Med Clin N Am 92 (2008) 813837

The Hepatorenal Syndrome

Santiago J. Munoz, MDa,b,*
a

Division of Hepatology, Department of Medicine, Albert Einstein Medical Center,

Philadelphia, PA 19141, USA
b
Jeerson Medical College, Philadelphia, PA 19107, USA

The onset of renal failure in a patient with cirrhosis or acute liver failure
(ALF, also known as fulminant liver failure) is alarming because it raises
the possibility of the hepatorenal syndrome (HRS). HRS is a distinct form
of renal failure that occurs in the setting of severe liver disease. HRS is the
most frequently fatal complication of cirrhosis, because nearly half of patients die within 2 weeks of this diagnosis (Fig. 1) [1]. The annual incidence
of HRS is estimated at 8% to 40% in cirrhosis [2,3]. The Model for End
Stage Liver Disease (MELD) score [46] in patients with cirrhosis and ascites parallels the risk of developing HRS [3,7]. Onset of ascites in patients
with MELD scores of about 10 is associated with an 8% and 11% risk of
HRS at 1 and 5 years, respectively [7]. If the MELD score approaches 18,
nearly 40% of patients develop HRS within 1 year [3]. The frequency of
HRS in severe acute alcoholic hepatitis and in fulminant liver failure is
about 30% and 55%, respectively [8,9]. Most episodes of renal failure in
patients with liver disease, however, are not related to HRS. Common
high-risk scenarios for HRS include diuretic-resistant tense ascites, severe
hyponatremia or coagulopathy, and a MELD score greater than 18. Profound jaundice is often present, but HRS can develop in patients with
minimal hyperbilirubinemia. Periodic surveillance of renal function is helpful in patients with severe liver disease to detect HRS early and to help
correct reversible contributing factors. Once established, HRS responds
relatively poorly to medical management, although recent advances have
brought hope for an improved prognosis. In this article, the diagnosis,

* P.O. Box 403, Moorestown, NJ 08057.

E-mail address: orolonco@comcast.net
0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2008.03.007
medical.theclinics.com

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Fig. 1. Severe impact on survival associated with onset of hepatorenal syndrome. (From Arroyo
V, Terra C, Gines P. Advances in the pathogenesis and treatment of type 1 and type-2 hepatorenal
syndrome. J Hepatol 2007;45:93546; with permission.)

pathophysiology, and management of HRS are discussed in detail, with an

emphasis on recent diagnostic and therapeutic advances.
Denition
HRS is a distinct form of acute or subacute renal failure characterized by
severe renal vasoconstriction, which develops in decompensated cirrhosis or
ALF. This denition, developed by expert consensus in 1996, has been recently updated to include albumin as a volume expander [1012]. With greater
understanding of HRS, the denition should be rened further to include
more specic parameters and improved tests of renal injury [13,14].

Clinical presentation and classication

Patients with liver failure can develop two distinct clinical forms of HRS,
designated as type 1 and type 2, based on the time course and precipitating factors. These syndromes reect renal injury from circulatory disturbances
caused by profound liver failure. Patients with HRS and underlying acute or
chronic kidney disease do not t into this classication, and are denoted as
type 3 HRS (Box 1). The major diagnostic criteria of HRS are shown in Box 2.
Type 1 hepatorenal syndrome
In type 1 HRS the serum creatinine level doubles to greater than 2.5 mg/
dL within 2 weeks [1012]. The key features of type 1 HRS are its rapid
progression and high mortality, with a median survival of only 1 to 2 weeks

THE HEPATORENAL SYNDROME

815

Box 1. Classification of the hepatorenal syndrome

Type 1: cirrhosis with rapidly progressive acute renal failurea
Type 2: cirrhosis with subacute renal failurea
Type 3: cirrhosis with types 1 or 2 HRS superimposed on chronic
kidney disease or acute renal injuryb
Type 4: fulminant liver failure with HRSb
The clinical characteristics, natural history, and laboratory features of types 3
and 4 HRS have not been studied.
a
As recently redefined by the International Ascites Club [12,95].
b
Chronic kidney diseases include diabetic nephropathy, chronic
glomerulonephritis, hypertensive nephropathy, and others. Acute renal injury
includes acute tubular necrosis and other causes.

(see Fig. 1) [7,11]. Common precipitating events in type 1 HRS include

bacterial infections, particularly spontaneous bacterial peritonitis; variceal
hemorrhage; major surgery; and acute alcoholic hepatitis. Sometimes acute
hepatic injury, superimposed on cirrhosis, may lead to liver failure and
HRS. The hepatic injury can occur from acute viral hepatitis; drug-induced
liver injury (acetaminophen; idiopathic drug-induced hepatitis); hepatic

Box 2. Major diagnostic criteria for hepatorenal syndromea

1. Chronic or acute liver disease with advanced hepatic failure
and portal hypertension
2. Serum creatinine >1.5 mg/dL, reflecting decreased glomerular
infiltration rate
3. Absence of shock, bacterial infection, and current or recent
treatment with nephrotoxic drugs; absence of gastrointestinal
or renal fluid losses
4. No sustained improvement in renal function (decrease in
serum creatinine to 1.5 mg/dL) after diuretic withdrawal and
plasma volume expansion with intravenous albumin (1 g/kg
body weight up to a maximum of 100 g)b
5. Proteinuria < 500 mg/dL and no evidence of parenchymal
renal disease by urinalysis, or of obstructive uropathy by
ultrasonographyc
a

As defined by expert consensus [1012].

Albumin favored over isotonic saline for plasma volume expansion [12,95].
c
This criterion does not apply to patients with liver disease who also have
intrinsic renal disease and develop HRS. No studies have been performed to
characterize HRS in the presence of renal disease.
b

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ischemia; are of chronic hepatitis B virus infection caused by an emergent

resistant viral strain or withdrawal of antiviral therapy; or superimposed
acute delta virus hepatitis. Early identication of a precipitating event is
clinically important because it is frequently preventable or treatable with
specic medical therapy.
Type 2 hepatorenal syndrome
In type 2 HRS, the serum creatinine increases slowly and gradually during several weeks or months with a reciprocal gradual reduction in glomerular inltration rate (GFR). This generally occurs without a precipitating
factor. The median survival of type 2 HRS is about 6 months, signicantly
longer than for type 1 [15]. Nonetheless, type 2 HRS still has an extremely
poor prognosis. Unless liver transplantation is performed, or a dramatic
response to therapy of the underlying liver disease occurs (such as HBVrelated cirrhosis responding to antiviral therapy), many patients with type
2 HRS eventually progress to type 1 HRS because of a precipitating factor.
The clinician should distinguish between type 1 and type 2 HRS. The
former is associated with a rapidly fatal prognosis. Type 1 HRS must be
urgently managed, with elimination of precipitating factors and evaluation
for liver transplantation. In contrast, type 2 HRS permits less frantic
evaluation and therapy [15]. Both types are part of a spectrum of renal dysfunction in the setting of severe liver disease. Patients may progress from
type 2 to type 1 HRS without an obvious precipitating factor other than
worsening liver failure. The mechanisms of this progression are unknown.
Type 3 hepatorenal syndrome: coexistent kidney disease
and hepatorenal syndrome
Patients with advanced liver disease frequently have coexistent intrinsic
renal dysfunction. A recent study found that 85% of end-stage cirrhotics
had intrinsic renal disease on renal biopsy [16,17]. Patients with pre-existing
renal disease do not meet the traditional diagnostic criteria for HRS [1012].
They have not been included in therapeutic clinical trials. Because they can
also develop HRS from circulatory derangements found in liver failure,
patients with pre-existing kidney disease and HRS are best categorized separately (see Box 1). A cirrhotic patient with long-standing diabetic nephropathy, obstructive renal disease, or chronic glomerulonephritis can develop
HRS from a precipitating event or worsening liver failure. Similarly, a patient may develop HRS simultaneous with acute tubular necrosis (ATN) because of the same precipitating factor, such as severe variceal hemorrhage.
Given the absence of diagnostic markers for HRS, the evaluation of a cirrhotic patient with multiple causes of renal failure is complex. It is unclear
whether a chronically reduced baseline GFR, from chronic intrinsic renal
disease, predisposes cirrhotic patients to develop HRS. Patients presenting
with multiple causes for renal failure should be carefully evaluated by

THE HEPATORENAL SYNDROME

817

a hepatologist and a nephrologist. In selected cases renal histology may be

necessary for the diagnosis and for selection of patients for liver transplant
alone versus combined liver-kidney transplant (see later).
Type 4 hepatorenal syndrome: acute liver failure
More than half of patients with ALF develop HRS, although the frequency varies depending on the ALF etiology [8,9]. HRS complicating
ALF is superimposed on the already poor prognosis of ALF, especially
when acetaminophen-related. Nonetheless, both organ failures can be
reversed by urgent liver transplantation. The pathophysiology of HRS in
ALF is believed to be similar to that postulated for HRS occurring in cirrhosis. This contention remains speculative because of a lack of pathophysiologic
studies. The clinical course, prognosis, and complications are very dierent
for patients with cirrhosis than for patients with ALF. The mechanism of
HRS may dier in the setting of ALF versus the setting of cirrhosis.
Diagnosis
A rising serum creatinine in a patient with cirrhosis or ALF is sucient
cause to investigate for possible HRS. In patients with advanced cirrhosis,
the normal serum creatinine level is typically 0.6 to 0.8 mg/dL because of
muscle wasting, and a serum creatinine above 1.4 mg/dL reects a substantially decreased GFR [1012]. Five major criteria must all be present for the
diagnosis of HRS [11,12,18]. Minor additional criteria are supportive but
not essential for the diagnosis (Box 3). Because of the lack of diagnostic
markers or tests, HRS is diagnosed by the clinical method outlined in
Box 2. Despite these straightforward diagnostic criteria, recent studies
found that HRS was misdiagnosed in 60% to 70% of cases at a tertiary
care center [19,20]. Misdiagnosed patients had intrinsic renal disease, active
sepsis, drug-induced renal disease, and ATN. Greater adherence to the
consensus guidelines for the diagnosis of HRS is necessary.
First, other causes of renal failure must be investigated in cirrhotics.
Relatively common other causes include volume depletion; obstructive
Box 3. Minor diagnostic criteria for hepatorenal syndromea
Urine volume < 500 mL/24 h
Urine sodium <10 mEq/L
Urine osmolality greater than plasma osmolality
Urine red blood cells < 50 per high power field
Serum sodium <130 mEq/L
The minor criteria are supportive but not required for the diagnosis.
a
Defined by expert consensus [1012].

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MUNOZ

uropathy; shock; drug-induced renal failure; and intrinsic renal disease (eg,
hepatitis Crelated chronic glomerulonephritis, diabetic nephropathy). It is
critical to ensure an adequate intravascular volume by discontinuing diuretics and expanding the plasma volume. A signicant improvement in renal function (serum creatinine) after these maneuvers is inconsistent with
HRS. Plasma volume expansion was previously accomplished by intravenous administration of 1.5 L of normal saline [10], but sodium chloride
can readily escape from the intravascular compartment, particularly in patients with severe hypoalbuminemia (!22.5 g/dL), and minimally expands
the intravascular volume. Intravenous albumin (1 g/kg body weight up to
100 g) is now used (with packed erythrocytes if concomitant severe anemia
is present) because of greater ecacy in volume expansion and in achieving
a sustained reduction in serum creatinine [11]. In one study, 55% of patients
with HRS who failed a trial of volume expansion with isotonic saline had
reversal of HRS following albumin administration alone [21]. Patients
who respond to volume expansion with albumin do not have HRS, but renal
failure from hypovolemia. If renal failure persists after vigorous volume replacement with colloids, HRS is likely. A history of recent shock or administration of nephrotoxic agents, imaging evidence of urinary obstruction or
scarred kidneys, and a urinary sediment consistent with glomerular disease
suggest etiologies other than HRS. If intrinsic renal disease is identied, the
dilemma consists of determining whether the kidney disease is the sole cause
of the renal failure, or whether HRS is a contributing factor (type 3 HRS).
Infections (particularly spontaneous bacterial peritonitis, but also sepsis,
cellulitis, urinary tract infection, or pneumonia) can cause transient renal
dysfunction in cirrhotics that typically resolves with control of the infection.
Infections can, however, precipitate type 1 HRS (see later). This scenario is
suspected when the renal failure persists or worsens despite resolution of the
infection. Nonoliguric HRS (urine volumes O500 mL per 24 hours) and
HRS with urinary sodium excretion greater than 10 mEq/L can occasionally
occur [2224].

Pathophysiology
Type 1 hepatorenal syndrome
A series of clinical and experimental studies during the last two decades
has considerably increased the understanding of the pathophysiology of
HRS (Figs. 2, 3) [11,2527]. Hepatic brosis, architectural distortion, and
inammation from hepatic injury result in portal hypertension that is generally progressive. Both chronic liver disease and ALF can cause portal hypertension. Portal hypertension leads to arterial vasodilatation and pooling of
blood in the splanchnic bed, with a decrease in systemic vascular resistance.
In response, a systemic hyperdynamic circulatory state develops. Eventually,
activation of the renin-angiotensin-aldosterone system and the sympathetic

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THE HEPATORENAL SYNDROME

Progression of liver failure

and portal hypertension

Central
hypovolemia

Decrease in
cardiac output

Increase in arterial
vasodilation

Impaired cardiac
chronotropic function

Reduction in effective
arterial blood volume

moderate

severe

extreme

Sodium
retention

Water retention
Hyponatremia

Hepatorenal
syndrome

Fig. 2. Pathophysiology of the hepatorenal syndrome. (From Arroyo V, Terra C, Gine`s P. New
treatments of hepatorenal syndrome. Semin Liver Dis 2006;26:25464; with permission.)

nervous system and stimulation of antidiuretic hormone release become

necessary to maintain arterial blood pressure. As the liver disease worsens
(ie, from chronic active hepatitis C virus infection), these circulatory changes
gradually increase until systemic hemodynamic stability depends on vasoconstriction of the extrasplanchnic vascular beds (renal, hepatic, brain,
muscle, skin, adrenal glands, and possibly other regional vascular territories). In very advanced liver disease, prolonged high-level activation of the
renin-angiotensin-aldosterone system, sympathetic nervous system, and
antidiuretic hormone leads to intense, sustained renal vasoconstriction, resulting in decreased renal perfusion, decreased GFR, rising serum creatinine
levels, and ultimately to HRS (see Fig. 2). Intrarenal imbalance of vasoactive mediators, such as prostaglandins, kallicreine, adenosine, leukotrienes,
F2-isoprostanes, and endothelin, may play an important role in this severe
and sustained renal vasoconstriction [2831].
Cardiac and adrenal dysfunction may contribute to the circulatory disturbances in type 1 HRS (Fig. 3) [11,32]. Unlike compensated cirrhotics
without renal failure, the cardiac output is normal or even subnormal in
patients with HRS [26,27]. Similarly, tachycardia is less prominent with
HRS. Despite intense sympathetic nervous system activation, inotropic
and chronotropic cardiac functions are depressed in HRS. A decreased
cardiac preload and a cirrhotic cardiomyopathy may cause the decreased
cardiac performance in patients with HRS. Additional studies are needed
to ascertain the reason for this impaired cardiac function.
In a recent report, 80% of patients with HRS precipitated by sepsis had
adrenal dysfunction [33]. Replacement therapy with hydrocortisone in

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Spontaneous bacterial peritonitis

or other precipitating event
Adrenal
dysfunction
Increase in arterial vasodilation
Decrease in cardiac output
A-II, NE, ADH
resistance to
portal venous flow

Aggravation of
portal hypertension

Regional arterial
vasoconstriction
Kidneys

HRS

Brain

Encephalopathy

Liver

Liver failure

Fig. 3. Pathophysiology of the hepatorenal syndrome and multiorgan failure in advanced

cirrhosis. (From Arroyo V, Terra C, Gine`s P. New treatments of hepatorenal syndrome. Semin
Liver Dis 2006;26:25464; with permission.)

cirrhotics with sepsis and adrenal insuciency improved systemic hemodynamics and in-hospital survival [34]. The arterial response to endogenous
vasoconstrictors depends on adequate levels of adrenal corticosteroid
hormones. Adrenal dysfunction may be important in the hemodynamic
mechanism of type 1 HRS related to sepsis.
The precipitating event for type 1 HRS is believed rapidly to worsen the
hemodynamic disturbances that led to acute renal failure. The magnitude
and pace of circulatory derangement induced by this precipitating event
may exceed a threshold beyond which the hepatic, brain, and adrenal vascular beds join with the renal vasculature in vasoconstriction, which results in
multiorgan failure (see Fig. 3) [11]. Conceptual dierences between HRS
types 1 and 2 have clinical implications for the prevention of HRS and
the management of precipitating events.
Type 2 hepatorenal syndrome
The hemodynamic and humoral abnormalities described previously for
type 1 HRS also operate in type 2 HRS, but are present to a lesser extent.
Type 2 HRS is related to gradually deteriorating liver function that results
in circulatory dysfunction. In contrast to type 1 HRS, precipitating factors
are generally not present in type 2 HRS. Many patients with type 2 HRS eventually progress to type 1 HRS, however, often because of a precipitating event.
A better understanding of circulatory abnormalities associated with HRS
has led to a combination of therapeutic interventions to correct these abnormalities (ie, the decreased intravascular eective arterial volume, the renal
vasoconstriction, and the peripheral arterial vasodilatation).

THE HEPATORENAL SYNDROME

821

Type 3 hepatorenal syndrome: pre-existing kidney disease

and hepatorenal syndrome
Cirrhotics often have long-standing intrinsic renal disorders, such as diabetic nephropathy, chronic glomerulonephritis, and nephrolithiasis
[16,17]. Such patients were traditionally excluded from HRS [1012], and
the presence of the renal vasoconstriction of HRS in the presence of intrinsic
renal disease has not been analyzed. Without these data, specic diagnostic
criteria have not been developed for type 3 HRS. Except for the absence of
pre-existing kidney disease, clinicians use the other diagnostic criteria of
HRS to assess whether patients with underlying renal disease have HRS.
This approach, however, has not been validated. Patients with cirrhosis
and pre-existing renal disease may be at higher risk to develop HRS. The
pathophysiology is likely more complex than pure forms of HRS. Studies
are needed to address this growing and complex group of patients at risk
for HRS (see Box 1).
Type 4 hepatorenal syndrome: acute liver failure
ALF patients rarely develop refractory ascites or severe portal hypertension, with a hyperdynamic circulatory state. Acute renal failure in ALF
may share certain pathways with HRS of cirrhosis, but little is known
concerning the events and mechanisms leading to HRS in the setting of
ALF.
Therapy
General management
Patients with types 1 and 4 HRS require monitoring in an intensive care
unit. Patients with type 2 and 3 HRS may alternate between intensive care,
monitored bed, or standard hospital care. Diuretics are discontinued when
HRS is suspected. The status of the intravascular volume is assessed, and
this volume is restored as needed. It may be dicult to assess the intravascular volume status in the presence of ascites and edema. Determination of
the central venous pressure, and a trial of volume expansion with intravenous albumin may be helpful. If acidosis, hyperkalemia, uremic symptoms,
or volume overload occurs, continuous hemoltration or hemodialysis may
be helpful. Discontinuation of nephrotoxic agents is essential, including
nonsteroidal anti-inammatory agents and aminoglycosides. Angiotensinconverting enzyme inhibitors, nitrates, and other vasodilators should be
withheld during HRS. In a prospective study, administration of radiologic
contrast media to cirrhotics did not precipitate renal failure [35].
Type 1 HRS should be diagnosed early, with vigorous treatment of
the precipitating event, and management of any multiorgan failure.
Because septic processes (spontaneous bacterial peritonitis, urosepsis, and

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MUNOZ

gastrointestinal or biliary infections) are the most common precipitating

events, early systemic antibiotic therapy is critical in patients at high risk
for, or with established, HRS [36,37]. In type 1 HRS, adrenal function should
be tested with cosyntropin or another synthetic adrenocorticotropic hormone. If adrenal insuciency is detected, administration of stress doses of intravenous hydrocortisone improves survival [33,34]. Likewise, control of
esophagogastric variceal hemorrhage in a patient with type 1 HRS enhances
the probability of reversal or bridging to liver transplantation. If a patient
with type 1 HRS has severe or tense ascites, large-volume paracentesis with
albumin replacement is performed as needed. It is unclear how much massive
ascites impairs renal vein outow and hinders recovery from HRS.
Specic therapy for the underlying liver disease is promptly initiated, as
appropriate, such as antiviral therapy for HBsAg-positive cirrhosis (at doses
adjusted for renal failure); alcohol abstinence and nutritional support for
acute alcoholic hepatitis; and antidotes for toxic causes of ALF.
Patients with type 2 HRS often survive for several months. During this
time patients should receive prophylaxis for spontaneous bacterial peritonitis (SBP) and avoid precipitating events that can lead to type 1 HRS,
including volume depletion. This is particularly true during large-volume
paracentesis, because patients with type 2 HRS often have recurrent severe
ascites. Administration of intravenous albumin during large-volume paracentesis (approximately 10 g/L of ascites removed) is important to maintain
the intravascular volume and minimize circulatory disturbances after paracentesis. Primary or secondary prophylaxis of variceal hemorrhage with variceal band ligation is important [38]. Many cirrhotics take nonselective beta
receptor antagonists as prophylaxis against bleeding from esophagogastric
varices [38]. The eects of adrenergic beta receptor antagonists in HRS
are unstudied. Beta receptor antagonism in a patient with HRS may be
undesirable because of a decrease in cardiac output, but may be desirable
because of an antirenin eect of these agents. Duhamel and colleagues
[39] suspected that propranolol therapy may have precipitated HRS in
3 of 12 analyzed patients. Responders to beta receptor antagonists had
a lower risk of developing HRS in one study [40]. In an informal survey,
most experts believed that beta receptor antagonists should be discontinued
during HRS, but all considered that this issue should be investigated
(P. Gines, V. Arroyo, F. Wong, F. Salerno, A. Gerbes, personal communications, 2007). Avoidance of hepatotoxic and nephrotoxic therapeutic
agents, such as aminoglycoside antibiotics and nonsteroidal anti-inammatory agents, is also essential during the course of type 2 HRS. Vasodilators,
such as angiotensin-converting enzyme inhibitors, prazosin, and nitrates,
should be discontinued.
No data on the optimal care of patients with type 3 HRS are available.
The medical support for patients with type 4 HRS is similar to that for
patients with type 1 HRS, but there are no studies specically addressing
the treatment of type 4 HRS.

THE HEPATORENAL SYNDROME

823

Patients with types 1, 2, or 4 HRS should undergo prompt evaluation for

liver transplantation. If a patient is on an active liver transplant waiting list,
development of HRS prompts a high priority status. Patients with type 3
HRS should be evaluated for combined liver-kidney transplantation (see
later). Specic treatments described next may be additionally considered
in these desperately ill patients, with the understanding that knowledge
about these therapies and their limitations is incomplete.
Specic treatments
Medical therapies that target the circulatory abnormalities of HRS have
been developed during the last decade [11,12,22,23,4147]. Although the
results are generally promising, the total number of patients analyzed in
prospective trials is small. Furthermore, some studies may have included
patients without HRS or with potentially reversible renal failure. Because
of these trial shortcomings, these treatments may have limitations and
unappreciated toxicity. Despite these problems, the new therapies seem reasonably safe and possibly eective in sometimes reversing HRS [48]. Conventional renal replacement therapy (RRT) does not improve the
prognosis of HRS, but can help manage specic complications of HRS, including uid overload in anuric patients, acidosis, uremic symptoms, or severe hyperkalemia. Adjuvant therapy of these complications with RRT is
appropriate in liver transplant candidates, or in patients with severe acute
alcoholic hepatitis and HRS. RRT is unjustied, however, for HRS with terminal liver failure. RRT may be useful in patients with chronic renal disease
who develop superimposed HRS (see Box 1), but these patients have been
inadequately studied.
Renal vasodilator therapy with low-dose intravenous dopamine infusion
or the prostaglandin E1 analogue misoprostol did not prove ecacious and
are rarely used for HRS [49,50]. Experimental therapy with N-acetylcysteine
seems logical, but has not been evaluated in large studies [51,52]. Administration of the nonselective endothelin antagonist tezosentan was associated
with further deterioration of renal function in patients with type 2 HRS [53].
As knowledge increases on the mechanisms of renal vasoconstriction, renal
vasodilator therapy may be re-evaluated for HRS in the future.
Specic therapies for type 1 hepatorenal syndrome
Vasoconstrictors plus plasma volume expansion
Use of vasoconstrictors in HRS is intended to increase renal perfusion
caused by vasoconstriction of the splanchnic vascular bed. Intravenous
albumin is simultaneously infused to support the eective plasma volume.
These simultaneous interventions presumably reduce renal vasoconstriction
and improve renal perfusion (Table 1). Vasoconstrictor therapy for HRS is
inappropriate in the setting of terminal liver failure, intractable hepatocellular carcinoma, or when otherwise contraindicated (Box 4).

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Table 1
Eect of noradrenaline and albumin versus terlipressin and albumin in hepatorenal syndrome

Serum creatinine (mg/dL)

Mean arterial
pressure (mm Hg)
Central venous
pressure (mm H2O)
Urine volume (mL/d)
MELD score
Plasma renin (ng/mL/h)

Noradrenaline and albumin

(N 10)

Terlipressin and albumin

(N 12)

Baseline

End of therapy

Baseline

End of therapy

2.3  0.2
71  2

1.3  0.1a
84  2a

2.5  0.3
74  3

1.3  0.2a
84  3a

11  1

12  1

12  1

13  3

788  84
26  1
15  3

1583  243a
24  2
93

698  113
26  2
21  5

1578  314a
20  2a
7  3a

Abbreviation: MELD, Model for End Stage Liver Disease.

a
P!.05 with respect to baseline.
Data from Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenaline vs terlipressin in patients with hepatorenal syndrome: a prospective randomized unblinded pilot study.
J Hepatol 2007;47:499505.

About 12 pilot studies conducted during the last decade have suggested
that vasopressor therapy plus intravenous albumin improves the prognosis
of HRS. The total number of studied patients is less than 250, however,
and the results may be subject to sampling bias because of inconsistent study
inclusion criteria [54,55]. Nevertheless, prudent use of this combined therapy
seems justied in type 1 HRS given the consistently reported benets in the
context of the otherwise rapidly fatal outcome of type 1 HRS. In some reports, responders to vasoconstrictor plus albumin therapy had improved
survival, and a signicant proportion of patients were successfully bridged
to liver transplantation [5660]. Patients with type 1 HRS typically have

Box 4. Contraindications to vasoconstrictor therapy

in hepatorenal syndrome
Coronary artery disease
Cardiomyopathies
Cardiac arrhytmias
Cardiac or respiratory failure
Arterial hypertension
Cerebrovascular disease
Peripheral vascular disease
Bronchospasm, asthma
Terminal liver disease
Advanced hepatocellular carcinoma
Age >70 years

THE HEPATORENAL SYNDROME

825

actual or impending multiorgan failure. Use of vasoconstrictors and plasma

volume expansion should be closely monitored, with continuous monitoring
of central venous and arterial blood pressures.
The eect of these therapies on the probability of liver transplantation is
controversial. In countries where organ allocation is determined by the
MELD score, such as the United States, the signicant improvement in
MELD score, induced by vasoconstrictor therapy, can reduce the chances
of receiving a liver transplantation, particularly for type 1 HRS patients.
Whether improvement of HRS induced by vasopressor therapy is better
than liver transplantation is debatable. HRS often recurs after discontinuation of vasoconstrictor therapy and then has a high mortality. These
patients should be maintained at a high level on the waiting list, despite their
reduced MELD score secondary to vasoconstrictor therapy, by an exception
request to the regional review boards.
Therapies with a vasoconstrictor plus albumin are very promising for
type 1 HRS, an entity with nearly universal mortality without urgent liver
transplantation, but the risks of noradrenaline infusions require further
study.
Terlipressin plus albumin
Terlipressin is the most studied vasopressor agent, given its ecacy and
better safety prole [56,5868]. This synthetic vasopressin derivative is believed to have a much greater eect on vascular receptors (V1) than renal
vasopressin receptors (V2) [48]. A recent meta-analysis of 10 clinical trials
of terlipressin reported that this therapy was well tolerated and reversed
HRS in 52% of cases [48]. About 29% of treated patients experienced
side eects, including abdominal pain, self-limited cardiac arrythmias, cutaneous necrosis, nger ischemia, bronchospasm, and diarrhea. Most side
eects did not mandate treatment discontinuation and responded to lowering the dosage [48]. Terlipressin therapy is associated with improved serum
creatinine, urinary output, urinary sodium excretion, and plasma renin and
aldosterone levels (see Table 1) [56]. The terlipressin dose schedules used in
the prospective randomized studies are shown in Box 5. A randomized,
prospective, placebo-controlled clinical trial completed in the United States
used terlipressin at doses of 1 mg intravenously every 6 hours until the serum creatinine level decreased to less than 1.5 mg/dL on two measurements
48 hours apart, or for up to 14 days [60,61]. If after 3 days the serum creatinine did not decline by at least 30% from baseline, the dose of terlipressin
was increased to 2 mg every 6 hours. In this clinical trial, terlipressin was signicantly more eective than placebo in reversing type 1 HRS with a similar
safety prole [60,61]. A later report from the same group demonstrated that
earlier therapy with terlipressin increases the probability of HRS reversal,
whereas patients with a baseline serum creatinine greater than 5.6 mg/dL
had no reversal of HRS in this study [61]. The minimum duration for successful therapy is 3 to 5 days [56,61].

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Box 5. Typical treatment protocol of noradrenaline

or terlipressin for hepatorenal syndrome
Noradrenaline
Initial dose: 0.1 mg/kg/min intravenous infusion
If no increase in mean arterial pressure by 10 mm Hg:
increase dose by 0.05 mg/kg/min every 4 h up to
a maximum dose of 0.7 mg/kg/min
Or
Terlipressin
Initial dose: 1 mg intravenous bolus every 4 h
At day 3: if baseline serum creatinine not reduced 25%
increase terlipressin dose up to 2 mg every 4 h
Albumin
With either noradrenaline or terlipressin, administer IV
albumin as needed to maintain central venous pressure
of 1015 cm H2O
Treatment duration: until reversal of HRS or a maximum of 2 weeks.
Therapy can be repeated if HRS recurs.
Diuretics: not used during vasoconstrictor plus albumin therapy in this
protocol [56], but others use furosemide in combination with albumin to keep
central venous pressure within desirable range [23].
Data from Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenaline
vs terlipressin in patients with hepatorenal syndrome: a prospective randomized
unblinded pilot study. J Hepatol 2007;47:499505.

For patients whose HRS reversed with terlipressin and albumin, the
prognosis after liver transplantation is excellent and similar to that of transplanted patients without HRS [57]. The rate of postoperative hemodialysis,
severe infections, bleeding complications, recurrence of renal failure, and
survival and the mean hospital length of stay are similar to recipients transplanted without HRS [57]. Limitations of terlipressin therapy include a failure to reverse HRS in 40% to 45% of patients, high cost, and a high rate of
HRS recurrence after treatment discontinuation. Terlipressin cannot be
used in patients with vascular disorders (see Box 4). It is presently unavailable in the United States. Where available, terlipressin plus albumin therapy
seems relatively safe, well tolerated, and able to reverse the renal failure in
about half of treated patients. Additional studies are necessary to optimize
this therapy [54,55].
Noradrenaline plus albumin
Intravenous noradrenaline plus albumin has been evaluated as a therapy
for HRS in countries where terlipressin is unavailable. Alessandria and

THE HEPATORENAL SYNDROME

827

colleagues [56] recently reported a prospective randomized comparison of

noradrenaline versus terlipressin for HRS, according to the protocol outlined in Box 5. Both study groups received volume expansion with albumin.
Therapy with noradrenaline led to a complete response in 75% of type 1
HRS patients, similar to the 80% response achieved with terlipressin.
Eighty-three percent of the patients responding to noradrenaline were successfully bridged to liver transplantation, with improved survival (Fig. 4).
No signicant ischemic complications occurred in either group. HRS recurred after discontinuation of therapy, however, in 33% to 50% of patients
[56]. The costs of terlipressin therapy are about 15-fold greater than the
costs of noradrenaline therapy [56]. This study conrms previous observations and suggests that noradrenaline plus albumin may be a useful alternative to terlipressin. Patients included in this clinical trial, however, had early,
moderately severe HRS (mean baseline serum creatinine, 2.4 mg/dL). Half
of the patients had baseline serum creatinine levels less than 2 mg/dL, and
substantial urinary output (see Table 1). Whether these favorable results
apply to patients with severe or advanced HRS (creatinine O4 mg/dL, or
severe hepatic decompensation with bilirubin O10 mg/dL, and INR O3)
is unknown.

Fig. 4. Response of hepatorenal syndrome to vasoconstrictor plus albumin therapy results in

improved probability of survival. Solid line, responders; broken line, nonresponders. (From
Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenaline vs terlipressin in
patients with hepatorenal syndrome: a prospective randomized unblinded pilot study. J Hepatol
2007;47:499505; with permission.)

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Midodrine and octreotide

An oral a-adrenergic agonist (midodrine) in combination with octreotide
has been shown in three clinical trials, using variable dose regimens, to
improve type 1 HRS with results comparable with those reported for
terlipressin [22,50,69,70]. Midodrine is a direct vasoconstrictor, whereas
octreotide inhibits endogenous vasodilators. In two of the studies the intravascular volume was supported with albumin [22,50]. In a recent report of
81 patients treated with midodrine-octreotide (without concurrent albumin),
40% of patients responded with sustained reduction in serum creatinine, and
the 30-day survival was 57%, signicantly superior to the 30% survival of
controls [69]. The combination of oral midodrine and subcutaneous octreotide is appealing because of its suitability for outpatient use. The protocol
of midodrine-octreotide in the most recent study is summarized in Box 6
[69].
Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt (TIPS) is a theoretically
attractive therapy because it dramatically lowers both the portal pressure
and the pooling of blood in the splanchnic vascular bed, key pathogenetic
factors in HRS. The increased venous return produced by TIPS may be inappropriately handled, however, and even aggravate the cardiac dysfunction
observed in HRS. Furthermore, patients with HRS often have contraindications for TIPS, such as hepatic encephalopathy, severe jaundice, or very
advanced liver disease. TIPS in these circumstances may lead to liver failure

Box 6. Typical protocol of midodrine plus octreotide for therapy

of type 1 hepatorenal syndrome
Octreotide
Initial dose: 100 mg tid subcutaneous
Goal to increase dose up to 200 mg tid
Midodrine
Initial doses: 5 mg, 7.5 mg, or 10 mg tid orally
Goal to increase dose up to 12.5 mg or 15 mg tid if necessary
Doses of both agents are increased to induce a 15 mm Hg increase in mean
arterial pressure.
During diagnostic phase of HRS: volume expansion with 1.5 L normal saline
plus 120 g albumin. Discontinue albumin once HRS is established, and start
midodrine plus octreotide.
Data from Estrailian E, Pantangco ER, Kyulo NL, et al. Octreotide/midodrine
therapy significantly improves renal function and 30-day survival in patients
with type 1 hepatorenal syndrome. Dig Dis Sci 2007;52:7428.

THE HEPATORENAL SYNDROME

829

or intractable hepatic encephalopathy. Three studies have evaluated the

ecacy of TIPS in type 1 HRS in a combined total of only 35 patients
[22,71,72]. Improved serum creatinine and reversal of HRS was observed
in some patients who later became long-term survivors. The hazards and irreversible nature of TIPS have prevented broad application of this modality
for type 1 HRS. Many patients with type 1 HRS do not meet the criteria for
TIPS insertion (ie, serum bilirubin !5 mg/dL, INR !2, and Childs-Pugh
score !12). Further studies are needed to determine if and when TIPS is
helpful for HRS. TIPS is currently considered an experimental therapy
for HRS, that can be considered in a Childs-Pugh class A or B patient,
who meets the criteria for TIPS insertion, and who fails to respond to vasoconstrictor therapy and plasma volume expansion.
Specic therapy for type 2 hepatorenal syndrome
Type 2 HRS is more commonly seen in clinical practice than type 1 HRS.
All patients with type 2 HRS should be evaluated for liver transplantation.
Transplantation can potentially permanently reverse HRS and other complications of chronic liver failure. Severe ascites and hyponatremia are often
associated with type 2 HRS. Treatment expectations include HRS reversal
and survival improvement, and control of ascites and hyponatremia. The
available therapies for type 2 HRS are summarized in Box 7.
Vasoconstrictor therapy in type 2 hepatorenal syndrome
In four small pilot studies of therapy with terlipressin and albumin
[47,63,65] and one prospective controlled trial of therapy with noradrenaline
plus albumin [56], the combined reversal rate of type 2 HRS was about 80%.
HRS, however, frequently recurred after discontinuation of therapy.
Further studies are needed on vasoconstrictor therapy and plasma volume
expansion for type 2 HRS to determine the optimal vasoconstrictor and
the optimal dosing schedules. Currently, intravenous vasoconstrictor therapy can be cautiously considered in selected patients with type 2 HRS. A
liver transplant is substantially more benecial if HRS is reversed by vasoconstrictor and albumin therapy before transplantation [57]. The eect of
oral midodrine plus subcutaneous octreotide in type 2 HRS has not been
studied. This combination is appealing because a signicant proportion of
type 2 HRS patients are ambulatory.

Box 7. Available treatments for type 2 hepatorenal syndrome

Terlipressin plus albumin
Noradrenaline plus albumin
Liver transplantation
Transjugular intrahepatic portosystemic shunt

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Transjugular intrahepatic portosystemic shunt for type 2 hepatorenal

syndrome
Several studies on the use of TIPS in type 2 HRS noted improvement in
ascites control, serum creatinine level, and GFR, but no rm conclusions
can be made on reversal rate, eect on survival, or bridging to transplantation [47,71,7375]. Given the potential hazards of TIPS in patients with very
advanced liver disease, it should be cautiously applied as therapy for type 2
HRS. Refractory ascites often precedes development of type 2 HRS. A recent meta-analysis concluded that refractory ascites treated with TIPS was
associated with better survival and less portal hypertensive complications,
including HRS, than large-volume paracentesis [76].
Specic therapies for type 3 and type 4 hepatorenal syndrome
No specic therapies have been investigated for these types of HRS because of their exclusion from the traditional HRS classications and the
low frequency of ALF. Controlled therapeutic trials with vasoconstrictors
and albumin are needed. Terlipressin has been evaluated in patients with
ALF to treat arterial hypotension, but the eects on HRS were not reported
[77,78]. One report found that terlipressin caused a slight increase in intracranial pressure in ALF [77], but a more recent study found that terlipressin
increased cerebral perfusion without increasing intracranial pressure [78].
Patients with ALF and HRS may require dialysis. Continuous venovenous
hemoltration is preferred over intermittent hemodialysis because of
enhanced hemodynamic and intracranial pressure stability [79].
Articial liver support
Liver-assist technology may help in HRS by eliminating circulating
mediators of splanchnic vasodilatation and renal vasoconstriction. Several
systems have been tested in pilot studies of patients with acute or chronic liver
failure, with and without HRS [8083]. Hemodynamic benet and improvement of hepatic encephalopathy have been observed and lowered serum
creatinine. The latter eect is predictable in systems that include standard dialysis or continuous venovenous hemoltration [81,82]. ALF patients treated
with a porcine hepatocyte-based bioarticial liver developed renal failure at
half the rate of controls [80]. No details were provided, however, regarding
the specic types of renal failure observed in this prospective randomized,
controlled study. Recently, selective plasma hemoltration liver-assist devices have been used in HRS with acute-on-chronic end-stage liver disease
[83,84]. Currently, liver-assistance therapies cannot be advocated for HRS.
Liver transplantation
Because a failing liver and portal hypertension are the key initial events in
the development of HRS, liver transplantation is the ultimate treatment of

THE HEPATORENAL SYNDROME

831

choice for either type of HRS. Indeed, many reports have demonstrated resolution of HRS and long-term survival following liver transplantation.
Patients with HRS undergoing liver transplantation, however, have a slightly
increased perioperative morbidity and mortality compared with transplanted patients without HRS [8588]. Nevertheless, HRS is not a contraindication to liver transplantation. Allocation of liver donors is now primarily
guided by the MELD score, an index of disease severity and indicator of
short-term prognosis [46]. Serum creatinine is the highest weighted factor
in calculating the MELD score. Patients with HRS, particularly type 1, frequently achieve the highest priority for donor organ allocation. Despite
their generally high priority, patients with HRS often are not transplanted.
The precipitating event, such as SBP or sepsis, may prevent transplant surgery [36,37]. Additionally, type 1 HRS patients are often extremely ill, with
multiorgan failure, in whom the risks of transplant surgery may be prohibitive. In regions with a severe shortage of liver donors, the progression of
type 1 HRS within several weeks may provide insucient time to receive
a donor liver. In contrast, liver transplantation may be more practical and
successful in type 2 HRS, because of an absence of precipitating events,
its longer clinical course, and the relatively less severe renal failure. Patients
with any type of HRS have a very poor short-term prognosis without liver
transplantation [15]. They should have the highest priority for liver allocation, even if this requires requesting an exception to upgrade the MELD
score.
With MELD scores governing liver allocation, more patients with simultaneous liver and renal failure are achieving a high priority for transplantation. An important dilemma is whether to transplant both the liver and the
kidney in these extremely ill patients. Some patients have HRS, whereas
others have coexisting intrinsic renal disease (type 3 HRS; see Box 1). These
mixed clinical syndromes include chronic renal failure plus HRS, and nonHRS acute renal failure (ATN) plus simultaneous HRS. Determining the
diagnostic category in a specic patient is complex and requires urgent consultation by a team consisting of a hepatologist, nephrologist, and liver
transplant surgeon because of the poor short-term prognosis of HRS.
This determination should be done as expeditiously and as precisely as possible given the time constraints. Liver transplantation without renal transplantation is the best choice for patients with pure forms of HRS, and
perhaps in those with HRS and ATN, given the prospects of recovery
with postoperative RRT. Two recent reports found a possible benet of
combined liver-kidney transplantation in HRS patients selected on the basis
of requirement for RRT for longer than 8 weeks [89,90]. Simultaneous liverkidney transplantation may be the preferred approach for HRS in a patient
with chronic renal failure or with ATN superimposed on chronic renal
failure. Unfortunately, little data are available on these combined clinical
scenarios. Several large studies have reported the outcomes of patients
with elevated serum creatinine undergoing liver transplantation, but these

832

MUNOZ

studies did not report the proportion of patients with HRS, chronic renal
failure, ATN, or combinations thereof [91]. Cohorts with elevated serum
creatinine include dierent types of renal dysfunction [89].
The success of vasoconstrictor therapy for HRS in liver transplant candidates is important. Reversal of HRS before liver transplantation lowers the
postoperative risks of severe infections, bleeding complications, need for
hemodialysis, and recurrence of renal failure, while improving survival
and shortening postoperative hospital length of stay [57].
After liver transplantation, patients with HRS slowly recover renal function. The persistent postoperative renal impairment frequently requires
decreasing the dosage of calcineurin inhibitors (cyclosporine A, tacrolimus),
or renal-sparing immunosuppressive protocols.
Prevention of hepatorenal syndrome
Sepsis, variceal hemorrhage, shock, severe acute alcoholic hepatitis, or
use of nephrotoxic drugs often precipitate type 1 HRS. The risk of HRS
may be lowered by following standard guidelines to prevent these events,
particularly SBP or variceal bleeding [18,38]. Infections other than SBP
should be promptly identied and vigorously treated to minimize the risk
of HRS. Debilitated patients with advanced cirrhosis often have chronic
leukopenia and may not develop leukocytosis or fever, even with severe
infections. A high index of suspicion is necessary to identify infections early
in decompensated cirrhotics.
Prevention of type 1 HRS has been demonstrated in three prospective
randomized clinical trials [3,92,93]. In the most recent trial, administration
of noroxacin for primary prophylaxis for SBP reduced the 1-year probability of HRS to 28%, compared with 41% in controls not administered antibiotic prophylaxis (Fig. 5) [3]. This study strongly suggested that HRS can
be prevented in patients with advanced cirrhosis and ascites with a low
protein content (!1.5 g/dL). In another study, the administration of albumin (1 g/kg intravenously) at diagnosis and at day 3 in patients with SBP
signicantly reduced the incidence of type 1 HRS and the 3-month mortality
[92]. Administration of pentoxifylline, 400 mg three times a day, to patients
with severe acute alcoholic hepatitis was associated with a marked reduction
in HRS incidence and in-hospital mortality [93]. A recent prospective controlled trial, however, failed to conrm these benets [94]. Prevention of
HRS by use of antibiotic prophylaxis for SBP [3], or of albumin for SBP
[92], in patients with liver failure or acute alcoholic hepatitis [94] has not
yet been conrmed by subsequent large studies. The magnitude of these
eects in the context of the otherwise poor prognosis of HRS, however,
has led to broad acceptance of these prophylactic measures.
Specic preventive measures for type 2 HRS have not been identied. Patients developing this variant of HRS do not usually have precipitating
events. Because type 2 HRS is often associated with tense refractory ascites

THE HEPATORENAL SYNDROME

833

Fig. 5. Primary prophylaxis of hepatorenal syndrome with noroxacin. (From Fernandez J,

Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:81824; with
permission.)

or severe hyponatremia, optimal management of refractory ascites or severe

hyponatremia could reduce the risk of developing type 2 HRS [7,76].
Further research is necessary to determine how to prevent type 2 HRS in
patients with advanced cirrhosis.
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