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REVIEW Article

Hepatorenal Syndrome : A Decade Later

CK Pandey1, ST Karna2, A Singh2, VK Pandey2, M Tandon2, V Saluja3
Abstract
Hepatorenal syndrome is a unique form of acute kidney injury seen in patients with acute liver failure or
chronic liver disease in absence of any other identifiable cause of renal failure. It is primarily a diagnosis
of exclusion. Despite of good pathophysiological understanding and better available therapeutic options
for management of hepatorenal syndrome, it is still associated with significant morbidity and mortality.
Liver transplantation forms the cornerstone for its management. In this review article, we have attempted
to assimilate and summarise the advances made in the previous decade with regards to pathophysiology,
classification and management of this entity.

Introduction

epatorenal syndrome (HRS) is a unique form of acute kidney injury seen in

patients with acute liver failure or chronic liver disease in absence of any other
identifiable cause of renal failure. It is primarily a diagnosis of exclusion. We have
come a long way in understanding the pathophysiology and treatment of hepatorenal
syndrome. In this review article, we have attempted to assimilate and summarise the
advances made in the previous decade with regards to pathophysiology, classification
and management of this entity, which was once considered ambiguous.
Diagnostic criteria: The International Ascites Club (IAC) revised the criteria for
diagnosis of HRS in 2007. 1,2 These consist of:
1. Cirrhosis with ascites
2. Serum creatinine >1.5 mg/dL
3. No improvement of serum creatinine (a decrease in serum < 1.5 mg/dL) after 2
days off diuretics and volume expansion with albumin (1g/kg body weight up to
a maximum of 100 g/d)
4. Absence of shock
5. No current or recent treatment with nephrotoxic drugs
6. Absence of signs of parenchymal renal disease, as suggested by proteinuria (> 500
mg/d) or haematuria (> 50 red blood cells per high-power field) and/or abnormal
renal ultrasound
The main differences from the old diagnostic criteria (1996) are:
1. The use of creatinine clearance has been abandoned for the diagnosis of HRS
2. As long as septic shock is absent, the presence of ongoing bacterial infection does
not preclude the diagnosis of HRS

1
Professor and Head,
Assistant Professor, 3Senior
Resident, Department of
Anaesthesiology, Institute of
Liver and Biliary Sciences, New
Delhi-110070
Received; 25.06.2013;
Accepted: 02.09.2013
2

696

3. Albumin is preferred over saline for plasma volume expansion to exclude pre-renal
aetiology of acute kidney injury (AKI)
4. Minor diagnostic criteria including low fractional excretion of sodium and oliguria
have now been omitted.
Even the new diagnostic criteria have been scrutinised and criticised in view of the
following shortcomings and pitfalls. 3,4

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1. Patients with chronic kidney disease (CKD)/

Anuric patients cannot be diagnosed with HRS.
2. The discrepancy between acute kidney injury
network (AKIN) diagnostic definition and
classification of AKI and IAC diagnostic criteria
f o r H R S p r e ve n t s e a r l y d i a g n o s i s o f r e n a l
dysfunction in cirrhotic patients. A patient
having increase in creatinine of 0.3 mg/dl in 48
hrs. will be classified as having AKI but if the
serum creatinine is < 1.5mg/dl, the diagnosis
of HRS is not possible. In cirrhotics, where the
baseline creatinine is low, this excludes a group of
patients with impending HRS who may benefit by
instituting specific treatment at an earlier stage.
A c u t e d i a l y s i s q u a l i t y i n i t i a t i ve ( A D Q I ) i n
their 8 th international consensus conference on
hepatorenal syndrome 5 has tried to address the
various shortcomings of previous definitions. Their
recommendations are to be considered as the first step
towards standardisation of the definition of AKI in
patients with cirrhosis.
As the diagnosis of AKI as defined by ri f le
criteria has been shown to be a predictor of hospital
survival. The consensus of the workgroup has been
to apply the modified RIFLE criteria to define AKI
in patients with cirrhosis irrespective on the causestructural or functional.
The early identification of change in serum
creatinine in patients with AKI not fulfilling the
criteria for HRS but having low GFR will allow early
institution of therapy for these patients and prevent
rapid progression of the pathology.
The workgroup also goes on to suggest the
term hepatorenal disorders be used to describe all
patients with advanced cirrhosis and concurrent
kidney dysfunction encompassing both functional
and structural. The classification of the severity of
dysfunction will be based on the RIFLE criteria.
This will allow cirrhotic patients with renal
dysfunction to be properly classified allowing
studies to be conducted to define their prognosis and
to devise treatment options.

Classification of HRS
The classification of hepatorenal syndrome into two
types has remained unchanged even in the updated
diagnostic criteria. It is crucial to differentiate between
the 2 types, not just for the clinical management,
but also for appropriate prognostication and risk
assessment.
Type 1 HRS: Defined as doubling of the serum
creatinine to more than 2.5 mg/dl in duration of
less than 2 weeks. It is more acute, associated with
precipitating factors and has a grave prognosis.

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37

Type 2HRS: Defined as a slowly progressive rise in

serum creatinine to more than 1.5 mg/dl. It is usually
associated with diuretic resistant refractory ascites.

Epidemiology
HRS occurs almost exclusively in patients with
ascites and the estimated probability of developing
HRS at 1 and 5 years in patients with ascites being 18
and 39% respectively. 6
In a retrospective multicentric study conducted
a decade back by Moreau et al. found that in 423
patients with cirrhosis and AKI; Type 1 and 2 HRS
were implicated in 20% and 6.6% cases respectively. 7
In a recent study Montoliu et al. assessed the
incidence and prognosis of different types of
functional renal failure in 263 consecutive cirrhotic
patients with ascites. All patients were followed up
for 413 months after their first incidence of ascites.
During the follow-up period, out of the 129 (49%)
patients who developed some type of functional
renal failure, hepatorenal syndrome was causative in
only 7.6%. The cumulative probability of developing
HRS was 11.4%. The independent predictors for
development of functional renal failure were age,
Child-Pugh score, and serum creatinine. 8 However,
another prospective study conducted in a tertiary
transplant centre documented that 40% patient with
cirrhosis and kidney failure had HRS. 9

Pathogenic Mechanisms
Many interrelated pathophysiological processes
have been implicated in the development of HRS
which include the diseased liver, portal hypertension
and development of ascites, splanchnic vasodilation,
myocardial depression, abnormal systemic and renal
neurohumoral regulation, lower renal prostaglandin
production and adrenal insufficiency.10 The severity of
deterioration of liver function affects the development
of renal dysfunction.
A r t e r i a l h y p o t e n s i o n a l o n g w i t h r e l a t i ve l y
insufficient CO (in spite being high) is the key
factor in development of compensatory mechanisms
contributing to development of HRS. The traditional
model of the hepato-renal axis and HRS includes
s p l a n c h n i c h y p e r a e m i a a n d va s o d i l a t i o n w i t h
compensatory activation of the reninangiotensin
aldosterone (RAAS) and sympathetic systems (SNS)
to maintain blood pressure. Contributory to this is
the non-osmotic release of endogenous vasopressin.
The resultant increase in serum catecholamine and
angiotensin levels causes intra-renal vasoconstriction
and hypoperfusion resulting in a decrease in
glomerular filtration rate (GFR). With increasing
serum creatinine levels, HRS ensues especially when
additional precipitating factors like- spontaneous

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Table 1 : Pathophysiological phases in the development of

ascites and HRS14

below along with the review of other literature for

prevention of HRS:

Phase Term

Ascites

Na+ and
H2O

Pre-ascitic
cirrhosis
MildModerate
Ascites
ModerateTense
Ascites
Type 2 HRS
Type 1 HRS

No

No/Yes

1. C a r e f u l a s s e s s m e n t , c l o s e m o n i t o r i n g a n d
prevention of precipitating factors in cirrhotics
with ascites.

Yes

Yes

No/Yes

No

Yes

Yes

Yes

No/Yes

Yes
Yes

Yes
Yes

Yes
Yes

Yes
Yes

Increased in Decreased
RAAS and
RBF and
SNS
GFR
No
No

Abbreviations : RAAS-Reninangiotensinaldosterone system; SNSsympathetic nervous system; RBF-renal blood flow; GFR-glomerular
filtration rate; HRS-hepatorenal syndrome

bacterial peritonitis, upper GI bleeding, large volume

paracentesis, further increase renal vasoconstriction.11
Translocation of bacteria from the intestinal lumen to
mesenteric lymph nodes (MLNs) and then into the
systemic circulation lead to an inflammatory state and
vasodilation. 10,12 Recent studies have shown the role
of the Reninangiotensinaldosterone system (RAAS)
not only in propagating renal injury through intrarenal vasoconstriction but also as a cause for hepatic
fibrosis. 13 For pathophysiological phases responsible
for the development of ascites and HRS is summarised
in Table 1. 14

Precipitating Factors for HRS

In 50% cases, the development of HRS is
spontaneous, whereas in other half 1 or more
identifiable triggers may be found which include. 15
1. Bacterial infectionsAscitic fluid, respiratory
system, urinary tract, GI tract infections and
infections of the biliary tract.
2. Diarrhoea and vomiting
3. Diuretics
4. Gastrointestinal bleeding-variceal bleeding
5. Large volume paracentesis (LVP)more than 5
litres without adequate blood volume expansion.

Prevention of HRS
The development of HRS is associated with
significantly increased morbidity and mortality.
With better understanding of the pathophysiology of
HRS, certain specific strategies have been identified
to prevent HRS in specific clinical situations. A
systematic literature review was conducted by acute
dialysis quality initiative (ADQI) in 2010, where the
experts developed a consensus recommendation
for standardised care of cirrhotics with HRS. 16 The
preventive strategies outlined by ADQI are mentioned

698

2. Consider covert hypoadrenalism in patients with

cirrhosis to improve response to vasopressors and
survival. 17
3. Drugs which reduce renal perfusion and those
causing nephrotoxicity have been reported to
precipitate HRS, should be avoided.
4. Antibiotic prophylaxis has shown to reduce
spontaneous bacterial peritonitis (SBP). Studies
using norfloxacin have reported not only a
reduction in SBP (7 versus 61%) but also a
reduction in the incidence of HRS (28 versus
41%). 18
5. A l b u m i n i n f u s i o n s h a ve b e e n r e p o r t e d t o
decrease the incidence of HRS in patients with
SBP. 19 Consecutive trials have shown that in
context of SBP, albumin infusion is more effective
than other plasma expanders. 20 In severely
ill cirrhotic patients, volume expansion with
albumin has been shown to reduce plasma renin,
suggesting an improvement in the effective
circulating volume. In randomised controlled
clinical trials, albumin infusions reduced both
the incidence of HRS and mortality 19
6. Prophylactic pentoxifylline, a tumour necrosis
factor- antagonist, reduces complications in
patients with advanced cirrhosis including renal
dysfunction. 21
7. Large volume paracentesis (LVP) may induce
paracentesis induced circulatory dysfunction
(PICD) leading to development or exacerbation of
AKI and HRS. Administration of albumin 8 g/litre
of fluid aspirated (specially if the aspiration is
more than or equal to 5 litres) leads to prevention
of PICD. 22

General Management
Once the diagnosis of HRS is confirmed, it is
important to classify the disease into either of the two
types. Patients with Type 1 HRS need to be managed
in an intensive care unit, in view of the associated
inherent risk of multi-organ failure. Patients with
Type 2 HRS may be managed on an outpatient basis
with thorough workup and supportive care.

Monitoring
Patients with type 1 HRS should be monitored
carefully. Parameters to be monitored include urine
output, fluid balance, and arterial pressure, and
standard vital signs. Ideally central venous pressure
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39

should be monitored to help with the management of

fluid balance and prevent volume overload.

administration in divided doses without the need for

an infusion, and minimises systemic toxicity. 24

Screening for Sepsis

Te r l i p r e s s i n h a s a p r e f e r e n t i a l e f f e c t o n V 1
receptors, which are densely located in the splanchnic
bed. The improvement in renal perfusion is attributed
to splanchnic vasoconstriction, rise in the effective
circulating volume, mean arterial pressure, and
decrease in the plasma renin and aldosterone and
overall improvement in renal perfusion pressure. 25
Terlipressin is not yet approved by the Food and Drug
Administration (FDA) in the USA for use in HRS,
though it is commonly used in Europe and Asia. In a
recent meta-analysis of randomised controlled trials,
it was observed that the therapy with terlipressin
and albumin improves the renal function in patients
with cirrhosis and HRS type 1. This improvement was
sustained in most of the patients for the duration of
follow-up (90 to 180 days) leading to an improvement
in overall and transplant-free survival. The pooled
percentage of HRS reversal was 46% and recurrence
in 8%. 26

Bacterial infection should be identified early, by

blood, urine and ascitic fluid cultures, and treated
with antibiotics. Patients who do not have signs
of infection should continue taking prophylactic
antibiotics, if previously prescribed.

Use of Paracentesis
There are few data on the use of paracentesis in
patients with type 1 HRS. Nevertheless, if patients
have tense ascites, large-volume paracentesis with
albumin may be useful. 23

Volume Resuscitation
Excessive administration of fluids should be
avoided to prevent volume overload due to the
presence of kidney injury and development or
progression of dilutional hyponatraemia. Use of
Functional haemodynamic monitoring to assess
the dynamic response to a fluid volume bolus is
desirable. 5All diuretics should be stopped in patients
at the initial evaluation and diagnosis of HRS. There
are no data to support the use of furosemide in
patients with ongoing type 1 HRS. Nevertheless
furosemide may be useful to maintain urine output
a n d t r e a t c e n t r a l v o l u m e o ve r l o a d i f p r e s e n t .
Spironolactone is contraindicated because of high risk
of life-threatening hyperkalaemia. Patients with HRS
should be optimally resuscitated, with intravenous
administration of albumin (initially 1 g of albumin/kg
of body weight up to a maximum of 100 g, followed by
20-40 g/day) in combination with vasopressor therapy,
for up to 14 days. 16,23

Pharmacological Treatment of HRS

Most of these therapies have targeted the
haemodynamic perturbations that are thought to
underlie the pathophysiology of HRS, including
systemic and splanchnic vasodilation.

Vasopressin Analogues
Va s o p r e s s i n a n a l o g u e s f o r m t h e f i r s t l i n e
management of type 1 HRS as a bridge to transplant.
Among all vasopressin analogues, the drug most
widely used for treatment of type1 HRS is terlipressin
(three glycyl residues and lysine-VP). Following
intravenous administration, the glycyl residues are
cleaved by endothelial peptidases allowing slow,
prolonged release of lysine-VP. This mechanism
prolongs the half-life of terlipressin, enabling

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In recent randomised, prospective, placebocontrolled clinical trials, terlipressin was found

significantly more effective than placebo in reversing
type 1 HRS with a similar safety profile. 27Caraceni
et al. reported their experience with terlipressin and
albumin treatment as a bridge to liver transplantation
in three patients with cirrhosis and recurrent HRS.
They concluded that terlipressin prevents irreversible
renal failure and the need for dialysis until an
organ becomes available. 28 Though most studies
on terlipressin have been conducted in patients
with Type 1 HRS, but recently its use has also been
evaluated in patients with type 2 HRS. This study
demonstrated a combined reversal rate for type 2 HRS
with terlipressin and albumin of about 80% which,
recurred after discontinuation of therapy. 29
The ADQI recommends that patients with Type 1
HRS should be optimally resuscitated with albumin
(initially 1 g of albumin/kg of body weight for 2
days, up to a maximum of 100 g/day, followed by
20-40 g/day) in combination with a vasoconstrictor,
preferentially terlipressin. The terlipressin treatment
protocol comprises an initial dose of 0.5-1 mg
terlipressin applied by intravenous injection every
4-6 h or continuous intravenous infusion starting
at an initial dose of 2 mg/d. The therapy is aimed
to improve renal function and to decrease serum
creatinine to less than 1.5 mg/dl (complete response).
If serum creatinine does not decrease at least 25% of
its base value or < 133 mol/L after 3 days, the dose
of terlipressin should be increased in a stepwise
manner up to a maximum of 2 mg/4 hour. For patients
with partial response (serum creatinine does not
decrease < 133 mol/L) or in those patients without
reduction of serum creatinine, treatment should

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be discontinued within 14 days. If terlipressin is

not available, alternative vasoconstrictors, such as
norepinephrine or combination octreotide/midodrine,
together with albumin should be considered.
Therapy should be discontinued after 14 days in
non-responders and only continued thereafter in
partial responders while awaiting the outcome of
salvage techniques.16 Contraindications to terlipressin
therapy include ischaemic cardiovascular diseases.
Patients on terlipressin should be carefully monitored
for development of cardiac arrhythmias or signs
of splanchnic or digital ischaemia, and treatment
modified or stopped accordingly. Recurrence of type
1 HRS after discontinuation of terlipressin therapy
is relatively uncommon. Treatment with terlipressin
should be repeated and is frequently successful. 23

Norepinephrine
Norepinephrine, an -1 adrenergic agonist drug,
has been found to be effective in the treatment of
HRS. 29 Noradrenaline (0.5-3 mg/h) is administered
as a continuous infusion and the dose is increased
to achieve a raise in arterial pressure and also
improves renal function in patients with type 1 HRS.
In a prospective, randomised study of 46 patients,
the safety and efficacy of norepinephrine was
compared with terlipressin in treatment of type 1
HRS. Albumin was administered in both the groups.
Noradrenaline was found to be as safe and effective
as terlipressin, but less expensive in the treatment
of HRS. On multivariate analysis, only baseline CTP
score was found to be predictive of response. 30It is
also recommended by ADQI as an alternative to
terlipressin along with albumin for the treatment of
HRS. 16 A recent meta analysis also confirmed that nor
epinephrine and terlipressin are equivalent in efficacy
and side effect profile in reversing HRS. 31

Midodrine and Octreotide

Midodrine, an -1 agonist has been used in both
type 1 and 2 HRS. It causes vascular smooth muscle
constriction and the availability of an oral preparation
makes administration of this drug on an outpatient
basis feasible. Studies have shown that it is the
combination of thrice daily midodrine (7.5- 12.5 mg)
with octreotide (100- 200 g subcutaneously) and
albumin, which actually improves renal plasma flow,
GFR, urinary sodium excretion along with a reduction
in renin, vasopressin and glucagon after 3 weeks of
treatment.32 In a recent study of 162 patients with HRS
type 1 and type 2, the effect of octreotide, midodrine,
and albumin on survival and renal function was
compared with a cohort that did not receive this
therapy. Transplantation could be performed in 45%
of patients in the treatment group as compared with

700

26% of patients in the control group. It was concluded

that the therapeutic regimen of octreotide, midodrine,
and albumin significantly improved short-term
survival and renal function in both HRS type 1 and
type 2 and provided a significant benefit as a bridge
to liver transplantation in HRS type 1 and prevent
progression of HRS type 2 to HRS type 1. 33

Transjugular Intrahepatic Portosystemic

Shunt (TIPS)
In a recent study, 61 TIPS patients who had a
subsequent liver transplantation were evaluated
and compared with 591 patients transplanted with
cirrhosis without TIPS. It was shown that TIPS
improves post-transplant graft and patient survival
significantly, possibly due to an improved pretransplant renal function and portal blood supply of
the graft. 34 EASL guidelines recommend that though
the insertion of TIPS may improve renal function in
some patients, there are insufficient data to support
the use of TIPS as a treatment of patients with type 1
HRS. 23 Recent ADQI editorial reviews recommend use
of TIPS as a treatment option for patients with type-2
HRS with refractory ascites who require large-volume
paracentesis. 5

Renal replacement therapy (RRT)

Although there is a preference for continuous
renal replacement therapy (CRRT) over intermittent
haemodialysis in haemodynamically unstable
patients, analysis of the currently published studies
does not provide enough evidence for the selection
of RRT as a modality for the treatment of AKI in the
setting of HRS. 35 CRRT use may be advantageous in
the management of HRS patients with AKI who are
haemodynamically unstable or those patients at risk
of elevated intracranial pressure such as patients with
acute fulminant liver failure or acute on chronic liver
failure. In type-1 HRS, RRT should be avoided unless
there is either an acute reversible component or a plan
for liver transplantation. 5 EASL recommends that
renal replacement therapy may be useful in patients
who do not respond to vasoconstrictor therapy, and
who fulfill criteria for renal support. 23

Artificial Liver Support Systems

There are very limited data on artificial liver support
systems, and further studies are needed before its use
in clinical practice can be recommended. 16,23

Transplantation
HRS is a marker of poor hepatic function, which
will recover only when there is some degree of
improvement in liver function. In most patients, this

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will occur only after liver transplantation, which is

the best treatment for both type 1 and type 2 HRS.
HRS should be treated before liver transplantation,
s i n c e t h i s m a y i m p r o ve p o s t - l i ve r t r a n s p l a n t
outcome. 23 Patients with HRS who do not respond to
vasopressor therapy, and who require renal support
should generally be treated by liver transplantation
alone, since the majority will achieve a recovery
of renal function post-liver transplantation. There
is a subgroup of patients who require prolonged
renal support (> 12 weeks), and it is this group that
should be considered for combined liver and kidney
transplantation. 23 Nadim et al. have suggested liver
transplantation alone for candidates with type 1
HRS for less than 4 weeks and simultaneous liverkidney (SLK) for those at risk of non recovery of
renal function. 5 The united network of organ sharing
(UNOS) recommendations for SLK transplant in
patients with AKI include those with hepatorenal
syndrome with creatinine 2 mg/dl and duration of
dialysis more than 8 weeks. 36
For any given value of MELD or MELD-Na score,
patients with HRS have a shorter survival expectancy
than patients with chronic liver disease who are
candidates for LT. 37 However, patients with HRS are
not given priority to liver transplantation as per the
policy of exceptions to the MELD score that are
currently used in several Western countries. 38 In a
recent article, Angelli et al. suggested that to optimise
the results of the pharmacological treatment of HRS,
responders should receive the right priority in the
waiting list, taking into account not only the value of
HRS per se on three-month mortality beyond the MELD
score, but also considering that the pharmacological
treatment of HRS can reduce the baseline MELD score
in these patients. 39

Prognosis
The median survival of patients with type 1 HRS
is only 10% at 90 days, whereas for type 2 HRS it is
6 months without treatment. Prognosis is however
improved with treatment with the 3 month survival
of 20 and 40% respectively for type 1 and 2 HRS. 40
The survival in these groups of patients is dictated
by the deterioration in liver function, and the
response to pharmacological treatment. If there is no
improvement with treatment of vasoconstrictors for
10-14 days, it indicates a poor prognosis.

Conclusion
Despite of good pathophysiological understanding
a n d b e t t e r a va i l a b l e t h e r a p e u t i c o p t i o n s f o r
management of hepatorenal syndrome, it is still
associated with significant morbidity and mortality.
Liver transplantation forms the cornerstone for its

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41

management. Timely identification, prioritisation

for transplant, and early initiation of vasoconstrictor
therapy may contribute to better management plan.

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