Diagnosis and treatment of hepatorenal syndrome

Authors
Burton D Rose, MD
Bruce A Runyon, MD
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc
Disclosures

All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: feb 2012. | This topic last updated: jun 13,
2010.
INTRODUCTION The hepatorenal syndrome refers to the development of acute
renal failure in a patient who usually has advanced liver disease due to cirrhosis,
severe alcoholic hepatitis, or (less often) metastatic tumor, but can occur in a
substantial proportion of patients with fulminant hepatic failure from any cause [1-3].
The hepatorenal syndrome usually represents the end-stage of a sequence of
reductions in renal perfusion induced by increasingly severe hepatic injury.

The pathogenesis, diagnosis, and treatment of the hepatorenal syndrome is discussed

in this review. Overviews of the complications of fulminant hepatic failure and cirrhosis
are provided elsewhere. (See "Acute liver failure: Prognosis and management" and
"Overview of the complications, prognosis, and management of cirrhosis".)

PATHOGENESIS Arterial vasodilatation in the splanchnic circulation, which is

triggered by portal hypertension, appears to play a central role in the hemodynamic
changes and the decline in renal function in cirrhosis [1-3]. The presumed mechanism
is increased production or activity of vasodilators, mainly in the splanchnic circulation,
with nitric oxide thought to be most important [1,4,5].

As the hepatic disease becomes more severe, there is a progressive rise in cardiac
output and fall in systemic vascular resistance; the latter change occurs despite local
increments in renal and femoral vascular resistance that result in part from
hypotension-induced activation of the renin-angiotensin and sympathetic nervous
systems (figure 1) [1-3,6]. Thus, the reduction in total vascular resistance must be
occurring in the splanchnic circulation [6], perhaps in part under the influence of nitric
oxide derived from the endothelium. Bacterial translocation from the intestine into the
mesenteric lymph nodes may play an important role in this process [1,7,8]. A review
of the hemodynamic changes seen with progressive cirrhosis can be found in a
separate topic review. (See "Pathogenesis of ascites in patients with cirrhosis".)
The decline in renal perfusion in this setting is associated with reductions in glomerular
filtration rate and sodium excretion (often to less than 10 meq/day in advanced
cirrhosis) [9,10] and a fall in mean arterial pressure, despite the intense renal
vasoconstriction [10]. The importance of splanchnic vasodilatation in these changes
can be indirectly illustrated by the response to ornipressin, an analog of antidiuretic
hormone (arginine vasopressin) that is a preferential splanchnic vasoconstrictor [11].

In patients with advanced cirrhosis, the administration of ornipressin or other

vasopressin analogues partially corrects many of the systemic and renal hemodynamic
abnormalities that are present (figure 2); these include an elevation in mean arterial
pressure, reductions in plasma renin activity and norepinephrine concentration, and
increases in renal blood flow, glomerular filtration rate (from 18 to 29 mL/min), and
urinary sodium excretion and volume.

The response to creation of a portasystemic shunt also supports the importance of

splanchnic hemodynamics in the genesis of the hepatorenal syndrome. Portasystemic
shunting has improved renal function in a limited number of patients with the
hepatorenal syndrome [12], although it is not currently used as treatment for this
disorder. One report, however, suggested that the reduction in intrahepatic pressure
induced by this modality may prevent the development of the hepatorenal syndrome.
This retrospective study evaluated 204 patients with variceal bleeding who were
treated with either a portasystemic shunt or sclerotherapy (or other nonshunt
modality) [13]. Shunting was associated with a lower incidence of ascites (15 versus
73 percent) and hepatorenal syndrome (4 versus 21 percent), a higher incidence of
encephalopathy, and no difference in overall patient survival.

ESTIMATION OF RENAL FUNCTION Regardless of the mechanism, the reduction

in glomerular filtration rate in patients with hepatic disease is often masked clinically.
Both urea and creatinine production may be substantially reduced in this setting, due
to the liver disease and to decreased muscle mass and decreased protein and meat
intake. The net effect is that a plasma creatinine concentration that appears to be
within the normal range (1 to 1.3 mg/dL [88.4 to 115 mol/L]) may be associated with
a glomerular filtration rate that ranges from as low as 20 to 60 mL/min to a clearly
normal value above 100 mL/min, depending primarily upon muscle mass.

The BUN is variable in these patients. It may be lower than expected from the GFR if
urea production is markedly reduced or it may be elevated, seemingly out of
proportion to the plasma creatinine concentration, if urea production is adequate. The
intense sodium avidity in the hepatorenal syndrome will also tend to raise the BUN by
increasing sodium and water and therefore passive urea reabsorption in the proximal
tubule. (See "Etiology and diagnosis of acute tubular necrosis and prerenal disease".)

The GFR can be estimated more accurately by measurement of the creatinine

clearance, since the 24-hour urine collection will demonstrate any fall in creatinine
production and subsequent excretion. However, the clearance value obtained in
patients with renal insufficiency will tend to overestimate the true GFR by as much as
40 percent or more due to increased creatinine secretion [14,15]. (See "Assessment of
kidney function: Serum creatinine; BUN; and GFR".), for a detailed discussion of this
issue as well as other methods to evaluate renal function in this setting and (see
"Renal function and nonrenal solid organ transplantation")

CLINICAL PRESENTATION The hepatorenal syndrome is classically characterized

by oliguria, a generally benign urine sediment, a very low rate of sodium excretion,
and a progressive rise in the plasma creatinine concentration [1-3,10,16]. The last
parameter may increase by as little as 0.1 mg/dL (9 micromol/L) per day, with
intermittent periods of stabilization or even slight improvement. (See 'Diagnostic
criteria' below.)

However, urine volumes may be higher than previously appreciated, with a marked
decrease in output only occurring just prior to death. As an example, some studies
have found that the urine volume may exceed 400 mL per day, with markedly lower
output being observed only within a few days from death [17,18].

Based upon the speed of onset of renal failure, two forms of hepatorenal syndrome
have been described [1,16,19]:

Type I hepatorenal syndrome is the more serious type; it is defined as at least a

50 percent lowering of the creatinine clearance to a value below 20 mL/min in
less than a two week period or at least a twofold increase in serum creatinine
to a level greater than 2.5 mg/dL (221 mol/L). Such patients may be
classified as oliguric if oliguria is defined as less than 500 mL of urine per day,
but most are nonoliguric at the time of diagnosis of HRS if oliguria is defined
as less than 400 mL per day [16,18].

Type II hepatorenal syndrome is defined as less severe renal insufficiency than

that observed with type I disease; it is principally characterized by ascites
that is resistant to diuretics.

Incidence The incidence of hepatorenal syndrome was evaluated in a prospective

study of 229 nonazotemic patients with cirrhosis and ascites: the hepatorenal
syndrome developed in 18 and 39 percent at one and five years, respectively [10].
Patients with hyponatremia and a high plasma renin activity were at highest risk.
These signs of neurohumoral activation presumably reflected a more severe decline in
effective perfusion [1,6].

Hepatorenal syndrome can also occur without established cirrhosis. In a study of

patients with acute hepatic failure (alcoholic hepatitis), hepatorenal syndrome occurred
in 28 of 101 patients [20].

Although hepatorenal syndrome can be seen in most forms of severe hepatic disease,
patients with primary biliary cirrhosis appear to be relatively protected [21]. Sodium
retention, ascites formation, and the hepatorenal syndrome tend to occur less often or
later in this condition, a possible reflection of the natriuretic and renal vasodilator
actions of retained bile salts.

Precipitants The onset of renal failure is typically insidious, but can be precipitated
by an acute insult, such as gastrointestinal bleeding or infection [10,16,22].
Spontaneous bacterial peritonitis, for example, can trigger progressive hepatorenal
syndrome, although it is more likely to occur in patients who already have some
degree of renal insufficiency [23,24]. (See "Treatment and prophylaxis of spontaneous
bacterial peritonitis", section on 'Renal failure'.)

Overly rapid diuresis, which is more likely to cause volume depletion in patients who
have ascites but no peripheral edema, has often been mentioned as an additional
precipitant of hepatorenal syndrome. However, diuretics do not cause hepatorenal
syndrome. This association is inappropriately suggested, because most patients are
taking diuretics when the hepatorenal syndrome is diagnosed.

However, diuretics can cause azotemia, particularly if fluid is removed too rapidly in
patients without peripheral edema. Diuretic-induced azotemia improves with the
cessation of therapy and fluid repletion. In comparison, the hepatorenal syndrome
typically worsens inexorably, even after diuretics are stopped. (See "Initial therapy of
ascites in patients with cirrhosis", section on 'Concerns'.)

DIAGNOSTIC CRITERIA The following definition and diagnostic criteria have been
proposed for the hepatorenal syndrome [16,19]:

Chronic or acute hepatic disease with advanced hepatic failure and portal
hypertension

A plasma creatinine concentration above 1.5 mg/dL (133 micromol/L) that

progresses over days to weeks. As noted above, the rise in plasma creatinine
 with reductions in glomerular filtration rate may be minimized by the marked
reduction in creatinine production. (See 'Estimation of renal function' above.)

The absence of any other apparent cause for the renal disease, including shock,
ongoing bacterial infection, current or recent treatment with nephrotoxic
drugs, and the absence of ultrasonographic evidence of obstruction or
parenchymal renal disease. It is particularly important to exclude
spontaneous bacterial peritonitis, which is complicated by acute renal failure
that may be reversible in 30 to 40 percent of patients. (See "Treatment and
prophylaxis of spontaneous bacterial peritonitis", section on 'Renal failure'.)

Urine red cell excretion of less than 50 cells per high power field (when no
urinary catheter is in place) and protein excretion less than 500 mg/day.

Lack of improvement in renal function after volume expansion with intravenous

albumin (1 g/kg of body weight per day up to 100 g/day) for at least two
days and withdrawal of diuretics.

DIFFERENTIAL DIAGNOSIS The diagnosis of the hepatorenal syndrome is one of

exclusion, entertained only after other potential causes of acute renal failure have
been ruled out [25]. As an example, both glomerulonephritis and vasculitis can occur
in patients with liver disease and should be suspected in patients with an active urine
sediment containing red cells and red cell and other casts. (See "Clinical presentation
and diagnosis of IgA nephropathy" and "Renal disease associated with hepatitis B virus
infection".)

In most cases, however, the differential diagnosis of the hepatorenal syndrome

includes acute tubular necrosis (ATN) and other causes of prerenal disease [25].

Acute tubular necrosis Patients with cirrhosis may develop ATN after a course of
aminoglycoside therapy, the administration of a radiocontrast agent, or an episode of
sepsis or bleeding [1]. The presence of ATN is usually suspected from the history and
from the often rapid rise in the plasma creatinine concentration which is contrast to the
gradual rise in hepatorenal syndrome. An unresolved issue is whether the prolonged
renal ischemia in the hepatorenal syndrome can, in some cases, lead to ATN [1,16].

Some of the traditional laboratory methods used to distinguish prerenal disease from
ATN may not be helpful in the patient with hepatic disease. As an example, ATN is
usually associated with a fractional excretion of sodium above 2 percent and granular
and epithelial cell casts in the urine sediment (calculator 1) or, for standard units,
(calculator 2). However, the fractional excretion of sodium may remain below 1 percent
in patients with cirrhosis due to the persistent renal ischemia induced by the hepatic
disease [26]. The urinalysis also may be misleading. Granular and epithelial cell casts
may be seen with marked hyperbilirubinemia alone and are therefore not diagnostic of
ATN; how this occurs is not understood. (See "Etiology and diagnosis of acute tubular
necrosis and prerenal disease" and "Fractional excretion of sodium and urea in acute
kidney injury".)

Prerenal disease The hepatorenal syndrome is a prerenal disease, as the kidneys

are histologically normal and have been used successfully for renal transplantation
[27]. However, decreased renal perfusion can also be induced by gastrointestinal
losses, bleeding, or therapy with a diuretic or a nonsteroidal antiinflammatory drug
(since renal vasodilator prostaglandins in part maintain renal perfusion in this setting)
[1,28]. (See "NSAIDs: Acute kidney injury (acute renal failure) and nephrotic
syndrome".) Thus, the diagnosis of the hepatorenal syndrome requires lack of
improvement in renal function following discontinuation of potential nephrotoxins and a
trial of fluid repletion.

Distinguishing the hepatorenal syndrome from these other disorders is clinically

important because of the marked difference in prognosis. Acute tubular necrosis and
other causes of prerenal disease are generally reversible. On the other hand, the
prognosis is poor in the hepatorenal syndrome, with most patients dying within weeks
of the onset of renal failure unless liver transplantation is performed or effective
treatment is given [10,29]. Concurrent hepatic encephalopathy is common, and death
is usually due to a complication of the hepatic disease, such as gastrointestinal
bleeding.

TREATMENT As mentioned above, the GFR falls progressively in cirrhosis as the

liver disease progresses [9,30]. In the early stages, acutely lowering renal sympathetic
tone and renal vascular resistance by the intravenous administration of the
sympatholytic agent clonidine can raise the GFR by as much as 25 percent [31].
However, this benefit does not appear to be sustained with chronic oral therapy,
despite a persistent reduction in sympathetic activity [32].

The best hope for reversal of the renal failure is an improvement in hepatic function
due to partial resolution of the primary disease or to successful liver transplantation
[30,33,34]. Improvement in the underlying liver disease is most impressive in patients
with alcoholic liver disease (particularly severe alcoholic hepatitis) with abstinence or
with decompensated cirrhosis due to hepatitis B virus infection treated with
lamivudine [35,36].
The following sections will review the different therapies that have been evaluated in
the treatment of hepatorenal syndrome. Issues related to the treatment of ascites in
patients with cirrhosis (eg, fluid and sodium intake, diuretic therapy) are discussed
separately. (See "Initial therapy of ascites in patients with cirrhosis" and "Treatment of
diuretic-resistant ascites in patients with cirrhosis" and 'Precipitants' above.)

Midodrine and octreotide Growing data suggest that combination therapy with
midodrine (a selective alpha-1 adrenergic agonist) and octreotide (a somatostatin
analog) may be highly effective and safe. The rationale for such therapy is that, since
midodrine is a systemic vasoconstrictor and octreotide is an inhibitor of endogenous
vasodilator release, combined therapy would improve renal and systemic
hemodynamics [37]. In comparison, octreotide alone does not appear to be beneficial
[38].

In one study of 13 patients with the hepatorenal syndrome, five were given
midodrine (7.5 to 12.5 mg TID) and octreotide (100 to 200 g subcutaneous TID)
(both titrated to increase the mean arterial pressure at least 15 mmHg), while eight
were administered dopamine (2 to 4 g/kg per min) [39]. Both groups also received
daily doses of intravenous albumin and had similar clinical characteristics. The
following results were reported:

Among the five who received combined therapy (group B), three survived to be
discharged from the hospital. Of these, one successfully underwent liver
transplantation, another was alive at 472 days, and the third discontinued
treatment after two months and died 15 days later. Among the two who were
never discharged, one discontinued therapy after two months and was
successfully transplanted, while the other died at 29 days of pneumonia
despite total recovery of renal function. Minimal side effects, including
tingling, goose bumps, and diarrhea, were observed.

Seven of the eight patients who received dopamine (group A) died during the
first 12 days. One patient recovered renal function and survived to be
transplanted.

Significant improvements in renal function were observed in those in group B,

including a lower serum creatinine (1.8 versus 5.0 mg/dL [159 versus 442
mol/L] at 20 days and baseline, respectively, P<0.01), a higher glomerular
filtration rate (46 versus 10 mL/min, P<0.001), and increased urine volume
(1540 versus 680 mL/day, P<0.001). By comparison, there was a
nonsignificant trend toward a deterioration of renal function in group A.
Additional data substantiate the efficacy and safety of octreotide and midodrine [18].
In this retrospective study of 53 patients administered octreotide and midodrine and
21 concurrent (but nonrandomized) control subjects, the following regimen was
utilized: the routine dose of octreotide was 200 mcg TID, which was administered after
a few doses at 100 mcg TID; the midodrine dose was increased to a maximum of 15
mg TID in an attempt to increase the mean arterial blood pressure at least 15 mmHg;
all patients received intravenous albumin.

Treatment was associated with a significant reduction in mortality (49 versus 67

percent in the control group) and a significantly higher incidence of a reduction in
serum creatinine concentration to less than 1.5 mg/dL (133 mol/L) (30 versus 14
percent). Seven of eight patients who received 15 mg TID of midodrine had a
reduction in serum creatinine concentration to <1.5 mg/dL [133 mol/L], and only one
patient (who was 82 years of age) required a reduction in midodrine dose because of
hypertension.

In both studies [18,39], some patients survived to be discharged to home on the

regimen of octreotide plus midodrine.

Norepinephrine An uncontrolled pilot study of 12 patients with type I hepatorenal

syndrome treated with norepinephrine plus albumin reported an 83 percent rate of
reversal and a significant reduction in serum creatinine concentration [40]. Patients
required care in an intensive care unit, and one subject sustained an episode of
myocardial hypokinesia.

We also have had success (unpublished) with the use of norepinephrine plus albumin in
patients in the intensive care unit. Norepinephrine also provides significant blood
pressure support, a frequent requirement in such patients. The target increase in mean
arterial pressure is at least 10 mmHg.

Other medical therapies A number of other drugs have been tried for the
treatment of hepatorenal syndrome, with variable evidence of benefit. None of the
described approaches are recommended, but some data suggest a potential benefit
with vasopressin analogs.

Vasopressin analogs Vasopressin analogs (ornipressin and terlipressin) should

reduce splanchnic vasodilation, and when ornipressin was administered with effective
circulating volume expansion achieved via the infusion of albumin or a peritoneovenous
shunt (to reduce the release of renal vasoconstrictors such as angiotensin II and
norepinephrine), there was an increase in glomerular filtration rate (figure
2) [11,41,42]. However, this regimen may also induce significant renal ischemia [41].
Another vasopressin analog, terlipressin, has also been studied in hepatorenal
syndrome [43-45]. A systemic analysis of three small trials involving a total of 51
patients, with co-interventions that included albumin, fresh frozen plasma, and
cimetidine, suggested that terlipressin significantly lowers mortality rates (risk
difference -0.34, 95% CI -0.56 to -0.12) and improved renal function (as assessed by
creatinine clearance, serum creatinine levels, and urine output) [43]. Although
promising, these data were suspect because of the small number of patients studied
and inadequate bias control.

Two larger randomized, controlled trials were subsequently published:

In one trial, 46 patients with hepatorenal syndrome were randomly assigned to

terlipressin plus albumin or albumin alone [44]. Improved renal function
occurred significantly more often with terlipressin plus albumin had improved
renal function (44 versus 9 percent with albumin alone), although survival
was the same in both groups at three months. Cardiovascular complications
were more common with terlipressin plus albumin (10 versus 4 patients), but
permanent terlipressin withdrawal was required in only three patients.

Similar benefits with terlipressin were observed in a second prospective,

randomized, double blind, placebo-controlled trial of 112 patients with
hepatorenal syndrome [45]. At 14 days, terlipressin therapy was associated
with a significant reduction in the serum creatinine (by 0.7 mg/dL versus no
change with placebo). As in the preceding trial, overall survival was the same
in both groups and serious adverse events, although uncommon, were more
frequent with terlipressin (five patients versus one patient).

It is notoriously difficult to demonstrate a survival advantage in trials of advanced

cirrhosis complications. These trials regularly improve the outcome of the complication
under investigation, but survival is not affected.

Terlipressin is not available in the United States. Further study is needed to better
define its risks and benefits in the hepatorenal syndrome, particularly whether the
drug's salutary effect on renal function outweighs its ischemic complications.

Other agents Other agents that have been tried with conflicting evidence of
benefit, or evidence of harm, include misoprostol, N-acetylcysteine, and angiotensin
converting enzyme (ACE) inhibitor.
 Renal vasodilation can be directly induced by the combination of albumin-
induced volume expansion and the oral ingestion of high doses of the
prostaglandin analog, misoprostol (0.4 mg four times daily). There are only
preliminary and conflicting data on the efficacy of prostaglandin
administration in the hepatorenal syndrome [46,47]. Use of misoprostol for
treatment of hepatorenal syndrome cannot be recommended.

It has been suggested that the administration of N-acetylcysteine (NAC), an

agent shown to improve renal function in an experimental model of acute
cholestasis and renal failure [48], may have a similar effect in patients with
hepatorenal syndrome. In a series of 12 such patients, the intravenous
infusion of NAC increased the creatinine clearance (24 to 43 mL/min), urine
output, and sodium excretion without altering the systemic blood pressure
[49]. NAC may minimize splanchnic vasodilation and nitric oxide production
via reduced formation of reactive oxygen species [50]. A review of the
hemodynamic changes that occur with progressive cirrhosis is available in a
separate topic review. (See "Pathogenesis of ascites in patients with
cirrhosis".) Further studies are needed before this novel treatment can be
recommended.

Angiotensin converting enzyme (ACE) inhibitors have been evaluated in an

attempt to reverse the renal ischemia. However, these drugs have two
deleterious effects: they can, at higher doses, induce systemic hypotension;
and, even at lower nonhypotensive doses, they tend to reduce the glomerular
filtration rate by causing preferential efferent arteriolar dilatation and a fall in
intraglomerular pressure [51]. This interference with renal autoregulation is
similar to that seen in patients with bilateral renal artery stenosis. Use of
these agents to treat hepatorenal syndrome cannot be recommended. (See
"Renal effects of ACE inhibitors in hypertension".)

Transjugular intrahepatic portosystemic shunt The transjugular intrahepatic

portosystemic shunt (TIPS) has been used in the treatment of refractory ascites. (See
"Indications for the use of transjugular intrahepatic portosystemic shunts".) When used
in this setting, there may also be a delayed improvement in renal function [52-56]. In
one study, for example, the average plasma creatinine concentration was 1.5 mg/dL
(132 mol/L) at baseline, was unchanged at one week, and fell to 0.9 mg/dL (80
mol/L) by six months [52]. In another series, there was a nonsignificant trend toward
an increase in glomerular filtration rate (65 mL/min at baseline to 76 mL/min at four
weeks) [54].

There is much less information on the use of TIPS in patients who fulfill criteria for the
hepatorenal syndrome. One report described 16 such patients, six of whom had severe
hepatorenal syndrome (defined as a plasma creatinine concentration 2.5 mg/dL [220
mol/L] or a creatinine clearance below 20 mL/min) [55]. Within two weeks, there was
an approximate doubling of the creatinine clearance with a proportionate reduction in
the plasma creatinine concentration and an increase in urinary sodium excretion.
Modest further improvement in creatinine clearance occurred over the ensuing six to
eight weeks. Only three patients were nonresponders; all three died within six weeks
after TIPS.

Another series evaluated seven patients with cirrhosis and hepatorenal syndrome
(defined as a doubling of the plasma creatinine concentration to more than 2.5 mg/dL
[221 mol/L] or a 50 percent reduction in creatinine clearance to below 20 mL/min in
less than two weeks despite volume expansion) [56]. Insertion of TIPS was associated
with a gradual improvement in glomerular filtration rate (9 to 27 mL/min), reductions
in the BUN and plasma creatinine concentration, and a reduction in the activity of the
renin-angiotensin and sympathetic nervous systems in six, all of which suggest an
improvement in systemic hemodynamics. (See "Pathogenesis of ascites in patients with
cirrhosis".) The average survival following TIPS placement was approximately five
months, which is longer than the expected survival of such patients.

Unfortunately, many patients with hepatorenal syndrome are too ill to undergo TIPS. A
model scoring system based upon the survival of 231 patients who underwent elective
TIPS was devised to predict survival after the procedure [57].

Based upon this model and with current scoring values, patients with a MELD risk score
greater than 18 probably should not undergo TIPS. Such patients have a median
survival of three months or less following the procedure.

Overall, these results suggest that, in selected patients with hepatorenal syndrome,
TIPS may provide short-term benefit. Given the risks associated with this procedure
(particularly the high incidence of encephalopathy), it should be considered only as a
last resort in patients who are not a candidate for or are awaiting liver transplantation.

Peritoneovenous shunt Insertion of a peritoneovenous shunt can improve

systemic hemodynamics and modestly reduce the plasma creatinine concentration
[29]. However, survival is not improved and complications limit use of this procedure.
(See "Peritoneovenous shunt for ascites and hepatorenal syndrome".)
Dialysis Patients with hepatorenal syndrome who progress to renal failure can be
treated with dialysis, which is most commonly done when patients are awaiting a liver
transplant or when there is the possibility of improvement in liver function. In addition,
dialysis improves the priority score for the transplant. In one retrospective single
center study, 30 percent of patients who required dialysis survived to liver
transplantation [58].

Survival on dialysis is generally limited by the severity of the hepatic failure [59], as
well as concurrent respiratory failure [60]. Patients with an acute and potentially
reversible hepatic insult may particularly benefit from dialysis, since renal function will
recover in parallel with improving hepatic function [33].

Hemodialysis is frequently difficult to perform in patients with hepatorenal syndrome

since decompensated hepatic function is associated with hemodynamic instability.
Some success has been realized with more stable modalities, particularly continuous
renal replacement modalities [61].

Another dialysis technique, termed ascites reinfusion dialysis, has been associated with
some success in a very limited number of patients with refractory ascites and acute
renal failure [62]. With this approach, ascites is conveyed via an infusion pump into
the arterial inlet of a hemodialysis apparatus. This results in an ascites/blood mixture
of 5 percent ascites/95 percent blood, which is pumped through the dialysis
membrane. This mix is then reinfused back into the patient. However, the general
concept of reinfusing ascitic fluid, either intravascularly or intraperitoneally, is not a
new one; one early study, for example, was published in 1961 [63]. Attempts have
been made to ultrafilter the fluid to concentrate the proteins [64], and retention of
these opsonically-active proteins has theoretical benefit in preventing bacterial
infection [65]. Disseminated intravascular coagulation and lack of controlled data
regarding survival have limited the general use of this approach.

Summary and recommendations Although the results are preliminary and must
be verified in a larger number of patients from other centers, combination therapy with
midodrine and octreotide or single agent therapy with norepinephrine should be
considered in patients with hepatorenal syndrome, given the apparent absence of
significant side effects and the dismal prognosis with other available therapies
(excluding liver transplantation). We also administer intravenous albumin at
approximately 1 g/kg per day (100 g maximum) for two or more days.

In the United States, liver transplant candidates who develop end-stage renal disease
usually undergo hemodialysis; those who are not transplant candidates commonly
receive the combination of midodrine and octreotide when they are not in an intensive
care unit (ICU) and norepinephrine when they are in an ICU. Whether terlipressin will
be approved for use in the United States has not been determined.

PREVENTION Hepatorenal syndrome regularly develops in patients with systemic

bacterial infection (eg, spontaneous bacterial peritonitis) and/or severe alcoholic
hepatitis. The following therapies may prevent the development of hepatorenal
syndrome in these patients:

In patients with spontaneous bacterial peritonitis, the administration of

intravenous albumin (1.5 g/kg) at the time of diagnosis of infection and
another dose of albumin (1.0 g/kg) on day three of antibiotic treatment may
reduce the incidence of both renal impairment that does not reverse during
hospitalization and mortality during hospitalization and at three months [24].
Although these findings need to be confirmed in additional controlled studies,
it seems appropriate to give intravenous albumin as part of the treatment
regimen of spontaneous bacterial peritonitis because of the possible survival
advantage. (See "Treatment and prophylaxis of spontaneous bacterial
peritonitis", section on 'Intravenous albumin'.)

A randomized trial reported significant benefits with the oral administration of

norfloxacin at 400 mg/day to 68 patients with cirrhosis and ascitic fluid total
protein <1.5 g/dL who fulfilled either of the following two criteria: a Child-
Pugh score >9 points and serum bilirubin >3 mg/dL (51.3 micromol/L); or a
serum creatinine >1.2 mg/dL [106 micromol/L] or blood urea nitrogen >20
mg/dL or serum sodium <130 meq/L [66]. Norfloxacin was associated with
the following significant benefits: decreased one-year probability of SBP (7
versus 61 percent) and hepatorenal syndrome (28 versus 41 percent), and
improved survival at three months (94 versus 62 percent) and one year (60
percent versus 48 percent). Based upon these findings, we recommend the
use of norfloxacin in patients who meet the inclusion criteria in this trial. (See
"Treatment and prophylaxis of spontaneous bacterial peritonitis", section on
'Efficacy of prophylaxis'.)

PROGNOSIS Overall, the mortality of patients with liver failure is substantially

worse if they develop hepatorenal syndrome [67]. In turn, the outcome of patients
with hepatorenal syndrome, as well as recovery of kidney function, is strongly
dependent on reversal of the hepatic failure, whether spontaneous, following medical
therapy, or successful liver transplantation [68].
 The rate of recovery of kidney function following recovery of liver failure is uncertain;
reported rates are affected by varying pretransplant kidney function, and differences
over time in indications for dialysis and in eligibility for liver transplantation. However,
a substantial proportion of patients who have progressed to dialysis and survive to
receive a liver transplant do recover kidney function [69]. (See "Renal function and
nonrenal solid organ transplantation".)

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