pISSN 2287-2728

eISSN 2287-285X

https://doi.org/10.3350/cmh.2023.0024
Review Clinical and Molecular Hepatology 2023;29:891-908

Hepatorenal syndrome: Current concepts and

future perspectives
Chan-Young Jung and Jai Won Chang
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea

Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major
complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates
in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and
diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe
impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors,
severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction,
and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers
that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other
forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment
options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by
intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional
indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may
be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic
shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently
developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to
validate the efficacy of these novel agents. (Clin Mol Hepatol 2023;29:891-908)
Keywords: Hepatorenal syndrome; Liver cirrhosis; Acute kidney injury; Biomarkers; Terlipressin

INTRODUCTION when there is a marked reduction in GFR, and in the absence

of evidence of intrinsic kidney diseases, such as hematuria,
Hepatorenal syndrome (HRS) is a serious complication of proteinuria, or abnormal kidney ultrasonography. This is con-
end-stage cirrhosis and portal hypertension that is character- trary to what occurs in most cases of intrinsic kidney damage,
ized by increased splanchnic blood flow, a state of decreased in which there are marked changes in kidney histology.1,2 This
central volume, kidney blood flow and glomerular filtration review focuses on several conceptual issues that have
rate (GFR).1 Hepatorenal syndrome is typically diagnosed emerged in the hepatorenal field.

Corresponding author : Jai Won Chang

Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-
gu, Seoul 05505, Korea
Tel: +82-2-3010-3260, Fax: +82-2-3010-6963, E-mail: jwchang@amc.seoul.kr
https://orcid.org/0000-0003-0296-5992

Editor: Salvatore Piano, University of Padova, Italy Received : Jan. 25, 2023 / Revised : Apr. 10, 2023 / Accepted : Apr. 10, 2023

Copyright © 2023 by Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

DEFINITION OF HEPATORENAL SYNDROME mg/dL. Functional kidney injury that does not meet the crite-
ria of HRS-AKI is termed HRS-NAKI (i.e., non-AKI), of which
The definition of HRS has significantly evolved over the NAKI is further divided into HRS-acute kidney disease (HRS-
past several decades (Table 1). In 1996, the International Club AKD) if the estimated glomerular filtration rate (eGFR) is be-
of Ascites (ICA) defined acute kidney injury (AKI) in cirrhosis low 60 mL/min/1.73m2 for less than 3 months and HRS-
as an increase in serum creatinine of ≥50% from baseline to chronic kidney disease (HRS-CKD) if eGFR is below 60 mL/
≥1.5 mg/dL.3 Other important components of AKI in cirrhosis min/1.73m2 for more than 3 months.14
included oliguria, as well as proteinuria <500 mg/dL. In 2007,
HRS was further classified into two types: type 1, character-
ized by a rapid deterioration of kidney function by doubling PATHOPHYSIOLOGY
of initial serum creatinine to ≥2.5 mg/dL or a 50% reduction
in less than 2 weeks in the initial 24-hour creatinine clearance The pathophysiology of HRS is characterized by reduced
to below 20 mL/min that often occurs due to a precipitating systemic vascular resistance due to splanchnic arterial vaso-
event; and type 2, in which kidney failure progression did not dilation, which occurs secondary to portal hypertension, a
meet the criteria for type 1. Importantly, urinary sodium and key feature of advanced cirrhosis. However, recent studies
oliguria were removed from the new diagnostic criteria.4 Sev- have suggested that a systemic inflammatory state may lead
eral studies indicating that the diagnosis of AKI in patients to an increase in the release of inflammatory mediators, and
with cirrhosis, based on an absolute increase in serum creati- therefore may play a role in the circulatory and kidney dys-
nine by ≥0.3 mg/dL or 50% from baseline, leads to earlier function observed in HRS.17,18 Therefore, it is now recognized
identification of patients with poorer outcomes led to the that HRS not only involves circulatory dysfunction but also
ICA to revise the definition of HRS in 2015, incorporating a systemic inflammation (Fig. 1).
new definition and classification of AKI with modifications
(Table 2). 5-12 Serum creatinine obtained in the previous 3 Circulatory dysfunction
months can be used as baseline when a baseline level ob-
tained during the previous 7 days is not available. Although End-stage liver disease resulting in cirrhosis leads to in-
oliguria was not included in the definition of AKI in patients creased intrahepatic vascular resistance, which subsequently
with cirrhosis, a study indicating that urine output was found causes splanchnic vasodilation triggered by increased pro-
to be significantly associated with adverse outcomes in pa- duction of vasodilators including nitric oxide, prostacyclins,
tients with AKI and cirrhosis led to calls for a new definition carbon monoxide, and endocannabinoids. Splanchnic vaso-
and overall a new classification for HRS that expands on the dilation subsequently leads to decreased vascular resistance
2015 ICA consensus document.13,14 Most recently, the ICA and reduced effective arterial blood volume (EABV). Al-
completely revised the nomenclature and diagnostic criteria though the heart is able to compensate for this decrease in
for HRS type 1, which is now called HRS-AKI.12 Results of sev- EABV in the early stages of cirrhosis by increasing cardiac
eral studies showed that the higher the initial serum creati- output, but subsequent development of cirrhotic cardiomy-
nine level at the start of treatment, the lower the probability opathy, aggravation of portal hypertension and splanchnic
of HRS reversal.15,16 This led to the ICA removing the minimum vasodilation results in effective arterial hypovolemia and ar-
creatinine value for diagnosis, and therefore HRS-AKI can be terial hypotension.19 This decrease in EABV subsequently acti-
diagnosed even when the serum creatinine level is below 2.5 vates various vasoconstriction factors that include the renin-

Abbreviations:
ADMA, asymmetric dimethylarginine; AKD, acute kidney disease; AKI, acute kidney injury; ATN, acute tubular necrosis; CKD, chronic kidney disease; CKRT, continuous
kidney replacement therapy; DAMP, damage-associated molecular pattern; EABV, effective arterial blood volume; eGFR, estimated glomerular filtration; FeNa, fractional
excretion of sodium; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; ICA, International Club of Ascites; IL-6, interleukin-6; IV, intravenous; KRT, kidney
replacement therapy; LT, liver transplantation; MARS, molecular adsorbent recirculating system; NAKI, non-AKI; NGAL, neutrophil gelatinase associated lipocalin;
NO, nitric oxide; NOS, nitric oxide synthase; PAMP, pathogen-associated molecular pattern; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow;
SBP, spontaneous bacterial peritonitis; SDMA, symmetric dimethylarginine; SKLT, simultaneous liver-kidney transplantation; SNS, sympathetic nervous system; TIPS,
transjugular intrahepatic portosystemic shunt; TLR, tool-like receptor; TNF-a; tumor necrosis factor-α

892 https://doi.org/10.3350/cmh.2023.0024 http://www.e-cmh.org

 Table 1. Previous and current definitions of hepatorenal syndrome
Year
Criteria 3 4
1996 2007 201512 201914
Serum creatinine and/ Serum creatinine ≥1.5 g/dL Serum creatinine ≥1.5 mg/dL Increase in serum creatinine by ≥0.3 Rename HRS-1 to HRS-AKI
or change in serum OR OR mg/dL within 48 hours Increase in serum creatinine by ≥0.3
creatinine 24-hr Creatinine clearance <40 mL/ Doubling of serum creatinine to ≥2.5 OR mg/dL within 48 hours
min mg/dL within 2 weeks Increase in serum creatinine ≥1.5 OR

http://www.e-cmh.org
times from baseline (Creatinine Increase in serum creatinine ≥1.5
value within previous 3 months, times from baseline (Creatinine
when available, may be used as value within previous 3 months,
baseline, and value closest to when available, may be used as
presentation should be used) baseline, and value closest to
within 7 days presentation should be used)
within 7 days
Urinary sodium <10 mEq/L - - FENa <0.2%
Urine volume <500 mL/day - <0.5 mL/kg/hr for 6 hours <0.5 mL/kg/hr for 6 hours
Urine sediment Absence of structural kidney Absence of structural kidney Absence of structural kidney Absence of structural kidney
damage, as defined by proteinuria damage, as defined by proteinuria damage, as defined by proteinuria damage, as defined by proteinuria
<500 mg/dL and/or urine RBC <50/ <500 mg/dL and/or urine RBC <50/ <500 mg/dL and/or urine RBC <50/ <500 mg/dL and/or urine RBC <50/
HPF HPF HPF HPF, and/or NGAL <220 μg/g Cr
Miscellaneous criteria 1. Cirrhosis or acute liver disease with 1. Cirrhosis or acute liver disease with 1. Cirrhosis or acute liver disease with 1. Cirrhosis or acute liver disease with

https://doi.org/10.3350/cmh.2023.0024
portal hypertension portal hypertension portal hypertension portal hypertension
2. Absence of shock, ongoing 2. Absence of shock, ongoing 2. Absence of shock, ongoing 2. Absence of shock, ongoing
bacterial infection, or current/ bacterial infection, or current/ bacterial infection, or current/ bacterial infection, or current/
recent treatment with recent treatment with recent treatment with recent treatment with
nephrotoxic drugs nephrotoxic drugs nephrotoxic drugs nephrotoxic drugs
RBC, red blood cell; HRS-1, hepatorenal syndrome type 1; HRS-AKI, hepatorenal syndrome-acute kidney injury; FENa, fractional excretion of sodium; NGAL, neutrophil gelatinase
associated lipocalin.

893
Updates in hepatorenal syndrome
Chan-Young Jung, et al.
 Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

angiotensin-aldosterone system (RAAS),20 the sympathetic

*Baseline serum creatinine is defined as a value of serum creatinine obtained in the previous 3 months. In patients with more than one value obtained within the previous 3 months,
the value closest to admission time to hospital should be used. In patients without a previous serum creatinine value, the serum creatinine on admission should be used as baseline.
nervous system (SNS),21 and the non-osmotic secretion of ar-
ginine vasopressin. Although these vasoconstriction factors
Increase in serum creatinine at least threefold from baseline or serum creatinine ≥4.0 mg/dL with an acute increase ≥0.3 mg/dL or initiation of kidney assist in maintaining arterial pressure near normal limits,
their activation has detrimental effects on kidney function,
resulting in renal vasoconstriction, impaired solute-free wa-
ter excretion, and subsequent decline in kidney function. The
AKI stages 1A and 1B are adaptations of the International Club of Ascites definitions of AKI stages by the European Association for the Study of the Liver.101
kidneys are also able to compensate for such changes during
earlier stages, owing to the vasodilatory effects of renal pros-
taglandins (prostaglandins E2 and I2) on afferent renal arteri-
oles. This maintains glomerular pressure despite reduced re-
nal blood flow (RBF). Progression of liver disease and the use
of concomitant non-steroidal anti-inflammatory drugs that
inhibit prostaglandin synthesis disrupts this balance and,
Increase in serum creatinine ≥0.3 mg/dL or increase in serum creatinine ≥1.5-fold to twofold from baseline*

therefore, causes AKI.22

Diastolic dysfunction may be present in up to 60% of pa-
tients with cirrhosis; however, the relationship between dia-
stolic and circulatory dysfunction or development of HRS has
not been demonstrated.23 Nevertheless, decreased cardiac
Definition

output in patients with cirrhotic cardiomyopathy is associat-

ed with the development of kidney hypoperfusion and HRS.
For example, in a study of 66 patients who had cirrhosis with
ascites and normal serum creatinine levels, baseline mean ar-
Increase in serum creatinine at least twofold to threefold from baseline

terial pressure and cardiac output were significantly higher in

patients who did not develop HRS than in those who devel-
Table 2. Stages of acute kidney injury according to the International Club of Ascites12

oped HRS. Plasma renin activity and cardiac output were in-
dependent predictors of HRS. Complications occurred in the
setting of a significant reduction in mean arterial pressure,
cardiac output, and wedged pulmonary pressure, as well as
an increase in plasma renin activity, norepinephrine concen-
Stage 1A: Serum creatinine <1.5 mg/dL†

tration, and hepatic venous pressure gradient. In another

Stage 1B: Serum creatinine ≥1.5 mg/dL

study of 23 patients with spontaneous bacterial peritonitis

(SBP) at diagnosis and after resolution of infection, those who
developed HRS had a significantly lower cardiac output at
the time of diagnosis of SBP, compared with those who did
replacement therapy

not develop HRS, indicating a relationship between HRS and

diminished cardiac output.24
The pathophysiological hallmark of HRS is vasoconstriction
of the renal circulation.27-30 Marked renal vasoconstriction in
AKI, acute kidney injury.

patients with HRS has been demonstrated in a number of

studies.27-30 This phenomenon may most likely be due to sev-
eral factors and may involve alterations in systemic hemody-
AKI stage

namics, activation of multiple vasoconstrictor factors, and

Stage 1

Stage 2
Stage 3

suppression of vasodilatory factors that act on renal circula-

tion. Two major vasoconstrictor systems that are important
†

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 Chan-Young Jung, et al.
Updates in hepatorenal syndrome

Bacterial Cirrhotic
Translocation Cardiomyopathy
Inflammatory Responese
• ↑Pro-inflammatory cytokines
• ↑Vasodilatory factors
• PAMPs
• DAMPS
Effective Arterial
Splanchnic Arterial Blood Volume
Portal Nitric oxide Vasidilation Activation of vasoconstriction factors
Hypertension Prostacyclins
• RAAS
Carbon monoxide
• SNS
Endocannabinoids
• AVP
• Endothelin
• Cysteinyl leukotrienes
Renal
• Prostaglandins
vasoconstriction

Figure 1. Pathophysiology of hepatorenal syndrome. PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular
patterns; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; AVP, arginine vasopressin.

in this pathophysiological process is the RAAS and the enes, and prostaglandins.33-35
SNS.20,21 In several studies of patients with cirrhosis, activity
of the RAAS, as estimated by plasma renin activity, was Nitric oxide dysfunction
shown to increase from compensated to decompensated cir-
rhosis. Peak activity was seen in patients with HRS and it was In cirrhosis, a reduction in RBF is also partly due to either
shown to correlate inversely with kidney function.19,20,22 More- excessive or insufficient nitric oxide (NO) production.36-39 Ex-
over, in patients with infection associated HRS, patients with cess NO production results in splanchnic vasodilation, re-
higher RAAS activity had a significantly lower probability of duced EABV, RAAS, and SNS activation, and renal vasocon-
HRS reversal than those with lower RAAS activity.31 Plasma striction. However, insufficient NO release may also cause
levels of norepinephrine, which reflects SNS activity, are in- reduced RBF. This may be partly due to the increased produc-
creased in patients with HRS than in those with ascites and tion of dimethylarginines, such as symmetric (SDMA) and
intact kidney function, and were shown to be inversely cor- asymmetric dimethylarginine (ADMA). ADMA levels are in-
related with GFR.21 However, considering that both RAAS and creased in advanced liver disease, and therefore NO synthesis
SNS are two vasoconstrictor systems that act to increase arte- from NO synthase (NOS) is inhibited, and therefore RBF is
rial blood pressure and counteract splanchnic vasodilation, compromised.36-38,40 SDMA, an ADMA isomer, also increases
studies have been unable to assess whether the blockade of in the setting of decreased hepatic and kidney function. High
these RAAS and SNS lead to improved outcomes in patients concentrations of SDMA also reduces NO production, result-
with cirrhosis.32 Other than the aforementioned vasoconstric- ing in reduced RBF. This has led to some studies indicating
tor systems, other factors with a potential role in kidney va- that SDMA may be a potential marker for HRS.36 Indeed, sev-
soconstriction in HRS include endothelin, cysteinyl leukotri- eral studies have indicated that both SDMA and ADMA are

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Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

potential independent predictors of measured GFR in cir- increase TLR4 expression in the kidneys.50
rhotic patients.41

Systemic inflammation DIFFERENTIAL DIAGNOSIS AND BIOMARKERS

It is now recognized that systemic inflammation also plays As the treatment of AKI in patients with cirrhosis depends
a part in HRS pathophysiology. Systemic inflammatory re- on the type of AKI, determining the etiology is essential.25,51
sponse syndrome has been observed in almost half of pa- Although the differential diagnosis of AKI in patients with cir-
tients with HRS-AKI, independent of the presence of actual rhosis is broadly similar to that in other patient populations,
infection.42 In particular, those with the most extensive base- the differential diagnosis is often not so straightforward. In
line systemic inflammation also had the highest risk of liver addition to HRS, other types of AKI that can occur include
failure development and mortality.43 Plasma levels of pro-in- volume-responsive pre-renal AKI due to infection, hypovole-
flammatory cytokines (interleukin-6 [IL-6] and tumor necrosis mia, vasodilators, obstructive post-renal AKI, and intra-renal
factor-α [TNF-α]), and urinary levels of monocyte chemoat- AKI that may be caused by toxin or ischemia induced acute
tractant protein-1 are increased in patients with HRS-AKI tubular necrosis (ATN), or glomerulonephritis. Considering
than in those with decompensated cirrhosis without AKI and that patients with ATN and HRS have the worst survival
those with AKI secondary to pre-renal azotemia.44 among those with AKI and cirrhosis,52 accurate differential di-
The main mechanism by which the systemic inflammatory agnosis of the etiology is important.
state primarily contributes to the pathogenesis of HRS is the HRS remains a diagnosis of exclusion. A key component in
translocation of gut bacteria from the gut to mesenteric HRS diagnosis is exclusion of structural kidney damage,
lymph nodes due to altered intestinal permeability.45 This which relies on urine microscopy and urine sodium excretion.
bacterial translocation not only induces increased levels of Other requirements include the absence of shock, protein-
pro-inflammatory cytokines,45 in particular IL-6 and TNF- uria (>500 mg/day), and microscopic hematuria (>50 red
a,46,47 but also increased levels of various vasodilating factors, blood cells per high power field), along with normal kidney
such as NO,48 which contribute to the decreased EABV, as well morphology on ultrasonography. However, possibly due to
as a wide spectrum of molecules (pathogen-associated mo- systemic inflammation that can also cause ATN, differentiat-
lecular patterns [PAMPs] and damage-associated molecular ing between ATN and HRS is often very difficult. Although
patterns [DAMPs]) that are responsible for inducing inflam- urinary sodium (>40 mEq/L), fractional excretion of sodium
matory responses through activation of pattern recognition (FeNa >2%), and low urine osmolality (<400 mOsm/L) are
receptors such as toll-like receptors (TLRs). PAMPs are prod- suggestive of ATN, other conditions, such as the use of diuret-
ucts of bacteria that include lipopolysaccharide, flagellin, and ics that are commonly used in patients with large volume as-
nigericin, whereas DAMPS are intracellular components re- cites, may confound the interpretation of FeNa.53 Moreover,
leased from injured hepatocytes that include high-mobility low FeNa was also found in biopsy proven-ATN,54 and there-
group protein B1, heat shock proteins, and hyaluronic acid. fore urinary sodium and FeNa are no longer part of the most
Not only are both PAMPs and DAMPs known to have system- recent diagnostic criteria of HRS-AKI.14 A more useful marker
ic effects by promoting inflammation and the release of pro- in differentiating between ATN and HRS may be the fraction-
inflammatory cytokines, but both molecules may also have al excretion of urea,55,56 because unlike sodium, reabsorption
direct effects on the kidney. For example, in a study of pa- of urea occurs primarily in the proximal tubules of the kidney,
tients with kidney dysfunction and cirrhosis, patients showed and therefore is not affected by commonly used diuretics
increased renal expression and urinary excretion of TLR4, such as loop diuretics and spironolactone, which act in the
suggesting a potential role of TLR4 as a mediator of kidney loop of Henle and distal convoluted tubules, respectively.
injury.49 Moreover, gut decontamination in rodent models of Several novel biomarkers that may be useful in the differ-
cirrhosis has been shown to reduce renal TLR4 expression ential diagnosis of AKI in patients with cirrhosis have recently
and subsequently prevent kidney dysfunction, suggesting been investigated.57-62 Most of these biomarkers originate
that exposure to PAMPs from gut bacterial translocation may from kidney tubular proteins released during cell damage,

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 Chan-Young Jung, et al.
Updates in hepatorenal syndrome

upregulated during kidney injury, proteins with diminished be prevented by administration of intravenous (IV) albumin
tubular reabsorption, and markers of inflammation. Of the in addition to antibiotic treatment in the setting of SBP and
above markers, to date, the most widely investigated is uri- may also reduce overall mortality.66,67 In the setting of SBP, IV
nary neutrophil gelatinase associated lipocalin (NGAL).58-62 In albumin may be administered 1.5 g/kg on day 1 followed by
a multicenter, prospective cohort study involving 188 pa- 1 g/kg on day 3. In patients undergoing large-volume para-
tients with AKI and cirrhosis, median values of urinary NGAL, centesis (>5 L), albumin administration has been shown to
IL-18, kidney injury molecule-1, liver-type fatty acid binding decrease the incidence of HRS.68 However, data on whether
protein, and albumin were all elevated in patients with ATN.60 albumin prevents HRS or improves overall survival has been
In another study involving 241 patients with cirrhosis, urinary conflicting.69-73 For example, in the ANSWER (human Albumin
NGAL levels were markedly higher in patients with ATN than for the treatmeNt of aScites in patients With hEpatic ciRrho-
in those with pre-renal azotemia, CKD, and HRS.59 In a more sis) study, long-term administration of human albumin was
recent study involving 320 patients with AKI hospitalized for associated with improved overall 18-month survival com-
decompensated cirrhosis, urinary NGAL measured at day 3 pared to standard medical treatment.72 However, in the
had the greatest accuracy for differential diagnosis between MACHT (midodrine and albumin for cirrhotic patients in the
ATN and other etiologies of AKI.61 waiting list for liver transplantation) study, treatment with
Not only are biomarkers important for the differential diag- midodrine and albumin failed to prevent complications of
nosis of AKI, but they may also play an important role in pre- cirrhosis or improve survival.73 Most recently, in the ATTIRE
dicting treatment response of HRS, and even for progno- (Albumin to Prevent Infection in Chronic Liver Failure) trial
sis.63,64 For example, in 162 patients with AKI and cirrhosis, that investigated whether higher doses of albumin therapy
not only was urinary NGAL an adequate biomarker in the dif- to increase and maintain serum albumin levels to 30 g/L or
ferential diagnosis of AKI, but it also predicted the response more improved outcomes in hospitalized patients with cir-
to terlipressin and albumin in patients with HRS-AKI, and was rhosis, the results were largely disappointing, and therefore,
also an independent predictor of in-hospital mortality.63 Sim- supporting the need for a re-evaluation of the use of albumin
ilarly, in a study consisting of 213 United States (US) hospital- in patients with cirrhosis.74 The ongoing PRECIOSA12 (Effects
ized patients with decompensated cirrhosis, not only did uri- of Long term Administration of Human Albumin in Subjects
nary NGAL differentiate the type of AKI in cirrhosis, but also With Decompensated Cirrhosis and Ascites) trial will hopeful-
significantly predicted 90-day transplant-free survival, and ly clarify the role of long term albumin use in this popula-
outperformed Model for End-Stage Liver Disease score in tion.75
terms of survival prediction.64 β-blockers are effective in preventing variceal bleeding,
Although the most ideal biomarker would be one that dis- which can precipitate HRS. Although they are widely used in
tinguishes structural from functional AKI, but in reality, no patients with cirrhosis and portal hypertension,76 therapy
biomarkers to date perform optimally in the differential diag- must be individualized based on the severity of hepatic de-
nosis of AKI in patients with cirrhosis. Further validation stud- compensation.77 In patients with compensated cirrhosis,
ies are warranted for their generalized applications. treatment with β-blockers was associated with a preserva-
tion in kidney function, and an increase in decompensation-
free survival, mainly by reducing the incidence of ascites.78
RISK FACTORS AND PREVENTION However, in patients with decompensated cirrhosis with asci-
tes, reports have been conflicting. While a recent meta-anal-
The most common risk factors for HRS are those related to ysis suggested that the use of β-blockers in patients with cir-
systemic inflammation and acute hemodynamic changes. rhosis and ascites was not associated with a significant
Therefore, the most commonly known precipitants of HRS increase in mortality,79 some reports have suggested that the
are SBP, other systemic infections, and large volume paracen- decrease in cardiac output caused by β-blockers could pre-
tesis without albumin administration. HRS develops in as cipitate AKI, and therefore increase mortality in this patient
many as 30% of patients with SBP, and is associated with sig- group.77,80 Therefore, clinicians should carefully weigh the
nificantly worse outcomes.31,65 Infection-associated HRS may risks and benefits of continuation of β-blockers in patients

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Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

with cirrhosis. erally administered by IV boluses at starting doses of 0.5–1

In patients with ascites and a high risk of developing SBP, as mg every 4–6 hours. The dose can be increased to a maxi-
determined by a low ascitic fluid protein (<1.5 g/dL), con- mum of 2 mg every 4 hours in cases of nonresponse, defined
comitant advanced liver failure (Child-Pugh score ≥9 points as less than a 25% reduction in serum creatinine level after 3
with serum bilirubin level ≥3 mg/dL) or kidney dysfunction days and no side effects occur.89-91 Doses should be main-
(serum creatinine level ≥1.2 mg/dL, blood urea nitrogen level tained for a maximum of 14 days depending on responses to
≥25 mg/dL, or serum sodium level ≤130 mEq/L), antibiotic treatment. Doses of terlipressin in combination with albumin
prophylaxis using either norfloxacin or rifaximin has shown should be continued until serum creatinine reaches a final
to prevent the development of SBP and HRS, as well as re- value <1.5 mg/dL, or until baseline creatinine level. If patients
duce overall mortality.68,81 show nonresponse or partial response, the treatment should
be discontinued within 14 days. The efficacy of continuous
infusion of terlipressin has been supported in a single center
TREATMENT OF HEPATORENAL SYNDROME study of 78 patients, where continuous IV terlipressin infu-
sion was shown to be not only better tolerated than IV bolus-
The management of AKI in patients with cirrhosis should es, but was also effective at doses lower than those required
begin immediately once a diagnosis has been made and the for IV bolus administration.92 The INFUSE (Terlipressin for
etiology of AKI identified because patients with AKI and cir- HRS-AKI in Liver Transplant Candidates) trial that will evalu-
rhosis often deteriorate rapidly (Fig. 2). Once a diagnosis of ate the use of continuous terlipressin infusion in patients on
AKI has been made, management of AKI should typically be- the liver transplant waiting list with HRS-AKI is currently on-
gin with a fluid challenge of 20–25% IV albumin at 1 g/kg/ going.93
day for 2 days and withdrawal of any diuretics (expert opin- According to two previous randomized controlled clinical
ion, not evidence-based).12 Low volume therapeutic paracen- trials performed in Europe, the response rate of terlipressin
tesis with albumin to control ascites should also be per- plus albumin is around 50%.92,94 Most recently, the efficacy
formed if necessary.82,83 This not only rules out pre-renal and safety of terlipressin plus albumin for the treatment of
azotemia, but also promotes early circulating volume expan- type 1 HRS have been proven in a multicenter phase 3 trial,
sion in the context of reduced EABV. The initial phase of in which enrolled patients were randomly assigned in a 2:1
treatment also consists of temporary discontinuation of non- ratio to receive terlipressin or placebo for up to 14 days. In
selective β-blockers given their negative inotropic effect,84,85 this trial involving 300 patients with cirrhosis and type 1 HRS,
and other potential nephrotoxic agents and vasodilators. terlipressin was more effective than placebo in improving
kidney function.95 Despite the high response rates of terlip-
Pharmacologic therapy ressin plus albumin, recurrence of HRS is not uncommon,
with recurrences occurring in <20% of patients with type 1
Vasoconstrictors HRS. These patients may be re-treated with vasoconstrictors
The rationale behind the use of vasoconstrictors in the and albumin. The patient’s response to terlipressin is not only
treatment of HRS is to counteract splanchnic arterial vasodi- important for HRS reversal, but it has also shown to be an im-
lation.25,86 Of the currently available vasoconstrictors, terlip- portant prognostic factor in liver transplantation (LT) pa-
ressin, a synthetic vasopressin analog with a predominant tients.96 For example, in two cohorts of patients with cirrhosis
vasopressin 1A receptor effect acting primarily as a splanch- listed for LT, one with and one without HRS-AKI, response to
nic vasoconstrictor,87 is the most commonly used vasopressin terlipressin and albumin reduced the need for KRT after LT,
analog. and also reduced the risk of CKD at 1 year after LT.98 Factors
To date, terlipressin is the vasopressin with the most con- associated with lower response to terlipressin and albumin
vincing data to date.88 Several positive results from clinical include higher baseline serum creatinine, urinary NGAL and
trials have led to the US Food and Drug Administration re- serum bilirubin, lower increases in arterial pressure, presence
cently approving the use of terlipressin in the US for improv- of systemic inflammatory response syndrome, and more se-
ing kidney function in patients with HRS. Terlipressin is gen- vere acute on chronic liver failure grade.15,63,97-99

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 Chan-Young Jung, et al.
Updates in hepatorenal syndrome

Workup and Management of Acute Kidney Injury

Acute increase in serum creatinine ≥0.3 mg/dL

AKI Stage 1A AKI Stage 1B, 2 or 3

Close monitoring Risk factor management

Risk factor management (discontinue any nephrotoxic drugs, vasodilators,
(discontinue any nephrotoxic drugs, vasodilators, NSAIDS and diuretics)
NSAIDs and diuretics) Treatment of any infections
Treatment of any infections Plasma volume expansion with albumin
Plasma volume expansion (1 g/kg) for 2 days

Resolution Resolution

Yes No Yes No

Surveillance Criteria of HRS-AKI

No Yes

Consider kidney Vasoconstrictor

replacement therapy therapy and albumin

Figure 2. Algorithm for the management of acute kidney injury in patients with cirrhosis. AKI stages 1A and 1B are adaptations of the Interna-
tional Club of Ascites definitions of AKI stages by the European Association for the Study of the Liver.101 NSAIDs, non-steroidal anti-inflammato-
ry drugs; AKI, acute kidney injury; HRS-AKI, hepatorenal syndrome-acute kidney injury.

Common side effects of terlipressin include diarrhea and nephrine, and the combination of midodrine and octreotide.
abdominal pain, which are reported in around 10–20% of pa- Norepinephrine is a systemic vasoconstrictor that acts
tients. More serious side effects are related to vasoconstric- through the activation of α-1 adrenergic receptors on vascu-
tion with a risk of myocardial infarction and intestinal isch- lar smooth muscle cells. Norepinephrine is administered at
emia, with a rate of 2–13%.100 In the recent CONFIRM trial, the 0.5–3 mg/h continuous IV infusion, titrating dosing to
use of terlipressin was also associated with a higher risk of re- achieve an increase of 10 mmHg in mean arterial pres-
spiratory failure. Patients on terlipressin should be monitored sure.89-91,102,103 Norepinephrine in combination with albumin is
for signs of ischemia while on therapy, and the drug should also effective and safe,104 with response rates ranging from
be avoided in patients with a history of coronary artery dis- 39–70%.105-107 It is a cheaper drug than terlipressin; however,
ease or peripheral artery disease.101 Furthermore, as the re- unlike terlipressin, which can be administered peripherally,
sponse to treatment is attenuated in patients with higher de- norepinephrine can only be administered through a central
grees of kidney injury and acute on chronic liver failure venous line. When using norepinephrine, close monitoring
grade,99 the risk-benefit of administering vasoconstrictors in for tachyarrhythmias or bradycardia is needed.94
combination with IV albumin should be carefully considered. A combination of midodrine, an α-adrenergic agonist, plus
Other vasoconstrictor treatment options include norepi- octreotide, a somatostatin analogue, may also be used. Mid-

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Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

odrine is administered as 7.5 mg up to 12.5 mg orally three provements in kidney function and systemic hemodynamics
times a day; doses should be titrated to achieve an increase are not observed upon administration of IV albumin, despite
of 15 mmHg in mean arterial pressure.89-91,102,103 Octreotide is a reduction in NO concentrations.120
administered as 100–200 μg subcutaneously every 8 hours.
In case of nonresponse, doses of both drugs can be increased Role of kidney replacement therapy in the
on day 3 of treatment. In a pilot study, the combination of treatment of hepatorenal syndrome
midodrine and octreotide, plus albumin restored kidney
function in approximately 40% of patients with HRS.108 Although there is no definite role of KRT in the treatment of
Several meta-analyses have evaluated and compared the AKI in patients with cirrhosis, KRT may be indicated in those
efficacy of vasoconstrictors, where studies have shown that unresponsive to pharmacological treatment and with con-
terlipressin, in combination with IV albumin, has the highest ventional indications for KRT such as volume overload, ure-
efficacy.16,94,95,105-107,109-111 Although comparisons of terlipressin mia, or electrolyte imbalances,121 as well as a bridging therapy
with norepinephrine and norepinephrine with octreotide to transplantation.122 According to a retrospective study that
and midodrine did not show any significant differences, terli- involved HRS patients who were non-responders to vasocon-
pressin had better efficacy in reversing HRS than midodrine strictor therapy, KRT did not provide any significant improve-
plus octreotide. In terms of overall mortality, meta-analyses ments in either 30-day or 180-day survival, and only led to
results have revealed that most vasoconstrictors did not significantly longer hospital stays.123 The ideal timing and the
show any significant reduction in overall mortality.100,112 Al- best modality of KRT has not been studied in patients with
though these results are disappointing, it must be noted that cirrhosis, and so the decision to initiate KRT should be made
interventions to improve kidney function do not improve the on clinical grounds, such as worsening kidney function with
underlying poor hepatic function in patients with HRS. intractable volume overload, diuretic intolerance or resis-
tance, or medically refractory electrolyte disturbances. To
Albumin prevent fluid accumulation, KRT should also be considered if
Albumin is often administered in combination with vaso- the daily fluid balance cannot be maintained, regardless of
constrictors to counteract the reduction in EABV and improve urine output. Continuous kidney replacement therapy (CKRT)
cardiac contractility.113-115 The efficacy of terlipressin when ad- should be used in hemodynamically unstable patients, and
ministered in combination with albumin has been proven in also has the advantage of not increase intracranial pressure,
a large number of studies. In the only study in which terlip- which is in contrast to conventional KRT. In cirrhotic patients
ressin was used alone for the treatment of HRS, the efficacy with hyperammonemia and encephalopathy, CKRT may be
of terlipressin was much lower than when it was used in used to mitigate cerebral edema and encephalopathy, but
combination with albumin.116 This may be due to the ability the cut-off ammonia level requiring initiation of CKRT is un-
of albumin to maintain or increase cardiac output even in the known.124
most advanced phases of liver disease.114 The recommended In the setting of CKRT, the molecular adsorbent recirculat-
dose is generally 20–40 g IV once daily after the initial dose ing system (MARS) is a potential therapeutic modality. MARS
of albumin is administered as 1 g/kg/day for 2 days.89-91,102,103 is an extracorporeal liver support system based on albumin
Accumulating experimental and clinical evidence is sug- dialysis, given that albumin is one of the most important
gesting that not only is albumin capable of increasing sys- molecules involved in the detoxification and the liver regula-
temic vascular resistance and cardiac output, its capacity of tion process. MARS removes albumin-bound toxins which
exerting anti-oxidant and anti-inflammatory actions also may have detrimental effects on hepatocytes and other or-
plays a role in mitigating the inflammatory state associated gans, as well as other water-soluble cytokines.125 A small pro-
with HRS.113,115,117 Albumin is able to bind a wide range of sub- spective controlled trial involving 13 patients with cirrhosis
stances, including various bacterial products, bile acids, cyto- and HRS demonstrated that mortality at day 7 was signifi-
kines, nitric oxide, and endotoxins.118 Although this results in cantly lower than in the control group,119 suggesting that the
a significant reduction in serum creatinine levels in patients removal of albumin-bound substances with the MARS meth-
with HRS,119 in patients refractory to vasoconstrictors, im- od may contribute to the treatment of HRS. However, in a

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 Chan-Young Jung, et al.
Updates in hepatorenal syndrome

larger study involving 189 patients with acute-on-chronic liv- defined as eGFR of <44 mL/min/1.73m2 for >90 days, or co-
er failure, although MARS significantly decreased serum cre- morbid presence of metabolic diseases.130 European guide-
atinine levels at day 4 compared to standard medical treat- lines recommend that patients with end-stage liver disease
ment, there was no significant difference in the 28-day who also have CKD G4 or 5, defined as eGFR <30 mL/
mortality between the two treatment groups.126 Given the min/1.73m2, or type 1 HRS requiring kidney replacement
conflicting results, further observational and prospective therapy of >8–12 weeks and patients with kidney biopsy
controlled trials are needed for the generalized application of samples revealing >30% glomerulosclerosis and fibrosis
supportive detoxification therapies. should receive SLKT.90 Nevertheless, in approximately 10% of
patients who receive LT may have persistent or progressive
Transjugular intrahepatic portosystemic shunt kidney dysfunction even after a successful transplant.131 In
particular, patients with ATN are at higher risk of CKD post-
In theory, a transjugular intrahepatic portosystemic shunt transplant, and the lack of ideal biomarkers often results in
(TIPS) that connects the portal vein with one of the hepatic misdiagnosis.132
veins may improve kidney function in HRS by decreasing
portal hypertension and reducing and reversing the hemo-
dynamic changes that precipitate HRS. However, there is only CONCLUSIONS
a paucity of studies that have looked into the role of TIPS in
HRS, so its use remains controversial in this population group. There have been considerable improvements in the diag-
Although results of a few studies have demonstrated that nosis and management of HRS, as well as evolving defini-
TIPS could improve kidney function by improving serum cre- tions, advances in pathophysiological understanding, and
atinine, serum sodium, and urine output, the relative liver biomarker discovery. Lowering of the serum creatinine level
ischemia that immediately follows TIPS insertion could po- threshold for the diagnosis of HRS-AKI has allowed for earlier
tentially precipitate hepatic failure in patients with predis- recognition and treatment. In terms of pathophysiology, it is
posed severe liver dysfunction.127 Hopefully, the ongoing Liv- now recognized that HRS not only involves circulatory dys-
er-HERO (HRS-AKI Treatment With Tips in Patients with function, but also systemic inflammation. New insights into
Cirrhosis) trial that compares the effectiveness and safety of the pathophysiological basis have allowed for further investi-
TIPS implantation in patients with stage 2 and 3 HRS-AKI and gation into novel therapeutic agents that target specific
liver cirrhosis with standard therapy of terlipressin and albu- pathophysiological pathways. Although the differential diag-
min will clarify the role of TIPS for use in this patient popula- nosis of AKI in patients with cirrhosis is difficult, recent stud-
tion.128 ies of novel biomarkers have allowed for further investiga-
tions into tools that may assist the clinician in the diagnosis
Liver transplantation and management of HRS-AKI. Moreover, the findings from
recent large-scale randomized clinical trials have further sup-
LT remains the definitive treatment for HRS. Although si- ported the use of terlipressin. While LT remains the optimal
multaneous liver-kidney transplantation (SKLT) is the proce- treatment option, particularly in patients with a high risk of
dure of choice if native kidney function recovery is not ex- persistent kidney dysfunction, SLKT may be warranted over
pected after LT, the decision to perform SKLT versus LT LT alone. During the patient’s time on the liver transplant
remains a challenge. Predicting the recovery of impaired kid- waiting list, CKRT may be considered as a bridging therapy to
ney function is challenging because various factors, particu- transplantation.
larly the duration of kidney injury, contributes to kidney
prognosis.129 In the US, the Organ Procurement and Trans- Future perspectives
plantation Network policy for simultaneous liver-kidney or-
gan allocation requires an eGFR of ≤25 mL/min/1.73m2 for 6 Despite the recent advances in HRS, much remains to be
weeks or a period of kidney replacement therapy of ≥6 uncovered. Although there have been consistent efforts into
weeks in patients with AKI, presence of CKD G3b, which is updating the definition of HRS over the past decades, the

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Clinical and Molecular Hepatology
Volume_29 Number_4 October 2023

clinical implications of the newly proposed diagnostic criteria clinical practice guidelines for liver cirrhosis: Varices, hepatic
are still unclear. Hopefully, results from future validation encephalopathy, and related complications. Clin Mol Hepatol
studies will further refine the diagnostic criteria to allow for 2020;26:83-127.
earlier recognition and thus, management of HRS. Although 2. Epstein M. Hepatorenal syndrome: emerging perspectives of
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these novel biomarkers have the potential to differentiate vention and treatment of hepatorenal syndrome in cirrhosis.
AKI etiology, but they also have the potential to predict treat- Gut 2007;56:1310-1318.
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domized clinical trials that have supported the use of ity and complications in hospitalized patients with cirrhosis.
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use to reduce risk of adverse events, but also assist in predict- et al. A modified acute kidney injury classification for diagno-
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8. Tsien CD, Rabie R, Wong F. Acute kidney injury in decompen-
Authors’ contribution sated cirrhosis. Gut 2013;62:131-137.
Conception and design: J.W. Chang; Writing, review, and/or 9. Wong F, O’Leary JG, Reddy KR, Patton H, Kamath PS, Fallon
revision of the manuscript: C.Y. Jung and J.W. Chang; Admin- MB, et al.; North American Consortium for Study of End-Stage
istrative, technical, or material support: J.W. Chang; Study su- Liver Disease. New consensus definition of acute kidney injury
pervision: J.W. Chang. accurately predicts 30-day mortality in patients with cirrhosis
and infection. Gastroenterology 2013;145:1280-1288.e1.
Acknowledgements 10. Altamirano J, Fagundes C, Dominguez M, García E, Michelena
The authors thank the Medical Illustration & Design team J, Cárdenas A, et al. Acute kidney injury is an early predictor of
of the Medical Research Support Services of Yonsei University mortality for patients with alcoholic hepatitis. Clin Gastroen-
College of Medicine for all artistic support related to this terol Hepatol 2012;10:65-71.e3.
work. 11. Angeli P, Rodríguez E, Piano S, Ariza X, Morando F, Solà E, et al.;
CANONIC Study Investigators of EASL-CLIF Consortium. Acute
Conflicts of Interest kidney injury and acute-on-chronic liver failure classifications
The authors have no conflicts to disclose. in prognosis assessment of patients with acute decompen-
sation of cirrhosis. Gut 2015;64:1616-1622. Erratum in: Gut
2016;65:1394.
12. Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et
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