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TAG0010.1177/1756283X14564673Therapeutic Advances in GastroenterologyK. Lenz et al.

Therapeutic Advances in Gastroenterology


Treatment and management of ascites and

hepatorenal syndrome: an update
Kurt Lenz, Robert Buder, Lisbeth Kapun and Martin Voglmayr

Ther Adv Gastroenterol

2015, Vol. 8(2) 83100
DOI: 10.1177/
The Author(s), 2014.
Reprints and permissions:

Abstract: Ascites and renal dysfunction are frequent complications experienced by patients
with cirrhosis of the liver. Ascites is the pathologic accumulation of fluid in the peritoneal
cavity, and is one of the cardinal signs of portal hypertension. The diagnostic evaluation of
ascites involves assessment of its granulocyte count and protein concentration to exclude
complications such as infection or malignoma and to allow risk stratification for the
development of spontaneous peritonitis. Although sodium restriction and diuretics remain the
cornerstone of the management of ascites, many patients require additional therapy when
they become refractory to this treatment. In this situation, the treatment of choice is repeated
large-volume paracentesis. Alteration in splanchnic hemodynamics is one of the most
important changes underlying the development of ascites. Further splanchnic dilation leads to
changes in systemic hemodynamics, activating vasopressor agents and leading to decreased
renal perfusion. Small alterations in renal function influence the prognosis, which depends
on the cause of renal failure. Prerenal failure is evident in about 70% of patients, whereas
in about 30% of patients the cause is hepatorenal syndrome (HRS), which is associated with
a worse prognosis. Therefore, effective therapy is of great clinical importance. Recent data
indicate that use of the new definition of acute kidney injury facilitates the identification and
treatment of patients with renal insufficiency more rapidly than use of the current criteria
for HRS. In this review article, we evaluate approaches to the management of patients with
ascites and HRS.

Keywords: acute kidney injury, ascites, diuretic therapy, hepatorenal syndrome

Ascites is the most common complication of cirrhosis with attendant portal hypertension [Moore
and Aithal, 2006]. The production of ascites is
related to inadequate renal sodium excretion,
which generates a positive sodium balance. A typical finding in patients with cirrhosis and portal
decompensation is arterial splanchnic vasodilation, which results in increased mesenteric blood
flow. Arterial splanchnic vasodilation causes a
decrease in effective blood volume, activating
baro and volume receptors, the sympathetic nervous system, and the reninangiotensinaldosterone system (RAAS) and triggering the nonosmotic
release of vasopressin. Increased renal sympathetic nerve activity leads to increased tubular
sodium retention and a positive sodium balance.
Renal sympathetic nerve activity is further
enhanced by activation of the hepatorenal reflex

secondary to increased sinusoidal pressure and/or

a decrease in sinusoidal blood flow [Ming et al.
2002]. Increased vasodilation in the splanchnic
area is counteracted by an increase in total blood
flow, maintaining normal blood pressure and an
adequate blood flow to all organs. However, further splanchnic vasodilation increases the activation of vasoconstrictor systems and leads to
central underfilling, which cannot be sufficiently
counteracted by increasing cardiac output. This
causes decreased blood flow to the kidney and
prerenal failure, termed hepatorenal syndrome
(HRS) in these patients.

Correspondence to:
Kurt Lenz, MD
Department of Internal
and Intensive Care
Medicine, Konventhospital
Barmherzige Brder
Linz, Seilersttte 2, Linz,
A-4020, Austria
Robert Buder, MD
Martin Voglmayr, MD
Department of Internal
and Intensive Care
Medicine, Konventhospital
Barmherzige Brder Linz,
Lisbeth Kapun, MD
HFR Meyriez-Murten,
Murten, Switzerland

Ascites is a major complication of cirrhosis of the
liver, and is mainly due to portal hypertension.
Within 10 years of the diagnosis of cirrhosis, over 83

Therapeutic Advances in Gastroenterology 8(2)

50% of patients develop ascites [Becker, 2011].
The development of ascites is associated with a
poor prognosis and a mortality rate of 20% per
year [DAmico et al. 2006]. Therefore, patients
with ascites should be considered for liver transplantation, preferably before the development of
renal dysfunction.
Because 15% of patients with cirrhosis of the liver
develop ascites of nonhepatic origin, the cause of
new-onset ascites must be evaluated in all patients
by abdominal paracentesis. The analysis of ascitic
fluid should include assessment of neutrophil count
and total protein concentration. Inoculation of
ascites into blood culture bottles should be performed at the bedside if infection of the ascitic fluid
is suspected. A diagnosis of spontaneous bacterial
peritonitis (SBP) is made in the presence of an elevated absolute polymorphonuclear leukocyte count
(i.e. >250 cells/mm3) in the ascitic fluid without evidence of a surgically treatable intra-abdominal
source of infection [Becker, 2011]. Determination
of the ascitic protein concentration is necessary to
identify patients at increased risk of the development of SBP: a protein concentration of <1.5 g/dl is
a risk factor for development of the condition
[Moore and Aithal, 2006]. In patients in whom a
cause of ascites other than cirrhosis of the liver is
suspected, determination of the serumascites albumin gradient (SAAG) is useful. The SAAG is
1.1 g/dl in ascites due to portal hypertension, with
an accuracy of 97% [Gines et al. 2010]. If ascites
associated with malignancy is suspected, positive
results of cytologic analyses of ascitic fluid can be
obtained in patients with peritoneal carcinomatosis,
but not in those with liver metastasis or hepatoma
[Runyon et al. 1988]. Paracentesis is considered a
safe procedure even in patients with an abnormal
prothrombin time, with an overall complication rate
not exceeding 1%. More serious complications,
such as bowel perforation or bleeding into the
abdominal cavity, occur in fewer than 1 in 1000
paracenteses. Data supporting cutoff values for
coagulation parameters are unavailable; routine
prophylactic use of fresh-frozen plasma or platelets
before paracentesis is therefore not recommended,
although if thrombocytopenia is severe (platelet
count 40,000/l), most clinicians would administer pooled platelets to reduce the risk of bleeding
[Gines etal. 2010, Moore and Aithal, 2006].
Decompensated cirrhosis due to chronic viral or
autoimmune hepatitis often shows marked

improvement in response to antiviral or immunosuppressive treatments, respectively. In most

patients with alcoholic liver disease, abstinence
from alcohol results in improvements in liver
function and ascites [Becker, 2011]. There are no
defined criteria for when the treatment of ascites
should be initiated. Patients with clinically unapparent ascites usually do not require specific therapy, but it is recommended that patients with
clinically evident and symptomatic ascites
undergo treatment [Moore etal. 2003].
Patients with ascites have a positive sodium balance, i.e. sodium excretion is low relative to
sodium intake. Hence, the mainstay of therapy
for ascites is sodium restriction and diuretic therapy (Table 1). Sodium intake should be restricted
to 56 g/day (83100 mmol/day of NaCl). More
stringent restriction is not recommended,
because it may worsen the malnutrition often
present in patients with cirrhosis [Soulsby etal.
1997]. Given that the spontaneous resolution of
ascites is obtained by reducing dietary sodium
content in only 1020% of patients, a negative
sodium balance cannot be achieved without the
use of diuretics in most patients with cirrhosis
and ascites. Activation of the RAAS in patients
with cirrhosis of the liver causes hyperaldosteronism and increased reabsorption of sodium
throughout the distal tubule [Bernardi et al.
1985]. Therefore, aldosterone antagonists, such
as spironolactone, or its active metabolite, potassium canrenoate [Perez-Ayuso etal. 1982], represent first-line diuretics in the treatment of
ascites in patients with cirrhosis. The initial dose
is 100200 mg/dl. Monotherapy with a loop diuretic such as furosemide is less effective than use
of spironolactone, and is not recommended (86)
Perez-Ayuso etal. 1982. Two different schedules
are used in clinical practice. The first (sequential
diuretic treatment) consists of the administration of increasing doses of spironolactone. If the
response to 200 mg spironolactone is insufficient
within the first 2 weeks, furosemide is added at
an initial dose of 2040 mg/day. If necessary, the
dose of spironolactone can be increased stepwise
to a maximum of 400 mg/day, and the dose of
furosemide can be increased to a maximum of
160 mg/day. The second schedule (combined
diuretic treatment) involves the simultaneous
administration of an aldosterone antagonist and
a loop diuretic from the beginning of treatment,
and the dose of both diuretics can be increased if
no response is achieved. An established scheme
for initial combined therapy is 100 mg


K Lenz, R Buder et al.

Table 1. Treatment of ascites.
Clinical findings


Ascites clinically not detectable

Clinically evident ascites

No treatment
Combined treatment with:
Dietary salt restriction
Aldosterone antagonists (starting dose of
spironolactone 50100 mg tapering to a
maximum of 400 mg until ascites is resolved)
Loop diuretics (starting dose of furosemide
40 mg tapering to a maximum of 160 mg until
ascites is resolved or hyponatremia occurs)
Reduce the diuretic dose by half every week under
weight control

Ascites completely mobilized by diuretic treatment

spironolactone and 40 mg furosemide per day,

administered in the morning. If this dosage is
insufficient, a stepwise increase, keeping the
spironolactone:furosemide ratio constant (e.g.
200 mg spironolactone:80 mg furosemide), is
possible. In a study by Angeli and colleagues
[Angeli etal. 2010], adverse effects (38% versus
20%; p<0.05), in particular hyperkalemia (18%
versus 4%; p < 0.05), were more common in
patients who received sequential therapy, and the
percentage of patients whose ascites resolved
without changing the effective diuretic step was
higher with combined treatment (56% versus
76%; p < 0.05). The combination of sodium
restriction, spironolactone, and furosemide is
sufficient therapy for ascites in 90% of patients
with cirrhosis of the liver [Becker, 2011].
To avoid hypovolemia, daily weight loss in patients
with ascites should not exceed 1000 g in the presence of peripheral edema or 500 g in the absence
of peripheral edema [Pockros and Reynolds,
1986]. The diuretic effect is sufficient when only
small amounts of ascitic fluid remain and peripheral edema has disappeared completely.
Complications of diuretic therapy include hepatic
encephalopathy, renal failure, gynecomastia, electrolyte disturbances such as hyponatremia and
hypokalemia or hyperkalemia, and muscle cramps
[Santos etal. 2003]. To minimize these complications, it is advisable to reduce the dosage of diuretic drugs after the mobilization of ascites.
Complications of diuretic therapy are most frequent in the first few weeks of therapy. Amiloride
is an alternative to spironolactone in patients with
painful gynecomastia. It is administered at a dose
of 1040 mg/day, but it is less effective than potassium canrenoate [Angeli et al. 1994]. Notably,
hyponatremia, which is caused by impaired free

water excretion, itself reduces the effect of loop

The level of hyponatremia at which diuretic
treatment should be stopped is contentious. It is
generally agreed that diuretics should be paused
when serum sodium is <120125 mmol/l
[Runyon, 2012]. Low serum sodium concentration is an independent predictor of mortality in
patients with cirrhosis. The prevalence of low
serum sodium concentration, as defined by
serum sodium concentrations of <135 mmol/l,
<130 mmol/l, <125 mmol/l, and <120 mmol/l,
was found to be 49.4%, 21.6%, 5.7%, and 1.2%,
respectively, in a large multicenter study involving 994 patients with cirrhosis [Angeli et al.
2006]. Given that total body sodium is usually
not decreased in patients with ascites and
hyponatremia (dilution hyponatremia = hypervolemic hyponatremia), fluid restriction is recommended. Albumin infusion can be considered
a treatment for hyponatremia in cirrhosis. The
available data are limited and derive from a
small number of patients with a short follow-up,
but they suggest a benefit of albumin administration that warrants further exploration in
larger randomized trials. A randomized pilot
study of 24 patients admitted with serum
sodium levels of <130 mmol/l found that the
administration of albumin significantly improved
serum sodium levels compared with matched
controls treated with fluid restriction, generating a mean increase of 9 mmol/l. There was also
a significant increase, compared with controls,
in free water clearance and a decrease in serum
vasopressin levels in patients treated with albumin [Jalan etal. 2007]. This suggests that albumin contributes to the mitigation of circulatory
dysfunction and decreases the nonosmotic 85

Therapeutic Advances in Gastroenterology 8(2)

release of arginine vasopressin [Gianotti and
Cardenas, 2014; Umgelter et al. 2012].
Hypervolemic hyponatremia should be differentiated from hypovolemic hyponatremia, a less
common condition in cirrhosis in which hypovolemia results from marked and prolonged loss
of sodium. In this condition, if the hyponatremia
is symptomatic, slow correction is indicated.
The desirable rate of sodium increase is considered to be 68 mEq/l in 24 hours, 1214 mEq/l
in 48 hours, and 1416 mEq/l in 72 hours. A
more rapid correction of serum sodium is not
recommended, because of the risk of severe
complications, especially pontine myelinolysis
[Tzamaloukas etal. 2013].
In recent years, new drugs known as vaptans,
which antagonize the vasopressin V2 receptor
[Decaux and Vassart, 2008], have been used to
treat hyponatremia caused by cardiac failure,
syndrome of inappropriate antidiuretic hormone secretion (SIADH), and cirrhosis. In randomized studies, administration of tolvaptan
induced a marked increase in urine flow and
serum sodium concentration in patients with
mild hyponatremia. However, in those with
marked hyponatremia and renal failure, there
was only a trend toward improvement of serum
sodium concentration, and the effect only
occurred during the administration of tolvaptan. One week after vaptan cessation, hyponatremia recurred [Cardenas et al. 2012].
Tolvaptan was associated with an as yet unexplained higher incidence of gastrointestinal
bleeding when compared with the administration of a placebo. Therefore, the use of tolvaptan
warrants further long-term studies to evaluate
its safety and efficacy.
Therapy for refractory and recurrent ascites
Refractory ascites is defined as ascites that does
not respond to sodium restriction and high-dose
diuretic treatment (400 mg/day spironolactone
and 160 mg/day furosemide) or that recurs rapidly after therapeutic paracentesis [Gines et al.
2010]. About 510% of patients with cirrhosis
and ascites are considered to have refractory
ascites (63) (Krag etal. 2007). The median survival of patients with ascites refractory to medical
treatment is approximately 6 months. Recurrent
ascites is defined as frequent admission to the
hospital (more than three admissions per year)
because of the reaccumulation of ascites [Arroyo,

Large-volume paracentesis (LVP) is the first-line

therapy in patients with refractory ascites. In
patients with recurrent ascites, the addition of
vasopressors (with or without albumin) or albumin alone can be tried, before invasive procedures
such as paracentesis are attempted (Table 2). In
patients with cirrhosis and activation of the sympathetic nervous system, the addition of clonidine
to diuretic therapy induced an earlier diuretic
response associated with reduced diuretic requirements, fewer complications, and a lower incidence
of readmission related to tense ascites [Laenerts
etal. 1997]. Several mechanisms may contribute
to the increased mobilization of ascites associated
with the use of clonidine. Clonidine induced a
reduction in norepinephrine concentration associated with an elevated glomerular filtration rate
in patients with refractory ascites [Laenerts etal.
2006]. By increasing glomerular filtration rate
and decreasing proximal reabsorption of sodium,
clonidine may increase the delivery of sodium to
the distal nephron, where spironolactone, initially
less effective, increases natriuresis by impairing
the distal reabsorption of sodium. In addition,
clonidine decreases the portosystemic gradient,
especially in patients with alcoholic cirrhosis.
Oral administration of midodrine is associated
with a significant improvement in systemic hemodynamics in nonazotemic patients with cirrhosis
and ascites. As a result, renal perfusion and renal
sodium excretion also improve in these patients
[Angeli etal. 1998]. In a randomized controlled
trial, midodrine and a combination of clonidine,
midodrine, and standard diuretic treatment controlled ascites significantly better than standard
diuretic treatment alone over a 1-month period
[Singh etal. 2013]. In a randomized trial involving patients with refractory or recurrent ascites,
oral midodrine at a dose of 7.5 mg three times
daily was shown to increase urine volume, urinary
sodium excretion, mean arterial pressure, and
survival. Therefore, midodrine can used in addition to diuretics to increase blood pressure and
convert refractory ascites to diuretic-sensitive
ascites [Singh etal. 2012a].
In a study by Krag and colleagues [Krag et al.
2007] of 15 patients with nonrefractory ascites
and 8 with refractory ascites, 2 mg of terlipressin
increased glomerular filtration rate, sodium clearance, lithium clearance, osmolal clearance, und
urinary sodium excretion, and decreased norepinephrine and plasma renin activity, compared
with a placebo infusion. All parameters remained


K Lenz, R Buder et al.

Table 2. Treatment of recurrent and refractory ascites.


Recurrent ascites: frequent admission due to

ascites reaccumulation (more than three per year)

Oral clonidine 0.075 mg once to twice daily in

alcoholic cirrhosis with systolic blood pressure
135 mm Hg 20 g albumin/week in addition to
sodium restriction and diuretic treatment
Oral midodrine 75 mg three times daily 20 g
albumin/week in addition to sodium restriction
and diuretic treatment
Intravenous terlipressin 2 mg daily 20 g
albumin /week in addition to sodium restriction
and diuretic treatment
Large-volume paracentesis in nonresponders to
clonidine or midodrine
TIPS in nonresponders to clonidine or midodrine
Large-volume paracentesis together with the
administration of 8 g albumin/l ascitic fluid
TIPS in nonresponders to large-volume

Therapy refractory ascites: no response to dietary

restriction and diuretic treatment

TIPS, transjugular intrahepatic portosystemic shunt.

unchanged after administration of the placebo. In

addition, 2 mg of terlipressin increased water
excretion during a water-loading test in nonazotemic patients with cirrhosis (ChildPugh
classes B and C) but without hyponatremia [Krag
etal. 2007; Kalambokis etal. 2010].
Albumin has been found to be effective for prophylaxis against ascites in small studies. This effect
could be based on the finding of the reduced
function of endogenous albumin in patients with
liver failure [Garcia-Martinez etal. 2013]. A randomized unblinded trial showed that the longterm administration of diuretics plus human
albumin (25 g/week in the first year and 25 g
every 2 weeks thereafter) improved survival and
reduced the risk of recurrence of ascites compared with the administration of diuretics alone
[Romanelli et al. 2006]. However, the relatively
small sample size precluded any firm conclusions.
In a randomized double-blind placebo-controlled
trial, Bari and colleagues [Bari etal. 2012] found
that albumin was not inferior to the combination
of octreotide and midodrine in preventing the
recurrence of ascites after LVP. In addition, the
outcome was worse in patients given octreotide
and midodrine.
Possible treatment options for refractory ascites
include LVP, transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation
(Table 3). The first-line treatment for patients

with refractory ascites is LVP, wherein a needle is

inserted into the peritoneal cavity to remove the
ascitic fluid [Gines etal. 1987]. This procedure is
easy to perform and safe in most instances.
However, complications are not completely
unknown, and may present after a delay [Martinet
et al. 2000]. Hemorrhagic complications are
infrequent, despite the presence of coagulopathy
in many patients. There are no data on the prophylactic use of fresh-frozen plasma or pooled
platelets, except in patients with a very low platelet count (<40,000/l). However, LVP should be
avoided in the presence of clinically overt disseminated intravascular coagulation. LVP larger than
5 l should be performed with the administration
of albumin to decrease the risk of postparacentesis circulatory dysfunction [Gines et al. 2010].
The dose of albumin most commonly used is 8 g/l
of ascitic fluid removed. However, lower doses
may be effective, which could reduce the cost of
the procedure. In an unblinded study, Allesandria
and colleagues [Allesandria et al. 2011] found
that half the dose of albumin (4 g/l of ascitic fluid
removed) was as effective as the standard dose in
preventing paracentesis-induced circulatory dysfunction and renal failure. However, the most
important factor in avoiding paracentesis-induced
circulatory dysfunction is to discontinue -blocker
therapy [Serste etal. 2010].
In selected patients, a TIPS is an alternative to
serial LVP [Gines et al. 2002]. This procedure 87

Therapeutic Advances in Gastroenterology 8(2)

Table 3. Diagnostic criteria of HRS [Salerno etal. 2007].
Cirrhosis with ascites
Serum creatinine > 1.5 mg/dl
No improvement of serum creatinine (decrease to a level 1.5 mg/dl) after at least 2 days of diuretic
withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body
weight per day up to a maximum of 100 g/day
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria
(> 50 red blood cells per high-power field), and/or abnormal renal ultrasonography

creates a shunt between the portal and suprahepatic veins, thereby reducing portal hypertension
and the rate of recurrence of ascites. Use of a
TIPS is associated with improved systemic hemodynamics and renal function. Many patients with
refractory ascites regain the ability to excrete urinary sodium and can be maintained free of ascites
without sodium restriction or diuretics. In controlled trials comparing paracentesis combined
with intravenous albumin versus a TIPS in patients
with cirrhosis and ascites, the TIPS was clearly
worse, in terms of improvement of ascites and
survival, in patients with refractory ascites than
recurrent ascites [Gines etal. 2002; Lebrec etal.
1996; Rssle etal. 2000; Sanyal etal. 2003]. The
most frequent complication of TIPS use is
encephalopathy [Sanyal etal. 1994]; the incidence
of new or worsening encephalopathy following
TIPS use was found to be 2031% [Salerno etal.
2004; Somberg etal. 1995]. In addition, a TIPS
cannot be applied in some patients with advanced
liver disease (ChildPugh class C), congestive
heart failure, and/or severe pulmonary hypertension owing to an increased risk of mortality, or in
patients with portal thrombosis or inadequate
anatomy of the portal and hepatic veins. Given
that TIPS use is not associated with an improvement in survival, total paracentesis with intravenous albumin for volume replacement is
considered the treatment of choice for refractory
ascites in cirrhosis.
During the past 50 years, several procedures
aimed at improving the treatment of refractory
ascites have been developed [Arroyo, 2013].
Peritoneovenous shunting (PVS) involves a multiperforated intraperitoneal tube connected to a
subcutaneously implanted unidirectional pump
that permits the passage of fluid out of, but not
into, the abdominal cavity, and a second subcutaneous tube that reaches the superior vena cava
through the internal jugular vein [LeVeen et al.
1974]. When ascites is significant, it circulates

through the prosthesis in response to a pressure

gradient (positive in the peritoneum, negative in
the intrathoracic circulation). However, the flow
decreases or even stops if central venous pressure
increases, thus preventing fluid overload. Many
studies have demonstrated that PVS is associated
with major improvements in circulatory and renal
function and a better response to diuretics in
patients with refractory ascites [Gines etal. 1991].
However, these beneficial effects did not result in
a significant improvement in the long-term management of patients or in a reduction in the total
time spent in hospital during follow up, because
of a very high rate of shunt obstruction requiring
reoperation. Moreover, these complications were
not prevented by a redesign of the valve (Denver
shunt) or by insertion of a thromboresistant titanium tip in the vascular end of the prosthesis
[Gines etal. 1995]. Recently, an automated system was developed to remove ascites from the
peritoneal cavity into the urinary bladder, from
which it can be eliminated by normal urination
[Bellot et al. 2013]. The pump system removed
90% of the ascitic fluid and significantly reduced
the median number of LVP sessions per month in
40 patients with recurrent ascites. Larger studies
are needed to confirm the safety and efficacy of
this procedure.
Hepatorenal syndrome
Renal failure is a serious complication in patients
with advanced cirrhosis. It occurs in about 20%
of patients hospitalized with decompensated cirrhosis [Garcia-Tsao et al. 2008; Moore, 2013].
Renal dysfunction is diagnosed based on levels of
creatinine and on creatinine-based equations.
However, a recent study [Francoz et al. 2010]
showed that creatinine-based formulae overestimate the true glomerular filtration rate, especially
in patients with cirrhosis aged under 50 years and
in those with ascites. In about 70% of patients,
renal failure is caused by prerenal failure due to


K Lenz, R Buder et al.

Table 4. Diagnostic criteria for kidney dysfunction in cirrhosis using the acute kidney injury definition [Wong etal. 2011].


Acute kidney injury

Chronic kidney disease
Acute on chronic kidney

A rise in serum creatinine 50% from baseline, or a rise of >0.3 mg/dl

Glomerular filtration rate (GFR) <60 ml/min for >3 months calculated using the MDRD-6 formula
A rise in serum creatinine 50% from baseline or a rise of serum creatinine >0.3 mg/dl in a patient
with cirrhosis whose GFR is <60 ml/min for >3 months, calculated using the MDRD-6 formula

MDRD-6 formula: GFR = 170 serum creatinine0.999 age0.176 1.180 (if black) 0.762 (if female) serum urea nitrogen0.170 Albumin0.138.

gastrointestinal hemorrhage, bacterial infection,

or hypovolemia (overuse of diuretics), and in
about 30%, it is caused by intrarenal causes, e.g.
hepatitis B- or C-associated glomerulonephritis
or toxins. In about 70% of patients with prerenal
failure, renal function can be restored with fluid
replacement, but the remaining 30% are unresponsive to volume expansion [Garcia-Tsao etal.
HRS is a fully reversible impairment of renal
function in patients with severe hepatic failure
unresponsive to volume expansion. The prevalence of HRS in patients affected by cirrhosis and
ascites was found to be 18% after 1 year, increasing to 39% at 5 years [Gines and Schrier, 2009].
Before HRS is diagnosed, primary causes of renal
failure, such as hypovolemia, infection, nephrotoxins, and other renal diseases, must be excluded.
Nevertheless, in many patients with HRS lacking
proteinuria or hematuria, some histologic
changes are evident in kidney biopsies [Trawal
etal. 2010]. In almost half of patients with HRS,
one or more precipitating factors were identified,
including bacterial infections (57%), gastrointestinal hemorrhage (36%), and therapeutic paracentesis (7%) [Angeli et al. 2010]. Although a
precipitating event is often identifiable, HRS can
also develop in an apparently spontaneous way.
Spontaneous HRS causes no morphologic
changes in the kidney, although morphologic
alterations in the course of oligoanuria may reveal
a transition from intermediate to irreversible kidney damage with necrosis of the tubules. In
patients with HRS scheduled for liver transplantation, it may be prudent to consider simultaneous kidney transplantation [Restuccia et al.
HRS is diagnosed by excluding other forms of
renal failure. The diagnostic criteria initially proposed by the International Ascites Club in 1996
were re-examined in 2007 [Salerno et al. 2007]
(see Table 4). Two types of HRS were identified.

Type 1, a rapid deterioration of renal function

defined as an increase in serum creatinine to a

value twice the baseline and >2.5 mg/dl
within 2 weeks.
Type 2, a slow and gradual deterioration of
renal function with serum creatinine
>1.5 mg/dl, often in parallel to the worsening
of cirrhosis and portal hypertension, and leading to refractory ascites.
The reduced glomerular filtration rate evident in
patients with HRS is due to poor renal circulation
on the one hand and a reduced filtration fraction
on the other. Several factors are considered to
induce the impairment of renal function (Table 5).
Vasodilation in the splanchnic region
This is considered the most important trigger of
renal hypoperfusion. This vasodilation is associated with enhanced formation of vasodilators
and vascular hyporesponsiveness to vasoconstrictors. To date, several mechanisms have been
identified that may contribute to this enhanced
vasodilation and impaired vasoconstriction.
Portal hypertension increases the production
and release of endogenous vasodilators, such as
nitric oxide, carbon monoxide, and cannabinoids, into the splanchnic arterial circulation,
but other factors seem to be involved as well.
Even in the dormant phase of alcoholic liver disease, vasoactive substances are produced in
large quantities in the liver when the production
of cytokines is increased. In the presence of
endotoxin stimulation, such activation is
increased disproportionately. Even in patients
with nonalcoholic liver disease, infiltration of
endotoxins may play a role. Thus, patients with
HRS prior to liver transplantation exhibited significantly higher concentrations of interleukins
2 and 6 and tumor necrosis factor than patients
lacking HRS before liver transplantation [Burke 89

Therapeutic Advances in Gastroenterology 8(2)

Table 5. Pathomechanism of hepatorenal syndrome.
Underlying causes


Splanchnic vasodilation
Central underfilling
Activated volume and baroreceptors

Central underfilling
Activation of volume- and baroreceptors
Increased sympathetic nerve activity, increased
RAAS, increased nonosmotic vasopressin release
Renal vasoconstriction
Abolished autoregulation of the kidney
Activation of the hepatorenal reflex, causing an
increase in renal sympathetic nerve activity and a
decrease in renal blood flow
Compensatory increase in cardiac output to
maintain renal perfusion is lowered
Intrarenal vasoconstriction

Increased sympathetic activity, increased RAAS,

increased nonosmotic vasopressin release
Increased intrahepatic pressure and decreased
sinusoidal blood flow
Cardiac insufficiency
Increased synthesis of vasoactive mediators
RAAS, reninangiotensinaldosterone system.

etal. 1993]. Furthermore, increased endothelin

concentrations have been observed, and regulatory disorders of the adenosine system have also
been discussed [Gerbes et al. 1998].
Translocation of bacteria and bacterial products
from the gut is likely to be a main factor underlying the development of a chronic inflammatory state [Israelsen et al. 2014]. Another
mechanism seems to be defective contractile
signaling in smooth muscle cells in response to
vasoconstrictor stimulation [Hennenberg et al.
2008]. In addition to the liver itself, little is
known about the factors responsible for these
defects. The consequences are vasodilation,
increased plasma volume, and increased blood
flow in the splanchnic circulation, leading to a
reduction in the effective arterial blood volume
and a drop in arterial pressure. Vasodilation is
associated with increased mesenteric blood flow,
which may in fact be a useful mechanism to
maintain liver function. In one study, liver function in patients who underwent transplantation
for liver failure was found to be dependent on
the in-vitro liver circulation [Cardoso et al.
Central underfilling
In the early stages of cirrhosis, increased cardiac
output compensates for the reduction in systemic
vascular resistance caused by vasodilation in the
splanchnic area, and allows arterial pressure and
effective blood volume to remain within normal
limits. In the advanced stages of cirrhosis, splanchnic vasodilation is markedly increased, and additional increases in cardiac output can no longer

compensate, leading to central underfilling.

Central underfilling activates baro and volume
receptors, with consequent stimulation of the
sympathetic nervous system and RAAS and the
nonosmotic release of vasopressin. This results in
renal hypoperfusion caused by an increase in
renal vascular resistance [Lenz etal. 1991], reabsorption of sodium in the tubules, and increased
reabsorption of water in the distal collecting
Abolished autoregulation of kidney perfusion
Increased sympathetic nervous system activity
abolishes autoregulation in the kidney [Esler and
Kye, 1998]. Consequently, the renal circulation
becomes pressure-dependent, even in the presence of physiologic blood pressure [Stadlbauer
et al. 2008]. This is because the mean arterial
blood pressure at which renin starts to be released
is shifted to <110 mmHg [Kirchheim and Ehmke,
1994; Persson etal. 1990].
Hepatorenal reflex
In cirrhosis, sinusoidal pressure is elevated by
increased resistance and enhanced mesenteric
blood flow. Elevated pressure, secondary to swelling in the course of glutamine infusion via the
superior mesenteric artery, led to a reduction of
renal circulation and the glomerular filtration
rate. This was due to direct hepatorenal interaction [Lang et al. 1991]. Increased intrahepatic
pressure leads to enhanced activity of sympathetic
efferents from the liver that, through synapses in
the lumbar spinal cord, cause enhanced renal


K Lenz, R Buder et al.

sympathetic activity (the hepatorenal reflex
[Kostreva etal. 1980]). A decrease in sinusoidal
blood flow also triggers the hepatorenal reflex
[Ming et al. 2002]. An increase in renal sympathetic nerve activity leads to renal vasoconstriction and increased tubular sodium reabsorption.
Denervation of the kidney eliminates this renal
sympathetic activity, thereby reducing the impairment of renal function. This can also be achieved
by hepatic vagal denervation [Levy and Wexler,
1987]. In a clinical study, Solis-Herruzo and colleagues [Solis-Herruzo et al. 1987] were able to
interrupt the hepatorenal reflex with lumbar sympathetic block in patients with portal hypertension and thereby improve renal function.
Cardiac insufficiency
An increase in cardiac output is important to
compensate for the reduction in systemic vascular
resistance caused by vasodilation in the splanchnic area, and permits the arterial pressure and
effective blood volume to remain within normal
limits. There is evidence that cardiac output
decreases as cirrhosis progresses. Clinical, but not
overt, cardiac insufficiency, caused by underlying
viral diseases, toxins such as alcohol, and/or by
cirrhotic cardiomyopathy per se, seems to be one
of the leading risk factors for the development of
HRS. Ruiz-del-Arbrol and colleagues [Ruiz-delArbrol et al. 2005] showed that cardiac insufficiency can be detected at an early stage in patients
developing HRS. In addition, the use of -blockers
in patients with refractory ascites has been shown
to be deleterious [Serste etal. 2010]. These findings suggest a cardiorenal link in advanced cirrhosis (Krag etal. 2012b).
Relative adrenal insufficiency
This is a common subclinical condition in patients
with cirrhosis, and is diagnosed as an inadequate
production of cortisol in response to stimulation
with synthetic adrenocorticotropic hormone.
Adrenal insufficiency increases the risk of bacterial infection, septic shock, and HRS [Acevedo
et al. 2013]. Cortisol plays an important role in
hemodynamic homeostasis: the response of the
heart and blood vessels to catecholamines and
angiotensin-II is increased by cortisol. Low levels
of cortisol lead to an inadequate increase in cardiac output and insufficient vasoconstriction in
response to stress. Accordingly, adrenal insufficiency may be involved in the development of cardiomyopathy and HRS [Krag etal. 2012].

Treatment of renal failure

Treatment should begin as soon as renal failure is
diagnosed. The criteria for diagnosis of HRS may
lead to renal failure being detected too late
[Nadim etal. 2012]. In addition, creatinine-based
formulae may overestimate the true glomerular
filtration rate, because of the low levels of muscle
proteins in patients with cirrhosis and ascites
[Francoz etal. 2010]. Cystatin C-based equations
have proven more accurate in the evaluation of
renal function and the staging of chronic renal
insufficiency [De Souza et al. 2014]. Use of the
new definition of acute kidney injury (AKI) developed by the Acute Kidney Injury Network as
adapted for cirrhotic patients [Wong etal. 2011]
(Table 6) allows renal failure to be identified
much earlier [Moore, 2013]. A prospective observational cohort study of patients with cirrhosis
and AKI showed that AKI is frequently progressive and associated with mortality [Belcher etal.
2013]. Therefore, the early identification and
treatment of its cause are the cornerstones of
therapy (Table 6). This includes withdrawal of
-blockers in patients with end-stage cirrhosis
[Krag et al. 2012], discontinuation of nonsteriodal drugs and diuretics and, in patients with
hypovolemia due to bleeding, prompt treatment
with fluids and blood products combined with
measures to stop the bleeding [Baradarian et al.
To treat hypovolemia, the recommended dose of
albumin is 1 g/kg body weight in all patients after
at least 2 days of diuretic withdrawal [Salerno
et al. 2007]. However, because the degree of
hypovolemia varies between patients, a more precise estimation of the volume required appears
logical. Indeed, using invasive instruments,
Umgelter and colleagues [Umgelter et al. 2012]
demonstrated that much more fluid (up to 2 g
albumin/kg body weight) may be necessary to
normalize renal function. The main problem in
clinical practice is that invasive hemodynamic
monitoring can only be performed in intensive
care units. Nevertheless, if there are clinical signs
that 1 g albumin/kg is inadequate, more fluid can
be infused under the careful observation of noninvasive hemodynamic parameters and lung
Antiviral therapy may be effective in some patients
with renal failure due to hepatitis C-related glomerulonephritis after consideration of the possible
adverse effects of this therapy in patients with
advanced cirrhosis and hepatitis B virus-associated 91

Therapeutic Advances in Gastroenterology 8(2)

Table 6. Prophylaxis against hepatorenal system.

Prompt and adequate treatment of hypovolemic situations

Albumin substitution in spontaneous bacterial peritonitis (SBP)
Albumin substitution with large-volume paracentesis
Antibiotic prophylaxis in patients at increased risk of SBP
Withdrawal of -blockers in patients with cirrhosis with recurrent and refractory ascites
Withdrawal of nonsteroidal drugs in portal decompensation
Nephroprophylaxis in patients with cirrhosis when radiologic studies using contrast medium are

kidney injury [Gane et al. 2014]. Bacterial infections must be identified and treated early. In
patients with SBP, the addition of albumin (1.5 g/kg
body weight at the time of diagnosis, followed by 1
g/kg on day 3) to antibiotic treatment reduces the
incidence of renal failure [Salerno etal. 2013; Sort
etal. 1999].
Ascites is a risk factor for the development of contrast-induced nephropathy. Although no reports
show that cirrhosis without ascites is a risk factor,
all patients with cirrhosis who undergo radiologic
studies and require contrast medium should
receive standard prophylactic saline hydration
[Lodhia etal. 2009]. A recent study [Mahmoodi
etal. 2014] involved patients with coronary heart
disease and chronic renal failure with a serum
creatinine level of up to 4 mg/dl who were undergoing coronary intervention, use of a bicarbonate
solution (prepared by adding 154 ml of 1000
mEq/l sodium bicarbonate to 846 ml of 5% dextrose in water) conferred greater protection than
hydration with normal saline against contrastinduced AKI. However, because metabolic alkalosis, mostly due to low albumin concentration, is
a frequent finding in liver failure [Funk et al.
2006], further studies are required in patients
with cirrhosis to confirm these results.

in the short term, but this effect is no longer evident after 6 months [Mathurin etal. 2013]. Oral
antibiotics are effective in reducing the incidence
of HRS in patients with advanced cirrhosis and
ascites. In a randomized placebo-controlled study,
primary prophylaxis with norfloxacin reduced the
incidence of SBP and delayed the development of
HRS in patients with cirrhosis, low-protein ascitic
fluid (<15 g/l), and advanced liver failure (Child
Pugh score >9) [Fernandez etal. 2007].
Knowledge of the pathophysiologic features of
HRS has led to a variety of therapeutic approaches.
It would be logical to assume that renal function is
improved by substances that abolish renal vasoconstriction. However, experiments performed
with prostaglandin to date have produced divergent results [Wong et al. 1994]. Likewise, the
administration of dopamine achieves improvements in cirrhotic patients with relatively good
renal function, but not in patients with massively
impaired renal function [Bennet etal. 1975; Peschl,
1987]. In patients with cirrhosis, renal failure, and
tense ascites, increased abdominal pressure (IAP)
may contribute to renal dysfunction. Reduction of
IAP following paracentesis and albumin substitution improves renal function, probably by improving renal blood flow [Umgelter etal. 2009).

In end-stage cirrhosis, -blockers may reduce

survival owing to their negative impact on the cardiac compensatory reserve. The inability to
increase cardiac output may compromise organ
perfusion in these patients [Krag etal. 2012]. The
use of -blockers is associated with increased
mortality in patients with refractory ascites at
high risk of paracentesis-induced circulatory dysfunction [Serste et al. 2010]. Although data on
this subject are scarce, the use of -blockers
should be avoided in patients with both cirrhosis
and renal failure.

The current therapeutic approach to HRS

includes the administration of vasoconstrictive
agents combined with albumin (Table 7). The
effect of vasopressors on renal function in this
situation is due to an increase in renal perfusion,
resulting from increased central blood volume
and elevated blood pressure. Given that autoregulation is diminished, increased blood pressure is
associated with increased renal perfusion. An
inadequate blood-pressure response to vasopressor therapy is a typical finding in nonresponders
[Nazar etal. 2011; Velez and Nietert, 2011].

Pentoxifylline has been shown to reduce the risk

of renal failure in patients with alcoholic hepatitis

The available vasoconstrictors comprise vasopressin analogues and alpha-adrenergic agents such as


K Lenz, R Buder et al.

Table 7. Treatment of hepatorenal syndrome.



Bolus: 0.52.0 mg intravenously every 46 hours, with stepwise dose

increments if there is no improvement of serum creatinine, to a maximum
of 12 mg/day or the occurrence of complications, in combination with
Continuous infusion: 4 mg/day with stepwise dose increments if there is
no increase in mean arterial blood pressure >10 mmHg or improvement
in serum creatinine level, up to a maximum of 12 mg/day or the
occurrence of complications, in combination with albumin.


Continuous infusion with a starting dose of 0.5 mg/h, with stepwise

increments if there is no increase in mean arterial blood pressure
>10 mmHg or improvement of serum creatinine level, up to a maximum
of 3 mg/h or the occurrence of complications, in combination with

Midodrine plus octreotide

Oral midodrine 7.512.5 mg three times daily to increase mean arterial

blood pressure >10 mmHg.
Octreotide 200 g subcutaneously three times daily.


1 g albumin/kg body weight on the first day, followed by 200400 g daily.

noradrenaline and midodrine. The first studies

were performed with octapressin, a vasopressin
derivative, more than 40 years ago [Kew et al.
1972]. Over 30 years ago, ornipressin (8-ornithinevasopressin: a vasopressin derivative that predominantly stimulates the vasopressin 1 receptor) was
found to improve central hypovolemia through
splanchnic vasoconstriction, leading to decreased
activation of vasopressor hormones (norepinephrine and renin) and decreased renal vascular resistance, resulting in improved renal perfusion in
patients with cirrhosis and HRS [Lenz etal. 1991].
Because ornipressin was removed from the market,
subsequent studies were performed using terlipressin. Terlipressin is a triglycyl-lysine-vasopressin
with a vasoconstrictive effect per se when given as a
bolus and an additional long-acting vasoconstrictive effect caused by lysine-vasopressin, which is
produced by triglycyl-lysine-vasopressin degradation [Ryckwaert etal. 2009]. Vasopressors such as
terlipressin induce vasoconstriction in the splanchnic vasculature by acting on vasopressin 1 receptors, resulting in redistribution of blood flow to the
kidneys. Vasopressin analogues have been shown to
decrease serum levels of vasoconstrictor hormones
such as norepinephrine and plasma renin activity,
leading to a decrease in renal vascular resistance
[Lenz etal. 1991]. The vasopressin analogue terlipressin has been shown not only to improve renal
function by peripheral actions, but also to significantly influence cardiac filling volumes [Krag etal.
2010]. In experimental ovine endotoxemia, intermittent bolus injections of terlipressin were linked

to decreased heart rate and cardiac index and

Continuous infusion of terlipressin reversed endotoxin-induced systemic arterial hypotension and
improved left-ventricular stroke-work index [Lange
etal. 2007]. Therefore, continuous administration
of terlipressin may be superior to bolus injection.
Norepinephrine has a positive inotropic effect,
which may be important in overcoming the cardiac insufficiency induced by chronic liver disease.
In patients with portal hypertension, terlipressin
increased thoracic and liver blood volumes and
altered portal pressure by causing vasodilation of
intrahepatic vessels [Kiszja-Kanowith etal. 2004].
The effect of terlipressin can be significantly
enhanced by the addition of high doses of human
albumin [Ortega etal. 2002]. Although the favorable effect of albumin in this context is traditionally linked to its role in volume replacement, other
mechanisms related to its nononcotic properties
are likely to be involved. Albumin binds to and
carries a variety of hydrophilic and hydrophobic
molecules, including metals, fatty acids, metabolites, and drugs. Many potentially toxic ligands
are neutralized and catabolized by binding to
albumin. Furthermore, albumin is the major
source of extracellular reduced sulfhydryl groups,
potent scavengers of reactive oxygen species generated by oxidative stress; thus, albumin is the
main circulating antioxidant in the body. Recent
studies have shown that both albumin 93

Therapeutic Advances in Gastroenterology 8(2)

concentration and function are reduced in
patients with cirrhosis [Jalan and Bernardi, 2013],
and that the degree of albumin dysfunction is
related to the prognosis of liver disease [Jalan and
Bernardi, 2013; Oettl et al. 2013]. In addition,
albumin has been shown to have a positive cardiac inotropic effect in cirrhotic rats [Bortoluzzi
et al. 2013]. Substitution of albumin therefore
seems to accomplish more than plasma
Many studies have been performed with terlipressin. Meta-analyses have demonstrated that the
combination of terlipressin and albumin improves
renal function in patients with HRS type 1 [Nazar
etal. 2011; Neri etal. 2008] and reduces mortality when compared with albumin alone. The
reduction in mortality was evident in patients
with type I, but not type II, HRS [Gluud et al.
2010]. Therefore, terlipressin plus albumin may
facilitate survival to transplantation and a better
outcome after transplantation, because normalization of renal function before transplantation is
associated with increased survival after transplantation [Restuccia etal. 2004]. In these studies, a
fixed dose of 1 g albumin/kg body weight on the
first day, with a reduction to 2040 g on subsequent days, was used. Terlipressin was started on
the first day at a dose of 0.5 mg every 46 hours,
with an increase to a maximum of 12 mg per day
until improvement of renal function occurred,
defined as a serum creatinine concentration of
<1.25 mg/dl. An improvement was seen within
14 days [Martin-Llahi et al. 2008; Neri et al.
2008; Sanyal etal. 2008]. Predictors of improved
renal function in patients with HRS include early
stage renal failure, increased blood pressure
induced by the vasopressor, normal sodium concentration, and ChildPugh score <11 [Boyer
etal. 2011; Nazar etal. 2011; Velez and Nietert,
2011; Wong et al. 2004]. Given that larger
amounts of albumin-containing fluids have been
shown to restore kidney function more effectively
[Umgelter et al. 2012], goal-oriented volume
therapy, using serial echocardiography to assess
changes in intravascular volume by measuring
inferior vena caval diameter, right-ventricular
end-diastolic volume index, left-ventricular enddiastolic area index, and global end-diastolic volume index, may be useful [Charron etal. 2006],
although studies on cirrhotic patients are scarce.
Also controversial are the parameters for titrating
the dose of terlipressin. Given that a close relationship exists between hemodynamics and the

improvement of renal function [Nazar etal. 2011;

Velez and Nietert, 2011], an increase in mean
arterial pressure of 10 mmHg, as used in studies with norepinephrine, may help to achieve an
earlier improvement in renal function [Maddukuri
et al. 2014]. Adverse effects of terlipressin (predominately ischemia) leading to the discontinuation of treatment occur in about 12% of patients
[Fagundes and Gines, 2012]. Therefore, patients
with coronary heart disease, peripheral vascular
disease, and/or cerebrovascular disease should
not be treated with terlipressin. Some of these
complications may be caused by the bolus injection, because of the acute effect of the prodrug
[Ryckwaert et al. 2009]. A continuous infusion
may overcome this problem [Angeli etal. 2009].
Studies on endotoxic shock in animal models, in
which continuous infusion of terlipressin exerted
a superior effect on cardiac contractility than
bolus injection [Lange et al. 2007], support the
advantages of continuous infusion of terlipressin.
Alpha-adrenergic agonists, such as norepinephrine [Sharma et al. 2008; Singh et al. 2012] or
midodrine, in combination with octreotide and
albumin [Angeli et al. 1999; Skagen et al. 2009;
Wong etal. 2004], are a reasonable alternative to
terlipressin because of their low cost and wide
availability. However, data on their use are limited. They are recommended in the guidelines of
the American Association for the Study of Liver
Diseases (AASLD) because terlipressin is not yet
available in the United States [Runyon, 2012],
but they are not recommended by the European
Association for the Study of the Liver (EASL)
[Gines etal. 2010]. If HRS reoccurs after the discontinuation of treatment, patients should be
retreated with the same drug combination [Gines
etal. 2010].
TIPS use was reported to be effective for HRS
Type 1 in an uncontrolled study of a small group
of patients [Guevara et al. 1998]. Insertion of a
TIPS further improved renal function and sodium
excretion in patients with HRS type 1, who
responded to a combination of midodrine, octreotide, and albumin [Wong et al. 2004]. More
studies are necessary to evaluate TIPS use in
patients with HRS type 1. TIPS use is not recommended in the guidelines of the EASL or AASLD.
Type 2 HRS is a type of renal dysfunction that
arises from the deterioration of several organ systems, and is primarily caused by liver failure and
portal hypertension. It is part of a gradually


K Lenz, R Buder et al.

developing multiorgan dysfunction, with central
hypovolemia and cardiac dysfunction as the main
pathogenic triggers [Lenz, 2005]. There are very
few data about the use of vasopressors in combination with albumin in patients with HRS type 2.
The clinical picture is dominated by therapy for
refractory ascites and hyponatremia. Therefore,
repeated paracentesis is the first-choice treatment; if renal function is deteriorating, the use of
vasopressors should be considered [Fagundes
and Gines, 2012]. Patients must be evaluated to
determine whether they are candidates for liver
Renal replacement therapy (RRT) has been used
in patients with type 1 HRS waiting for liver
transplantation. There are no data comparing
extracorporeal therapy with vasopressors plus
albumin in patients with HRS; nevertheless, RRT
is not considered to be a first-line treatment,
because it does not correct the underlying pathophysiologic changes. RRT should be reserved for
patients planned for liver transplantation. The
mortality of patients with HRS treated with
hemodialysis or hemofiltration in the intensive
care unit is reportedly high [Witzke etal. 2004].
In a small study [Mitzner etal. 2000], improvement of renal function followed use of an extracorporeal liver assist system (MARS). However,
in the recently published RELIEF trial, MARS
therapy did not demonstrate a positive effect on
patients with acute or chronic liver failure
[Banares etal. 2013]. EASL guidelines state that
RRT may be useful in patients who do not
respond to vasoconstrictor therapy [Gines et al.
2010]. It remains unclear what modality of RRT
should be the first-choice treatment for pharmacologic nonresponders awaiting transplantation.
Conflict of interest statement
The authors declare that they do not have anything to disclose regarding conflicts of interest
with respect to this manuscript.
This research received no specific grant from any
funding agency in the public, commercial, or notfor-profit sectors.

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