Kidney Problems in Cirrhosis

Dig Dis 2015;33:548554

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
a

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

Abstract
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 3545% 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 0.51 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. -Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been

2015 S. Karger AG, Basel

02572753/15/03340548$39.50/0
E-Mail karger@karger.com
www.karger.com/ddi

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

Introduction

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 [14]. 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, IT35128 Padua (Italy)
E-Mail pangeli@unipd.it

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

Key Words
Albumin Acute kidney injury Cirrhosis Terlipressin
-Adrenergic drug

Use of Terlipressin in the Treatment of HRS

To date, four randomized controlled clinical trials

comparing terlipressin and albumin in the treatment of
HRS, mainly of AKI-HRS, with albumin alone have been
published [811]. In addition, terlipressin plus albumin
has been used in several uncontrolled clinical studies.
Taking these studies as a whole, terlipressin has been used
in more than 300 patients [1223]. In most of these patients, terlipressin was administered as an intravenous bolus starting from an initial dose of 0.5 mg every 46 h [12
20, 23]. Only in a few studies was the drug administered
as a continuous intravenous infusion starting from an initial dose of 2 mg/day [21, 22]. In patients without a clinical
response, defined as a reduction of serum creatinine (sCr)
<25% within 3 days, the initial dose of terlipressin was
doubled. The maximal doses of terlipressin used in the
treatment of HRS were 2 mg every 46 h by intravenous
boluses, or 12 mg/day by continuous intravenous infusion, respectively. In most of the patients, terlipressin was
used together with albumin with a priming dose of 1 g/kg
of body weight followed by 2040 g/day monitoring central venous pressure. Response to the treatment has been
defined by a decrease of sCr >50% in patients with AKIHRS. The response was further defined as complete or
partial according to the final sCr: <1.5 mg/dl or equal to
>1.5 mg/dl, respectively. The rate of response commonly
ranges between 40 and 50% when terlipressin was given
alone [14, 15]; however, the rate of reversal of HRS, which
is the achievment of normal serum creatinine levels, is
lower in patients receiving terlipressin than in patients reThe Treatment of HRS

ceiving both terlipressin and albumin [18, 19]. 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, 23].
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.
Nevertheless, 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, 25].
During the treatment with terlipressin plus albumin,
the normalization or decrease in sCr can take several
days. Therefore, the treatment is usually continued for up
to 1015 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]. As a result, in patients with continuous recurrence
of type 1 HRS, 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], this therapeutic strategy can result in a longterm administration of terlipressin and albumin, continuing for months rather than weeks [27, 28].
The most common side effect of terlipressin is diarrhea, 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. The most severe adverse effects of terlipressin are cardiovascular or ischemic
complications (chest pain, abdominal pain or arrhythmia), which have been reported in an average of 12% of
patients treated. This is the reason why severe cardiovascular ischemic conditions should be considered contraindications to the use of terlipressin in patients with cirrhosis, and a close clinical and ECG monitoring should be
performed during the treatment.

Use of Other Pharmacological Approaches:

-Adrenergic Drugs

The rationale for the use of -adrenergic drugs such as

norepinephrine alone or oral midodrine combined with
subcutaneous octreotide, together with intravenous albumin, in the treatment of AKI-HRS deserves some comment. First, unlike terlipressin, there has so far been no
clinical study in which the effect of either norepinephrine
or midodrine has been evaluated in patients with cirrhosis. In an experimental model of cirrhosis, it can be observed that norepinephrine was capable of increasing the
Dig Dis 2015;33:548554
DOI: 10.1159/000375346

549

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

endogenous vasodilators due to portal hypertension and/

or hepatic failure, while the inadequate cardiac output can
be the extreme manifestation of a systolic dysfunction
which is part of the so-called cirrhotic cardiomyopathy
[5]. Based on pharmacodynamic studies on the effects of
terlipressin on the splanchnic circulation in patients with
cirrhosis [6], 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. Albumin was combined with terlipressin to further
improve the effective circulating volume and, as a consequence, arterial renal perfusion. This rationale for the use
of terlipressin plus albumin was later proved in patients
with cirrhosis and ascites without renal failure [7]. This
review will mainly focus on the use of terlipressin and other vasoconstrictors plus albumin in the treatment of acute
kidney injury (AKI)-HRS.

Table 1. 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; + = mild effect; ++ = moderate effect; +++ = high effect; No = no effect. Data specifically obtained in patients with HRS are in italics.

550

Dig Dis 2015;33:548554

DOI: 10.1159/000375346

circulation in cirrhosis (table 1), 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, 37]. 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, because these
compounds counteract the action of vasoconstrictors on
renal perfusion [38, 39]. No controlled clinical study has so
far been performed with midodrine plus octreotide administered together with albumin. In the largest uncontrolled
studies this therapeutic option was shown to be effective in
almost 40% of patients with AKI-HRS [40, 41]. In all studies except one [42], treatment was administered according
to the originally proposed schedule [35]. Thus, octreotide
was administered via the subcutaneous route with a starting dose of 100 mg 3 times a day, which was titrated up to
200 mg thrice daily as necessary. Midodrine was started at
an oral dose of 7.5 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. Albumin was given in differing concentrations at a dose ranging from 20 to 100 g/
day. Similarly to what has been said about noradrenalin, in
total midodrine plus octreotide and albumin have so far
been used in less than 120 patients with AKI-HRS [4042].
Thus, we need further studies to clarify its role in the treatment of HRS. Octreotide alone has no impact on improving renal function [42, 43].

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]. However, the treatment is effective in 35
Cavallin/Fasolato/Marenco/Piano/Tonon/
Angeli

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

superior mesenteric artery resistance but not reducing

portal pressure. In addition, in cirrhotic rats, norepinephrine was not capable of improving renal perfusion [29].
In spite of these potential disadvantages, when norepinephrine was compared to terlipressin in the treatment of
AKI-HRS in three small controlled clinical studies, similar results were found in terms of both the rate of response
and 30-day survival [3032]. It should be emphasized that
most of the patients included in one of these studies had
CKD-HRS [32]. Furthermore, none of these controlled
clinical studies had an adequate sample size to offer assessment of the equivalence between terlipressin and norepinephrine with certainty. However, 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, thanks to its property
of volemia expansion [33]. In all the controlled and uncontrolled studies, noradrenalin was used by continuous
intravenous infusion at the initial dose of 0.5 mg/h. In the
case of a nonresponse, the dose was progressively increased up to a maximum of 3 mg/h [3032, 34]. In all the
studies, noradrenalin was always used together with albumin with doses ranging from 20 to 70 g/day [3032, 34].
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.
Nevertheless, norepinephrine has been used in less than
70 patients with AKI-HRS to date [3134]. Therefore, according to the conclusion of a recent study [35] about the
treatment of HRS type 1, further studies are needed to
clarify its role in the treatment of AKI-HRS.
The rationale for the use of oral midodrine and subcutaneous or intravenous octreotide is slightly more complex
and deserves to be clarified [35]. It is based not only on the
simple sum of the effects of the two drugs on the splanchnic

study by the EASL-Clif Consortium [66]. More precisely,

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]. This observation
opens a further discussion on potential specific features
of the pathophysiology of AKI-HRS in patients with
ACLF. Moreover, it introduces a limit in the prognostic
value of the KDIGO (Kidney Disease: Improving Global
Outcome) criteria (which, like AKIN, evaluate serum creatinine and urine output to diagnose AKI, but furthermore to assess its severity) in patients with 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.
More specifically, 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, 68].
The management of nonresponse to vasoconstrictors
plus albumin in patients with AKI-HRS is the subject of
intense discussion at present. Combinations of different
drugs have been suggested but never tested. A second
strategy a combination of drugs and nonpharmacological support has not only been suggested, but also tested.
The combination between midodrine plus octreotide and
albumin and TIPS (transjugular intrahepatic portosystemic shunt), even if exciting from a clinical point of view,
is of limited value since TIPS is contraindicated in a high
percentage of patients with AKI-HRS [48]. 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]. However, this observation is the result of
the analysis of only a subgroup of patients. Thus, while we
are waiting for further studies specifically designed for
patients with AKI-HRS who do not respond to vasoconstrictors plus albumin, renal replacement therapy (RRT)
is often applied in clinical practice, particularly in patients
who are candidates for liver transplantation (LT), even
though the risk, the best approach and the outcome of
RRT have never been evaluated specifically in these patients.
In the perspective of LT, two final points should be
briefly discussed, since they are not completely solved or
established. 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. With regard to the first point,
it has been observed that the degree of tubular damage in

The Treatment of HRS

Dig Dis 2015;33:548554

DOI: 10.1159/000375346

551

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

65% of patients and we still need to solve three major

problems. First, how to explain nonresponse to the treatment, second, how to predict a nonresponse and, finally,
how to manage it. AKI-HRS has been defined as a functional renal failure, thus, by definition, without any evidence of renal parenchymal damage [50, 51]. Nevertheless, the current criteria for the diagnosis of HRS are not
capable of excluding renal parenchymal damage. Indeed,
when new diagnostic tools were used (i.e. renal biopsy or
new biomarkers), evidence of renal parenchymal damage
was found in patients with AKI-HRS [52, 53]. 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. Terlipressin per
se does not change stroke volume [54], and can reduce
cardiac output by increasing peripheral resistances [55]
in patients with cirrhosis. Thus, 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, as previously discussed
[33]. Moving to factors which can predict the nonresponse to treatment with vasoconstrictors plus albumin
in patients with AKI-HRS, we need to focus only on terlipressin and albumin because no data referring to the
-adrenergic drugs exist to date. High baseline values of
both sCr and serum total bilirubin as well as a small increase in mean arterial pressure (MAP) with treatment
[5658] have been identified as predictors of nonresponse
in patients with AKI-HRS. Focusing on baseline sCr, 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, 35 mg/dl and more than 5 mg/dl, respectively [56]. These findings emphasize the need to diagnose and treat AKI-HRS as early as possible. Accordingly, the current diagnostic criteria of AKI-HRS in patients with cirrhosis have been revised and this should
lead to improved treatment in these patients [5965]. A
small increase in MAP, defined as being <5 mm Hg on
day 3 of treatment, was also found to be a predictor of
nonresponse to terlipressin and albumin [57]. The increase in MAP required for a response may be closely related to the baseline sCr, 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]. With regard to the baseline value of serum
total bilirubin, 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), as recently defined in the Canonic

nonresponders to vasoconstrictors plus albumin can progressively worsen and proceeds towards acute tubular necrosis (ATN) [35]. The progress of AKI-HRS to ATN in
nonresponders may have very important clinical implications since LT in patients with cirrhosis and ATN is associated with a high rate of chronic kidney disease and
5-year mortality after LT [65]. So, a severe degree of reduction of GFR and/or the need for RRT for a period of
time >6 weeks before LT should be considered as an indication to combined simultaneous liver kidney transplantation [66].
With regard to the second point, a new policy of priority allocation in the waiting list should be applied to responders to terlipressin and albumin. Indeed, these patients suffer from a serious injustice. As a matter of fact,
their 3-month mortality rate is higher than that predicted
by their baseline-calculated MELD score [67]. By lowering sCr with response to terlipressin and increasing the
serum sodium concentration, the treatment can significantly lower the MELD as well as the MELD Na score [47]
by up to 89 points in our experience, thereby delaying
for several weeks or months the time of LT. Taking into
account that the survival rate in responders at 3 months
is almost 50% [18], a new and specific policy of priority
organ allocation is needed for these patients. In particular, 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. In responders who experience a continuous
recurrence of AKI-HRS, the paradoxical effect is even
more important and should be studied, considering the
pharmacological treatment of HRS as RRT in the calculation of the MELD [68].

Conclusions

The introduction of vasoconstrictors and albumin in

the treatment of AKI-HRS represents a landmark in the
treatment of this complication in patients with advanced
cirrhosis. Nevertheless, 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.

Disclosure Statement
The authors received no financial support for the research and/
or authorship of this article.

1 Schrier RW, Arroyo V, Bernardi M, Epstein

M, Henriksen JH, Rods J: Peripheral arteriolar vasodilation hypothesis: a proposal for the
initiation of renal sodium and water retention
in cirrhosis. Hepatology 1988;8:11511157.
2 Ruiz del Arbor L, Urman J, Fernandez J,
Gonzlez M, Navasa M, Monescillo A, Albillos A, Jimnez W, Arroyo V: Systemic, renal
and hepatic haemodynamic derangement in
cirrhotic patients with spontaneous bacterial
peritonitis. Hepatology 2003;38:12101218.
3 Ruiz del Arbol L, Monescillo A, Arocena C,
Valer P, Gins P, Moreira V, Milicua JM, Jimnez W, Arroyo V: Circulatory function
and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439447.
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:
105110.
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, Garca-Pagan JC, Bosch J, Rods J: Time profile of

552

Dig Dis 2015;33:548554

DOI: 10.1159/000375346

10

the haemodynamic effects of terlipressin in

portal hypertension. J Hepatol 1997; 26: 621
627.
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;24:17911797.
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;18:152156.
Sanyal A, Boyer T, Garcia-Tsao G, Regenstein
F, Rossaro L, Appenrodt B, Blei A, Glberg 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;134:13601368.
Martin-Llahi MM, Pepin MN, Guevara M,
Daz F, Torre A, Monescillo A, Soriano G,
Terra C, Fbrega E, Arroyo V, Rods J, Gins
P, TAHRS Investigators: Terlipressin and al-

11

12

13

14

bumin versus albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352
1359.
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;53:830855.
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;41:10541056.
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:
268270.
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;95:29842985.

Cavallin/Fasolato/Marenco/Piano/Tonon/
Angeli

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

References

The Treatment of HRS

26 Gins P, Angeli P, Lenz K, Mller 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;53:347417.
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;
55:491496.
28 Caraceni P, Santi L, Mirici F, Montanari G,
Bevilacqua V, Pinna AD, Bernardi M: Longterm treatment of hepatorenal syndrome as a
bridge to liver transplantation. Dig Liver Dis
2011;43:242245.
29 Coll M, Rodriguez S, Raurell I, Ezkurdia N,
Brull A, Augustin S, Guardia J, Esteban R,
Martell M, Genesc J: Droxidopa, an oral norepinephrine precursor, improves hemodynamic and renal alterations of portal hypertensive rats. Hepatology 2012;56:18491660.
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;103:16891697.
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;56:12931298.
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;47:499505.
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:
374380.
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;57:266276.
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.

Dig Dis 2015;33:548554

DOI: 10.1159/000375346

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;
28:937943.
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;100:631635.
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,
Mrquez S, Iturriaga H: Effects of acute octreotide infusion on renal function in patients
with cirrhosis and portal hypertension. Rev
Med Chil 2004;132:144150.
40 Sieber CC, Lee FY, Groszmann RJ: Long term
octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats. Hepatology 1996;23:12181223.
41 Sieber CC, Groszmann RJ: In vitro hyporeactivity to methoxamine in portal hypertensive
rats: reversal by nitric oxide blockade. Am J
Physiol 1992;262:G996G1001.
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;100:879885.
43 Pomier-Layrargues GI, Paquin SC, Hassoun
Z, Lafortune M, Tran A: Octreotide in hepatorenal syndrome: a randomized, doubleblind, placebo-controlled, crossover study.
Hepatology 2003; 38: 238243.
44 Angeli P: Review article: prognosis of hepatorenal syndrome has it changed with current practice? Aliment Pharmacol Ther 2004;
20(suppl 3):14.
45 Arroyo V, Gines P, Gerbes AL, Dudley FJ,
Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Schlmerich J: Definition and diagnostic criteria a of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology
1996;23:164176.
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;56:13101318.
47 Trawal JM, Paradis V, Rautou PE, Francoz
C, Escolano S, Salle 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.

553

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

15 Halimi C, Bonnard P, Bernard B, Mathurin P,

Mofredj A, di Martino V, Demontis R, HenryBiabaud 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;14:153158.
16 Mulkay JP, Louis H, Donckier V, Bourgeois
N, Adler M, Deviere J, Le Moine O: Longterm terlipressin administration improves renal function in cirrhotic patients with type 1
hepatorenal syndrome: a pilot study. Acta
Gastroelerologica Belg 2001;64:1519.
17 Uriz J, Gines P, Cardenas A, Sort P, Jimnez
W, Salmern JM, Bataller R, Mas A, Navasa
M, Arroyo V, Rods 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, Crdenas A, Calahorra B, De Las Heras D, Guevara M, Bataller
R, Jimnez W, Arroyo V, Rods J: Terlipressin
therapy with and without albumin for patients with hepatorenal syndrome: results of a
prospective, nonrandomized study. Hepatology 2002;36:941948.
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:
923930.
20 Colle I, Durand F, Pessione F, Rassiat E, Bernuau J, Barrire 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;17:882888.
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;23:7584.
22 Gerbes AL, Huber E, Glberg V: Terlipressin
for hepatorenal syndrome: continuous infusion as an alternative to i.v. bolus administration. Gastroenterology 2009;137:1179.
23 Rodrguez E, Elia C, Sol E, Barreto R, Graupera I, Andrealli A, Pereira G, Poca M, Snchez J, Guevara M, Soriano G, Alessandria C,
Fernndez J, Arroyo V, Gins P: Terlipressin
and albumin for type-1 hepatorenal syndrome associated with sepsis. J Hepatol 2014;
60:955961.
24 Gluud LL, Christensen K, Krag A: Systematic
review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology 2010;51:576584.
25 Gluud LL, Christensen K, Christensen E, Krag
A: Terlipressin for hepatorenal syndrome.
Cochrane Database Syst Rev 2012;
9:CD005162.

554

Dig Dis 2015;33:548554

DOI: 10.1159/000375346

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;
57:753762.
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;59:482489.
57 Fagundes C, Barreto R, Guevara M, Garcia E,
Sol E, Rodrguez E, Graupera I, Ariza X,
Pereira G, Alfaro I, Crdenas A, Fernndez J,
Poch E, Gins P: A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in
cirrhosis. J Hepatol 2013;59:474481.
58 Tsien CD, Rabie R, Wong F: Acute kidney injury in decompensated cirrhosis. Gut 2013;
62:131137.
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:e21e26.
60 Wong F, OLeary 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;145:12801288.
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;144:14261437.

62 Angeli P, Rodrguez E, Piano S, Ariza X, Morando F, Sol E, Romano A, Garcia E, Pavesi

M, Risso A, Gerbes A, Willars C, Bernardi M,
Arroyo V, Gins 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):900901.
64 Kribben A, Gerken G, Haag S, et al: Effects of
fractionated plasma separation and adsorption on survival in patients with acute-onchronic liver failure. Gastroenterology 2012;
142:782789.
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;18:539548.
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;
8:22432251.
67 Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jimnez W, Arroyo V, Rods J, Gins
P: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to
liver transplantation. Hepatology 2005; 41:
12821289.
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.

Cavallin/Fasolato/Marenco/Piano/Tonon/
Angeli

Downloaded by:
University of Alabama, Lister Hill Library
198.143.47.1 - 7/14/2015 9:20:25 AM

48 Fagundes C, Ppin MN, Guevara M, Barreto

R, Casals G, Sol E, Pereira G, Rodrguez E,
Garcia E, Prado V, Poch E, Jimnez W,
Fernndez J, Arroyo V, Gins P: Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012;57:267273.
49 Solanki P, Kiszka-Kanowitz M, Henriksen JH,
Hansen EF, Mller S, Bendtsen F: Effect of
terlipressin on blood volume distribution in
patients with cirrhosis. Scand J Gastroenterol
2004;39:486492.
50 Krag A, Bendtsen F, Mortensen C, Henriksen
JH, Mller S: Effects of a single terlipressin administration on cardiac function and perfusion in cirrhosis. Eur J Gastroenterol Hepatol
2010;22:10851092.
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;
55:315321.
52 Nazar A, Pereira GH, Guevara M, MartnLlahi M, Pepin MN, Marinelli M, Sol E, Baccaro ME, Terra C, Arroyo V, Gins P: Predictors of response to therapy with terlipressin
and albumin in patients with cirrhosis and
type 1 HRS. Hepatology 2010;51:219226.
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;58:928938.
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;60:702709.