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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
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
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Key Words
Albumin Acute kidney injury Cirrhosis Terlipressin
-Adrenergic drug
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.
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Drug
Effect on
Effect on portal Effect on MAP
splanchnic arterial pressure
vasodilation
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.
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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].
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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
Conclusions
Disclosure Statement
The authors received no financial support for the research and/
or authorship of this article.
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