Pathogenesis and Treatment of Hepatorenal Syndrome

ABSTRACT

Hepatorenal syndrome (HRS) is a functional renal failure that frequently develops in patients with advanced cirrhosis and severe impairment in systemic circulatory function. Traditionally it has been considered to be the consequence of a progression of the splanchnic arterial vasodilation occurring in these patients. However, recent data indicate that a reduction in cardiac output also plays a significant role. There are two different types of HRS. Type-2 HRS consists of a moderate and steady or slowly progressive renal failure. It represents the extreme expression of the circulatory dysfunction that spontaneously develops in patients with cirrhosis. The main clinical problem in these patients is refractory ascites. Type-1 HRS is a rapidly progressive acute renal failure that frequently develops in closed temporal relationship with a precipitating event, commonly spontaneous bacterial peritonitis. In addition to renal failure, patients with type-1 HRS present deterioration in the function of other organs, including the heart, brain, liver, and adrenal glands. Type-1 HRS is the complication of cirrhosis associated with the worst prognosis. However, effective treatments of HRS (vasoconstrictors associated with intravenous albumin, transjugular intrahepatic portacaval shunt, albumin dialysis) that can improve survival have recently been introduced.

Cirrhosis - type-1 HRS - type-2 HRS - pharmacological treatment - transjugular intrahepatic portacaval shunt - extracorporeal albumin dialysis

REFERENCES

• 1 Ginès P, Rodés J. Clinical disorders of renal function in cirrhosis with ascites. In: Arroyo V, Ginès P, Rodés J, Schrier RW Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. Malden; Blackwell Science 1999: 36-62
• 2 Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure.  Lancet. 1956;  271 1121-1125
• 3 Ginès A, Escorsell A, Ginès P et al.. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.  Gastroenterology. 1993;  105 229-236
• 4 Koppel M H, Coburn J W, Mims M M et al.. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome: evidence for functional nature of renal failure in advanced liver disease.  N Engl J Med. 1969;  280 1367-1373
• 5 Iwatsuki S, Popovtzer M M, Corman J L et al.. Recovery from hepatorenal syndrome after orthotopic liver transplantation.  N Engl J Med. 1973;  289 1155-1159
• 6 Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome.  Lancet. 2003;  362 1819-1827
• 7 Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome.  J Hepatol. 2007;  46 935-946
• 8 Arroyo V, Terra C, Ginès P. New treatments of hepatorenal syndrome.  Semin Liver Dis. 2006;  26 254-264
• 9 Arroyo V, Ginès P, Gerbes A et al.. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.  Hepatology. 1996;  23 164-176
• 10 Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.  Gut. 2007;  56 1310-1318
• 11 Papadakis M A, Arieff A I. Unpredictability of clinical evaluation of renal function in cirrhosis: prospective study.  Am J Med. 1987;  82 945-952
• 12 Caregaro L, Menon F, Angeli P et al.. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.  Arch Intern Med. 1994;  154 201-205
• 13 Sherman D S, Fish D N, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls.  Am J Kidney Dis. 2003;  41 269-278
• 14 Cabrera J, Arroyo V, Ballesta A M et al.. Aminoglycoside nephrotoxicity in cirrhosis: value of urinary beta-2-microglobulin to discriminate functional renal failure from acute tubular damage.  Gastroenterology. 1982;  82 97-105
• 15 Dudley F J, Kanel G C, Wood L J, Reynolds T B. Hepatorenal syndrome without avid sodium retention.  Hepatology. 1986;  6 248-251
• 16 Fernandez J, Monteagudo J, Bargallo X et al.. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.  Hepatology. 2005;  42 627-634
• 17 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
• 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
• 19 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. 2001;  96 2206-2210
• 20 Brater D C, Anderson S A, Browncartwright D, Toto R D. Effects of nonsteroidal antiinflammatory drugs on renal function in patients with renal insufficiency and in cirrhotics.  Am J Kidney Dis. 1986;  8 351-355
• 21 Westphal J F, Brogard J M. Drug administration in chronic liver disease.  Drug Saf. 1997;  17 47-73
• 22 Toledo C, Salmeron J M, Rimola A et al.. Spontaneous bacterial peritonitis in cirrhosis: predictive factors of infection resolution and survival in patients treated with cefotaxime.  Hepatology. 1993;  17 251-257
• 23 Follo A, Llovet J M, Navasa M et al.. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.  Hepatology. 1994;  20 1495-1501
• 24 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
• 25 Rodés J, Arroyo V, Bosch J. Clinical types and drug-therapy of renal impairment in cirrhosis.  Postgrad Med J. 1975;  51 492-497
• 26 Goyal R K, Hirano I. Mechanisms of disease: the enteric nervous system.  N Engl J Med. 1996;  334 1106-1115
• 27 Gupta S, Morgan T R, Gordan G S. Calcitonin gene-related peptide in hepatorenal syndrome: a possible mediator of peripheral vasodilation.  J Clin Gastroenterol. 1992;  14 122-126
• 28 Bendtsen F, Schifter S, Henriksen J H. Increased circulating calcitonin gene-related peptide (CGRP) in cirrhosis.  J Hepatol. 1991;  12 118-123
• 29 Martin P Y, Ginès P, Schrier R W. Nitric oxide as a mediator of hemodynamic abnormalitites and sodium and water retention in cirrhosis.  N Engl J Med. 1998;  339 533-541
• 30 Schrier R W, 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
• 31 Benoit J N, Granger D N. Splanchnic hemodynamics in chronic portal hypertension.  Semin Liver Dis. 1986;  6 287-298
• 32 Vorobioff J, Bredfeldt J E, Groszmann R J. Increased blood flow through the portal system in cirrhotic rats.  Gastroenterology. 1984;  87 1120-1126
• 33 Vorobioff J, Bredfeldt J E, Groszmann R J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal-hypertension.  Am J Physiol. 1983;  244 G52-G57
• 34 Lee F Y, Albillos A, Colombato L A, Groszmann R J. The role of nitric-oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats.  Hepatology. 1992;  16 1043-1048
• 35 Sieber C C, Lopez-Talavera J C, Groszmann R J. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats.  Gastroenterology. 1993;  104 1750-1754
• 36 Maroto A, Ginès P, Arroyo V et al.. Brachial and femoral artery blood-flow in cirrhosis: relationship to kidney dysfunction.  Hepatology. 1993;  17 788-793
• 37 Maroto A, Ginès A, Salo J et al.. Diagnosis of functional kidney failure of cirrhosis with doppler sonography: prognostic value of resistive index.  Hepatology. 1994;  20 839-844
• 38 Fernandez-Seara J, Prieto J, Quiroga J et al.. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure.  Gastroenterology. 1989;  97 1304-1312
• 39 Guevara M, Bru C, Ginès P et al.. Increased cerebrovascular resistance in cirrhotic patients with ascites.  Hepatology. 1998;  28 39-44
• 40 Tristani F E, Cohn J N. Systemic and renal hemodynamics in oliguric hepatic failure: effect of volume expansion.  J Clin Invest. 1967;  46 1894-1906
• 41 Lebrec D, Kotelanski B, Cohn J N. Splanchnic hemodynamic factors in cirrhosis with refractory ascites.  J Lab Clin Med. 1979;  93 301-309
• 42 Ruiz-del-Arbol L, Urman J, Fernandez J et al.. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.  Hepatology. 2003;  38 1210-1218
• 43 Ruiz-del-Arbol L, Monescillo A, Arocena C et al.. Circulatory function and hepatorenal syndrome in cirrhosis.  Hepatology. 2005;  42 439-447
• 44 Schroeder E T, Eich R H, Smulyan H, Gould A B, Gabuzda G J. Plasma renin level in hepatic cirrhosis: relation to functional renal failure.  Am J Med. 1970;  49 186-191
• 45 Henriksen J H, Ring-Larsen H. Hepatorenal disorders: role of the sympathetic nervous system.  Semin Liver Dis. 1994;  14 35-43
• 46 Arroyo V, Planas R, Gaya J et al.. Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin-e2 in cirrhosis: relationship to functional renal failure and sodium and water excretion.  Eur J Clin Invest. 1983;  13 271-278
• 47 Rimola A, Ginès P, Arroyo V et al.. Urinary excretion of 6-keto-prostaglandin F1 alpha, thromboxane B2 and prostaglandin E2 in cirrhosis with ascites: relationship to functional renal failure (hepatorenal syndrome).  J Hepatol. 1986;  3 111-117
• 48 Moore K P. Arachidonic acid metabolites and the kidney in cirrhosis. In: Arroyo V, Ginès P, Rodés J, Schrier RW Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. Malden; Blackwell Science 1999: 249-272
• 49 Angeli P, Albino G, Carraro P et al.. Cirrhosis and muscle cramps: evidence of a causal relationship.  Hepatology. 1996;  23 264-273
• 50 Ma Z, Lee S S. Cirrhotic cardiomyopathy: getting to the heart of the matter.  Hepatology. 1996;  24 451-459
• 51 Braverman A C, Steiner M A, Picus D, White H. High-output congestive heart failure following transjugular intrahepatic portal-systemic shunting.  Chest. 1995;  107 1467-1469
• 52 Ginès P, Uriz J, Calahorra B et al.. Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.  Gastroenterology. 2002;  123 1839-1847
• 53 Myers R P, Lee S S. Cirrhotic cardiomyopathy and liver transplantation.  Liver Transpl. 2000;  6 S44-S52
• 54 Therapondos G, Flapan A D, Plevris J N, Hayes P C. Cardiac morbidity and mortality related to orthotopic liver transplantation.  Liver Transpl. 2004;  10 1441-1453
• 55 Lee S S. Cardiac dysfunction in spontaneous bacterial peritonitis: a manifestation of cirrhotic cardiomyopathy?.  Hepatology. 2003;  38 1089-1091
• 56 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.  N Engl J Med. 1999;  341 403-409
• 57 Wiest R, Groszmann R J. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance.  Semin Liver Dis. 1999;  19 411-426
• 58 Tsai M H, Peng Y S, Chen Y C et al.. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock.  Hepatology. 2006;  43 673-681
• 59 Fernandez J, Escorsell A, Zabalza M et al.. Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival.  Hepatology. 2006;  44 1288-1295
• 60 Gonwa T A, Morris C A, Goldstein R M, Husberg B S, Klintmalm G B. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome: experience in 300 patients.  Transplantation. 1991;  51 428-430
• 61 Gonwa T A, Klintmalm G B, Levy M et al.. Impact of pretransplant renal function on survival after liver transplantation.  Transplantation. 1995;  59 361-365
• 62 Seu P, Wilkinson A H, Shaked A, Busuttil R W. The hepatorenal syndrome in liver transplant recipients.  Am Surg. 1991;  57 806-809
• 63 Rimola A, Gavaler J S, Schade R R, el-Lankany S, Starzl T E, Van Thiel D H. Effects of renal impairment on liver transplantation.  Gastroenterology. 1987;  93 148-156
• 64 Guevara M, Ginès P, Fernandez-Esparrach G et al.. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.  Hepatology. 1998;  27 35-41
• 65 Gulberg V, Bilzer M, Gerbes A L. Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine.  Hepatology. 1999;  30 870-875
• 66 Angeli P, Volpin R, Gerunda G et al.. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.  Hepatology. 1999;  29 1690-1697
• 67 Uriz J, Ginès P, Cardenas A et al.. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.  J Hepatol. 2000;  33 43-48
• 68 Mulkay J P, Louis H, Donckier V et al.. Long-term terlipressin administration improves renal function in cirrhotic patients with type 1 hepatorenal syndrome: a pilot study.  Acta Gastroenterol Belg. 2001;  64 15-19
• 69 Colle I, Durand F, Pessione F et al.. Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with terlipressin: a retrospective analysis.  J Gastroenterol Hepatol. 2002;  17 882-888
• 70 Halimi C, Bonnard P, Bernard B et al.. Effect of terlipressin (Glypressin (R)) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study.  Eur J Gastroenterol Hepatol. 2002;  14 153-158
• 71 Ortega R, Ginès P, Uriz J et al.. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.  Hepatology. 2002;  36 941-948
• 72 Duvoux C, Zanditenas D, Hezode C et al.. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study.  Hepatology. 2002;  36 374-380
• 73 Solanki P, Chawla A, Garg R et al.. Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial.  J Gastroenterol Hepatol. 2003;  18 152-156
• 74 Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome.  Hepatology. 2004;  40 55-64
• 75 Alessandria C, Ottobrelli A, Debernardi-Venon W et al.. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.  J Hepatol. 2007;  47 499-505
• 76 Linas S L, Schaefer J W, Moore E E, Good J T, Giansiracusa R. Peritoneovenous shunt in the management of the hepatorenal syndrome.  Kidney Int. 1986;  30 736-740
• 77 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. 2003;  38 238-243
• 78 Moreau R, Durand F, Poynard T et al.. Terlipressin in patients with cirrhosis and type-1 hepatorenal syndrome: a retrospective multicenter study.  Gastroenterology. 2002;  122 923-930
• 79 Fernandez J, Navasa M, Garcia-Pagan J C et al.. Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.  J Hepatol. 2004;  41 384-390
• 80 Brensing K A, Textor J, Perz J et al.. Long-term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study.  Gut. 2000;  47 288-295
• 81 Guevara M, Ginès P, Bandi J C et al.. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.  Hepatology. 1998;  28 416-422
• 82 Mitzner S R, Stange J, Klammt S et al.. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial.  Liver Transpl. 2000;  6 277-286
• 83 Catalina M V, Barrio J, Anaya F et al.. Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure.  Liver Int. 2003;  23 39-43
• 84 Jalan R, Sen S, Steiner C et al.. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis.  J Hepatol. 2003;  38 24-31
• 85 Stange I, Hassanein T I, Mehta R et al.. Short-term survival of patients with severe intractable hepatic encephalopathy: the role of albumin dialysis.  Hepatology. 2005;  42 286A
• 86 Lebrec D, Giuily N, Hadengue A et al.. Transjugular intrahepatic portosystemic shunts-comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial.  J Hepatol. 1996;  25 135-144
• 87 Rossle M, Ochs A, Gulberg V et al.. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.  N Engl J Med. 2000;  342 1701-1707
• 88 Sanyal A J, Genning C, Reddy K R et al.. The North American Study for the Treatment of Refractory Ascites.  Gastroenterology. 2003;  124 634-641
• 89 Salerno F, Merli M, Riggio O et al.. Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.  Hepatology. 2004;  40 629-635
• 90 Alessandria C, Venon W D, Marzano A et al.. Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2.  Eur J Gastroenterol Hepatol. 2002;  14 1363-1368
• 91 Fernandez J, Navasa M, Planas R et al.. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.  Gastroenterology. 2007;  133 818-824
• 92 Albillos A, de la Hera A, Gonzalez M et al.. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.  Hepatology. 2003;  37 208-217
• 93 Frances R, Benlloch S, Zapater P et al.. A sequential study of serum bacterial DNA in patients with advanced cirrhosis and ascites.  Hepatology. 2004;  39 484-491
• 94 Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis: a randomized trial.  Ann Intern Med. 2003;  139 186-193
• 95 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