Kidney Problems in Cirrhosis

Dig Dis 2015;33:548–554
DOI: 10.1159/000375346

The Treatment of Hepatorenal Syndrome
Marta Cavallin a Silvano Fasolato a, b Simona Marenco c Salvatore Piano a
Marta Tonon a, b Paolo Angeli a, b

U.O. Clinica Medica V and b Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine,
DIMED, University of Padua, Padua, and c Department of Internal Medicine, Gastroenterology Unit, University of
Genoa, Genoa, Italy

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

© 2015 S. Karger AG, Basel

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.
© 2015 S. Karger AG, Basel


A marked renal arterial vasoconstriction and the consequent reduction of renal arterial perfusion are thought
to be the main pathophysiological bases of hepatorenal
syndrome (HRS). It develops in patients with advanced
cirrhosis as a consequence of an extreme overactivation of
the endogenous systemic vasoconstrictor systems, namely
the renin-angiotensin system, the sympathetic nervous
system and the nonosmotic release of vasopressin due to
a severe reduction of effective circulating volume. This reduction is believed to be due to both an extreme splanchnic arterial vasodilation and an impairment of cardiac
output [1–4]. Splanchnic arterial vasodilation is thought
to be mainly the consequence of an increased release of
Prof. Paolo Angeli
Unit of Hepatic Emergencies and Liver Transplantation
Department of Medicine, University of Padua
Via Giustiniani 2, IT–35128 Padua (Italy)
E-Mail pangeli @

Downloaded by:
University of Alabama, Lister Hill Library - 7/14/2015 9:20:25 AM

Key Words
Albumin · Acute kidney injury · Cirrhosis · Terlipressin ·
α-Adrenergic drug

terlipressin was used together with albumin with a priming dose of 1 g/kg of body weight followed by 20–40 g/day monitoring central venous pressure. 15]. which is the achievment of normal serum creatinine levels.143. 23]. mainly of AKI-HRS. respectively. the rate of reversal of HRS. terlipressin plus albumin has been used in several uncontrolled clinical studies. Based on pharmacodynamic studies on the effects of terlipressin on the splanchnic circulation in patients with cirrhosis [6]. No controlled clinical study showed a significant effect of terlipressin plus albumin on survival when this association was compared to albumin alone or to placebo. 28].5 mg/dl.5 mg every 4–6 h [12– 20. In an experimental model of cirrhosis. it can be observed that norepinephrine was capable of increasing the Dig Dis 2015. is lower in patients receiving terlipressin than in patients reThe Treatment of HRS ceiving both terlipressin and albumin [18. First. there has so far been no clinical study in which the effect of either norepinephrine or midodrine has been evaluated in patients with cirrhosis. and a close clinical and ECG monitoring should be performed during the treatment. the initial dose of terlipressin was doubled. in patients with continuous recurrence of type 1 HRS. this therapeutic strategy can result in a longterm administration of terlipressin and albumin.7/14/2015 9:20:25 AM endogenous vasodilators due to portal hypertension and/ or hepatic failure. terlipressin was administered as an intravenous bolus starting from an initial dose of 0. This rationale for the use of terlipressin plus albumin was later proved in patients with cirrhosis and ascites without renal failure [7]. The most severe adverse effects of terlipressin are cardiovascular or ischemic complications (chest pain. with albumin alone have been published [8–11]. Use of Other Pharmacological Approaches: α-Adrenergic Drugs The rationale for the use of α-adrenergic drugs such as norepinephrine alone or oral midodrine combined with subcutaneous octreotide.33:548–554 DOI: 10. 23].47. Nevertheless.1159/000375346 549 Downloaded by: University of Alabama. while the inadequate cardiac output can be the extreme manifestation of a systolic dysfunction which is part of the so-called cirrhotic cardiomyopathy [5]. In patients without a clinical response. This is the reason why severe cardiovascular ischemic conditions should be considered contraindications to the use of terlipressin in patients with cirrhosis. In most of the patients. This review will mainly focus on the use of terlipressin and other vasoconstrictors plus albumin in the treatment of acute kidney injury (AKI)-HRS. or 12 mg/day by continuous intravenous infusion.1 .5 mg/dl or equal to >1. the normalization or decrease in sCr can take several days. . the treatment is usually continued for up to 10–15 days. It has been stated that after the withdrawal HRS can recur in up to 20% of cases and that recurrence can be efficiently retreated with terlipressin and albumin [26]. which have been reported in an average of 12% of patients treated. four randomized controlled clinical trials comparing terlipressin and albumin in the treatment of HRS. this drug was introduced in the treatment of HRS at the end of 1990s in order to reduce portal hypertension by counteracting the splanchnic arterial vasodilation. It is important also to emphasize that response rates above 65% were observed with terlipressin and albumin in patients with AKI-HRS associated with sepsis [21. Only in a few studies was the drug administered as a continuous intravenous infusion starting from an initial dose of 2 mg/day [21. Lister Hill Library 198. unlike terlipressin. terlipressin has been used in more than 300 patients [12–23]. respectively. continuing for months rather than weeks [27. as a consequence. arterial renal perfusion. In most of these patients. abdominal pain or arrhythmia). The response was further defined as complete or partial according to the final sCr: <1. 22]. defined as a reduction of serum creatinine (sCr) <25% within 3 days. During the treatment with terlipressin plus albumin.Use of Terlipressin in the Treatment of HRS To date. which in most cases is self-limiting and thus does not require the discontinuation of the drug unless it is associated with severe abdominal pain. 19]. a subsequent systematic review and metaanalysis of all the randomized controlled clinical trials showed that this treatment may slightly increase survival in patients with type 1 HRS [24. Taking these studies as a whole. The most common side effect of terlipressin is diarrhea. however. As a result. Therefore. together with intravenous albumin. Response to the treatment has been defined by a decrease of sCr >50% in patients with AKIHRS. Albumin was combined with terlipressin to further improve the effective circulating volume and. in the treatment of AKI-HRS deserves some comment. The maximal doses of terlipressin used in the treatment of HRS were 2 mg every 4–6 h by intravenous boluses. which has been recently defined as a relapse of type 1 HRS more than once within 72 h after the discontinuation of treatment with terlipressin and albumin [27]. 25]. The rate of response commonly ranges between 40 and 50% when terlipressin was given alone [14. In addition.

Albumin was given in differing concentrations at a dose ranging from 20 to 100 g/ day. norepinephrine has been used in less than 70 patients with AKI-HRS to date [31–34]. In the case of a nonresponse. noradrenalin was always used together with albumin with doses ranging from 20 to 70 g/day [30–32. but also on the experimental evidence that the responsiveness to vasoconstrictors of the mesenteric artery may be normalized by the inhibition either of glucagon or nitric oxide [36. 41]. Lister Hill Library 198. 34]. Thus. The new aspects of the action of albumin on cardiac tissue in cirrhosis and their possible effect favoring the action of norepinephrine in the treatment of HRS are exciting. 34].Table 1. Therefore. +++ = high effect. when norepinephrine was compared to terlipressin in the treatment of AKI-HRS in three small controlled clinical studies. Drug effects in cirrhosis Drug Effect on Effect on portal Effect on MAP splanchnic arterial pressure vasodilation Effect on renal Effect on urinary blood flow sodium excretion Terlipressin Noradrenalin Midodrine Octreotide +++ +++ NA ++ +++ No +/No No +++ No NA +/++ +++ +++ +/++ + ++ + +/No No NA = Not appropriate. similar results were found in terms of both the rate of response and 30-day survival [30–32]. norepinephrine was not capable of improving renal perfusion [29].47. In all studies except one [42]. It should be emphasized that most of the patients included in one of these studies had CKD-HRS [32]. However. 43]. treatment was administered according to the originally proposed schedule [35]. In spite of these potential disadvantages. No = no effect. The rationale for the use of oral midodrine and subcutaneous or intravenous octreotide is slightly more complex and deserves to be clarified [35]. which was titrated up to 200 mg thrice daily as necessary. Nevertheless.7/14/2015 9:20:25 AM superior mesenteric artery resistance but not reducing portal pressure. 39]. in total midodrine plus octreotide and albumin have so far been used in less than 120 patients with AKI-HRS [40–42]. because these compounds counteract the action of vasoconstrictors on renal perfusion [38. norepinephrine may potentially have a favorable effect on cardiac output by restoring the proper functioning of the adrenergic receptor pathway in the cardiac tissue through the simultaneous administration of albumin. Unsolved Issues in the Treatment of HRS The introduction of the use of vasoconstrictors and albumin represents a milestone in the management of AKI-HRS [49]. 37]. ++ = moderate effect. the dose was progressively increased up to a maximum of 3 mg/h [30–32. Data specifically obtained in patients with HRS are in italics. In addition. It is based not only on the simple sum of the effects of the two drugs on the splanchnic . In all the studies. In the largest uncontrolled studies this therapeutic option was shown to be effective in almost 40% of patients with AKI-HRS [40.1159/000375346 circulation in cirrhosis (table  1). Thus. Furthermore. In all the controlled and uncontrolled studies. + = mild effect. 550 Dig Dis 2015. in cirrhotic rats.5 mg 3 times a day and titrated up to a maximum dose of 15 mg 3 times a day as tolerated based on the systolic blood pressure. No controlled clinical study has so far been performed with midodrine plus octreotide administered together with albumin. Midodrine was started at an oral dose of 7. thanks to its property of volemia expansion [33]. noradrenalin was used by continuous intravenous infusion at the initial dose of 0.1 .33:548–554 DOI: 10. octreotide was administered via the subcutaneous route with a starting dose of 100 mg 3 times a day. the treatment is effective in 35– Cavallin/Fasolato/Marenco/Piano/Tonon/ Angeli Downloaded by: University of Alabama. The choice of inhibiting glucagon release is based on clinical and experimental data showing that the inhibition of prostacyclin or nitric oxide synthesis may induce renal failure per se in patients or animals with cirrhosis. none of these controlled clinical studies had an adequate sample size to offer assessment of the equivalence between terlipressin and norepinephrine with certainty. Similarly to what has been said about noradrenalin. we need further studies to clarify its role in the treatment of HRS.143. Octreotide alone has no impact on improving renal function [42.5 mg/h. according to the conclusion of a recent study [35] about the treatment of HRS type 1. However. further studies are needed to clarify its role in the treatment of AKI-HRS.

when new diagnostic tools were used (i. it has been recently observed that the efficacy of the treatment with terlipressin plus albumin seems to be limited in patients with acute-on-chronic liver failure (ACLF). The prognostic evaluation in patients with cirrhosis who are hospitalized for an acute decompensation should take into account the failures of organs other than the kidney. This observation opens a further discussion on potential specific features of the pathophysiology of AKI-HRS in patients with ACLF.33:548–554 DOI: 10. how to explain nonresponse to the treatment. we need to focus only on terlipressin and albumin because no data referring to the α-adrenergic drugs exist to date. and can reduce cardiac output by increasing peripheral resistances [55] in patients with cirrhosis. as recently defined in the Canonic . the best approach and the outcome of RRT have never been evaluated specifically in these patients. Lister Hill Library 198. like AKIN. 51]. 68]. These findings emphasize the need to diagnose and treat AKI-HRS as early as possible.1159/000375346 551 Downloaded by: University of Alabama.143. even though the risk. The increase in MAP required for a response may be closely related to the baseline sCr. is of limited value since TIPS is contraindicated in a high percentage of patients with AKI-HRS [48]. it introduces a limit in the prognostic value of the KDIGO (Kidney Disease: Improving Global Outcome) criteria (which. First. 53]. thus. particularly in patients who are candidates for liver transplantation (LT). how to predict a nonresponse and. However. as previously discussed [33]. since it has been observed that patients with a higher baseline value of sCr needed a greater increase of MAP in order to achieve a response to treatment [58]. Combinations of different drugs have been suggested but never tested. Terlipressin per se does not change stroke volume [54]. defined as being <5 mm Hg on day 3 of treatment. two final points should be briefly discussed. was also found to be a predictor of nonresponse to terlipressin and albumin [57]. The combination of terlipressin and albumin and an extracorporeal liver support system using fractionated plasma separation and adsorption improves survival in patients with AKI-HRS [68]. second. evaluate serum creatinine and urine output to diagnose AKI. With regard to the baseline value of serum total bilirubin. this observation is the result of the analysis of only a subgroup of patients. renal replacement therapy (RRT) is often applied in clinical practice. 3–5 mg/dl and more than 5 mg/dl. These are: (i) when to assign patients with AKI-HRS to a simultaneous liver kidney transplantation and (ii) how to evaluate the response to vasoconstrictors and albumin in prioritizing organ allocation for patients on the waiting list for LT. Thus. how to manage it. even if exciting from a clinical point of view. Another specific potential limit for the effectiveness of terlipressin plus albumin is the negative effect of terlipressin on the cardiac output in patients with cirrhosis. since they are not completely solved or established. A small increase in MAP.1 . but furthermore to assess its severity) in patients with ACLF.7/14/2015 9:20:25 AM 65% of patients and we still need to solve three major problems. Nevertheless. AKI-HRS has been defined as a functional renal failure. Focusing on baseline sCr. without any evidence of renal parenchymal damage [50. Thus. Moreover. by the EASL-Clif Consortium [66]. but also tested. Indeed. Accordingly. by definition. evidence of renal parenchymal damage was found in patients with AKI-HRS [52. Moving to factors which can predict the nonresponse to treatment with vasoconstrictors plus albumin in patients with AKI-HRS. With regard to the first point.47. the current criteria for the diagnosis of HRS are not capable of excluding renal parenchymal damage. High baseline values of both sCr and serum total bilirubin as well as a small increase in mean arterial pressure (MAP) with treatment [56–58] have been identified as predictors of nonresponse in patients with AKI-HRS. the CLIF-SOFA score has a better prognostic value compared to the AKIN (Acute Kidney Injury Network) criteria in these patients which are commonly used worldwide to identify AKI [67. the only positive effect on cardiac output in patients with AKI-HRS who receive terlipressin plus albumin is accounted for by albumin and is related to the expansion in blood volume and the consequent increase in cardiac preload. the current diagnostic criteria of AKI-HRS in patients with cirrhosis have been revised and this should lead to improved treatment in these patients [59–65]. it has been observed that a CLIF-SOFA score of >11 has a 92% sensitivity and 100% specificity in predicting no response to terlipressin therapy [23]. renal biopsy or new biomarkers). In the perspective of LT. More specifically. it has been observed that the degree of tubular damage in The Treatment of HRS Dig Dis 2015. More precisely. The management of nonresponse to vasoconstrictors plus albumin in patients with AKI-HRS is the subject of intense discussion at present. A second strategy – a combination of drugs and nonpharmacological support – has not only been suggested. it has been observed that the probability of response decreases from 50 to 30% and then to 10% for sCr values of less than 3 mg/dl. respectively [56]. The combination between midodrine plus octreotide and albumin and TIPS (transjugular intrahepatic portosystemic shunt).e. while we are waiting for further studies specifically designed for patients with AKI-HRS who do not respond to vasoconstrictors plus albumin.

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Disclosure Statement The authors received no financial support for the research and/ or authorship of this article. By lowering sCr with response to terlipressin and increasing the serum sodium concentration.1 . the paradoxical effect of treatment on the time of LT in responders to terlipressin and albumin with or without a single recurrence of HRS can be avoided by continuing to consider their baseline pre-HRS MELD score rather than the MELD during or after the end of vasoconstrictor treatment. Terlipressin Study Group: A randomized. J Hepatol 1997. Lister Hill Library 198. Erlinger S. Rodés J. Rodés J: Time profile of 552 Dig Dis 2015. thereby delaying for several weeks or months the time of LT. J Gastroenterol Hepatol 2003. Kanazawa H. it is important to recognize that much work remains to be done in order to solve the many contentious points before the solution to these issues can be established.

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