doi:10.1111/jgh.12709
R E V I E W A RT I C L E
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 kidney dysfunction in
classification of acute kidney injury:10 cirrhosis:11
• Cirrhosis with ascites Grade I Increase in serum creatinine AKI Increase in serum creatinine
• S-creatinine > 133 μmol/L ≥ 50–100% from baseline or ≥ 50% compared with
• No improvement in serum creatinine (i.e. S-creatinine ≥ 26.4 μmol/L within 48 h baseline or ≥ 26.4 μmol/L
< 133 μmol/L) within 48 h. HRS type 1 is a
after at least two days pausing of diuretics and specific form of AKI.
volume expansion Grade II Increase in serum creatinine CKD GFR of < 60 mL/min for > 3
therapy with albumin. The recommended dose of > 100–200% from baseline months calculated using
albumin is 1 /kg MDRD6 formula. HRS type 2
of body weight per day (maximum 100 /day) is a specific form of CDK
• Absence of shock Grade III Increase in serum creatinine to ACKD Increase in serum creatinine
• No current or recent treatment with nephrotoxic drugs > 200% from baseline or ≥ 50% compared with
• Absence of parenchymal kidney disease which is acute increase of ≥ 44 μmol/L baseline or ≥ 26.4 μmol/L
proteinuria < 500 mg/day, microhematuria (< 50 to ≥ 354 μmol/L within 48 in a patient with
erythrocytes/field) and/or pathology by ultrasound of CKD
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.
ACLF.35 The study evaluated the severity of the organ dysfunction changes in creatinine rather than the absolute creatinine level
based on a composite score known as the Chronic Liver failure- may improve early detection of HRS and other types of acute
Sequential Organ Failure Assessment (CLIF-SOFA) score. The kidney injury in patients with severe liver disease. In 2007, the
score is based on the SOFA score36 which predict mortality in Acute Kidney Injury Network (AKIN) established new criteria
intensive care unit patients. The SOFA score was modified to make for the classification of acute renal failure10 (Table 1). The clas-
it a liver specific score. Based on the observational study, patients sification is more sensitive to small changes in serum creatinine
with ACLF were classed into four groups, which reflect the and may improve the assessment of kidney injury in cirrhosis.
underlying mortality; no ACLF or grade 1, grade 2, or grade 3 The Acute Dialysis Quality Initiative Group proposes a new clas-
(Table 2). The study showed that acute kidney failure with serum sification of kidney dysfunction in cirrhosis based on the AKIN
creatinine > 177 μmol/L and kidney dysfunction with serum criteria (Table 1).11 Several observational studies of patients with
creatinine 133 μmol/L to 177 μmol/L were strong predictors of cirrhosis and renal insufficiency have evaluated the usefulness of
mortality.35 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
Classification of acute kidney injury AKIN criteria are useful, it has been argued that the criteria spe-
in cirrhosis cific to HRS are more accurate.46 A classification that combines
The diagnostic criteria for HRS include a serum creatinine above the AKIN criteria with the classic HRS criteria may provide a
133 μmol/L. However, patients with cirrhosis often have reduced better prediction than the AKIN criteria alone.40 Consensus on
levels of serum creatinine due to malnutrition and decreased this issue is not yet reached.48 In addition, no studies have inves-
muscle mass.37 Serum creatinine may therefore overestimate the tigated if the use of the AKIN criteria improves patients’ overall
renal function. A revised strategy that is more sensitive to prognosis.
Table 3 Studies conducted to evaluate the usefulness of the AKIN classification. In the majority of the studies they find AKIN 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.
increased serum creatinine and the development of HRS type 1.53 Table 4 Proposal for primary investigation of patients with cirrhosis,
Standard treatment is prednisolone or pentoxifylline. A double- ascites, and renal impairment
blind randomized controlled trial (RCT) on 270 patients with
Clinical examination
alcoholic hepatitis found no difference in mortality between Checking of volume status/hydration
patients allocated to prednisolone and pentoxifylline versus pred- Hemodynamics/blood pressure and pulse
nisolone and placebo.54 The trial found a potential benefit on HRS Signs of infection
in the pentoxifylline group, which is consistent with the results of Medical history
a meta-analysis on pentoxifylline.55 Thus pentoxifylline may be Examination of the medication list for nephrotoxic drugs
the preferred first-line treatment for patients with alcoholic hepa- Paraclinical tests
titis and high risk of HRS, which is in line with a recent multiple Broad blood screening including hemoglobin, electrolytes,
treatment comparison meta-analysis.56 creatinine, CRP, and differential count
Gastrointestinal bleeding may result in blood loss and infections Diagnostic ascites puncture with cell count, protein measurement
both of which may lead to HRS.57 Variceal bleeding is treated and culture
according to clinical guidelines including resuscitation, antibiotic Blood culture
prophylaxis, vasoactive drugs, and endoscopic therapy.57–59 For Urine analyses and culture
bleeding oesophageal varices, the administration of terlipressin Possible sputum culture
and antibiotics reduces bleeding, mortality and the risk of HRS.59 Radio diagnostic
Oral quinolones are the antibiotic recommended for most Chest X-ray when infection is suspected
patients.57 Intravenous cephalosporins should be considered in Ultrasound scan of kidney and urinary tract
patients with severer cirrhosis and patients in previous quinolone
prophylaxis.58
Paracentesis with large volume (> 5 liters) may affect hemody- Table 5 Drugs that should be avoided or used with caution in patients
namics and thereby result in post-paracentesis circulatory dysfunc- with cirrhosis and ascites
tion (PCD).60 This condition is characterized as a reduction in the NSAIDs Should be avoided
effective blood volume and may lead to HRS.5 A meta-analysis61 ACE inhibitors, AT-II Use with caution and avoid completely at
found that approximately 73% develops PCD after undergoing receptor antagonists elevated creatinine
large volume paracentesis (LVP) if the procedure is not combined and α1-adrenergic
with volume supportive treatment. This meta-analysis shows that receptor blockers
administration of albumin reduces the incidence of post-PCD, Diuretics Caution should be taken by monitoring of
HRS type 1, and mortality.61 Therefore albumin should be admin- creatinine, electrolytes and hydration
istrated to all patients undergoing LVP (8 g/L of drained ascites Laxatives Pay attention to diarrhoea and dehydration
fluid).5 Aminoglycosides Should be avoided
Contrast media Use with caution and avoid completely at
elevated creatinine
Management of patients with cirrhosis, Beta-blockers Careful titration and caution at elevated
ascites, and renal impairment creatinine and low blood pressure
Renal impairment in patients with cirrhosis and ascites should be ACE, angiotensin converting enzyme; AT, angiotensin; NSAID, non-
evaluated quickly. Correct handling of renal impairment is steroid anti-inflammatory drug.
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. increased preload and CO.15 The treatment of HRS type 1 should
The initial evaluation should include volume expansion by infu- be initiated rapidly, as early diagnosis and treatment improves the
sion of human albumin and discontinuation of diuretics and neph- prognosis.65 The effect of terlipressin and albumin has been
rotoxic drugs (Table 5). Other causes that can lead to renal assessed in several randomized clinical trials. When the results are
impairment (e.g. obstructive uropathy) should also be excluded. 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
Evidence-based intervention for small studies have compared the effect of terlipressin with norepi-
treatment of HRS nephrine or other vasoconstrictors. Since the trials have low sta-
tistical power, it is not possible to assess whether other
Vasoconstrictors and albumin. Terlipressin and vasoconstrictors are as effective as terlipressin. There is no stan-
albumin is the recommended treatment for patients with HRS type dardized dose of terlipressin, but the efficacy in HRS has been
1. The treatment improves the MAP and thereby the renal perfu- established in studies using an initial bolus injection of 1 mg four
sion. Terlipressin, which is an analogue of vasopressin, induces to six times daily and titrated to a maximum of 2 mg six times
vasoconstriction by stimulating vasopressin receptors in the daily based on the effect on creatinine (Table 6).5 Terlipressin is
smooth muscle cells in the vessel wall.63 Intravenous administra- considered effective if S-creatinine is reduced > 25% after 3 days
tion of albumin combined with terlipressin increases the effective of intervention. Treatment should be continued until S-creatinine
arterial blood volume and thereby preload to the heart.64 This is below 133 μmol/L. The treatment is effective in up to 40% of the
improves the circulation and stabilizes MAP as a result of an patients using current the diagnostic criteria and dose regime.11 An
Table 6 Evidence-based treatment of hepatorenal syndrome rotic cardiovascular disease, terlipressin can be administered at a
low dose or as continuous infusion with careful titration and
Treatment of HRS
monitoring.
Liver transplantation should be considered in all patients with HRS
and advanced liver disease
HRS type 1 Alternative vasoconstrictors. In some countries, includ-
Terlipressin: The recommended dose is 1 mg × 4–6/day. The dose ing the United States, terlipressin is not available. The American
may be increased by lack of effect to a maximum of Association for the Study of Liver Diseases’ guidelines on man-
2 mg × 6/day. Treatment continues to the S-creatinine level is agement of ascites suggests albumin infusion plus midodrine and
< 133 μmol/L octreotide or norepinephrine in the treatment of HRS type 1.68
Albumin: The recommended dose is 1 g/kg human albumin on the Even though some studies found benefits in these treatments,
first day of treatment followed by 20–40 g daily additional randomized controlled trials are still needed as the evi-
HRS type 2 dence to support these recommendations are weak.69
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 Transjugular intrahepatic portosystemic shunt.
refractory ascites HRS type 2 develops in patients with ascites refractory to treatment
with diuretics. Therapeutic paracentesis and Transjugular intrahe-
HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic
patic portosystemic shunt (TIPS) have been studied and both are
portosystemic shunt.
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
ongoing RCT (NCT01530711) is currently evaluating terlipressin
examined and a history of hepatic encephalopathy should be
titrated according to the hemodynamic response. The dose of
included when assessing the treatment strategy.70,71 The model of
terlipressin is increased every 8 h until the arterial blood pressure
end-stage liver disease (MELD) score predicts the survival in
is increased with more than 10 mmHg or S-creatinine is reduced
patients treated with elective TIPS.72 Therefore, the MELD score
with more than 25%.
should be included in monitoring of patients to better select the
patients who would benefit from TIPS placement.
Adverse events. Approximately 30% of patients develop
adverse events on terlipressin. In 4% of patients, treatment with Liver transplantation. Liver transplantation should be con-
terlipressin has to be stopped due to adverse events.63 Most adverse sidered in all patients with advanced liver disease, if there are no
events reflect vasoconstrictor effects with mild degrees of periph- obvious contraindications such as ongoing excessive use of
eral ischemia including cyanotic fingers and toes. Arrhythmias, alcohol or malignant disease. A successful liver transplantation
most commonly bradycardia, are seen in approximately 7% of will completely reverse HRS.73 The 5-year post-transplant mortal-
patients. Sixteen percent of patients develop abdominal pain and ity is 32% in patients with advanced liver disease and prerenal
diarrhea probably due to splanchnic ischemia. There has been one dysfunction.74 Simultaneous liver-kidney transplantation should be
case of intestinal ischemic necrosis. Rarely, ischemic necrosis is considered when renal failure reflects chronic kidney disease with
seen.63 glomerular filtration rate (GFR) < 30 mL/min or acute kidney
injury with dialysis > 8 weeks.75
AKIN criteria is suggested to detect those patients earlier who 19 Madsen BS, Havelund T, Krag A. Targeting the gut-liver axis in
have an increased risk of developing HRS and death by use of cirrhosis: antibiotics and non-selective beta-blockers. Adv. Ther.
small changes in serum creatinine. However, there is not at this 2013; 30: 659–70.
stage a consensus on the application of the criteria and more 20 Ruiz-del-Arbol L, Urman J, Fernandez J et al. Systemic, renal, and
hepatic hemodynamic derangement in cirrhotic patients with
research is needed in this area.
spontaneous bacterial peritonitis. Hepatology 2003; 38: 1210–8.
21 Ruiz-del-Arbol L, Monescillo A, Arocena C et al. Circulatory
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