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doi:10.1111/jgh.12709

R E V I E W A RT I C L E

Acute kidney injury and hepatorenal syndrome in cirrhosis

Mads Egerod Israelsen,* Lise Lotte Gluud† and Aleksander Krag*
*Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, and †Department of Gastroenterology,
Hvidovre University Hospital, University of Copenhagen, Hvidovre, Denmark

Key words Abstract

acute kidney injury, acute-on-chronic liver
failure, adrenal insufficiency, cirrhosis,
cirrhotic cardiomyopathy, hepatorenal
syndrome.
Accepted for publication 4 June 2014.
Correspondence
Professor Aleksander Krag, Department of
Gastroenterology, Entrance 126, 2nd floor,
Odense University Hospital, University of
Southern Denmark, Sdr. Boulevard 29,
Odense 5000, Denmark. Email:
aleksander.krag@rsyd.dk
Cirrhosis is the eighth leading cause of “years of lost life” in the United States and accounts
for approximately 1% to 2% of all deaths in Europe. Patients with cirrhosis have a high risk
of developing acute kidney injury. The clinical characteristics of hepatorenal syndrome
(HRS) are similar to prerenal uremia, but the condition does not respond to volume
expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course
often associated with refractory ascites. A number of factors can precipitate HRS such as
infections, alcoholic hepatitis, and bleeding. The monitoring, prevention, early detection,
and treatment of HRS are essential. This paper reviews the value of early evaluation of
renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1
include terlipressin combined with albumin. In HRS type 2, transjugular intrahepatic
portosystemic shunt (TIPS) should be considered. For both types of HRS patients should
be evaluated for liver transplantation.

Conflicts of interest: The authors declare that

they have no competing interests.

ing of the underlying pathophysiology of HRS leading to a number

Introduction
Cirrhosis is a chronic liver disease that accounts for approximately
1% to 2% of all deaths in Europe.1 In the United States, the number
of deaths caused by cirrhosis has increased over the last 20 years
and cirrhosis is responsible for more than 1.23 million years of lost
life. This makes cirrhosis the eighth leading cause of “years of lost
life” in the United States.2 Cirrhosis is a global burden and was the
cause of 493 300 alcohol-related deaths in 2010.3 In the United
Kingdom, hospital admissions due to liver disease are expected to
increase to 2 million per year by 2020.4 The increasing mortality
rate from chronic liver disease combined with falling hospital
admissions and mortality rates from other chronic diseases, such
as stroke and heart disease, calls for increased focus on complica-
tion to chronic liver diseases.4
Within a period of 10 years following the diagnosis of cirrhosis,
around 60% will develop ascites.5 Cirrhosis and ascites are asso-
ciated with high morbidity and mortality. Renal failure is one of
the most severe complications. More than 50% of patients with
renal failure and cirrhosis die within 1 month after the diagnosis.6
Twenty percent of hospitalized patients with cirrhosis and ascites
develop acute kidney injury. Twenty percent of these patients have
hepatorenal syndrome (HRS),7 a condition that occurs mainly in
patients with cirrhosis and ascites.8 The clinical characteristics of
HRS are similar to prerenal uremia, but the condition does not
respond to volume expansion. Other causes of kidney injury must
be excluded to make the diagnosis, for example nephrotoxic medi-
cations. In recent years, progress has been made in the understand-
of new diagnostic, therapeutic, and prophylactic options. The
purpose of this paper is to review the diagnostic criteria, patho-
physiology, and interventions for HRS and the latest findings on
acute kidney injury.
Definition of hepatorenal syndrome
The diagnostic criteria for HRS were defined in 19968 and revised
in 20079 (Table 1). Based on the course of the disease, HRS is
divided into two types:
• HRS type 1 is characterized by acute renal impairment with
doubling of serum creatinine to > 226 μmol/L within 2 weeks.9
The condition usually develops secondary to a decrease in blood
pressure as part of an inflammatory response caused by for
example spontaneous bacterial peritonitis (SBP), sepsis, severe
alcoholic hepatitis, or gastrointestinal bleeding.9,12 The median
survival without treatment is a few weeks.13
• HRS type 2 is characterized by a slow increase in serum creati-
nine from 133 to 226 μmol/L.9 It is an expression of a moderate
reduction of renal function as a complication to end-stage liver
disease and refractory ascites.9,14 The median survival is 6
months.8
The two types of HRS have different clinical courses and patho-
physiology. While HRS type 1 often develops after an acute reduc-
tion in the effective arterial blood volume, HRS type 2 develops
due to the hemodynamic derangement seen in end-stage liver
disease with refractory ascites.14

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M Egerod Israelsen et al.
Table 1 Current diagnostic criteria of hepatorenal syndrome, acute kidney injury and kidney dysfunction in cirrhosis
Diagnostic criteria of hepatorenal syndrome:9 Acute Kidney Injury Networks
classification of acute kidney injury:10
• Cirrhosis with ascites Grade I
• S-creatinine > 133 μmol/L
• No improvement in serum creatinine (i.e. S-creatinine
< 133 μmol/L)
after at least two days pausing of diuretics and
volume expansion Grade II
therapy with albumin. The recommended dose of
albumin is 1 /kg
of body weight per day (maximum 100 /day)
• Absence of shock Grade III
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal kidney disease which is
proteinuria < 500 mg/day, microhematuria (< 50
erythrocytes/field) and/or pathology by ultrasound of
the kidney and urinary tract
ACKD, acute-on-chronic kidney disease; AKI, acute kidney injury; CKD, chronic kidney injury; HRS, hepatorenal syndrome; MDRD6, modification of
diet in renal disease.
Pathophysiology
The pathophysiology leading to renal dysfunction includes several
factors associated with cirrhosis (Fig. 1). The main factors are the
hemodynamic changes seen in patients with cirrhosis, ascites, and
portal hypertension. Portal hypertension causes an increased pro-
duction and release of endogenous vasodilatation agents such as
nitric oxide, carbon monoxide, and cannabinoids mainly into the
splanchnic arterial circulation. The consequence is vasodilation,
increased plasma volume, and blood flow in the splanchnic circu-
lation leading to a reduction in the effective arterial blood volume
and a drop in mean arterial pressure (MAP).15 To maintain suffi-
cient perfusion of vital organs, compensation is initiated by
increased cardiac output (CO) and activation of the endogenous
vasoconstrictors including the renin-angiotensin-aldosterone
system, the sympathetic nervous system, and release of arginine
vasopressin.16 In severe cases, the heart cannot longer provide a
sufficient CO to maintain an adequate MAP and circulation. The
increased activity of the endogenous vasoconstrictors leads to
renal vasoconstriction and sodium and water retention. Renal
vasoconstriction combined with a reduced MAP may lead to
hypoperfusion of the kidneys and renal impairment. Fluid reten-
tion leads to the development of ascites in the majority of the
patients.17 The translocation of bacteria and bacterial products
from the gut is likely to be a main factor in the progression of
disease.18 Translocation increases with the severity of the under-
lying liver disease leading to a chronic inflammatory state, spon-
taneous infections, and complications including HRS.18,19
Understanding the circulatory dysfunction. The
circulatory changes in cirrhosis and portal hypertension affect
several organs and compromise the organism’s resistance to
hemodynamic instability due to infection, bleeding, or surgery.
Cardiomyopathy and relative adrenal insufficiency (AI) predict
renal impairment and death and might be important for the under-
standing of the pathophysiology and future treatment of HRS.
Journal of Gastroenterology and Hepatology 30 (2015) 236–243
© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Acute kidney injury
Classification of kidney dysfunction in
cirrhosis:11
Increase in serum creatinine AKI Increase in serum creatinine
≥ 50–100% from baseline or ≥ 50% compared with
≥ 26.4 μmol/L within 48 h baseline or ≥ 26.4 μmol/L
within 48 h. HRS type 1 is a
specific form of AKI.
Increase in serum creatinine CKD GFR of < 60 mL/min for > 3
> 100–200% from baseline months calculated using
MDRD6 formula. HRS type 2
is a specific form of CDK
Increase in serum creatinine to ACKD Increase in serum creatinine
> 200% from baseline or ≥ 50% compared with
acute increase of ≥ 44 μmol/L baseline or ≥ 26.4 μmol/L
to ≥ 354 μmol/L within 48 in a patient with
CKD
Cardiac hypertrophy, diastolic dysfunction, and impaired response
to inotropic and chronotropic stimuli are frequent subclinical
observations in cirrhosis.20–24 Renal failure in cirrhosis is associ-
ated with reduced CO.20 HRS type 1 is associated with a reduced
CO and a decreased cardiopulmonary pressure under hyperactive
vasoconstriction systems and reduced MAP.21 Cardiac dysfunction
is closely related to a poor outcome including in particular renal
impairment.23,24 These findings suggest a cardio renal link in
advanced cirrhosis.25 In theory, renal failure and decreased effec-
tive blood volume in HRS type 1 are the consequences of an
arterial vasodilatation and an impaired cardiac contractility that
compromise an increased CO in response to stress. Relative
adrenal insufficiency is a common subclinical condition in patients
with cirrhosis diagnosed as an inadequate production of cortisol in
response to stimulation with synthetic adrenocorticotropic
hormone.26–28 It is seen in approximately 10% of all cases of
cirrhosis and frequency increases with the severity of the liver
disease.29 Cirrhotic patients with adrenal insufficiency increase the
risk of bacterial infection, septic shock, and HRS.28 Cortisol plays
an important role in the hemodynamic homeostasis. The heart’s
and blood vessels’ response to catecholamines and angiotensin-II
is increased by cortisol. Low levels of cortisol lead to an inad-
equate increase in CO and inadequate vasoconstriction in response
to stress.30 Accordingly, adrenal insufficiency could be involved in
the development of cardiomyopathy and HRS.25,28,29 Treatment
with hydrocortisone in patients with cirrhosis and sepsis has been
investigated, but the results are equivocal and it can only be rec-
ommended in selected patients with documented AI.31,32
Acute-on-chronic liver failure
Patients who develop HRS or other types of acute kidney dysfunc-
tion often present with acute deterioration of their chronic liver
disease. Acute-on-chronic liver failure (ACLF) is associated with
a high risk of sequential organ failure and increased mortality.33,34
A large-scale observational study was conducted to describe
237
Acute kidney injury
Figure 1 Factors associated with renal dysfunction in patients with cirrhosis.
ACLF.35 The study evaluated the severity of the organ dysfunction
based on a composite score known as the Chronic Liver failure-
Sequential Organ Failure Assessment (CLIF-SOFA) score. The
score is based on the SOFA score36 which predict mortality in
intensive care unit patients. The SOFA score was modified to make
it a liver specific score. Based on the observational study, patients
with ACLF were classed into four groups, which reflect the
underlying mortality; no ACLF or grade 1, grade 2, or grade 3
(Table 2). The study showed that acute kidney failure with serum
creatinine > 177 μmol/L and kidney dysfunction with serum
creatinine 133 μmol/L to 177 μmol/L were strong predictors of
mortality.35
Classification of acute kidney injury
in cirrhosis
The diagnostic criteria for HRS include a serum creatinine above
133 μmol/L. However, patients with cirrhosis often have reduced
levels of serum creatinine due to malnutrition and decreased
muscle mass.37 Serum creatinine may therefore overestimate the
renal function. A revised strategy that is more sensitive to
238
© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
M Egerod Israelsen et al.
changes in creatinine rather than the absolute creatinine level
may improve early detection of HRS and other types of acute
kidney injury in patients with severe liver disease. In 2007, the
Acute Kidney Injury Network (AKIN) established new criteria
for the classification of acute renal failure10 (Table 1). The clas-
sification is more sensitive to small changes in serum creatinine
and may improve the assessment of kidney injury in cirrhosis.
The Acute Dialysis Quality Initiative Group proposes a new clas-
sification of kidney dysfunction in cirrhosis based on the AKIN
criteria (Table 1).11 Several observational studies of patients with
cirrhosis and renal insufficiency have evaluated the usefulness of
the AKIN classification.38–47 The main conclusion in most studies
is that the AKIN criteria predict mortality, infection, and poten-
tially the risk of progression to HRS (Table 3). Although the
AKIN criteria are useful, it has been argued that the criteria spe-
cific to HRS are more accurate.46 A classification that combines
the AKIN criteria with the classic HRS criteria may provide a
better prediction than the AKIN criteria alone.40 Consensus on
this issue is not yet reached.48 In addition, no studies have inves-
tigated if the use of the AKIN criteria improves patients’ overall
prognosis.
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M Egerod Israelsen et al. Acute kidney injury

Table 2 Prognostic stratification according to the CLIF-SOFA score

No ACLF (28-days mortality rate: 4.7%; 90-days mortality rate 14%)

1. Patients with no organ failure
2. Patients with a single “non-kidney” organ failure, a serum creatinine level < 133 μmol/L and no hepatic encephalopathy
3. Patients with a single cerebral failure who had a serum creatinine level < 133 μmol/L
ACLF grade 1 (28-days mortality rate 22.1%; 90-days mortality rate 40.7%)
1. Patients with single kidney failure
2. Patients with single “non-kidney” organ failure, a serum creatinine level ranging from 133 to 177 μmol/L and/or mild to moderate hepatic
encephalopathy
3. Patients with a single cerebral failure who had a serum creatinine level ranging from 133 to 177 μmol/L
ACLF grade 2 (28-days mortality rate 32.0%, 90-days mortality rate 52.3%)
1. Patients with 2 organ failures
ACLF grade 3 (28-days mortality rate 76.7%, 90-days mortality rate 79.1%)
1. Patients with 3 or more organ failures

ACLF, acute-on-chronic liver failure.

Table 3 Studies conducted to evaluate the usefulness of the AKIN classification. In the majority of the studies they find AKIN useful

Type Author Year Time Sample Main conclusion Find AKINs

size criteria useful

Full-paper Wong41 2013 Prospective 337 The consensus definition of AKI accurately predicts 30-day mortality, Yes
length of hospital stay, and organ failure.
Full-paper Fagundes40 2013 Prospective 375 A classification that combines the AKIN criteria and classical criteria of Medium
kidney failure in cirrhosis provides a better risk stratification than
AKIN criteria alone.
Full-paper Piano46 2013 Prospective 233 Conventional criteria are more accurate predicting the 30-days No
in-hospital mortality.
Full-paper Tsien42 2013 Prospective 90 Minor increases in serum creatinine are clinically relevant and can Yes
adversely affect survival.
Full-paper de Carvalho38 2012 Retrospective 198 AKIN criteria are useful in cirrhotic patients with ascites, as it identifies Yes
earlier patients with worse prognosis.
Full-paper Belcher43 2012 Prospective 192 AKI in patients with cirrhosis is frequently progressive and severe and Yes
is independently associated with mortality in a stage dependent
fashion.
Full-paper Altamirano45 2012 Retrospective 103 The AKIN criteria are useful and more accurate than traditional criteria Yes
in predicting mortality.
Full-paper Scott39 2013 Prospective 162 Decompensated liver disease and AKI appear to be independent Yes
variables predicting death in cirrhotics.
Letter Ferreira44 2011 Retrospective 92 The “Working Party Statement” definition of [AKI] though more No
sensitive but may not be better than [conventional criteria] in
defining the inhospitality mortality risk.
Letter Lopes47 2011 Retrospective 182 AKI was associated with increased in-hospital mortality in critically ill Yes
patients with cirrhosis.

Prevention and treatment of the cephalosporins, amoxicillin-clavulanic acid, or quinolones.49

triggering event
Volume depletion due to infection, severe alcoholic hepatitis, and
gastrointestinal bleeding can trigger HRS type 1.5,49 SBP is the
predominant infection leading to HRS. It is defined as an infection
in the ascites fluid with > 250 neutrophils/mm3 ascites fluid.
Patients with cirrhosis and ascites have a compromised immune
system and an increased risk of translocation of intestinal bacte-
ria.49,50 This leads to HRS in approximately 30% of the patients.
SBP is often associated with Gram-negative aerobic bacteria.
Several antibiotics have been recommended for the initial
treatment of SBP including cefotaxime or other third-generation
Ascites puncture should be repeated after 2–3 days to assess the
effect of treatment on neutrophil count if a lack of response is
suspected. A meta-analysis51 found that albumin infusion com-
bined with antibiotics reduces the incidence of renal impairment
and mortality. Patients with low ascites protein (< 15 g/L) com-
bined with advanced disease or with a history of SBP should be
treated prophylactically with norfloxacin (400 mg daily, orally) to
prevent SBP.5,49,52
Alcoholic hepatitis occurs after an excessive use of alcohol over
a longer period (> 100 g/day) and usually after withdrawal of
alcohol intake. Symptoms include jaundice, fever, ascites, and
proximal loss of muscles. Severe cases are often associated with

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Acute kidney injury
increased serum creatinine and the development of HRS type 1.53
Standard treatment is prednisolone or pentoxifylline. A double-
blind randomized controlled trial (RCT) on 270 patients with
alcoholic hepatitis found no difference in mortality between
patients allocated to prednisolone and pentoxifylline versus pred-
nisolone and placebo.54 The trial found a potential benefit on HRS
in the pentoxifylline group, which is consistent with the results of
a meta-analysis on pentoxifylline.55 Thus pentoxifylline may be
the preferred first-line treatment for patients with alcoholic hepa-
titis and high risk of HRS, which is in line with a recent multiple
treatment comparison meta-analysis.56
Gastrointestinal bleeding may result in blood loss and infections
both of which may lead to HRS.57 Variceal bleeding is treated
according to clinical guidelines including resuscitation, antibiotic
prophylaxis, vasoactive drugs, and endoscopic therapy.57–59 For
bleeding oesophageal varices, the administration of terlipressin
and antibiotics reduces bleeding, mortality and the risk of HRS.59
Oral quinolones are the antibiotic recommended for most
patients.57 Intravenous cephalosporins should be considered in
patients with severer cirrhosis and patients in previous quinolone
prophylaxis.58
Paracentesis with large volume (> 5 liters) may affect hemody-
namics and thereby result in post-paracentesis circulatory dysfunc-
tion (PCD).60 This condition is characterized as a reduction in the
effective blood volume and may lead to HRS.5 A meta-analysis61
found that approximately 73% develops PCD after undergoing
large volume paracentesis (LVP) if the procedure is not combined
with volume supportive treatment. This meta-analysis shows that
administration of albumin reduces the incidence of post-PCD,
HRS type 1, and mortality.61 Therefore albumin should be admin-
istrated to all patients undergoing LVP (8 g/L of drained ascites
fluid).5
Management of patients with cirrhosis,
ascites, and renal impairment
Renal impairment in patients with cirrhosis and ascites should be
evaluated quickly. Correct handling of renal impairment is
required to avoid further deterioration and reduce the risk of renal
failure and death.62 Table 4 describes a proposal for primary inves-
tigation of patients with cirrhosis, ascites, and renal impairment.
The initial evaluation should include volume expansion by infu-
sion of human albumin and discontinuation of diuretics and neph-
rotoxic drugs (Table 5). Other causes that can lead to renal
impairment (e.g. obstructive uropathy) should also be excluded.
Evidence-based intervention for
treatment of HRS
Vasoconstrictors and albumin. Terlipressin and
albumin is the recommended treatment for patients with HRS type
1. The treatment improves the MAP and thereby the renal perfu-
sion. Terlipressin, which is an analogue of vasopressin, induces
vasoconstriction by stimulating vasopressin receptors in the
smooth muscle cells in the vessel wall.63 Intravenous administra-
tion of albumin combined with terlipressin increases the effective
arterial blood volume and thereby preload to the heart.64 This
improves the circulation and stabilizes MAP as a result of an
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M Egerod Israelsen et al.
Table 4 Proposal for primary investigation of patients with cirrhosis,
ascites, and renal impairment
Clinical examination
Checking of volume status/hydration
Hemodynamics/blood pressure and pulse
Signs of infection
Medical history
Examination of the medication list for nephrotoxic drugs
Paraclinical tests
Broad blood screening including hemoglobin, electrolytes,
creatinine, CRP, and differential count
Diagnostic ascites puncture with cell count, protein measurement
and culture
Blood culture
Urine analyses and culture
Possible sputum culture
Radio diagnostic
Chest X-ray when infection is suspected
Ultrasound scan of kidney and urinary tract
Table 5 Drugs that should be avoided or used with caution in patients
with cirrhosis and ascites
NSAIDs Should be avoided
ACE inhibitors, AT-II Use with caution and avoid completely at
receptor antagonists elevated creatinine
and α1-adrenergic
receptor blockers
Diuretics Caution should be taken by monitoring of
creatinine, electrolytes and hydration
Laxatives Pay attention to diarrhoea and dehydration
Aminoglycosides Should be avoided
Contrast media Use with caution and avoid completely at
elevated creatinine
Beta-blockers Careful titration and caution at elevated
creatinine and low blood pressure
ACE, angiotensin converting enzyme; AT, angiotensin; NSAID, non-
steroid anti-inflammatory drug.
increased preload and CO.15 The treatment of HRS type 1 should
be initiated rapidly, as early diagnosis and treatment improves the
prognosis.65 The effect of terlipressin and albumin has been
assessed in several randomized clinical trials. When the results are
combined in a meta-analysis, terlipressin and albumin reduce the
mortality and improve renal function in patients with HRS type
1.66 There is little evidence for this treatment of HRS type 2. A few
small studies have compared the effect of terlipressin with norepi-
nephrine or other vasoconstrictors. Since the trials have low sta-
tistical power, it is not possible to assess whether other
vasoconstrictors are as effective as terlipressin. There is no stan-
dardized dose of terlipressin, but the efficacy in HRS has been
established in studies using an initial bolus injection of 1 mg four
to six times daily and titrated to a maximum of 2 mg six times
daily based on the effect on creatinine (Table 6).5 Terlipressin is
considered effective if S-creatinine is reduced > 25% after 3 days
of intervention. Treatment should be continued until S-creatinine
is below 133 μmol/L. The treatment is effective in up to 40% of the
patients using current the diagnostic criteria and dose regime.11 An
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M Egerod Israelsen et al.
Table 6 Evidence-based treatment of hepatorenal syndrome
Treatment of HRS
Liver transplantation should be considered in all patients with HRS
and advanced liver disease
HRS type 1
Terlipressin: The recommended dose is 1 mg × 4–6/day. The dose
may be increased by lack of effect to a maximum of
2 mg × 6/day. Treatment continues to the S-creatinine level is
< 133 μmol/L
Albumin: The recommended dose is 1 g/kg human albumin on the
first day of treatment followed by 20–40 g daily
HRS type 2
Therapeutic paracentesis: Should be offered to cirrhotic patients
with refractory ascites who do not qualify for treatment with TIPS
TIPS: Should be considered in all patients with HRS type 2 and
refractory ascites
HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic
portosystemic shunt.
ongoing RCT (NCT01530711) is currently evaluating terlipressin
titrated according to the hemodynamic response. The dose of
terlipressin is increased every 8 h until the arterial blood pressure
is increased with more than 10 mmHg or S-creatinine is reduced
with more than 25%.
Adverse events. Approximately 30% of patients develop
adverse events on terlipressin. In 4% of patients, treatment with
terlipressin has to be stopped due to adverse events.63 Most adverse
events reflect vasoconstrictor effects with mild degrees of periph-
eral ischemia including cyanotic fingers and toes. Arrhythmias,
most commonly bradycardia, are seen in approximately 7% of
patients. Sixteen percent of patients develop abdominal pain and
diarrhea probably due to splanchnic ischemia. There has been one
case of intestinal ischemic necrosis. Rarely, ischemic necrosis is
seen.63
Dealing with adverse events. There is no specific anti-
dote to terlipressin. Careful selection of patients without
contraindications, close surveillance of adverse events, and daily
adjustments of the dose and duration of therapy is recommended to
prevent serious adverse events and treatment withdrawals. Myo-
cardial infarctions and malignant arrhythmias are absolute
contraindications to continued therapy. The efficacy of terlipressin
is established in studies with bolus infusion;66 however, continuous
infusion may be as effective as bolus and have fewer adverse
events.67 This is being examined in an ongoing equivalence trial
(NCT00742690). Continuous low dose infusion can therefore,
until further data document non-inferiority to bolus infusion, only
be recommended in patients with an increased risk of adverse
events (AEs) or in case of moderate AEs. Less severe side-effects
such as skin cyanosis without necrosis can usually be managed by
a reduction in dose and oxygen therapy or shifting from bolus to
continuous infusion therapy. Abdominal pain and loose stools are
usually self-limiting. In patients with mild to moderate atheroscle-
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Acute kidney injury
rotic cardiovascular disease, terlipressin can be administered at a
low dose or as continuous infusion with careful titration and
monitoring.
Alternative vasoconstrictors. In some countries, includ-
ing the United States, terlipressin is not available. The American
Association for the Study of Liver Diseases’ guidelines on man-
agement of ascites suggests albumin infusion plus midodrine and
octreotide or norepinephrine in the treatment of HRS type 1.68
Even though some studies found benefits in these treatments,
additional randomized controlled trials are still needed as the evi-
dence to support these recommendations are weak.69
Transjugular intrahepatic portosystemic shunt.
HRS type 2 develops in patients with ascites refractory to treatment
with diuretics. Therapeutic paracentesis and Transjugular intrahe-
patic portosystemic shunt (TIPS) have been studied and both are
considered effective treatments. Randomized controlled trials
suggest that TIPS improves survival compared with therapeutic
paracentesis.70 TIPS can cause heart failure and increases the risk of
hepatic encephalopathy. Therefore, cardiac function should be
examined and a history of hepatic encephalopathy should be
included when assessing the treatment strategy.70,71 The model of
end-stage liver disease (MELD) score predicts the survival in
patients treated with elective TIPS.72 Therefore, the MELD score
should be included in monitoring of patients to better select the
patients who would benefit from TIPS placement.
Liver transplantation. Liver transplantation should be con-
sidered in all patients with advanced liver disease, if there are no
obvious contraindications such as ongoing excessive use of
alcohol or malignant disease. A successful liver transplantation
will completely reverse HRS.73 The 5-year post-transplant mortal-
ity is 32% in patients with advanced liver disease and prerenal
dysfunction.74 Simultaneous liver-kidney transplantation should be
considered when renal failure reflects chronic kidney disease with
glomerular filtration rate (GFR) < 30 mL/min or acute kidney
injury with dialysis > 8 weeks.75
Conclusion
Cirrhosis is a growing global problem. Worldwide death caused by
cirrhosis is increasing. Acute kidney injury is an important prog-
nostic marker in cirrhosis. HRS is seen in approximately 20% of
cirrhotic patients hospitalized with renal impairment. A number of
well-known factors can trigger HRS. The risk of developing HRS
can be reduced by prevention of these events as well as adequate
treatment. HRS type 2 is associated with end-stage liver disease
and patients should be evaluated for TIPS or liver transplantation.
For HRS type 1, the first-line treatment is the combination of
terlipressin and albumin. This treatment is effective in up to 40%
of the patients under current diagnostic criteria and dose regime,
which is why a more aggressive dose titration as well as earlier
detection of renal impairment is under evaluation. The SOFA-
CLIF score is a prognostic tool to estimate the survival in patients
with cirrhosis and acute deterioration. In this scoring system,
kidney dysfunction is associated with very poor outcome. The
241
Acute kidney injury
AKIN criteria is suggested to detect those patients earlier who
have an increased risk of developing HRS and death by use of
small changes in serum creatinine. However, there is not at this
stage a consensus on the application of the criteria and more
research is needed in this area.
Acknowledgment
Figure 1 is made in a collaboration of designer Jalte Windum and
the authors.
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