Journal of Intensive Care Medicine

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Hepatorenal Syndrome in the Intensive Care Unit

Hani M. Wadei and Thomas A. Gonwa
J Intensive Care Med 2013 28: 79 originally published online 21 August 2011
DOI: 10.1177/0885066611408692

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Analytic Review
Journal of Intensive Care Medicine
28(2) 79-92
Hepatorenal Syndrome in the ª The Author(s) 2011
Reprints and permission:
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Intensive Care Unit DOI: 10.1177/0885066611408692
jicm.sagepub.com

Hani M. Wadei, MD1 and Thomas A. Gonwa, MD1

Abstract
Hepatorenal syndrome (HRS) is a functional form of acute kidney injury (AKI) associated with advanced liver cirrhosis or
fulminant hepatic failure. Various new concepts have emerged since the initial diagnostic criteria and definition of HRS was
initially published. These include better understanding of the pathophysiological mechanisms involved in HRS, identification of
bacterial infection (especially spontaneous bacterial peritonitis) as the most important HRS-precipitating event, recognition that
insufficient cardiac output plays a role in the occurrence of HRS, and evidence that renal failure reverses with pharmacotherapy.
Patients with HRS are often critically ill and, by definition, have multiorgan failure. The purpose of this review is to provide an
update on novel advances in HRS, with emphasis on the different aspects of management of these patients in the intensive care
unit.

Keywords
acute kidney injury, liver cirrhosis, vasopressin analogs, liver transplantation, simultaneous liver-kidney transplantation

Received September 28, 2010, and in revised form December 22, 2010. Accepted for publication February 14, 2011.

Introduction which occurs primarily in the splanchnic circulation and is

mediated by the release of potent vasodilators, the most impor-
Acute kidney injury (AKI) often develops in patients with tant of which is nitric oxide (NO).4 Nitric oxide production is
hepatic cirrhosis, and in many cases it necessitates admission
increased in cirrhosis due to shear stress-induced upregulation
to the intensive care unit. Potential causes of AKI in patients
of endothelial NO synthase (eNOS) activity in the splanchnic
with cirrhosis are diverse and sometimes hard to differentiate.
and systemic circulations, as well as endotoxin-mediated
Hepatorenal syndrome (HRS) is a form of functional renal fail-
eNOS activation.5,6 Increased inducible NOS (iNOS) activity
ure that is specific only to patients with end-stage liver disease
has also been documented.7 With arterial vasodilatation,
or fulminant hepatic failure and is related to intense renal vaso-
the resultant decrease in effective blood volume activates the
constriction. Renal histology shows no pathological changes
renin-angiotensin-aldosterone system (RAAS), unloads the
severe enough to justify the deterioration in renal function, and high-pressure baroreceptors in the carotid body and aortic arch
kidney function recovers following liver transplantation or
with subsequent activation of the sympathetic nervous system
when kidneys from patients with HRS are transplanted in
(SNS), and induces nonosmotic release of vasopressin. These
healthy participants.1,2 Because of its poor prognosis and lack
changes lead to intense renal vasoconstriction and reduced glo-
of effective therapy, the term ‘‘terminal functional renal fail-
merular filtration rate (GFR). Other vascular beds show similar
ure’’ was synonymous with HRS.3 Over the last 2 decades,
changes, and studies have correlated renal blood flow with
major advances in our understanding of the pathophysiological
blood flow in the cerebral, femoral, and upper extremities in
mechanisms involved in HRS and the availability of pharmaco-
patients with HRS.8-10 With worsening of the liver disease and
logical and nonpharmacological interventions have translated progression of cirrhosis, further splanchnic vasodilation occurs,
into improvement in the short-term survival of patients with
creating a vicious cycle that favors further activation of the
HRS, but without liver transplantation, long-term survival
RAAS, SNS, and vasopressin release, and subsequent
remains dismal. The challenging role of the intensivist is to
prolong the survival of patients with HRS long enough to
receive transplant. 1
Department of Transplantation, College of Medicine, Mayo Clinic,
Jacksonville, FL, USA

Pathophysiology Corresponding Author:

Hani M. Wadei, Department of Transplantation, Mayo Clinic, 4500 San Pablo
The key pathophysiological change responsible for HRS devel- Road., Jacksonville, FL 32224, USA.
opment in patients with cirrhosis is arterial vasodilatation, Email: wadei.hani@mayo.edu

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80 Journal of Intensive Care Medicine 28(2)

Table 1. Hemodynamic Changes Occurring in Different Stages of Cirrhosis.

Compensated Diuretic-Responsive Diuretic-Resistant

Cirrhosis (Preascites) Ascites (refractory) Ascites HRS

Splanchnic and systemic arterial vasodilatation Normal to þ þ þþ þþþ

Effective circulating volume Normal - – —
Renin, aldosterone, vasopressin, and Normal þ þþ þþþ
norepinephrine
Renal sodium retention þ þþ þþþ þþþþ
Plasma volume þ þþ þþþ þþþþ
Renal vasoconstriction Normal Normal þþ þþþþ
Abbreviations: HRS, hepatorenal syndrome; þ, mild increase; þþ, moderate increase; þþþ, severe increase; þþþþ, very severe increase; -, mild
decrease; –, moderate decrease; —, severe decrease.

intensification of renal vasoconstriction.4 Hepatorenal

syndrome constitutes the end of the spectrum of these patho-
physiological derangements, which start long before
HRS manifests clinically. Table 1 and Figure 1 summarize the
different pathophysiological changes occurring in cirrhotic
patients from early disease stage (preascites) to HRS. It is impor-
tant to mention that other mechanisms may also be responsible
for the early sodium retention in cirrhotic patients.11
In the kidney, the renal vasoconstriction is counterbalanced
by increased intrarenal production of vasodilating prostaglan-
dins and kallikreins. Indeed, urinary excretion of vasodilating
prostaglandins is higher in patients with ascitic cirrhosis com-
pared to normal participants with subsequent decline in urinary
prostaglandin excretion in those with HRS.12,13 Similarly, the
administration of cyclooxygenase inhibitors to patients with
ascitic cirrhosis precipitate HRS, indicating a role of vasodilat-
ing prostaglandins in maintaining GFR.14 Immnohistochemical
studies have documented reduced cyclooxygenase staining in
renal medullary tissue of patients with HRS, while the enzyme
shows normal expression in kidneys of patients with other
cause of AKI.15 Factors associated with reduced prostaglandin
production in HRS are unknown but intense renal vasoconstric-
tion may contribute to reduced prostaglandin synthesis.16 Figure 1. Pathophysiological mechanisms involved in HRS. HRS
indicates hepatorenal syndrome. Adapted with permission from
In addition to the vascular changes outlined above, recent Wadei et al.130
studies indicate that a relative inadequacy in cardiac output
(CO) contributes to the renal hypoperfusion. The role of car-
diac dysfunction in HRS was studied by Ruiz-del-Arbol disturbed relaxation, (2) diminished myocardial b-adrenergic
et al17 who demonstrated reduction in CO at time of diagnosis receptor signal transduction, and (3) an inhibitory effect of cir-
of spontaneous bacterial peritonitis (SBP) without a change in culating cytokines, including tumor necrosis factor-a (TNF-a)
systemic vascular resistance in patients who had cirrhosis and and NO, on ventricular function.19-21 In alcoholic patients, a
subsequently developed HRS. Cardiac output further decreased variable degree of alcoholic cardiomyopathy can also be a con-
after resolution of infection in the HRS group but not in those tributing factor.
without renal failure.17 The same group studied the systemic Two recent studies indicate that relative adrenal dysfunction
and hepatic hemodynamics of 66 patients with cirrhosis and is common in patients with cirrhosis and might play a role in
tense ascites and normal serum creatinine at baseline with the pathophysiology of HRS especially in the intensive care
repeat measurement in 27 patients who subsequently developed setting.22,23 In the first study, adrenal insufficiency was
HRS. At baseline, arterial BP and CO were significantly lower, detected in 80% of patients with HRS but only in 34% with
whereas RAAS and SNS activity were significantly higher in serum creatinine below 1.5 mg/dL.22 Since normal adrenal
the group that developed HRS with further reduction in CO function is essential for an adequate response of the arterial cir-
at the onset of renal dysfunction.18 The mechanism of impaired culation to endogenous vasoconstrictors, adrenal insufficiency
cardiac function is complex and may include (1) neurohumoral could be an important contributory mechanism of circulatory
hyperactivity leading to myocardium growth and fibrosis with dysfunction associated with HRS, especially in patients with

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Wadei and Gonwa
Table 2. Diagnostic Criteria of HRS.
Cirrhosis with ascites
Serum creatinine >1.5 mg/dL
No improvement in serum creatinine (a decrease in serum
<1.5 mg/dL) after 2 days off diuretics and volume expansion with
albumin (1 g/kg body weight up to a maximum of 100 g/d)
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of signs of parenchymal renal disease, as suggested by
protienuria (>500 mg/d) or hematuria (>50 red blood cells per
high-power field) and/or abnormal renal ultrasound
Adapted from Salerno et al.26
severe bacterial infections. Other features associated with adre-
nal insufficiency were severe liver failure, arterial hypotension,
vasopressor dependency, and increased hospital mortality.22
The second study showed that treatment with hydrocortisone
in patients with cirrhosis with severe sepsis and adrenal insuf-
ficiency is associated with a rapid improvement in systemic
hemodynamics, reduction of vasopressor requirements, and
lower hospital mortality.23 The mechanisms of adrenal dys-
function in cirrhosis with severe sepsis have not been explored,
but a reduction in adrenal blood flow secondary to regional
vasoconstriction is a possible mechanism.
Diagnosis of HRS and its Evolution
Pinpointing the etiology of AKI in patients with cirrhosis is
important for both prognostic and therapeutic purposes (dis-
cussed below). In HRS, the tubular function is preserved with
the absence of proteinuria or histological changes in the kidney.
Urine sodium level is usually very low (<10 mEq/L), which dif-
ferentiates HRS from acute tubular necrosis (ATN). There is no
diagnostic test for HRS, and the diagnosis relies mainly on
excluding other causes of renal failure in cirrhosis and relying
on established diagnostic criteria.24 Type 1 HRS is defined
as doubling of the serum creatinine to a level >2.5 mg/dL in
<2 weeks’ duration, whereas in type 2 HRS there is a gradual
rise in serum creatinine to >1.5 mg/dL. The diagnostic criteria
of HRS were originally developed in a consensus meeting of
the International Ascites Club (IAC) in 199625 and were subse-
quently modified in 2007 (Table 2).26 The main points of
difference between the 2 definitions are as follows:
1. Creatinine clearance is no longer incorporated in the
diagnosis.
2. 2.Ongoing bacterial infection does not exclude the diagno-
sis of HRS, provided septic shock is not present.
3. Albumin is preferred to saline for plasma volume
expansion.
4. Nonessential minor diagnostic criteria including low urine
sodium level have been omitted.
It is important to think of the 2 types of HRS, type 1 and
type 2, as 2 different clinical entities rather than stages of
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81
progression of the same disease. Type 1 HRS is more acute,
commonly follows a precipitating event, is associated with
multiorgan failure, has a very grim prognosis, and overlaps
with other causes of AKI. In many cases, it is virtually impos-
sible to separate type 1 HRS from ATN. Type 2 HRS can be
considered the genuine form of renal failure in cirrhotics. It
represents the extreme expression of cirrhosis-induced circula-
tory failure and is heralded by refractory ascites. Renal failure
in type 2 HRS is slowly progressive and parallels the degree of
deterioration in liver function. The median survival for patients
with type 2 HRS is 6 months, whereas the survival for patients
with type 1 HRS is only 10% at 90 days from diagnosis.27
Table 3 highlights the major differences between type 1 and
type 2 HRS. Figure 2 shows the probability of survival in
patients with type 1 and type 2 HRS, compared to cirrhotic
patients with ascites and no HRS.
Precipitating and Contributing Factors
In type 1 HRS, a precipitating event is identified in 70% to
100% of patients with HRS and more than 1 event can occur
in a single patient.28-31 Identifiable precipitating factors include
bacterial infections, large volume paracentesis without albumin
infusion, gastrointestinal bleeding, and acute alcoholic hepati-
tis. Of the bacterial infections, a clear chronological and patho-
genetic relationship is established for SBP with 20% to 30% of
patients with SBP develop HRS despite appropriate treatment
and resolution of infection.32,33 Similarly, large-volume para-
centesis without albumin expansion precipitates type 1 HRS
in 15% of cases, and 25% of patients presenting with acute
alcoholic hepatitis eventually develop HRS.34,35 Although AKI
following gastrointestinal hemorrhage occurs more frequently
in patients with cirrhosis compared to those without liver dis-
ease with similar amount of bleeding (8% vs 1%, P < .05), AKI
develops almost exclusively in patients with hypovolemic
shock, making ATN a more plausible diagnosis.36
Why would a precipitating event lead to HRS or the progres-
sion of type 2 to the more severe type 1 HRS? Most of the
above described precipitating events will lead to aggravation
of the circulatory dysfunction with further stimulation of the
RAAS, SNS, and worsening renal vasoconstriction.16 Another
possible explanation is that the deterioration in renal function is
secondary to deterioration in cardiac function due to either the
development of septic cardiomyopathy or worsening of a latent
cirrhotic cardiomyopathy.18 In either case, the resultant renal
hypoperfusion will lead to deterioration in renal function that
might not reverse to baseline values without vasoconstrictor
therapy and/or liver transplantation.
Epidemiology
Although the actual prevalence of AKI in patients with cirrho-
sis is unknown, AKI is reported to develop in 20% to 35% of
hospitalized patients with liver cirrhosis37,38 and is associated
with higher mortality, both in the hospital and in the ambula-
tory settings.37,39,40 Patients with cirrhosis with ascites are at
82
Table 3. Characteristics of Type 1 and Type 2 Hepatorenal Syndrome (HRS).
Course Precipitating Event
Type 1 HRS Precipitous doubling of serum Present in >50% of cases May or may not be present
creatinine in <2 weeks
Type 2 HRS Gradually progressive Absent Always present
Figure 2. Probability of survival in patients with type 1 and type 2 HRS
compared to cirrhotic patients with ascites and normal kidney func-
tion. HRS indicates hepatorenal syndrome. Adapted with permission
from Arroyo et al.131
greater risk of developing AKI, and a recent study confirmed
that almost 50% of patients with cirrhosis develop AKI within
41 + 3 months of developing ascites.39 Hepatorenal syndrome,
however, is not the most common cause of AKI in patients with
cirrhosis. For example, in 1 study, HRS was the cause of AKI in
only 7.6% of 129 patients with cirrhosis with ascites and
AKI.39 In another multicenter retrospective study that included
423 patients with cirrhosis and AKI, the most common cause of
AKI was either ATN (35%) or prerenal failure (32%), whereas
type 1 and type 2 HRS were the cause of AKI in 20% and 6.6%
of cases, respectively.41
The prevalence of HRS parallels the progression of liver
disease in patients with cirrhosis. With the absence of ascites,
the likelihood of deteriorating kidney function is minimal. In
patients with cirrhosis with ascites, Gines et al34 estimated the
1-year and 5-year probability of HRS at 18% and 39%, respec-
tively, whereas the prevalence of HRS in patients with cirrhosis
having advanced liver disease waiting for liver transplantation
is as high as 48%.42
Natural History and Prognosis
Hepatorenal syndrome is a functional renal failure without sig-
nificant histological changes, and therefore is potentially rever-
sible. However, if left untreated, intense renal vasoconstriction
precipitates irreversible renal damage. This explains as to why
not all cases of HRS recover kidney function following liver
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Journal of Intensive Care Medicine 28(2)
History of Diuretic-Resistant Ascites Prognosis
Without therapy, 90-day survival
of 10%
Median survival, 6 months
transplantation. Untreated type 1 HRS carries a grim prognosis,
with mortality as high as 80% in 2 weeks, and only 10% of
patients survive more than 3 months.25,34 By contrast, survival
of type 2 HRS patients is slightly better, with a median survival
of 6 months.27 Model of end-stage liver disease (MELD) score
is also an independent predictor of death in type 2 HRS, with
the median survival of only 1 month for patients with a MELD
score of 20 or more compared to 8 months in those with a
MELD score <20 (P < .001). Interestingly, patients with type
1 HRS have very poor prognosis (median survival of 1 month),
irrespective of their MELD score.43 A recent study has demon-
strated that the 3-month survival of patients with cirrhosis hav-
ing HRS is much worse than those with cirrhosis and other
forms of AKI.44 In this study that included 562 patients with
cirrhosis having AKI, 3-month survival for patients with HRS
was 15% compared to 31% for patients with infection-induced
AKI, 46% for hypovolemia-induced AKI, and 73% for AKI
associated with evidence of parenchymal renal disease (eg pro-
teinuria or hematuria; P < .0005). Therefore, determining the
etiology of AKI in patients with cirrhosis does not only deter-
mine the treatment plan but it also foretells the prognosis in
these patients.
Treatment
Prevention
Some interventions are beneficial in reducing the risk of HRS,
in specific, clinical settings. For example, prophylactic antibio-
tic therapy in patients at high risk of SBP has proven effective
in reducing HRS risk. In a study by Fernandez et al,44
68 patients with cirrhosis were randomized to receive either
daily norfloxacin (n ¼ 35) or placebo (n ¼ 33). Daily norflox-
acin reduced the 1-year probability of developing SBP from
61% to 7% (P < .001) and the 1-year probability of HRS from
41% to 28% (P ¼ .02). The beneficial effect of norfloxacin in
preventing HRS is probably related to its ability to prevent bac-
terial translocation, suppress proinflammatory cytokines, and
improve circulatory function.45,46 Once SBP has developed,
treatment with intravenous albumin (1.5 g/kg of body weight
at diagnosis followed by 1 g/kg 48 hours later) in addition to
ceftriaxone reduced the incidence of HRS to 10%, compared
to 33% in those who received ceftriaxone alone (P ¼ .002).33
Hospital mortality (10% vs 29%) and 3-month mortality rates
(22% vs 41%) were also lower in patients receiving albumin
and antibiotic compared with those who received antibiotic
alone.33 The mechanism by which albumin prevents HRS is
incompletely understood but may be related to albumin’s
Wadei and Gonwa
positive effect on circulatory function and its antioxidant
properties.47,48 In patients with acute alcoholic hepatitis, the
administration of the TNF inhibitor pentoxifylline for 28 days
or until death reduced the probability of HRS by 8% in the pen-
toxifylline group vs 35% in the placebo group (relative risk
[RR] ¼ 0.32, 95% confidence interval [CI] ¼ 0.13-0.79, P ¼
.0015) and hospital mortality by 24% vs 46% (RR ¼ 0.59,
95% CI ¼ 0.35-0.97, P ¼ .037).35 Following large-volume
paracentesis (5 L), albumin is more superior than other
plasma expanders in preventing postparacentesis circulatory
dysfunction and renal impairment.49,50 Other measures of pre-
venting HRS include avoiding nonsteroidal anti-inflammatory
drugs, aminoglycoside antibiotics, and the judicious use of
diuretics.
General Measures
Patients with type 1 HRS usually require hospitalization,
preferably in the intensive care unit, whereas those with
type 2 HRS can be managed on an outpatient basis. Assessing
the intravascular volume status using central venous access or,
preferably, global end-diastolic volume index (GEDVI) is
essential to guide the fluid and albumin infusion.51 Although
in other critically ill patients there is no clear benefit for colloid
over crystalloid use for fluid resuscitation, albumin infusion is
clearly beneficial in patients with cirrhosis and should be
aggressively used prior to labeling patients with cirrhosis and
AKI as having HRS (Table 2).52,53 Diuretics should be stopped,
and a trial of large-volume paracentesis with albumin infusion
(8 g for every liter of ascitic fluid removed) is warranted in all
patients with cirrhosis presenting with tense ascites and HRS.
In some of these cases, the increased intra-abdominal pressure
will impair renal blood flow and compress the renal veins,
reducing the effective renal filtration fraction.54 In 1 study,
goal-directed albumin infusion to maintain a stable GEDVI fol-
lowing large-volume paracentesis resulted in reduction in the
intra-abdominal pressure and systemic vascular resistance and
an increase in cardiac index, urine output, and creatinine clear-
ance in 19 patients with HRS admitted to the intensive care unit
with tense ascites.51 A similar study has also documented an
increase in renal-resistive indices following paracentesis and
albumin infusion in 12 HRS patients with tense ascites.55
Associated adrenal insufficiency should be diagnosed and
treated with hydrocortisone administration.22,23 Every effort
should be made to exclude other causes of AKI and to identify
and treat precipitating factors especially SBP and gastrointest-
inal bleeding. Special consideration should be made to nutri-
tion as these patients are usually malnourished; however,
high-protein diet may precipitate hepatic encephalopathy and
aggravate the metabolic abnormalities. Low-salt diet should
be reinforced in all cases and free water restriction in those who
develop hyponatremia.56 Once the patient is stabilized, realistic
assessment of the overall patient’s prognosis and concurrent
medical condition will determine future management plans.
Given the dismal prognosis of patients with type 1 HRS,
aggressive therapy is usually indicated only for patients waiting
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83
for liver transplant or undergoing evaluation to determine
candidacy for transplantation. There are 4 therapeutic options
for the patient with HRS: pharmacological treatment, transjugular
intrahepatic portosystemic shunt (TIPS), renal replacement
therapy (RRT), and liver transplantation.
Pharmacological Therapy
The goals of ideal treatment for HRS must include the follow-
ing: (1) reversal of renal failure, (2) prolong survival at least
slightly to increase the chance of liver transplantation, and
(3) have minimal side effects.
Various renal vasodilator agents, including dopamine,
fenoldopam, and prostaglandins, have been studied and found
to be ineffective and associated with increased side effects;
therefore, the use of renal vasodilators in patients with HRS has
been largely abandoned.57-60 Based on the current knowledge
of the underlying pathophysiological mechanisms, administra-
tion of vasoconstrictor agents such as vasopressin analogs and
a1 agonists is the best approach to managing HRS.
Vasopressin analogs ornipressin and terlipressin are potent
vasoconstrictors that exert their action through binding to the
vasopressin (V1) receptor, which is preferentially expressed
on the vascular smooth muscle cells within the splanchnic cir-
culation. Although associated with remarkable improvement in
renal function, increase in RPF, GFR, and sodium excretion in
almost 50% of the treated cases, ornipressin use has largely
been abandoned due to significant ischemic side effects that
develop in almost 30% of the treated patients.61-63
Terlipressin is a long-acting synthetic vasopressin analog
composed of 1 molecule of lysine vasopressin and 3 glycine
residues. It is metabolized through exopeptidases to release
small amounts of lysine vasopressin over a sustained period,
allowing it to be administered by bolus injection rather than
by continuous infusion.64 The administration of terlipressin and
albumin is associated with significant improvement in GFR, an
increase in arterial pressure, near normalization of neurohor-
monal levels (including plasma renin activity, serum aldoster-
one, and norepinephrine levels), and reduction of serum
creatinine in 42% to 77% of cases.29,41,65-68 Hemodynamic
studies have also documented improvement in renal arterial
resistive index following terlipressin infusion in 19 patients
with cirrhosis and portal hypertension.69 Multiple clinical stud-
ies evaluated the role of terlipressin in HRS reversal (Table 4).
From these studies, terlipressin appears to have an acceptable
side effect profile, with ischemic events occurring in 5% to
30% of cases, but most studies excluded patients at high risk
of ischemic events (Table 5). Following completion of therapy,
HRS recurred in up to 50% of cases. Factors associated with
HRS recurrence are unknown, but renal function responds to
the reintroduction of terlipressin.29 The benefits of terlipressin
also seem to extend to type 2 HRS, with a slightly better
response rate and longer survival than in type 1.65,67,70 All
studies used terlipressin until serum creatinine decreased to
<1.5 mg/dL or for a maximum of 15 days; therefore, it is
84 Journal of Intensive Care Medicine 28(2)

Table 4. Summary of Some of the Studies of Terlipressin in HRS.

Type 1 Type 2 Response Adverse Terlipressin Duration of Therapy

Reference Randomized Study HRS HRS Rate (%) Events (%) Dose (mg/d) Mean (Range) in Days

Uriz et al.66 No 6 3 78 11 3-12 9 (5-15)

Ortega et al.65 No 16 5 67 5 3-12 7 (4-14)
Colle et al.29 No 18 0 61 NA 2-4 NA
Halimi et al.129 No 16 2 72 17 2-12 7 (2-16)
Moreau et al.41 No 99 0 58 23 3.2 + 1.3 11 + 12
Solanki et al.68 Terlipressin/albumin vs 24 0 42 21 2 4-15
placebo/albumin
Sanyal et al.71 Terlipressin/albumin vs 62 0 34 32 * 4-8 14
placebo/albumin
Martin-Llahi et al.70 Terlipressin/albumin vs 17 6 43 31y 6-12 15
albumin only
Average 258 16 57 16 1-12 2-16
* Similar to placebo.
y Including arrhythmia, myocardial infarction, suspected intestinal ischemia, and arterial hypertension requiring discontinuation of therapy.

Table 5. Contraindications to Terlipressin Use.
History of coronary artery disease
Dilated and nondilated cardiomyopathies
Cardiac arrythmias
Cerebrovascular disease
Peripheral vascular disease of the lower extremities
Arterial hypertension
Asthma or obstructive lung disease
Age >70 years
unclear whether longer duration of therapy will be of any
benefit in increasing the HRS reversal rate.
Of the studies listed in Table 4, 2 recent prospective rando-
mized studies are worth mentioning. The first is a multicenter,
double-blinded study that included 112 patients with type 1
HRS randomized in 1:1 fashion to either terlipressin plus albu-
min or placebo plus albumin. More patients in the terlipressin
arm (34% compared to 13% in the placebo arm, P ¼ .008)
achieved reversal of HRS defined as a serum creatinine of
1.5 mg/dL on 2 separate occasions 48 hours apart.71 The most
important predictor of HRS reversal was a low serum creatinine
at initiation of therapy. In fact, none of the HRS cases with a
serum creatinine 5.6 mg/dL responded to terlipressin (per-
sonal communication, Dr. Sanyal, November 2010). Although
HRS reversal was associated with improvement in survival at 90
days (P ¼ .025), this beneficial effect became less apparent at
day 180 (P ¼ .07). Also, the overall and transplantation-free sur-
vival was similar between study groups (P ¼ .84).71 The second
study intended to investigate whether the effect of terlipressin
infusion on HRS reversal is independent of albumin, as earlier
studies suggested that albumin alone is beneficial in improving
kidney function in HRS.72,73 This study included 46 patients
with either type 1 or type 2 HRS randomized to receive either
terlipressin and albumin or albumin alone.70 There was signifi-
cant difference in favor of terlipressin in the likelihood of HRS
reversal (44% in study group vs 8.7% in the control group,
P ¼ .017) but 3-month survival was not different between those
who did or did not receive terlipressin (27% in the terlipressin
arm vs 19% in the albumin arm, P ¼ .7).70 Again, a lower base-
line serum creatinine level at initiation of therapy predicted a
favorable response to terlipressin, suggesting that earlier
initiation of therapy might confer the best probability
of improvement in kidney function. Other predictors of
favorable response to terlipressin include young age and a
Child-Pugh score of <13.29,41
Terlipressin is unavailable in many countries, including the
United States. Cost of terlipressin might also be prohibitive.
Unlike terlipressin, a1 adrenergic receptor agonists such as
midodrine and norepinephrine are readily available and have
been shown to be effective in the treatment of HRS. When
given as monotherapy, oral midodrine slightly improved sys-
temic hemodynamics but failed to improve renal function in
8 type 2 HRS cases.74,75 However, when combined with the
glucagon inhibitor octreotide (glucagon mediates splanchnic
vasodilatation) and in combination with albumin infusion, a
significant improvement in renal function and survival were
observed. Two nonrandomized studies evaluated the efficacy
of oral midodrine and octreotide combination on HRS rever-
sal.30,76 The first study was a prospective trial that included
5 patients with type 1 HRS. In this study, the dose of midodrine
was increased from 7.5 mg 3 times daily to 12.5 mg 3 times
daily, and the dose of subcutaneous octreotide was titrated from
100 mg 3 times daily to 200 mg 3 times daily if the central
venous pressure did not increase or the plasma renin activity
was not reduced, compared to baseline values on day 3 of ther-
apy. After 20 days, the mean arterial pressure increased, plasma
renin activity decreased, and all patients achieved reversal of
HRS defined as a serum creatinine less than 2mg/dL.76 In the
second study, continuous intravenous octreotide infusion (25
mg/h) and fixed dose oral midodrine (2.5 mg/d) were used in
14 patients with type 1 HRS. Therapy was administered until
serum creatinine was <1.5 mg/dL for 3 days or for a total of
15 days. Hepatorenal syndrome reversal was achieved in

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Wadei and Gonwa
70% of cases. In both studies, no significant treatment-related
side effects were reported and therapy was well tolerated.30
It is important to mention that midodrine is a prodrug that is
metabolized in the liver into an active metabolite, desglymido-
drine, which is later eliminated in the urine. The pharmacoki-
netics of midodrine and desglymidodrine in patients with
HRS have not been studied and deserve further research. Also,
it is still unclear whether terlipressin is superior to octreotide
and midodrine in reversing HRS. One study suggested that
terlipressin-treated patients have a higher HRS recovery rate,
longer survival, and are more likely to receive a liver trans-
plant, but this study was nonrandomized and the results could
have been affected by selection bias.77 Finally, the Food and
Drug Administration (FDA) is considering withdrawing oral
midodrine from the markets due to the lack of long-term benefit
data, mainly in patients with orthostatic hypotension; however,
doing so would limit the treatment options for patients with
HRS who do not have access to terlipressin.
Finally, the effect of continuous norepinephrine infusion
(starting at 0.5 mg/h and titrated to achieve 10 mm Hg increase
in mean blood pressure and/or increase in urine output by
>200 mL/4 h) in association with albumin and furosemide on
HRS reversal was studied in 12 type 1 HRS patients.78 Nore-
pinephrine was given, either until serum creatinine decreased
<1.5 mg/dL or for a maximum of 15 days. The mean norepi-
nephrine dose given was 0.8 mg/h for a mean duration of 10
days. Of the 12 patients, 10 (83%) achieved HRS reversal (ter-
lipressin had previously failed in 2). Ischemic episodes were
observed in 2 (17%) patients.78 Improvement of kidney
function was associated with improvement in patient’s sur-
vival, and 4 of the responders did not require liver trans-
plantation 6 to 18 months after recovery of renal
function.78 In a recent meta-analysis, terlipressin and nore-
pinephrine were equivalent in terms of side effect profile
and probability of HRS reversal.79
Transjugular Intrahepatic Portosystemic Shunt
The association between the reduction of portal pressure
induced by TIPS insertion and beneficial changes in neurohu-
moral factors and renal function in patients with cirrhosis and
refractory ascites, a forerunner of HRS, is well documen-
ted.80-84 Guevara et al prospectively investigated the biochem-
ical, hemodynamic, and neurohumoral changes following TIPS
insertion in 7 type 1 HRS cases.85 One month after TIPS, renal
function improved in 6 patients (86%), with significant reduc-
tion in serum creatinine and increase in urine volume. These
clinical changes paralleled amelioration in renal hemody-
namics and reduction in the plasma levels of different media-
tors of vasoconstriction. Patient’s survival ranged from 10 to
570 days with 30 days survival achieved in 5 patients
(71%).85 Another prospective nonrandomized study evaluated
the effect of TIPS on long-term outcome of 31 patients with
type 1 or type 2 HRS who are not candidates for liver transplan-
tation.86 After TIPS, the 3, 6, 12, and 18 months survival were
81%, 71%, 48%, and 35%, respectively. Importantly, survival
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85
at 10 weeks of type 1 HRS patients managed with TIPS was
53%, a significant improvement compared to historical cases.34
Of the 7 dialysis-dependent cases, 4 discontinued dialysis fol-
lowing TIPS insertion, and liver transplantation was performed
in 2 cases 7 and 24 months after TIPS, when the medical con-
dition precluding transplantation has abated.86 An important
observation from these 2 studies is the slow and delayed recov-
ery of renal function following TIPS (within 2-4 weeks), unlike
vasoconstrictor therapy, in which responders have faster recov-
ery of renal function (1-2 weeks). It is important to mention that
all patients with advanced cirrhosis (bilirubin >15 mg/dL,
Child-Pugh score >12, or history of hepatic encephalopathy)
were excluded from these 2 studies, limiting TIPS as a viable
treatment option in many patients with HRS. Nevertheless, the
results of these studies demonstrate that there is occasionally a
group of patients with HRS in whom TIPS insertion might pro-
long survival long enough either to receive a liver transplant or,
if they are not candidates, to stay off dialysis.
Combination Therapy
In all, 14 cirrhotic patients with type 1 HRS were treated with
oral midodrine, octreotide, and albumin, followed by TIPS
insertion in 5 of the 10 patients who responded to vasoconstric-
tor therapy and were at low risk of hepatic encephalopathy.30
All 5 patients who received combination therapy were alive 6
to 30 months following TIPS, with only 1 patient requiring
liver transplantation 13 months later. On the other hand,
responders to vasoconstrictors who did not receive TIPS either
died (3 patients) or required a liver transplantation (2 patients).
Another study of combination therapy that included 11 type 2
HRS cases managed with sequential terlipressin and TIPS
showed further improvement in kidney function following
TIPS insertion.67 However, due to the small number of patients
and the fact that many patients with advanced cirrhosis are
inherently not candidates for TIPS, it is difficult to draw firm
conclusions on the exact role of combination therapy in the
treatment of HRS.
Effect of Therapy on Patients’ Survival
Vasoconstrictors may improve renal function in HRS, but their
effect on mortality is unclear. In a recent study, Gluud and col-
leagues87 performed a systematic review of 10 trials compris-
ing 376 patients with either type 1 or type 2 HRS who
received terlipressin alone or with albumin, octreotide plus
albumin, or norepinephrine plus albumin. Mortality was the
primary outcome measure. Overall, vasoconstrictors used
alone or with albumin reduced mortality compared with no
intervention or albumin alone (74% vs 58%, RR: 0.82, 95%
CI: 0.70-0.96). In subgroup analyses, the improved survival
was apparent at day 15 of therapy (RR: 0.60, 95% CI: 0.37-
0.97) but not at 30, 60, 90, and 180 days. When compared to
albumin alone, terlipressin plus albumin conferred a survival
advantage in type 1 but not in type 2 HRS. There was no sig-
nificant difference between the type of vasoconstrictor and the
86 Journal of Intensive Care Medicine 28(2)

Table 6. Thirty-day and 90-day Survival Following Treatment of HRS by Treatment Modality.

Number of Patients 30-day Survival (%) 90-day Survival (%) Reference

No treatment 25 10 Gines et al.34

Octreotide þ midodrine 5 80 33 Angeli et al.76
NE 12 50 NA Duvoux et al.78
Terlipressin 21 61 12 Ortega et al.65
99 40 22 Moreau et al.41
23 NA 27 Martin-Llahi et al.70
TIPS 7 71 42 Guevara et al.85*
14 81 64 Brensing et al.86*
Vasoconstrictor þ TIPS 5 100 100 Wong et al.30*
NE: norepinephrine; TIPS: transjugular intrahepatic protosystemic shunt; NA: not available.
* Patients with advanced cirrhosis were not candidates for TIPS insertion.

patient’s survival.87 Despite the lack of clear survival advan-
tage, the limited number of days gained with vasoconstrictor
therapy might be crucial to allow for liver transplantation.
Also, current evidence indicates that posttransplant outcomes
in patients with HRS who responded to pretransplant vasocon-
strictors are similar to patients with normal renal function who
received transplant.88 Therefore, all attempts to improve kid-
ney function prior to liver transplantation should be made.
Table 6 summarizes the 30- and 90-day survival of untreated
patients with HRS and those who received therapy with differ-
ent vasoconstrictor agents, TIPS, or a combination of vasocon-
strictor and TIPS. The important observations are (1) compared
to no treatment, the 30-day survival of HRS did improve with
different treatment modalities, and (2) 90-day survival of HRS
remains to be dismal, irrespective of the treatment offered.
Renal Replacement Therapy
Pretransplant RRT
For those waiting for a liver transplant, who did not respond to
vasoconstrictors or developed volume overload, intractable
metabolic acidosis, or hyperkalemia, RRT may be a reasonable
option as a bridge to transplantation. Patients with HRS often
manifest complications of advanced liver cell failure including
encephalopathy, hypotension, and coagulopathy, which com-
plicates the decision to initiate RRT especially since early stud-
ies have found that initiation of RRT was associated with
increased risk of hemorrhage and hypotension, which directly
contributed to mortality in some cases.89,90 However, mortality
is even higher in patients with HRS not receiving RRT. In a ret-
rospective study by Keller et al,91 7 (44%) of 16 cases on RRT
survived to transplantation compared to only 1 (10%) of the 10
who did not receive dialysis. This improved patient survival
was incurred at the cost of increased hospital stay with 33%
of the survival days gained being spent in the hospital.92 There-
fore, in patients with HRS who are waiting for a liver trans-
plant, RRT is justifiable as a bridge to transplantation but is
associated with an increase in morbidity and mortality. How-
ever, initiation of RRT is controversial in patients with HRS
who are not candidates for liver transplantation due to their
dismal chance of survival without transplantation and the high
morbidity and mortality associated with RRT. In these patients,
the decision to initiate RRT may be considered futile and
should be individualized.
Predictors of mortality following RRT initiation have been
studied in 82 cirrhotic patients with AKI, 26 of them with HRS.
In all, 46% received intermittent hemodialysis (HD), whereas
the remaining group received continuous RRT (CRRT). The
relative risk of dying following RRT initiation was increased
by 8.2-fold in patients with thrombocytopenia <100/nL, by
3.9-fold in those with hepatic encephalopathy and by 2.8-fold
in patients with malignancy. Importantly, the etiology of renal
failure, whether related to HRS or not, did not affect survival.91
There is still controversy regarding the best modality of
RRT in orthotopic liver transplant (OLT) candidates. Daven-
port et al and Detry et al demonstrated that CRRT is better tol-
erated than intermittent HD in patients with liver failure as
evidenced by better cardiovascular stability, gradual correction
of hyponatremia, and less fluctuation in intracranial pressure.93-96
Furthermore, CRRT has the potential advantage of removing
inflammatory cytokines including TNF-a and interleukin 6,
both have been implicated in the development of AKI and
HRS and the exacerbation of hepatic injury.16,35,97-99 Despite
these presumed advantages, in a prospective study by Witzke
et al, CRRT did not confer a survival benefit in 30 patients
with HRS waiting for liver transplantation.100 In this study,
cases were subjected to either CRRT if they were mechani-
cally ventilated or HD if they were not. Eight cases (53%)
treated with HD survived for 30 days, whereas none of the
CRRT patients survived for the same duration. At 1 year,
only 3 were still alive. All received either liver transplanta-
tion (2 patients) or combined liver-kidney transplantation
(1 patient). None required posttransplant HD. The author con-
cluded that CRRT in patients with HRS on mechanical ventila-
tion is futile.100 In contrast to this experience, the group from
Baylor reported on their experience in patients undergoing RRT
before liver transplantation in 2 separate time periods.101 From
1985 to 1995, 10 patients received preoperative RRT (all HD),
and their 1-year survival posttransplant was 89.5%. From
1996 to 1999, a total of 19 patients also received preoperative
RRT. One had HD, and 18, CRRT. The 1-year patient survival

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Wadei and Gonwa
Figure 3. Survival of liver transplant candidates with acute renal
failure receiving different modalities of renal replacement therapy
(RRT). P value is calculated for comparing CRRT versus HD. CRRT,
continuous RRT; HD, intermittent hemodialysis; ALL, all patients.
Adapted with permission from Wong et al.42
in this group was lower at 73.6%, possibly reflecting the more
serious nature of their illness. In another study of 102 cirrhotic
patients with AKI requiring RRT, 48% of them with HRS who
were awaiting liver transplantation showed increased mortality
for those maintained on CRRT compared to HD (78% vs 50%,
P ¼ .02; Figure 3).42 Nevertheless, those who received CRRT
had a higher APACHE II score, lower blood pressure, and were
more likely to be on vasopressors and mechanical ventila-
tion.42 On a multivariate logistic model, a high mean arterial
pressure, but not duration of RRT, was associated with lower
risk of mortality (OR ¼ 0.97, P ¼ .03). Approximately, half
of the patients died in the first 7 days after initiating RRT, sug-
gesting that these patients were seriously ill and would have
died regardless of RRT initiation. The authors concluded that
RRT is still justifiable in acute renal failure and called for early
liver transplantation in these patients, especially since the high
mortality rate is a reflection of the severity of illness and is
comparable to similarly ill noncirrhotic patients with AKI.42
One drawback of CRRT is the need for continuous systemic
anticoagulation, which might increase the risk of bleeding; how-
ever, patients with cirrhosis are often coagulopathic, and anticoa-
gulation may be safely avoided. Other alternatives include
regional citrate or regional heparin/protamine anticoagulation;
both have been used in patients with cirrhosis and provided filter
life span similar to those obtained using systemic anticoagula-
tion.102 However, caution should be exercised with citrate antic-
oagulation, as hepatic citrate metabolism is impaired in patients
with cirrhosis increasing the risk of citrate toxicity.103
Hence, although the best modality of RRT in HRS is not
well defined, OLT candidates in need of RRT can be managed
with either HD or CRRT before transplantation with similar
outcomes. The choice of best modality is dictated by hemody-
namic stability and severity of illness and should be tailored to
individual patients. One clear indication for CRRT is in
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87
patients with fulminant hepatic failure and increased intracra-
nial tension due to the adverse effect of intermittent HD on
intracranial pressure.95
The ultimate dialysis dose and timing for RRT initiation
have not been studied in cirrhotic patients with HRS, but data
can be inferred from other studies of AKI in critically ill
patients, which suggest that early RRT initiation and mainte-
nance of negative fluid balance improve patient survival.104,105
Two recent randomized studies that included a large number of
critically ill patients with AKI (many of them with concomitant
liver cell failure) showed no clear benefit of higher dialysis
dose on hospital mortality or the probability of renal function
recovery.106,107 However, other studies demonstrated an
improvement in gas exchange, lower norepinephrine dose, ear-
lier weaning from mechanical ventilation, shorter ICU stay,
and better survival in septic patients with AKI who received
early high-dose isovolemic hemofitration (45 mL/kg per h for
6 hours), followed by conventional CRRT at 20 mL/kg per h,
compared to a similar group of patients who received conven-
tional dose CRRT.108 Therefore, it remains unclear whether
critically ill patients with HRS will benefit from higher RRT
dose. A randomized study specifically addressing this question
is needed.
The molecular adsorbent recirculating system (MARS) is an
albumin-based form of RRT that combines a conventional
CRRT circuit and albumin-enriched dialysate that is then
regenerated by passage through a charcoal and ion exchange
cartridge. The assumption is that, by removing albumin-
bound toxins (eg bile acids and nitric oxide) and water-
soluble cytokines (TNF-a and interleukin 6, both have been
implicated in HRS pathogenesis), liver function will stabilize
and end-organ damage will improve.109-111 Although studies
have demonstrated improved survival with MARS compared
to conventional CRRT, the overall survival is still low, with
7-day survival of 37% and 30-day survival of 25%.109,112 Other
albumin-based dialysis techniques include single-pass albumin
dialysis which can be performed using a standard CRRT circuit
and fractionated plasma separation, adsorption, and dialysis
(Prometheus system).113 Molecular adsorbent recirculating
system is currently approved by the Food and Drug Adminis-
tration (FDA) for the treatment of drug overdose but not for
HRS while Prometheus system is not FDA approved.
Intraoperative RRT
Intraoperative complications, including hemodynamic instabil-
ity and hyperkalemia, are more prevalent in patients with HRS
undergoing liver transplantation. Derek et al114 described their
experience with intraoperative CRRT in 41 patients at the time
of liver transplantation. Indications for the procedure were pre-
operative CRRT in almost 50% of the cases; hyperkalemia,
dysnatremia, and metabolic acidosis in the rest of the group.
Despite the presence of elevated international normalized ratio
(INR) in all the patients, filter circuit clotting occurred in 40%
of the cases. However, heparin or regional citrate anticoagula-
tion was not used except in 3 patients for fear of bleeding
88
diathesis. Nevertheless, CRRT was administered for almost
50% of the operative time, and filter clotting did not affect the
duration of CRRT. This study demonstrates that intraoperative
CRRT is feasible and useful in providing negative or even fluid
balance, despite the large number of blood transfusions in this
cohort.
Liver Transplantation
Orthotopic liver transplant is the treatment of choice for
patients with HRS. Indeed, subsequent to OLT, renal sodium
excretion and hemodynamic abnormalities normalize within
1 month and renal-resistive indices decreases to normal values
over the first posttransplant year.115,116 Survival of type 2 HRS
patients is sufficiently prolonged enabling them to receive a
liver transplant; however, the clinical applicability of trans-
plantation in patients with type 1 HRS is limited by their shor-
tened survival expectancy and long waiting times. Not all cases
of HRS will recover kidney function following OLT.117,118 In
1 study, only 58% of HRS cases recovered kidney function
4 to 110 days after OLT.117 Predictors of renal recovery
included younger recipient age, nonalcoholic liver disease, and
low bilirubin level at day 7 posttransplantation. There was a
trend for better renal recovery with younger donor age, implying
that marginal livers should be avoided in patients with HRS.117
Patients with HRS who undergo transplantation have a
lower probability of postoperative survival and a higher prob-
ability of developing postoperative complications than those
without HRS. In 2 studies by Gonwa et al.,119,120 although the
2-year patient-and-graft survival was similar in those with or
without HRS, the actuarial 5-year patient-and-graft survival
rates were decreased in those with HRS. Posttransplantation,
patients with HRS were sicker, required longer hospitaliza-
tions, prolonged ICU stays, and more dialysis treatments.
At 6 weeks following OLT, 10% of the patients with HRS
were still in need of RRT.119,121 The risk of end-stage renal dis-
ease (ESRD) is also higher in the patients with HRS compared
to those with normal kidney function at the time of OLT
(7% vs 2%).119
In an attempt to limit posttransplant complications, another
approach is to provide simultaneous liver-kidney transplanta-
tion (SLK). Indeed, since the introduction of the MELD score
to guide liver allocation in the United States, the number of
SLK transplants has dramatically increased, with associated
lower survival compared to the pre-MELD era.122-124 In gen-
eral, there is no survival advantage of SLK compared to OLT
in patients with HRS.121,125 The only exception may be patients
with HRS who have been on RRT for more than 8 weeks, as
previous studies have suggested a low probability of renal func-
tion recovery in this group of patients.121
Another approach is to offer kidney after liver (KAL)
transplantation to patients with HRS who remain on RRT for
60 days following OLT.118 Although prospective studies are
lacking, observational studies suggested a lower renal half-life
with this approach.126
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Journal of Intensive Care Medicine 28(2)
Our approach has been to provide OLT in the majority of
HRS patients, with the exception of those who have been on
RRT for 8 weeks or more. In cases where the etiology of renal
failure is unclear, or if there are overlapping features of chronic
kidney disease (proteinuria, hematuria, etc) and HRS, we rely
on histological information to direct the transplant options.127
In our hands, percutaneous kidney biopsy has been providing
adequate tissue for analysis with acceptable complication pro-
file. Other centers have been utilizing transjugular renal biop-
sies.128 For those not on RRT, we try to reverse HRS with
vasoconstrictor therapy in an attempt to improve posttransplant
outcomes as previously described.43,88
Conclusions and Future Directions
In summary, HRS is associated with increased morbidity and
mortality in patients with cirrhosis and has a negative impact
on postliver transplant outcomes. Hepatorenal syndrome can
be reversed with pharmacotherapy in more than 50% of
patients, but improvement in kidney function translates into
improvement in short-term survival only, with dismal long-
term survival without liver transplantation. Nevertheless, every
attempt to achieve HRS reversal should be made, as HRS rever-
sal has been associated with improvement in post-liver trans-
plant outcomes. The best therapeutic intervention, including
dialysis modality, should be tailored according to patient can-
didacy for liver transplantation, comorbid conditions, and
hemodynamic status. Simultaneous liver-kidney transplanta-
tion is generally not indicated in patients with HRS unless they
have been on RRT for 8 weeks or more. Kidney biopsy might
be helpful, both in differentiating HRS from other causes of
AKI and guiding the decision of liver vs SLK transplantation
in selected cases.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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