P, Krones E, Pollheimer MJ, Thueringer A, Moustafa T, Silbert D, Halilbasic E, Yang M, Jaeschke H, Stokman G, Wells RG, Eller K, Rosenkranz AR, Eggertsen G, Wagner CA, Langner C, Denk H, Trauner M: Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology 2013;58:2056-2069.
66.
Popper H, Schaffner F: Pathophysiology of cholestasis. Hum Pathol 1970;1:1-24.
67.
Zollner G, Trauner M: Mechanisms of cholestasis. Clin Liver Dis 2008;12:1-26, vii.
68.
Denk GU, Soroka CJ, Takeyama Y, Chen WS, Schuetz JD, Boyer JL: Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. J Hepatol 2004;40:585-591.
69.
Mennone A, Soroka CJ, Cai SY, Harry K, Adachi M, Hagey L, Schuetz JD, Boyer JL: Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology 2006;43:1013-1021.
70.
Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, Moustafa T, Zollner G, Lee JY, Ballatori N: Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 2006;290:G1124-G1130.
71.
Wagner M, Zollner G, Trauner M: New molecular insights into the mechanisms of cholestasis. J Hepatol 2009;51:565-580.
72.
Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, Fuchsbichler A, Halilbasic E, Denk H, Marschall HU, Trauner M: Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol 2006;290:G923-G932.
73.
Uslu A, Taşli FA, Nart A, Postaci H, Aykas A, Bati H, Coşkun Y: Human kidney histopathology in acute obstructive jaundice: a prospective study. Eur J Gastroenterol Hepatol 2010;22:1458-1465.
74.
Kawaguchi K, Koike M: Glomerular alterations associated with obstructive jaundice. Hum Pathol 1987;18:1149-1154.
75.
van der Wijngaart H, van Dam B, van den Berg JG, Krul-Poel YH, Klemt-Kropp M, Bax WA: A 73-year-old male with jaundice and acute kidney injury. Bile cast nephropathy. Neth J Med 2014;72:95, 99.
76.
Sequeira A, Gu X: Bile cast nephropathy: an often forgotten diagnosis. Hemodial Int 2014, Epub ahead of print.
77.
Rafat C, Burbach M, Brochériou I, Zafrani L, Callard P, Rondeau E, Hertig A: Bilirubin-associated acute tubular necrosis in a kidney transplant recipient. Am J Kidney Dis 2013;61:782-785.
78.
Song J: Jaundice-associated acute kidney injury. NDT Plus 2009;2:82-83.
79.
Marschall HU, Wagner M, Bodin K, Zollner G, Fickert P, Gumhold J, Silbert D, Fuchsbichler A, Sjövall J, Trauner M: Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 2006;47:582-592.
80.
Kume S, Uzu T, Maegawa H, Koya D: Autophagy: a novel therapeutic target for kidney diseases. Clin Exp Nephrol 2012;16:827-832.
81.
Levine B, Kroemer G: Autophagy in the pathogenesis of disease. Cell 2008;132:27-42.
82.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069-1075.
83.
Wang Z, Choi ME: Autophagy in kidney health and disease. Antioxid Redox Signal 2014;20:519-537.
84.
Huber TB, Edelstein CL, Hartleben B, Inoki K, Jiang M, Koya D, Kume S, Lieberthal W, Pallet N, Quiroga A, Ravichandran K, Susztak K, Yoshida S, Dong Z: Emerging role of autophagy in kidney function, diseases and aging. Autophagy 2012;8:1009-1031.
85.
Liu S, Hartleben B, Kretz O, Wiech T, Igarashi P, Mizushima N, Walz G, Huber TB: Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 2012;8:826-837.
86.
Suzuki C, Isaka Y, Takabatake Y, Tanaka H, Koike M, Shibata M, Uchiyama Y, Takahara S, Imai E: Participation of autophagy in renal ischemia/reperfusion injury. Biochem Biophys Res Commun 2008;368:100-106.
87.
Inoue K, Kuwana H, Shimamura Y, Ogata K, Taniguchi Y, Kagawa T, Horino T, Takao T, Morita T, Sasaki S, Mizushima N, Terada Y: Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo. Clin Exp Nephrol 2010;14:112-122.
88.
Jiang M, Liu K, Luo J, Dong Z: Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am J Pathol 2010;176:1181-1192.
89.
Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z: Autophagy in proximal tubules protects against acute kidney injury. Kidney Int 2012;82:1271-1283.
90.
Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, Blei A, Gülberg V, Sigal S, Teuber P; Terlipressin Study Group: A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134:1360-1368.
91.
Martín-Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, Soriano G, Terra C, Fábrega E, Arroyo V, Rodés J, Ginès P; TAHRS Investigators: Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352-1359.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.