Hepatorenal syndrome (HRS) is a severe complication that often occurs in patients with cirrhosis and ascites. HRS is a functional renal failure that develops mainly as a consequence of a severe cardiovascular dysfunction which is characterized by an extreme splanchnic arterial vasodilation and a reduction of cardiac output. HRS may develop in two clinical types: as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS). Several small studies and some randomized control studies have been published on the use of terlipressin plus albumin in the treatment of HRS, mainly on AKI-HRS. Terlipressin plus albumin was shown to improve renal function in almost 35-45% of patients with AKI-HRS, as well as to improve short-term survival in these patients. Terlipressin was most commonly used by intravenous boluses moving from an initial dose of 0.5-1 mg every 4 h to 3 mg every 4 h in the case of a nonresponse. In other studies, terlipressin was also given by continuous intravenous infusion. Thus, the best way to administer terlipressin in the treatment of HRS has not yet been defined. α-Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been used in the treatment of AKI-HRS, with promising results. However, we need further studies in order to define whether they can represent a real therapeutic alternative. In conclusion, available data are sufficient to state that the use of terlipressin plus albumin has really changed the management of HRS. Nevertheless, some crucial unsolved issues still exist, in particular: (a) how to predict nonresponse to treatment, (b) how to manage nonresponse to treatment and (c) how to consider the response in those patients who are candidates for liver transplant in the priority allocation process.

Keywords:
Albumin, Acute kidney injury, Cirrhosis, Terlipressin, α-Adrenergic drug
1.
Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J: Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151-1157.
2.
Ruiz del Arbor L, Urman J, Fernandez J, González M, Navasa M, Monescillo A, Albillos A, Jiménez W, Arroyo V: Systemic, renal and hepatic haemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210-1218.
3.
Ruiz del Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, Milicua JM, Jiménez W, Arroyo V: Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439-447.
4.
Krag A, Bendtsen F, Henriksen JH, Moller S: Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 2010;59:105-110.
5.
Alqahtani SA, Fouad TR, Lee SS: Cirrhotic cardiomyopathy. Sem Liver Dis 2008;28:59-69.
6.
Escorsell A, Bandi JC, Moitinho E, Feu F, García-Pagan JC, Bosch J, Rodés J: Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997;26:621-627.
7.
Narahara Y, Kanazawa H, Taki Y, Kimura Y, Atsukawa M, Katakura T, Kidokoro H, Harimoto H, Fukuda T, Matsushita Y, Nakatsuka K, Sakamoto C: Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis. J Gastroenterol Hepatol 2009;24:1791-1797.
8.
Solanki P, Chawala A, Garg R, Gupta R, Jain M, Sarin SK: Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003;18:152-156.
9.
Sanyal A, 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.
10.
Martin-Llahi MM, Pepin 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.
11.
Neri S, Pulvirenti D, Malaguarnera M, Cosimo BM, Bertino G, Ignaccolo L, Siringo S, Castellino P: Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Dig Dis Sci 2008;53:830-855.
12.
Ganne-Carrie N, Hadegue A, Mathurin P, Durand F, Erlinger S, Benhamou JP: Hepatorenal syndrome: long-term treatment with terlipressin as a bridge to liver transplantation. Dig Dis Sci 1996;41:1054-1056.
13.
Le Moine O, El Nawar A, Jagodzinski R, Bourgeois N, Adler M, Gelin M, Cremer M: Treatment with terlipressin as a bridge to transplantation in a patient with hepatorenal syndrome. Acta Gastroenterol Belg 1998;61:268-270.
14.
Duhamel C, Mauillon J, Berkelmans J, Bourienne A, Tranvuez JL: Hepatorenal syndrome in cirrhotic patients: terlipressin is a safe and efficient treatment; propoanolol and digitalic treatment: precipitating and preventing factors? Am J Gastroenterol 2000;95:2984-2985.
15.
Halimi C, Bonnard P, Bernard B, Mathurin P, Mofredj A, di Martino V, Demontis R, Henry-Biabaud E, Fievet P, Opolon P, Poynard T, Cadranel JF: Effect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicenter pilot study. Eur J Gastroenterol Hepatol 2002;14:153-158.
16.
Mulkay JP, Louis H, Donckier V, Bourgeois N, Adler M, Deviere J, Le Moine O: Long-term terlipressin administration improves renal function in cirrhotic patients with type 1 hepatorenal syndrome: a pilot study. Acta Gastroelerologica Belg 2001;64:15-19.
17.
Uriz J, Gines P, Cardenas A, Sort P, Jiménez W, Salmerón JM, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J: Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000;33:43-48.
18.
Ortega R, Giniss P, Uriz J, Cárdenas A, Calahorra B, De Las Heras D, Guevara M, Bataller R, Jiménez W, Arroyo V, Rodés J: Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002;36:941−948.
19.
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.
20.
Colle I, Durand F, Pessione F, Rassiat E, Bernuau J, Barrière E, Lebrec D, Valla DC, Moreau R: 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.
21.
Angeli P, Guarda S, Fasolato S, Miola E, Craighero R, Piccolo F, Antona C, Brollo L, Franchin M, Cillo U, Merkel C, Gatta A: Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost. Aliment Pharmacol Ther 2006;23:75-84.
22.
Gerbes AL, Huber E, Gülberg V: Terlipressin for hepatorenal syndrome: continuous infusion as an alternative to i.v. bolus administration. Gastroenterology 2009;137:1179.
23.
Rodríguez E, Elia C, Solà E, Barreto R, Graupera I, Andrealli A, Pereira G, Poca M, Sánchez J, Guevara M, Soriano G, Alessandria C, Fernández J, Arroyo V, Ginès P: Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis. J Hepatol 2014;60:955-961.
24.
Gluud LL, Christensen K, Krag A: Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology 2010;51:576-584.
25.
Gluud LL, Christensen K, Christensen E, Krag A: Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev 2012;9:CD005162.
26.
Ginès P, Angeli P, Lenz K, Møller S, Moore K, Moreau R, Merkel C, Ring-Larsen H, Bernardi M, Garcia-Tsao G, Hayers P: EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:347-417.
27.
Piano S, Morando F, Fasolato S, Cavallin M, Boscato N, Boccagni P, Zanus G, Cillo U, Gatta A, Angeli P: Continuous recurrence of type 1 hepatorenal syndrome and long-term treatment with terlipressin and albumin: a new exception to MELD score in the allocation system to liver transplantation? J Hepatol 2011;55:491-496.
28.
Caraceni P, Santi L, Mirici F, Montanari G, Bevilacqua V, Pinna AD, Bernardi M: Long-term treatment of hepatorenal syndrome as a bridge to liver transplantation. Dig Liver Dis 2011;43:242-245.
29.
Coll M, Rodriguez S, Raurell I, Ezkurdia N, Brull A, Augustin S, Guardia J, Esteban R, Martell M, Genescà J: Droxidopa, an oral norepinephrine precursor, improves hemodynamic and renal alterations of portal hypertensive rats. Hepatology 2012;56:1849-1660.
30.
Sharma P, Kumar A, Sharma BC, Sarin SK: 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 2008;103:1689-1697.
31.
Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, Sharma AK, Choudhary NS, Chawla Y, Nain CK: Noradrenaline versus terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol 2012;56:1293-1298.
32.
Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Torrani Cerenzia M, Martini S, Balzola F, Morgando A, Rizzetto M, Marzano A: Noradrenalin versus terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol 2007;47:499-505.
33.
Devoux C, Zanditenas D, Hezode C, Chauvat A, Monin JL, Roudot-Thoraval F, Mallat A, Dhumeaux D: Effects of noradrenalin and albumin in patients with type 1 hepatorenal syndrome: a pilot study. Hepatology 2002;36:374-380.
34.
Bortoluzzi A, Ceolotto G, Gola E, Sticca A, Bova S, Morando F, Piano S, Fasolato S, Rosi S, Gatta A, Angeli P: Positive cardiac inotropic effect of albumin infusion in rats with cirrhosis and ascites: molecular mechanisms. Hepatology 2013;57:266-276.
35.
Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A: Reversal of type 1 hepatorenal syndrome with the combined administration of midodrine and octreotide. Hepatology 1999;29:1690-1697.
36.
Angeli P, Volpin R, Piovan D, Bortoluzzi A, Craighero R, Bottaro S, Finucci GF, Casiglia E, Sticca A, De Toni R, Pavan L, Gatta A: Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 1998;28:937-943.
37.
Baik SK, Jeong PH, Ji SW, Yoo BS, Kim HS, Lee DK, Kwon SO, Kim YJ, Park JW, Chang SJ, Lee SS: Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a randomized comparison. Am J Gastroenterol 2005;100:631-635.
38.
Singh V, Singh A, Singh B, Vijayvergiya R, Sharma N, Ghai A, Bhalla A: Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. Am J Gastroenterol 2013;108:560-567.
39.
Silva G, Segovia R, Backhouse C, Palma M, Márquez S, Iturriaga H: Effects of acute octreotide infusion on renal function in patients with cirrhosis and portal hypertension. Rev Med Chil 2004;132:144-150.
40.
Sieber CC, Lee FY, Groszmann RJ: Long term octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats. Hepatology 1996;23:1218-1223.
41.
Sieber CC, Groszmann RJ: In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade. Am J Physiol 1992;262:G996-G1001.
42.
Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas C, Katsaraki A, Tsianos EV: The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. Am J Gastroenterol 2005;100:879-885.
43.
Pomier-Layrargues GI, Paquin SC, Hassoun Z, Lafortune M, Tran A: Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology 2003;38:238-243.
44.
Angeli P: Review article: prognosis of hepatorenal syndrome - has it changed with current practice? Aliment Pharmacol Ther 2004;20(suppl 3):1-4.
45.
Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Schölmerich J: Definition and diagnostic criteria a of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164-176.
46.
Salerno F, Gerbes A, Gines P, Wong F, Arroyo V: Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis: a consensus workshop of the International Ascites Club. Gut 2007;56:1310-1318.
47.
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.
48.
Fagundes C, Pépin MN, Guevara M, Barreto R, Casals G, Solà E, Pereira G, Rodríguez E, Garcia E, Prado V, Poch E, Jiménez W, Fernández J, Arroyo V, Ginès P: Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012;57:267-273.
49.
Solanki P, Kiszka-Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F: Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol 2004;39:486-492.
50.
Krag A, Bendtsen F, Mortensen C, Henriksen JH, Møller S: Effects of a single terlipressin administration on cardiac function and perfusion in cirrhosis. Eur J Gastroenterol Hepatol 2010;22:1085-1092.
51.
Boyer TD, Sanyal AJ, Garcia-Tsao G, Blei A, Carl D, Bexon AS, Teuber P, Terlipressin Study Group: Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011;55:315-321.
52.
Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, Marinelli M, Solá E, Baccaro ME, Terra C, Arroyo V, Ginès P: Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 HRS. Hepatology 2010;51:219-226.
53.
Velez JCQ, Nietert PJ: Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a polled analysis of clinical trials. Am J Kidney Dis 2011;58:928-938.
54.
Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, Angeli P, Moreau R, Davenport A, Jalan R, Ronco C, Genyk Y, Arroyo V: Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011;60:702-709.
55.
Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, Coca SG, Parikh CR, TRIBE-AKI Consortium: Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753-762.
56.
Piano S, Rosi S, Maresio G, Fasolato S, Cavallin M, Romano A, Morando F, Gola E, Frigo AC, Gatta A, Angeli P: Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J Hepatol 2013;59:482-489.
57.
Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, Graupera I, Ariza X, Pereira G, Alfaro I, Cárdenas A, Fernández J, Poch E, Ginès P: A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 2013;59:474-481.
58.
Tsien CD, Rabie R, Wong F: Acute kidney injury in decompensated cirrhosis. Gut 2013;62:131-137.
59.
De Carvalho JR, Villela-Nogueira CA, Luiz RR, Guzzo PL, da Silva Rosa JM, Rocha E, Moraes Coelho HS, de Mello Perez R: Acute kidney injury network criteria as a predictor of hospital mortality in cirrhotic patients with ascites. J Clin Gastroenterol 2012;46:e21-e26.
60.
Wong F, O'Leary JG, Reddy KR, Patton H, Kamath PS, Fallon MB, Garcia-Tsao G, Subramanian RM, Malik R, Maliakkal B, Thacker LR, Bajaj JS, North American Consortium for Study of End-Stage Liver Disease: New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection. Gastroenterology 2013;145:1280-1288.
61.
Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V, CANONIC Study Investigators of the EASL-CLIF Consortium: Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-1437.
62.
Angeli P, Rodríguez E, Piano S, Ariza X, Morando F, Solà E, Romano A, Garcia E, Pavesi M, Risso A, Gerbes A, Willars C, Bernardi M, Arroyo V, Ginès P, for the CANONIC Study Investigators of the EASL-CLIF Consortium: Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut 2015, Epub ahead of print.
63.
Bentley W: Towards evidence-based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: RIFLE criteria versus Acute Kidney Injury Network (AKIN) criteria for prognosis of acute renal failure. Emerg Med J 2011;28(10):900-901.
64.
Kribben A, Gerken G, Haag S, et al: Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 2012;142:782-789.
65.
Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, Selby R: Impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome. Liver Transpl 2012;18:539-548.
66.
Eason JD, Gonwa TA, Davies CL, Sung RS, Gerber D, Bloom RD: Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK). Am J Transplant 2008;8:2243-2251.
67.
Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jiménez W, Arroyo V, Rodés J, Ginès P: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005;41:1282-1289.
68.
Angeli P, Gines P: Hepatorenal syndrome, MELD score and liver transplantation: an evolving issue with relevant implications for clinical practice. J Hepatol 2012;57:1135-1140.
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