REVIEW

REVIEW

Current Treatment Strategies for Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a unique form of severe the reversal of kidney failure in order to provide a successful
functional kidney failure due to intense renal vasoconstric- bridge to transplantation. The best available therapy for HRS
tion that develops in patients with cirrhosis in the absence of (other than LT) is the use of vasoconstrictors plus albumin.1
significant histological abnormalities of the kidneys.1,2
General Management
Detailed discussions of the pathophysiology of HRS and the
diagnostic approach to HRS are presented in two other The general management of patients with HRS depends on
articles in this issue of Clinical Liver Disease and can also be the severity of kidney failure and associated complications.
found elsewhere.1,2 Patients with type 1 HRS (especially those awaiting LT)
The diagnosis of HRS is essentially a process of excluding should be treated in an intensive care setting. Decisions
other causes of kidney failure. Therefore, the identification of about the management of patients who are not candidates
objective parameters that can be used in the differential diag- for transplantation should be individualized. Once type 1
nosis between HRS and other causes of kidney failure in HRS has been diagnosed, treatment should be started as
patients with cirrhosis is of the utmost importance. Recent early as possible to prevent further progression of kidney
studies suggest that the measurement of the neutrophil gela- failure. There should be frequent clinical assessments for the
tinase-associated lipocalin concentration in urine, a bio- possibility of associated complications of cirrhosis (particu-
marker of tubular damage, may be of value in the differential larly bacterial infections), and if these occur, they should be
diagnosis between HRS and other causes of acute kidney fail- treated as quickly as possible. Intravenous fluids should be
ure in patients with cirrhosis, but information is still lim- administered carefully in order to prevent pulmonary edema
ited.3,4 The current diagnostic criteria for HRS have been and the development or progression of hypervolemic hypo-
reported elsewhere.5 There are two types of HRS correspond- natremia. Patients with type 2 HRS can be managed as out-
ing to the severity and progression of kidney failure (Table patients if there are no associated complications of cirrhosis
1). Type 1 HRS is associated with rapidly progressive kidney that require hospitalization.
failure and a very low survival expectancy, the median sur- Treatment of Type 1 HRS
vival time being only 2 weeks if it is not treated; type 2 HRS
is associated with stable or slowly progressive kidney failure Vasoconstrictor Drugs
and has a better prognosis than type 1 HRS.1,2 Terlipressin. The administration of vasoconstrictors associ-
ated with intravenous albumin is currently considered the
Management of HRS treatment of choice for the management of type 1 HRS.1,6
The main objective in the management of patients with The rationale behind this therapy is the improvement of cir-
HRS, particularly those awaiting liver transplantation (LT), is culatory function through vasoconstriction of the extremely

Abbreviations: GFR, glomerular filtration rate; HRS, hepatorenal syndrome; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; RRT, renal
replacement therapy; TIPS, transjugular intrahepatic portosystemic shunt.
From the Liver Unit, Hospital Clı́nic, University of Barcelona School of Medicine; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de
Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd); and Instituto Reina Sofı́a de Investigacio n Nefrolo gica (IRSIN),
Barcelona, Spain.
Elsa Sola was the recipient of a grant from the Carlos III Institute of Health (FI10/00438). Some of the studies reported in this review were performed with the
support of grants from the Health Research Fund (FIS PI080126 and EC/90077) and the Network Center for Biomedical Research in Hepatic and Digestive
Diseases. The Network Center for Biomedical Research in Hepatic and Digestive Diseases is funded by the Carlos III Institute of Health (Spanish Ministry of
Health). This study was partly funded by the FIS EC07/90077 - Instituto De Salud Carlos III.
Potential conflict of interest: Nothing to report.
View this article online at wileyonlinelibrary.com
C 2013 by the American Association for the Study of Liver Diseases
V

doi: 10.1002/cld.209

136 Clinical Liver Disease, Vol. 2, No. 3, June 2013 An Official Learning Resource of AASLD
 20462484, 2013, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.209 by EBMG ACCESS - ETHIOPIA, Wiley Online Library on [12/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
R E V I E W Treatment Strategies for Hepatorenal Syndrome Sola, Guevara, and Ginès

TABLE 1: Clinical Types of HRS terlipressin because of their low cost and wide availability.
Type 1. Rapidly progressive decrease in kidney function [defined as a 100% Administered as a continuous intravenous infusion, noradrena-
increase in the serum creatinine level to a final value > 2.5 mg/dL (> 221
mmol/L) in 2 weeks]. The clinical presentation is usually that of acute line appears to be effective for the treatment of type 1 HRS,
kidney failure. The median survival is only 2 weeks if it is not treated. although studies are still limited, and the number of treated
Type 2. Stable or slowly progressive decrease in kidney function that does
not meet the criteria for type 1 HRS. The typical clinical presentation is patients is relatively small. A recent randomized trial compared
that of refractory ascites. The median survival is approximately 6 months. the safety and efficacy of treatment with terlipressin versus nor-
adrenaline for patients with HRS.12 Approximately 40% of the
patients responded to treatment in both groups, and the
dilated splanchnic arterial bed, which subsequently improves adverse event profiles were similar in all patients. Therefore,
arterial underfilling, reduces the activity of the endogenous noradrenaline seems to be as effective and safe as terlipressin for
vasoconstrictor systems, and increases kidney perfusion.1,2 the treatment of HRS.
The available vasoconstrictors used for HRS include vaso- The combination of oral midodrine and octreotide in asso-
pressin analogues such as terlipressin and alpha-adrenergic ciation with albumin has been shown to improve kidney
agonists such as noradrenaline and midodrine (Table 2). function in patients with HRS, although the number of
Most published data concern the use of intravenous terlipres- treated patients is relatively small, and no randomized com-
sin. Results from recent randomized controlled studies and parative studies with other vasoconstrictors have been per-
systematic reviews indicate that treatment with terlipressin formed. A small study of 14 patients with type 1 HRS ana-
together with albumin is associated with marked improve- lyzed the efficacy of a transjugular intrahepatic portosystemic
ments of kidney function in approximately 40% to 50% of shunt (TIPS) for patients with type 1 HRS after the improve-
patients.7,8 Moreover, a systematic review of randomized ment of systemic hemodynamics and kidney function with a
controlled studies has shown that vasoconstrictor therapy for combination of midodrine, octreotide, and albumin. Medical
HRS improves survival.9 Although there are no dose-finding therapy improved kidney function and renal sodium excre-
efficacy studies, the treatment is typically started intrave- tion in 10 of the 14 patients before TIPS insertion. TIPS
nously with 1 mg/4-6 hours, and the dose is increased up to insertion in five of the responders further improved kidney
a maximum of 2 mg/4-6 hours after 3 days if there is no function and renal sodium excretion.13 A relatively large ret-
response to therapy (defined as a reduction of the serum cre- rospective study evaluated the effects of treatment with
atinine level > 25% of the pretreatment values). In respond- octreotide plus midodrine on kidney function and 1-month
ers, the goal is to achieve the lowest levels of serum creati- survival in 87 patients with type 1 HRS versus a control
nine possible. Treatment is stopped when there is no further group (21 subjects).14 A significantly higher proportion of
reduction of creatinine. In nonresponders, the duration of patients treated with octreotide plus albumin showed a sus-
treatment is based on the effect on serum creatinine. If there tained reduction in serum creatinine in comparison with the
is no decrease in creatinine or if its level increases, treatment control group (40% versus 10%, P < 0.05), and the 1-
should be stopped after 3 to 4 days of the maximum dose of month mortality rate was significantly lower (43% versus
terlipressin. If the reduction in serum creatinine is very slow, 71%, P < 0.05). Another recent study also analyzed the
treatment can be maintained as long as the serum creatinine effects of the combination of octreotide and midodrine plus
level decreases and there are no side effects of therapy. albumin on kidney function and survival in 75 patients with
Recent studies suggest that the administration of terlipressin
as a continuous intravenous infusion may improve its effi-
TABLE 2: Pharmacological Treatment for HRS
cacy and decrease adverse events.10,11 However, data are lim-
Vasoconstrictors
ited, and more studies are needed to confirm these results. A Terlipressin: 1 mg/4–6 hours intravenously. The dose is increased up to a
response to therapy is considered when there is a marked maximum of 2 mg/4–6 hours after 3 days if there is no response to ther-
apy (defined as a 25% or greater reduction in serum creatinine compared
reduction in high serum creatinine levels, at least below 1.5 to pretreatment levels). A response to therapy is defined as a decrease in
mg/dL. The incidence of ischemic side effects secondary to serum creatinine levels below 1.5 mg/dL (133 lmol/L). The treatment is
usually applied for 5 to 15 days.
treatment with vasoconstrictors that require the discontinua- Midodrine and octreotide: 7.5 mg of midodrine orally 3 times daily
tion of treatment is approximately 10%. The recurrence of (increased to 12.5 mg 3 times daily if needed) and 100 lg of octreotide
subcutaneously 3 times daily (increased to 200 lg 3 times daily if
HRS after the withdrawal of therapy occurs in less than 15% needed). The duration of treatment depends on the effects on serum
of patients, and retreatment with terlipressin is generally creatinine.
Norepinephrine: 0.5–3 mg/hour as a continuous intravenous infusion
effective. aimed at increasing the mean arterial pressure by 10 mm Hg. The
Other vasoconstrictors. Vasoconstrictors other than terli- treatment is continued until the serum creatinine level decreases below
1.5 mg/dL.
pressin that have been used in the management of HRS include Albumin Administration
noradrenaline and midodrine plus octreotide, both in combina- Concomitant administration of albumin and vasoconstrictor drugs (1 g/kg
of body weight on day 1 followed by 20–40 g/day).
tion with albumin.6 They represent alternative treatments to

137 Clinical Liver Disease, Vol. 2, No. 3, June 2013 An Official Learning Resource of AASLD
 20462484, 2013, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.209 by EBMG ACCESS - ETHIOPIA, Wiley Online Library on [12/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
R E V I E W Treatment Strategies for Hepatorenal Syndrome Sola, Guevara, and Ginès

FIGURE 1. Proposed treatment algorithm for patients with type 1 HRS. *A complete response is defined as a decrease in the serum creatinine level to a value less than 1.5
mg/dL (see the text for the duration of treatment). **See Angeli and Ginès.21 Adapted with permission from American Journal of Kidney Diseases.1 Copyright 2012, Elsevier, Inc.

type 1 or 2 HRS versus a cohort of 87 controls.15 The results groups for patients requiring long-term hemodialysis after LT
were similar to those of the previous study. Transplant-free (7.7% of cases versus 12.5% of controls, P ¼ 0.61). The
survival was higher for the treatment group (median ¼ 101 results of this analysis suggest that a pre-LT treatment with a
days) versus the control group (median ¼ 18 days, P < combination of midodrine and octreotide in association with
0.0001). Kidney function had significantly improved at 1 albumin is not associated with an additional benefit in
month in the treatment group [glomerular filtration rate improving kidney function after LT.16
(GFR) ¼ 48 mL/minute] versus the controls (GFR ¼ 34 mL/ Thus, although some studies suggest that treatment with
minute, P ¼ 0.03), and the 1-month survival rate was signif- oral midodrine plus octreotide in combination with albumin
icantly higher for the treatment group versus the control is effective for patients with HRS, the number of treated
group.15 Therefore, both studies suggest that treatment with patients is still limited, and the studies are retrospective.
oral midodrine plus octreotide may represent an effective al- Therefore, large randomized comparative trials with other
ternative to terlipressin for patients with HRS because it vasoconstrictors are needed.
improves kidney function and is associated with increased
short-term survival. Finally, a recent retrospective analysis
evaluated post-LT outcomes of patients treated with octreo- Other Treatments. The use of TIPS has been suggested as
tide, midodrine, and albumin.16 In that study, patients an alternative therapy to vasoconstrictor drugs for HRS, but
treated before LT were compared with a control cohort that its applicability in patients with type 1 HRS and such
underwent LT in the era before this therapy was used. Forty- advanced liver disease is very limited.17 Two small studies
three patients with HRS underwent LT (27 cases and 16 indicate that TIPS improves GFR and reduces the activity of
controls). There were no differences between the groups in the renin-angiotensin-aldosterone system and the sympa-
the proportion of patients requiring hemodialysis before LT thetic nervous system in approximately 60% of patients.
(48% of cases versus 50% of controls, P ¼ 1.00). After LT, However, these studies excluded patients with previous he-
the mean GFRs were similar for the cases and controls at 1 patic encephalopathy, Child-Pugh scores
12, and serum
month (57 versus 53 mL/minute/1.73 m2, P ¼ 0.61) and at bilirubin levels > 5 mg/dL.17,18 Therefore, the applicability
1 year (P ¼ 0.13). Eleven of the 27 cases responded to of TIPS to patients with type 1 HRS is very low because
octreotide, midodrine, and albumin before LT. In compari- TIPS is considered to be contraindicated in patients with fea-
son with the nonresponders, there was no difference in GFR tures of severe liver failure, which are common findings in
1 month after LT. There were no differences between the the setting of type 1 HRS.

138 Clinical Liver Disease, Vol. 2, No. 3, June 2013 An Official Learning Resource of AASLD
 20462484, 2013, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.209 by EBMG ACCESS - ETHIOPIA, Wiley Online Library on [12/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
R E V I E W Treatment Strategies for Hepatorenal Syndrome Sola, Guevara, and Ginès

Renal replacement therapy (RRT)---mainly hemodialysis--- transplantation is appropriate only for patients who have been
has been used in the management of patients with type 1 HRS on RRT for more than 6 to 8 weeks and have a low probability
and especially candidates for LT in an attempt to keep patients of recovery of kidney function.6,20
alive until LT is performed. Unfortunately, the potential benefi- An important issue is whether to treat patients with type 1
cial effect of this approach has not been evaluated in random- HRS with vasoconstrictors before transplantation with the
ized studies. Most patients with type 1 HRS develop side effects aim of performing LT in patients with normal or improved
during RRT, which can include severe arterial hypotension, kidney function. Although some data are in conflict, the
bleeding, and infections that may contribute to death during treatment of type 1 HRS before transplantation may improve
treatment. Additionally, indications for RRT (severe fluid over- outcomes after transplantation.16,18,21 Recent guidelines sup-
load, acidosis, and hyperkalemia) are uncommon in patients port such a treatment strategy.6
with type 1 HRS, at least in the early stages. The management of type 1 HRS is summarized in Fig. 1.
Other methods, including the molecular adsorbent recircu-
Treatment of Type 2 HRS
lating system and fractionated plasma separation and adsorp-
tion (Prometheus), are alternatives to dialysis that clear sub- Data on the use of vasoconstrictors in combination with albu-
stances from the circulation, including endogenous vasodila- min for patients with type 2 HRS are scarce. Uncontrolled trials
tors. They appear to be promising, but more data are needed support the efficacy of this therapy in improving kidney func-
to consider them useful therapeutic alternatives for HRS.19 tion, but recurrence after treatment withdrawal is very frequent.
More studies are required to understand the role of vasocon-
Liver transplantation. LT is the treatment of choice for both strictors plus albumin in these patients. TIPS may improve kid-
type 1 HRS and type 2 HRS.1 An important problem is that ney function and reduce the risk of progression to type 1 HRS,
patients with type 1 HRS have a high mortality rate on the wait- but randomized controlled studies are lacking.
ing list for LT. Therefore, these patients should be assigned a
high priority for transplantation. Because kidney failure is re- CORRESPONDENCE
P. Ginès, M.D., Liver Unit, Hospital Clinic, University of Barcelona School of
versible after LT, patients with HRS should not be treated with Medicine, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail:
combined liver-kidney transplantation. Combined liver-kidney [email protected]

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139 Clinical Liver Disease, Vol. 2, No. 3, June 2013 An Official Learning Resource of AASLD