In Translation

Pathogenesis of Hepatorenal Syndrome: Implications

for Therapy
Francois Durand, MD,1 Isabel Graupera, MD,2 Pere Gine`s, MD, PhD,2
Jody C. Olson, MD,3 and Mitra K. Nadim, MD4

Patients with cirrhosis are prone to develop acute kidney injury (AKI) due to a number of causes, including
bacterial infections with or without septic shock, hypovolemia, administration of nephrotoxic drugs, and intrinsic
kidney diseases, among others. Most importantly, patients with advanced cirrhosis develop a distinctive cause
of AKI, characterized by rapidly progressive glomerular filtration rate loss associated with marked disturbances
in circulatory function in the absence of obvious pathologic abnormalities in the kidneys, known as hepatorenal
syndrome (HRS). Decreased kidney function results from intense renal vasoconstriction secondary to the
complex circulatory changes of cirrhosis with splanchnic vasodilatation and effective hypovolemia. Beyond
activation of vasoactive systems, factors including impaired renal blood flow autoregulation and systemic
inflammation may play a role in the development of HRS. Most patients improve with albumin and vaso-
pressors; however, the prognosis of HRS remains very poor. Novel biomarkers may be helpful in distinguishing
HRS from other causes of AKI in patients with cirrhosis.
Am J Kidney Dis. 67(2):318-328. 2016 by the National Kidney Foundation, Inc.

INDEX WORDS: Hepatorenal syndrome (HRS); cirrhosis; acute kidney injury (AKI); biomarkers; liver
transplantation; pathophysiology; simultaneous liver-kidney transplantation; vasoconstrictor drugs; renal
function; review.

BACKGROUND receiving vasoconstrictors and/or renal replacement

Hepatorenal syndrome (HRS) occurs in patients
with end-stage cirrhosis and ascites and results from
the complex systemic and splanchnic circulatory
changes of cirrhosis, in which splanchnic vasodilata-
tion and effective hypovolemia play a central role.1
Although HRS is by denition related to effective
hypovolemia, it is not reversed by volume expansion.
In theory, HRS is not associated with structural
changes and is fully reversible with liver trans-
plantation. Reversal or improvement may be observed
with vasoconstrictors such as terlipressin.2 However,
in the absence of transplantation, HRS is associated
with an extremely poor prognosis, even in patients
From the 1Hepatology and Liver Intensive Care, Hospital
Beaujon, Clichy, University Paris VII Diderot, INSERM U1149,
Paris, France; 2Liver Unit, Hospital Clinic de Barcelona,
University of Barcelona, Institut dInvestigacin Biomediques,
Barcelona, Centro de Investigaciones Biomdicas en Red en
Enfermedades Digestivas y Hepticas (CIBEREHD), Spain;
3
Hepatology and Transplant Critical Care, University of Kansas
Medical Center, Kansas City, KS; and 4Division of Nephrology,
Keck School of Medicine, University of Southern California, Los
Angeles, CA.
Received May 19, 2015. Accepted in revised form September 6,
2015. Originally published online October 21, 2015.
Address correspondence to Mitra K. Nadim, MD, Division of
Nephrology, Department of Medicine, Keck School of Medicine,
University of Southern California, 1520 San Pablo St, Ste 4300,
Los Angeles, CA 90033. E-mail: nadim@usc.edu
 2016 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2015.09.013
therapy (RRT).
CASE VIGNETTE
A 57-year-old man with a 10-year history of insulin-dependent
diabetes mellitus was listed for liver transplantation 4 years after
hepatitis C virusrelated cirrhosis had been diagnosed following
an episode of variceal bleed. After his rst variceal bleed, he
developed encephalopathy and mild ascites, which was rapidly
controlled with a low-sodium diet and diuretics. Diuretic therapy
was discontinued 6 months later, and the patient remained
asymptomatic. After another 9 months, his ascites reappeared
without response to a low-sodium diet and a combination of high-
dose spironolactone and furosemide. Diuretic dose could not be
increased due to the occurrence of hyponatremia and an increase in
serum creatinine (Scr) level from 1.3 to 1.9 mg/dL. Laboratory
data included the following values: bilirubin, 7.6 mg/dL; interna-
tional normalized ratio (INR), 1.9; albumin, 2.8 g/dL; hemoglobin,
11 g/dL; and platelet count, 57 3 103/mL. During the subsequent
months, he required several large-volume paracenteses, each
compensated by intravenous albumin.
Three months after being placed on the liver transplant waiting
list, he had an episode of spontaneous bacterial peritonitis.
Antibiotic therapy was started on an empirical basis, but the
patients condition deteriorated, with the development of tense
ascites, diffuse edema, and oliguria (urine output, 250 mL/d).
Laboratory tests showed Scr level of 2.5 mg/dL, bilirubin level of
15 mg/dL, and INR of 2.5. Kidney function did not improve after
volume expansion (1 g of albumin per kilogram of body weight
for 2 days). Urinalysis results were unremarkable, with no he-
maturia or proteinuria. A diagnosis of type 1 HRS was made.
Treatment with midodrine, octreotide, and albumin was started
without improvement in kidney function. The patient was initi-
ated on RRT due to worsening kidney function and uid over-
load. However, the patients condition continued to deteriorate
and he died after 1 week.
This scenario of type 1 HRS in a patient with end-stage liver
disease awaiting liver transplantation is not uncommon. HRS

318 Am J Kidney Dis. 2016;67(2):318-328

Pathogenesis of Heptorenal Syndrome

carries an especially poor prognosis with medical management
alone. Important issues are: (1) how to bridge these patients to
liver transplantation and (2) how to identify patients with HRS
with superimposed chronic kidney disease (CKD) who are
unlikely to have recovery of kidney function after transplantation.
PATHOGENESIS
Denitions
In 1996, the International Club of Ascites (ICA)
proposed a denition and diagnostic criteria for
HRS3; these were subsequently revised in 2007
(Box 1).1 Clinically, HRS is divided into 2 types.
Type 1 HRS is characterized by a rapidly progressive
loss of kidney function over 2 weeks, whereas
type 2 HRS is considered the more chronic form in
which a reduction in kidney function occurs more
progressively.
Two major limitations of the HRS criteria are:
(1) a strict Scr level cutoff of 1.5 mg/dL prior to the
diagnosis of HRS and (2) exclusion of other forms of
acute kidney injury (AKI) or CKD, such as diabetic
nephropathy or other glomerular diseases occasion-
ally associated with liver disease. However, patients
with underlying kidney disease can still develop
hepatorenal physiology.
During the past decade, several denitions of AKI
in the general population have been proposed, which
are based on relative changes in Scr level and urine
output or initiation of RRT (Table 1).4,5 In 2010, the
Acute Dialysis Quality Initiative (ADQI) along with

Box 1. ICA Criteria for the Diagnosis of Hepatorenal Syndrome

1996 Criteria3

Major Criteria
 Chronic or acute liver disease with advanced hepatic failure and portal hypertension

 Scr . 1.5 mg/dL

 Absence of shock, ongoing bacterial infections, and current or recent treatment with nephrotoxic drugs
 Absence of gastrointestinal fluid losses or renal fluid losses
 No sustained improvement in kidney function (defined as a decrease in Scr to ,1.5 mg/dL or an increase in CLcr to $40 mL/
min) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline solution
 Proteinuria , 500 mg/dL and no ultrasonographic evidence of parenchymal kidney disease
Minor Criteria
 Urine volume , 500 mL/d
 Urine sodium , 10 mEq/L
 Urine osmolality . plasma osmolality
 Urine RBCs , 50/high-power field
2007 Criteria1
 Cirrhosis with ascites
 Scr . 1.5 mg/dL
 No improvement in Scr (decrease to ,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/d (up to 100 g/d)
 Absence of shock
 No current or recent treatment with nephrotoxic agents
 Absence of parenchymal kidney disease as indicated by proteinuria . 500 mg/d, microhematuria (.50 RBCs/high-power field)
and/or abnormal renal ultrasonography
2015 Criteria12
 Diagnosis and ascites
 Diagnosis of AKI according to ICA-AKI criteria
 No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg/d)
 Absence of shock
 No recent or current use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media, etc)
 No macroscopic signs of structural kidney injurya defined as:
 Absence of proteinuria (.500 mg/d)
 Absence of macrohematuria (.50 RBCs/high-power field)
 Normal findings on renal ultrasonography

Abbreviations: AKI, acute kidney injury; CLcr, creatinine clearance; ICA, International Club of Ascites; NSAID, nonsteroidal anti-
inflammatory drug; RBC, red blood cell; Scr, serum creatinine.
a
Patients who fulfill these criteria may still have structural damage such as tubular damage.

Am J Kidney Dis. 2016;67(2):318-328 319

 Durand et al

Abbreviations: ADQI, Acute Dialysis Quality Initiative; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; HRS, hepatorenal syndrome; ICA, International Club of Ascites; KDIGO,
for 24 h; or anuria

for 24 h; or anuria
several members of the ICA recommended adapta-
tion of the AKI Network (AKIN) criteria to dene
AKI in patients with cirrhosis instead of the tradi-

,0.5 mL/kg/h ,0.5 mL/kg/h ,0.3 mL/kg/h

[ to 2-3 3 [ to 3 3 baseline; or to .4 mg/dL ,0.5 mL/kg/h ,0.5 mL/kg/h ,0.3 mL/kg/h

AKI Stages by Urine Output Criteria

3 tional denition using a xed Scr level cutoff of

for 12 h

for 12 h
.1.5 mg/dL (Table 1).6,7 These criteria were irre-
spective of the cause of AKI. As such, HRS type 1

was categorized as a specic type of AKI. Since
then, the use of AKIN criteria in predicting mortality
for 12 h

for 12 h has been validated in several studies of hospitalized

2

patients with cirrhosis, including those in intensive

care units.8-11
Recently, ICA modied the denition of HRS and
for 6-12 h

for 6-12 h

AKI in patients with cirrhosis (Box 1).12 A new

1

denition of HRS based on the ICA-AKIN criteria

was proposed, which included removal of the
threshold value of Scr . 1.5 mg/dL to dene HRS.
.4 mg/dL with an acute increase

[ to 2-3 3 [ to 3 x baseline; or to .4 mg/dL

This may facilitate earlier diagnosis and treatment of

patients with type 1 HRS.
. 0.5 mg/dL; or on RRT

. 0.5 mg/dL; or on RRT

. 0.5 mg/dL; or on RRT

. 0.5 mg/dL; or on RRT

with an acute increase

with an acute increase

[ to 2-3 3 [ to 3 3 baseline; or to

The Arterial Vasodilation Theory

or to .4 mg/dL with
Table 1. Criteria for Definition and Classification of AKI

an acute increase

Currently, the arterial vasodilation theory is the

Kidney Disease: Improving Global Outcomes; RRT, renal replacement therapy; Scr, serum creatinine; UO, urine output.
[ to 2-3 3 [ to 3 3 baseline;
3

most widely accepted explanation for the circulatory

dysfunction that occurs in patients with advanced
AKI Stages by Scr Criteria

cirrhosis (Fig 1).13 Circulatory changes are charac-

terized by reduced systemic vascular resistance due to
splanchnic arterial vasodilation. In early stages of the
disease when patients have compensated cirrhosis,
baseline

baseline

baseline

baseline

portal hypertension is moderate. In this context, there

2

is a moderately intense splanchnic vasodilation. The

effect of the decrease in systemic vascular resistance
to $1.5-2 3 baseline

to $1.5-2 3 baseline

to $1.5-2 3 baseline

to $1.5-2 3 baseline

is a reduction in arterial pressure, which is balanced

by increased cardiac output. In advanced stages of
[ by $0.3 mg/dL

[ by $0.3 mg/dL

[ by $0.3 mg/dL

[ by $0.3 mg/dL
within 48 h or

within 48 h or

within 48 h or

within 48 h or

decompensated cirrhosis, splanchnic vasodilation in-

1

creases due to increased synthesis of vasodilatory

factors, possibly nitric oxide (NO), carbon monoxide,
and/or endogenous cannabinoids. Neoangiogenesis
in mesenteric vessels and impaired response to
the prior 7 d; or UO , 0.5 mL/kg/h for 6 h

vasoconstrictors may also contribute to the reduced

[ in Scr by $0.3 mg/dL within 48 h; or [ in
within 48 h; or UO , 0.5 mL/kg/h for 6 h

Scr to $1.5 3 baseline, which is known

[ in Scr by $0.3 mg/dL within 48 h; or [

in Scr to $1.5 3 baseline; HRS-1 is a

splanchnic vascular resistance. The relentless

or presumed to have occurred within

or [ in Scr by $50% from baseline

that is known or presumed to have

splanchnic vasodilation leads to a progressive reduc-

[ in Scr by $0.3 mg/dL within 48 h;

[ in Scr by $0.3 mg/dL within 48 h;

tion in systemic vascular resistance that cannot be

or [ in Scr to $1.5 3 baseline

occurred within the prior 7 d

balanced by the increased cardiac output. Therefore,

AKI Definition

effective arterial hypovolemia due to the disparity

between the intravascular blood volume and markedly
specific form of AKI

enlarged arterial circulation develops. Moreover,

evidence suggests that there is a decrease in cardiac
output, probably related to cirrhotic cardiomyopa-
thy.14 The so-called cirrhotic cardiomyopathy is
dened by impaired myocardial contractility with
systolic and diastolic dysfunction in combination with
electromechanical abnormalities.15 It has been shown
AKI in Cirrhosis

AKI in Cirrhosis

that some degree of diastolic dysfunction may be

KDIGO5 (2012)

ADQI6 (2010):

ICA12 (2015):
AKIN4 (2007)

present in .50% of patients with cirrhosis regardless

of the presence or extent of ascites.16 However, no
correlation has been found between diastolic
dysfunction and HRS.16 By contrast, invasive and

320 Am J Kidney Dis. 2016;67(2):318-328

Pathogenesis of Heptorenal Syndrome
ADVANCED CIRRHOSIS
Portal Hypertension
Increased cytokine producon
Increased vasodilator factors
Coagulopathy Cardiac Circulatory
dysfunc on failure
Eec ve arterial
blood volume
HEPATORENAL SYNDROME
Figure 1. Pathogenesis of hepatorenal syndrome. Abbreviation: SBP, spontaneous bacterial peritonitis.
noninvasive systemic hemodynamic assessments
suggest that advanced cirrhosis is characterized by
impaired chronotropic and inotropic responses that
may contribute to a reduction in kidney perfusion,
thus precipitating HRS.16,17 Cardiac output , 1.5 L/
min/m2 is associated with increased risk for HRS and
poor survival.17 These mechanisms could explain
why b-blocker use for the prevention of variceal
bleeding may be associated with a worse outcome in
patients with refractory ascites.18
In the context of arterial underlling, there is acti-
vation of systemic vasoconstrictor systems, including
the renin-angiotensin-aldosterone system (RAAS),
sympathetic nervous system, and arginine vasopressin
(AVP), to help maintain arterial pressure. A large body
of evidence indicates that plasma renin activity, a
marker of the RAAS, and plasma levels of norepi-
nephrine, the effector of the sympathetic nervous
system, are increased in advanced cirrhosis.19,20
Moreover, their inhibition results in arterial hypoten-
sion, suggesting that they are activated as a homeo-
static response to preserve arterial pressure.21-27 AVP
is released as a consequence of baroreceptor-activated
arterial underlling, and experimental studies suggest
that AVP also contributes to the maintenance of arte-
rial pressure in advanced cirrhosis.28 Although these
systems have positive effects in improving arterial
pressure, they have a negative impact on kidney
function, including renal sodium retention causing
edema and ascites, impaired solute-free water excre-
tion causing hypervolemic hyponatremia, and a
decrease in glomerular ltration rate that eventually
leads to HRS.13 It must be noted that experimental
studies have suggested the existence of baroreceptors
in liver tissue that could participate in the pathogenesis
of sodium retention and HRS through a hepatorenal
Am J Kidney Dis. 2016;67(2):318-328
SBP, sepsis, bacterial
translocaon, injured liver
Systemic inflammatory response
Rela ve adrenal Hepa c
insuciency encephalopathy
reex.29 Whereas the use of transjugular intrahepatic
portal shunts (TIPSs) induce only a moderate
improvement in kidney function in HRS, vasocon-
strictor drugs reverse HRS in the majority. Therefore,
these data demonstrate that the improvement in cir-
culatory function plays a crucial role in the patho-
genesis of HRS compared to that of the increased
portal pressure.
Other substances that may be involved include
endothelin and natriuretic hormones. Endothelin is a
powerful vasoconstrictor, the plasma levels of which
are increased in patients with HRS.30 However, in
the only study published to date of humans,
administration of an endothelin antagonist in pa-
tients with HRS did not improve kidney function.31
Natriuretic hormones (atrial and brain natriuretic
peptide) are present in elevated levels in patients
with cirrhosis and ascites.32,33 However, the role of
these peptides with vasodilator effects is not well
understood.
Kidney Factors
Prostaglandins are metabolites of arachidonic acid
that have protective effects in the kidney by
compensating the vasoconstrictor effects of the
RAAS, sympathetic nervous system, and AVP. The
main renal prostaglandins (prostaglandin I2 and
prostaglandin E2) have vasodilator effects in the
kidney and are present at higher levels in patients with
cirrhosis and ascites. Administration of nonsteroidal
anti-inammatory drugs, which inhibit prostaglandin
synthesis, is frequently associated with the develop-
ment of AKI in patients with cirrhosis and ascites.34
Changes in renal blood ow autoregulation likely
play a role in the development of reduced kidney
function and HRS in patients with cirrhosis. Patients
321

with advanced cirrhosis have a shift in the autor-
egulation curve, which means that for a given level of
kidney perfusion pressure, renal blood ow is lower
compared to that of patients with compensated
cirrhosis.35 Moreover, the increased activity of the
sympathetic nervous system likely plays a role in
blood ow autoregulation.35
Histologic abnormalities suggestive of AKI and/or
CKD have been found in kidney biopsy specimens
from patients with cirrhosis, raising the possibility
that HRS may not be of an exclusive functional na-
ture.36,37 Although this hypothesis is attractive, the
majority of these studies were not performed in pa-
tients with HRS and performed only post-mortem in
patients with HRS. Therefore, it would be important
to assess kidney histology and its relationship with
response to treatment in vivo in patients with cirrhosis
and HRS. Moreover, it should be acknowledged that
recent studies have shown complete reversibility of
kidney dysfunction after pharmacologic treatment of
type 1 HRS with terlipressin or norepinephrine and
albumin in more than two-thirds of patients.38-41
Therefore, this is a strong argument in favor of a
functional cause of type 1 HRS in a large proportion
of patients.
Systemic Inammation
There is accumulating evidence that decom-
pensated cirrhosis is characterized by the existence of
a systemic inammatory state that may play a role in
the pathogenesis of HRS, enhancing the already
impaired circulatory function (Fig 1).
Advanced cirrhosis is characterized by an increase in
serum levels of C-reactive protein and proinammatory
cytokines that correlate with portal hypertension and a
hyperdynamic circulatory state.42-45 These ndings have
been reported even in the absence of bacterial infections,
suggesting that inammation in cirrhosis cannot be
solely explained by sepsis. It has been shown that pa-
tients with advanced cirrhosis and bacterial translocation
to mesenteric lymph nodes have increased production of
proinammatory cytokines (tumor necrosis factor a
[TNF-a] and interleukin 6 [IL-6]) and vasoactive factors
(ie, NO) in the splanchnic area,46 as well as increased
serum levels of cytokines with reduction of sympathetic
nervous system and increased cardiac output, as
compared with patients without bacterial trans-
location.47 In addition, markers of oxidative stress such
as oxidized albumin have been shown to increase in
decompensated cirrhosis.48,49 Moreover, recent studies
suggest that impaired cardiac function may also be
related to inammation because rats with cirrhosis show
TNF-arelated activation of NO synthase and oxidative
stress in cardiac tissue.50
Evidence for the role of inammation derives
exclusively from clinical studies because there are no
322
Durand et al
good animal models of HRS. Early studies showed
that patients with spontaneous bacterial peritonitis and
HRS had a marked increase in plasma and ascitic uid
levels of IL-6 and TNF-a compared with those of
patients with spontaneous bacterial peritonitis without
HRS.51 It was also shown that this increase in cyto-
kines was associated with increased NO and carbon
monoxide levels.52 These ndings suggest that an
intense inammatory state in advanced cirrhosis could
be a triggering factor for the development of HRS by
worsening the impaired circulatory function and
leading to progressively decreased kidney perfusion.
Although the development of HRS was rst described
in patients with spontaneous bacterial peritonitis, all
types of infections may be associated with HRS.53-55 A
recent prospective study has shown that approximately
one-third of patients with cirrhosis and bacterial in-
fections develop HRS, and that HRS is rapidly progres-
sive (type 1) in almost half of them.56 The relationship
between type of reduced kidney function and inam-
matory events has been assessed in a prospective study
including 100 patients with cirrhosis and AKI.57 Most
patients with HRS (78%) had infection and/or systemic
inammatory response syndrome compared to only 14%
of patients with AKI due to hypovolemia. Remarkably,
almost one-third of patients with HRS had systemic in-
ammatory response syndrome without documented
bacterial infection. These data indicate that systemic
inammation, with or without infection, is common in
HRS and seems to be characteristic of this condition and
not simply related to decreased kidney function because
it does not occur in AKI due to hypovolemia.
Interventional studies inhibiting some of the in-
ammatory pathways or reducing bacterial trans-
location further support the important role of
inammation in the pathogenesis of HRS. Several
studies have shown that treatment with pentoxifylline,
a drug that inhibits TNF-a synthesis, may reduce the
risk for HRS in patients with alcoholic hepatitis, as well
as in patients with cirrhosis.58-60 However, these results
have not been conrmed in other studies.61,62 How-
ever, considering the role of bacterial translocation in
the inammatory state in cirrhosis, the possibility exists
that prevention of bacterial translocation may reduce
systemic inammation and subsequently decreases the
risk for HRS. In a randomized study of spontaneous
bacterial peritonitis primary prophylaxis in patients
with advanced cirrhosis at high risk for developing
spontaneous bacterial peritonitis, noroxacin reduced
the risk for HRS independent of the prevention of
spontaneous bacterial peritonitis.63 Accordingly,
treatment with noroxacin in patients with decom-
pensated cirrhosis has been shown to be associated with
a reduction in plasma lipopolysaccharide-binding
protein, serum cytokine, and NO levels and an in-
crease in systemic vascular resistance.47
Am J Kidney Dis. 2016;67(2):318-328
Pathogenesis of Heptorenal Syndrome

Relative Adrenal Dysfunction
The presence of relative adrenal insufciency,
characterized by inadequate production of cortisol to
meet peripheral demands, may also play a role in the
pathogenesis of HRS. Patients with cirrhosis and
relative adrenal insufciency have a higher probabil-
ity of developing type 1 HRS compared with those
with cirrhosis and normal adrenal function.64 The
potential role of relative adrenal insufciency in the
pathophysiology of HRS is likely related to the
impaired circulatory dysfunction characteristic of pa-
tients with relative adrenal insufciency, with low
arterial pressure and high plasma renin activity and
noradrenaline levels, together with an increased
probability of developing bacterial infections and
increased systemic inammatory response.64
RECENT ADVANCES
Prevention of HRS
Patients with cirrhosis and ascites who develop
spontaneous bacterial peritonitis are at higher risk for
the development of HRS and at increased risk for
mortality. Administration of concentrated albumin,
1.5 g/kg, on day 1 followed by 1 g/kg on day 3 has
been shown to be benecial in reducing the devel-
opment of HRS.65 In a 2013 meta-analysis of 4 ran-
domized controlled trials encompassing 288 patients,
patients with spontaneous bacterial peritonitis who
received albumin had a lower incidence of reduced
kidney function (8.3% vs 30.8% in those not
receiving albumin) and improved survival (84% vs
64.6% in patients without albumin administration).66
Spontaneous bacterial peritonitis prophylaxis in pa-
tients with low-protein ascites, antibiotic prophylaxis
following gastrointestinal bleed, and albumin infusion
during large-volume paracentesis have all been shown
to be effective in reducing the incidence of type 1
HRS.
Management of HRS
Medical therapies directed at improving systemic
and renal hemodynamics involve restoration of
effective circulating volume with concentrated al-
bumin solutions coupled with the use of vasocon-
strictors. Currently available strategies for the
treatment of type 1 HRS include the use of albumin
with either terlipressin, octreotide plus midodrine, or
norepinephrine (Table 2).38,39,41,67-79 In a pooled
analysis of 501 patients with type 1 HRS across 21
studies, increasing mean arterial pressure correlated
with improvement in kidney function irrespective of
the agent used.80 An increase in mean arterial pres-
sure of .5 mm Hg is independently associated with
reversal of HRS (odds ratio, 9.48; P 5 0.049).71
Albumin is given at an initial dose of 1 g/kg of
20% to 25% albumin, followed by daily doses of 20
to 50 g.
Numerous studies have demonstrated the efcacy
of terlipressin in the treatment of HRS, including
several randomized controlled trials.38,39,67-75 Studies
that have attempted to identify predictors of response
to therapy with terlipressin have shown both Scr
level , 5 mg/dL70 and serum bilirubin level , 10
mg/dL71 as being positive predictors of a response. In
both these studies, an increase in mean arterial pres-
sure was found to be associated with a positive
response to terlipressin. In the largest placebo-
controlled study to date, HRS reversal was more
likely to occur in the terlipressin group (34% vs 13%;
P 5 0.008).69 While no difference in overall survival
between groups was observed, 6-month survival was

Table 2. Vasoconstrictor Drugs for the Treatment of Hepatorenal Syndrome

Drug Mechanism of Action Dose Comments

Terlipressin Vasopressin analogue 1 mg IV every 4-6 h; increase to 2 mg Not available in the United States
every 4-6 h if there is no improvement in
Scr (decrease by 25% by day 3) up to a
maximum of 12 mg/d as long as there are
no side effects; maximal treatment 14 d
Norepinephrine a-Adrenergic agonist 0.5-3.0 mg/h (continuous infusion); titrate Requires ICU; in countries where
to achieve a 10mm Hg increase in MAP terlipressin is not available,
norepinephrine can be used as an
initial therapy in ICU patients or as
an alternative in patients in whom
midodrine 1 octreotide has failed
Midodrine 1 a-Adrenergic agonist Midodrine: 7.5-12.5 mg orally 33/d;
octreotide (midodrine); somatostatin titrate to achieve a 10mm Hg increase
analogue (octreotide) in MAP from baseline; octreotide:
100-200 mg SC 33/d
Note: All vasoconstrictors should be given in combination with 25% IV albumin.
Abbreviations: ICU, intensive care unit; IV, intravenous; MAP, mean arterial pressure; SC, subcutaneous; Scr, serum creatinine.

Am J Kidney Dis. 2016;67(2):318-328 323

 Durand et al

reported to be greater in those who achieved reversal
of HRS.69
In patients admitted to the intensive care unit,
norepinephrine plus albumin has been shown to be an
effective treatment for HRS. In 2 randomized trials
comparing terlipressin to norepinephrine, no signi-
cant differences in safety or efcacy between the 2
groups were noted.76,77 In patients who are not in the
intensive care unit but require long-term vasocon-
strictor therapy, midodrine in combination with
octreotide has been shown to be benecial in the
treatment of HRS.78,79 However, a more recent ran-
domized controlled trial of 49 patients comparing
terlipressin to octreotide/midodrine demonstrated a
signicantly higher rate of recovery in the terlipressin
group (70.4% vs 28.6%; P 5 0.01).39 The optimal
duration of medical treatment is not well established;
however, patients who have failed to demonstrate
improvement in Scr levels after day 4 are less likely to
have reversal of HRS,71 and an indication for treat-
ment beyond 14 days has not been established.
Limited studies have analyzed the role of TIPS in
the treatment of HRS.81-83 These studies have shown
that TIPS placement leads to improvement in both
type 1 and type 2 HRS, a decrease in recurrence rates
of HRS, and resolution of ascites. However, there is
an association between worsened survival after TIPS
placement in patients with more advanced liver
dysfunction. Thus, at this time, there is insufcient
evidence to routinely recommend TIPS placement for
treatment of HRS.
RRT may be indicated in patients with HRS who
do not respond to medical therapy as a bridge to
transplantation. However, in patients with type 1 HRS
in whom liver transplantation is not a viable option,
initiation and/or continuation of RRT remains
controversial and must be considered carefully
because long-term survival in such patients is not
likely to be sufciently improved by such therapy.
Albumin dialysis using a Molecular Adsorbent
Recirculating System (MARS) (Gambro) has been
reported to more efciently remove albumin-bound
substances potentially involved in the pathogenesis
of HRS.84-86 A controlled study with a very limited
number of patients suggested that MARS could
improve the survival of patients with HRS as
compared to conventional therapy85; however, the
survival benet of MARS was very modest.
Although HRS is considered to be reversible
following liver transplantation,87 several studies have
shown that this may not be the case all the time, espe-
cially in patients with alcoholic cirrhosis.88,89 In a
recent study by Wong et al89 of patients with type 1
HRS, 47% of whom were on dialysis therapy prior to
liver transplantation, only 76% had full recovery,
dened as a decrease in Scr level to ,1.5 mg/dL.89 In
that study, higher pretransplantation Scr level, pro-
longed duration of type 1 HRS, and longer duration of
pretransplantation dialysis therapy were found to be
associated with a signicant decrease in the rate of re-
covery of kidney function. Although HRS is not always
reversible with liver transplantation alone, it must be

Table 3. Guidelines for Simultaneous Liver-Kidney Transplantation

Author Year Recommendations

Davis et al91 2007  Patients with AKI/HRS on dialysis for $6 wk

 Patients with AKI with kidney biopsy showing fixed kidney damage
 Patients with CKD with measured CLcr # 30 mL/min
 SLK not recommended in patients with AKI who are not receiving dialysis
Eason et al92 2008  Patients with AKI/HRS on dialysis for $8 wk
 Patients with CKD with GFR # 30 mL/min
 Kidney biopsy showing . 30% glomerulosclerosis or 30% fibrosis
 Presence of comorbid conditions such as diabetes, hypertension, older age (.65 years), other
preexisting kidney disease; proteinuria, kidney size, and duration of elevated Scr were also
recommended criteria
Nadim et al93 2012 1. Candidates with AKI for $4 wk with 1 of the following:
 Stage 3 AKI (ie, 3-fold increase in Scr from baseline or on renal replacement therapy)
 eGFR # 35 mL/min/1.73 m2 (by the 6-variable MDRD Study equation) or mGFR # 25 mL/min
(by iothalamate clearance)
2. Candidates with CKD with 1 of the following:
 eGFR # 40 mL/min/1.73 m2 (by 6-variable MDRD Study equation) or mGFR # 30 mL/min
(iothalamate clearance)
 Proteinuria $ 2 g/d
 Kidney biopsy showing .30% global glomerulosclerosis or .30% interstitial fibrosis
 Metabolic disease
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; CLcr, creatinine clearance; eGFR, estimated glomerular
filtration rate; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; MDRD, Modification of Diet in Renal Disease; mGFR,
measured glomerular filtration rate; Scr, serum creatinine; SLK, simultaneous liver-kidney transplantation.

324 Am J Kidney Dis. 2016;67(2):318-328

Pathogenesis of Heptorenal Syndrome
noted that liver transplantation confers a major survival
benet compared to medical management.90
Because kidney function does not always recover
after liver transplantation in patients with a diagnosis
of type 1 HRS, recommendations for simultaneous
liver and kidney transplantation have been proposed
following several consensus meetings (Table 3).91-93
However, in an era of organ shortage, controversy
regarding the appropriate candidates for simultaneous
liver and kidney transplantation, especially patients
with type 1 HRS, continues to plague the trans-
plantation community.
Novel Biomarkers
In addition to general markers such as Scr level,
novel biomarkers are needed for differentiation of
HRS before liver transplantation.94,95 The diagnosis
of HRS is based on a series of clinical and laboratory
criteria as set forth by the ICA.1 However, a clinical
diagnosis of HRS does not exclude associated struc-
tural changes, in particular acute tubular necrosis
(ATN). In all studies comparing HRS and ATN, there
was no gold standard (ie, no histology) for the diag-
nosis of ATN or HRS; instead, diagnosis was solely
based on clinical criteria. Thus, a diagnosis of ATN
may be difcult to establish in patients with decom-
pensated cirrhosis. In addition, HRS and ATN may
coexist or even represent a continuum in some pa-
tients. Several recent studies have shown that some
urine biomarkers, such as neutrophil gelatinase-
associated lipocalin (NGAL), IL-6, albuminuria, or
fractional excretion of sodium, may be helpful in the
differential diagnosis.95-102
NGAL is secreted into urine by tubular cells of the
thick ascending limb of Henle and collecting ducts.
In patients with cirrhosis, median urinary NGAL has
been found to be markedly higher in patients with a
clinical diagnosis of ATN compared with patients
with HRS, CKD, and pre-renal azotemia.98,100 In
patients with cirrhosis and infections, urinary NGAL
was able to predict the presence of AKI, type
of AKI, and 3-month mortality in hospitalized
patients.99
A study of patients with cirrhosis found no corre-
lation between fractional excretion of sodium and
worsening of AKI.96 Albuminuria, a marker of
glomerular injury, has been observed to be signi-
cantly higher in patients with cirrhosis with a diag-
nosis of ATN compared with patients with HRS and
patients with decreased kidney perfusion.96 Although
this study proposed a cutoff albuminuria value of
44 mg/dL to differentiate ATN from HRS, there was
an overlap of albuminuria between groups. More data
are needed to better understand the interactions
among albuminuria, impaired liver function, and
glomerular changes in cirrhosis.
Am J Kidney Dis. 2016;67(2):318-328
Predicting recovery of kidney function after liver
transplantation is a challenging issue. Following
implementation of the Model of End-Stage Liver
Disease (MELD) scorebased allocation policy, the
number of candidates for liver transplantation with
reduced kidney function has increased. In parallel, the
number of simultaneous liver and kidney trans-
plantations has increased in recent years.93 A study
based on posttransplantation radionuclide scan of the
native and transplanted kidneys showed that w30%
of patients with combined transplantation had native
kidney recovery, with glomerular ltration rates .
30 mL/min.103 A recent study focusing on plasma
biomarkers in liver transplant recipients has shown
that pretransplantation increases in osteopontin and
tissue inhibitor of metalloproteinase (TIMP-1) are
predictive of recovery of kidney function after liver
transplantation.104
These tubular biomarkers may potentially help
identify patients who are less likely to benet from
volume resuscitation and vasopressor therapy and
those who are less likely to recover following liver
transplantation.
SUMMARY
HRS is a complication of end-stage cirrhosis
characterized by intense renal vasoconstriction and a
markedly decreased glomerular ltration rate resulting
from both splanchnic and systemic circulatory
changes of cirrhosis. The majority of patients respond
to a combination of albumin and vasopressors; how-
ever, prognosis is poor even in responders. It is
important to differentiate HRS from ATN because the
therapeutic approach is different. Recent biomarkers
are helpful but do not allow a clear distinction.
Whether nonresponders to vasopressors are those who
have developed ATN needs to be investigated.
Importantly, tools are needed to identify patients who
will have sufcient recovery of kidney function after
transplantation. In this latter group, simultaneous liver
and kidney transplantation should be considered.
ACKNOWLEDGEMENTS
Support: Dr Graupera was awarded the Rio Hortega Research
grant by the Instituto de Salud Carlos III for further research
training. Dr Gins was awarded a research grant by Fondo de
Investigacin (FIS) Instituto de Salud Carlos III. FIS 12/00330,
conanced by Fondo Europeo de Desarrollo Regional (FEDER).
Unin Europea.
Financial Disclosure: Drs Durand, Olson, and Graupera have
no relevant nancial relationships. Dr Nadim has served as an
advisor for Ikaria. Dr Gins has been advisor for Ikaria, Ferring,
Noorik, Salix, and Sequana Pharmaceuticals.
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