Advertisement

News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document

      Summary

      Renal dysfunction is a common, life-threatening complication occurring in patients with liver disease. Hepatorenal syndrome (HRS) has been defined as a purely “functional” type of renal failure that often occurs in patients with cirrhosis in the setting of marked abnormalities in arterial circulation, as well as overactivity of the endogenous vasoactive systems.4,5 In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2).5 HRS-1 is characterised by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a moderate and stable or slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterised by acute renal failure while HRS-2 is mainly characterised by refractory ascites. Nevertheless, after these two entities were first described, new concepts, definitions, and diagnostic criteria have been developed by nephrologists for renal dysfunction in the general population and hospitalised patients. In particular, the definitions and characterisation of acute kidney injury (AKI), acute kidney disease and chronic kidney disease have been introduced/refined.6 Accordingly, a debate among hepatologists of the ICA led to a complete revision of the nomenclature and diagnosistic criteria for HRS-1, which was renamed HRS-AKI.7 Additionally, over recent years, greater granularity has been gained regarding the pathogenesis of HRS; it is now increasingly recognised that it is not a purely “functional” entity with haemodynamic derangements, but that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly to its development. That is, HRS has an additional structural component that would not only make traditional diagnostic criteria less reliable, but would explain the lack of response to pharmacological treatment with vasoconstrictors plus albumin that correlates with a progressive increase in inflammation.
      Because classification, nomenclature, diagnostic criteria and pathogenic theories have evolved over the years since the traditional classification of HRS-1 and HRS-2 was first described, it was considered that all these novel aspects be reviewed and summarised in a position paper. The aim of this position paper authored by two hepatologists (members of ICA) and two nephrologists involved in the study of renal dysfunction in cirrhosis, is to complete the re-classification of HRS initiated by the ICA in 2012 and to provide an update on the definition, classification, diagnosis, pathophysiology and treatment of HRS.

      Keywords

      Introduction

      Renal dysfunction is a severe complication of advanced cirrhosis.
      • Ginès P.
      • Cárdenas A.
      • Schrier R.W.
      Liver disease and the kidney.
      • Tujios S.R.
      • Hynan L.S.
      • Vazquez M.A.
      • Larson A.M.
      • Seremba E.
      • Sanders C.M.
      • et al.
      Acute Liver Failure Study Group. risk factors and outcomes of acute kidney injury in patients with acute liver failure.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Traditionally, renal dysfunction in patients with liver disease has been defined by a serum creatinine (sCr) concentration of ≥1.5 mg/dl.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      In this context, acute kidney injury (AKI) has been defined by the abrupt doubling of the baseline value of sCr to a final value >1.5 mg/dl. Beyond the well-known types of AKI that can occur in the general population, namely, prerenal, intrarenal or intrinsic, and post-renal, patients with cirrhosis may develop a specific type of renal dysfunction that has been called hepatorenal syndrome (HRS).
      • Moreau R.
      • Lebrec D.
      Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.
      HRS has been defined as renal dysfunction that occurs because of reduced renal perfusion, due to haemodynamic alterations in arterial circulation, as well as overactivity of the endogenous vasoactive systems.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      HRS has been classified into two different clinical types; type I HRS (HRS-1) involves a rapid reduction in renal function, defined by a doubling of the initial sCr to a level greater than 2.5 mg/dl or a 50% reduction of the initial 24 h creatinine clearance to a level lower than 20 ml/min in less than 2 weeks. HRS-1 is most often precipitated by a bacterial infection,
      • Sort P.
      • Navasa M.
      • Arroyo V.
      • Aldeguer X.
      • Planas R.
      • Ruiz-del-Arbol L.
      • et al.
      Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
      • Follo A.
      • Llovet J.M.
      • Navasa M.
      • Planas R.
      • Forns X.
      • Francitorra A.
      • et al.
      Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.
      • Fasolato S.
      • Angeli P.
      • Dallagnese L.
      • Maresio G.
      • Zola E.
      • Mazza E.
      • et al.
      Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.
      • Terra C.
      • Guevara M.
      • Torre A.
      • Gilabert R.
      • Fernandez J.
      • Martin-Llahi M.
      • et al.
      Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.
      and to a lesser extent by gastrointestinal haemorrhage, large-volume paracentesis without albumin administration,
      • Ginès A.
      • Fernández-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domènech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      excessive response to diuretics
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • Okolicsanyi L.
      • Maresio G.
      • Velo E.
      • et al.
      Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
      and acute liver injury due to alcohol,
      • Akriviadis E.
      • Botla R.
      • Briggs W.
      • Han S.
      • Reynolds T.
      • Shakil O.
      Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.
      drugs, or a flare of viral hepatitis.
      • Leithead J.A.
      • Ferguson J.W.
      • Bates C.M.
      • Davidson J.S.
      • Lee A.
      • Bathgate A.J.
      • et al.
      The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure.
      Conversely, type 2 HRS (HRS-2) is characterised by renal dysfunction that does not progress rapidly and is associated with refractory ascites, which represents the main clinical problem. Regarding the pathophysiology of HRS, the main hypothesis in the last 20 years had been the “splanchnic arterial vasodilation theory”.
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      This theory posits that HRS occurs only as a consequence of a marked reduction of effective circulating volume, which is caused by splanchnic and systemic arterial vasodilation and inadequate cardiac output.
      • Ruiz del Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Gines P.
      • Moreira V.
      • et al.
      Circulatory function and hepato-renal syndrome.
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Møller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      • Angeli P.
      • Merkel C.
      Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis.
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      The favourable response of half of patients with HRS to the administration of systemic vasoconstrictors plus intravenous albumin has been considered proof of this pathophysiological mechanism.
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      • Allegretti A.S.
      • Israelsen M.
      • Krag A.
      • Jovani M.
      • Goldin A.H.
      • Schulman A.R.
      • et al.
      Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome.
      In recent years, many concepts have been changed in the setting of HRS. First, the Hepatology community has abandoned the traditional definition of AKI in favour of the new one, defining it as an absolute increase in sCr of ≥0.3 mg/dl from baseline or a percentage increase of ≥50% from baseline.
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      The prognostic relevance of this new definition has been confirmed in patients with cirrhosis by several prospective studies.
      • Piano S.
      • Rosi S.
      • Maresio G.
      • Fasolato S.
      • Cavallin M.
      • Romano A.
      • et al.
      Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
      • Wong F.
      • O'Leary J.G.
      • Reddy K.R.
      • Patton H.
      • Kamath P.S.
      • Fallon M.B.
      • et al.
      New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection.
      • Fagundes C.
      • Barreto R.
      • Guevara M.
      • Garcia E.
      • Solà E.
      • Rodríguez E.
      • et al.
      A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      Second, one relevant achievement – related to the recent description of acute-on-chronic liver failure (ACLF)
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      • Bajaj J.S.
      • O'Leary J.G.
      • Reddy K.R.
      • Wong F.
      • Biggins S.W.
      • Patton H.
      • et al.
      Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures.
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis.
      • Clària J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      • Trebicka J.
      • Amoros A.
      • Pitarch C.
      • Titos E.
      • Alcaraz-Quiles J.
      • Schierwagen R.
      • et al.
      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      – was proving that systemic inflammation induced either by pathogen-associated molecular patterns (PAMPs) or by damage-associated molecular patterns (DAMPS) plays a key role in the development not only of organ failure (OF) but also of acute decompensation (AD) in patients with cirrhosis.
      • Trebicka J.
      • Amoros A.
      • Pitarch C.
      • Titos E.
      • Alcaraz-Quiles J.
      • Schierwagen R.
      • et al.
      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      Finally, while in the past, patients with cirrhosis were unlikely to have underlying structural chronic kidney disease (CKD), this has become a more frequent finding as the number of patients with cirrhosis secondary to non-alcoholic steatohepatitis, with underlying metabolic syndrome (diabetes, hypertension), is increasing rapidly.
      • Sayiner M.
      • Koenig A.
      • Henry L.
      • Younossi Z.M.
      Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world.
      • Marengo A.
      • Jouness R.I.
      • Bugianesi E.
      Progression and natural history of nonalcoholic fatty liver disease in adults.
      As a consequence of all these changes, there is an urgent unmet need for the Hepatology and Nephrology communities to update the definition, classification, pathophysiology, and management of HRS. The development of a conceptual framework that could lead to the further characterisation of renal dysfunction in cirrhosis is the objective of this review.

      What is new in the definition and classification of renal dysfunction in cirrhosis?

      After the consensus definition of AKI in patients with cirrhosis by the International Club of Ascites (ICA) in 2015,
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      there has been confusion in the field regarding the definitions of HRS-1 and HRS-2. This section aims to provide a clearer definition of both of these clinical entities, moving to a new pragmatic definition of HRS and palcing it in the context of those of AKI, acute kidney disease (AKD) and CKD.
      We propose that HRS be defined as one possible phenotype of renal dysfunction that occurs in patients with liver disease, particularly in those with cirrhosis and ascites. In these patients, HRS is often precipitated by hepatic (alcohol abuse, drugs, flare of hepatitis) and/or extrahepatic (bacterial infections and/or bacterial translocation) factors. The specific subtypes of HRS and their definitions will be based on whether renal dysfunction is acute (AKI), sub-acute (AKD) or chronic (CKD).

       Acute kidney injury

      AKI is a broad clinical syndrome encompassing various aetiologies that cause either direct injury to the kidney (structural injury) or an acute impairment of function (functional injury).
      The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define AKI as any of the following: 1) increase in sCr by ≥0.3 mg/dl (≥26.5 μmol/L) within 48 h; or 2) increase in sCr to ≥1.5x baseline, which is known or presumed to have occurred within the prior 7 days; or 3) urine volume <0.5 ml/kg/h for 6 h.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      In patients with cirrhosis, previous consensus statements from the ICA had defined renal dysfunction as an sCr concentration of ≥1.5 mg/dl (≥133 μmol/).
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      However, in the most recent ICA consensus the definition of AKI in cirrhosis was modified to align with KDIGO sCr criteria
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      (Box 1).
      Once AKI is diagnosed, it is classified based on severity; with stage 1 defined as an increase in sCr ≥0.3 mg/dl (26.5 μmol/L) or an increase in sCr ≥1.5-fold to 2-fold from baseline; stage 2 defined as an increase in sCr >2-fold to 3-fold from baseline; and stage 3 defined as an increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 μmol/L), with an acute increase ≥0.3 mg/dl (26.5 μmol/L) or initiation of renal replacement therapy.
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      More recently it was observed that adding the urine output (UO) diagnostic criteria of AKI to the assessment of critically ill patients with chronic liver disease, in the intensive care unit, improved the identification of patients with AKI, as well as of those with stage 2–3 AKI.
      • Amathieu R.
      • Al-Khafaji A.
      • Sileanu F.E.
      • Foldes E.
      • DeSensi R.
      • Hilmi I.
      • et al.
      Significance of oliguria in critically ill patients with chronic liver disease.
      Additionally, patients identified based on UO criteria without sCr elevation had a significantly higher mortality.
      • Amathieu R.
      • Al-Khafaji A.
      • Sileanu F.E.
      • Foldes E.
      • DeSensi R.
      • Hilmi I.
      • et al.
      Significance of oliguria in critically ill patients with chronic liver disease.
      In patients with cirrhosis, as in patients without cirrhosis, AKI can be due to prerenal, intrarenal or intrinsic (acute tubular necrosis, acute interstitial nephritis, acute glomerular and vasculitic renal diseases) and/or post-renal (acute obstructive nephropathy) causes. Additionally, HRS-1 should be included in the differential diagnosis.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      In previous ICA consensus conferences,
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      different criteria defined HRS vs. HRS-1. Major criteria for HRS were 1) cirrhosis with ascites, 2) sCr >1.5 mg/dl, (133 mmol/L), 3) no improvement of sCr (decrease to a level of 133 mmol/L or 1.5 mg/dl) after at least 2 days of diuretic withdrawal and volume expansion with albumin, 4) absence of shock, 5) no current or recent treatment with nephrotoxic drugs, 6) absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, micro haematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      On the other hand, HRS-1 was defined as a “rapidly progressive reduction of renal function as defined by a doubling of the initial sCr to a level greater than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 ml/min in less than 2 weeks”.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      As a result of the 2015 ICA consensus definition of AKI in patients with cirrhosis,
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      it was proposed that the traditional nomenclature and definition of HRS and HRS-1 be revised.
      We propose that HRS-1 be renamed HRS-AKI and be defined based on changes in serum creatinine and/or changes in urinary output.
      Because HRS-1 is a form of AKI, we propose that it be renamed HRS-AKI and be defined based on changes in sCr and/or changes in UO, defined by KDIGO criteria, in addition to other criteria aimed at excluding other causes of AKI as specified in Table 1.
      The original definition of HRS-1 required that the diagnosis be established at an advanced stage of AKI (at least stage 2) that limits the efficacy of vasoconstrictor therapy.
      • Piano S.
      • Schmidt H.H.
      • Ariza X.
      • Amoros A.
      • Romano A.
      • Hüsing-Kabar A.
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Blei A.
      • Carl D.
      • Bexon A.S.
      • Teuber P.
      • et al.
      Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.
      Our new definition of HRS-AKI, without the final cut-off value of sCr ≥1.5 mg/dl from the most recent ICA consensus,
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      aims to encourage clinicians to initiate treatment of patients rapidly, even when increases in sCr are small, specifically, an absolute increase in sCr ≥0.3 mg/dl within 48 h or an increase in sCr ≥50% from an sCr obtained within the prior 3 months (Fig. 1). We have also added UO to the criteria defining HRS-AKI (Box 1 and Table 1). Because obtaining accurate UO measurements is challenging, this criterion would only apply when obtained through a urinary catheter.
      Figure thumbnail gr1
      Fig. 1Criteria for the diagnosis of AKI based on absolute or percent increase of serum creatinine based on the time of initial presentation (T0). AKI, acute kidney injury; sCr, serum creatinine.
      Table 1New classification of HRS subtypes.
      Old classificationNew classificationCriteria
      HRS-1
      Fulfillment of all the new International Ascites Club criteria for the diagnosis of HRS (Box 1).
      HRS-AKI
      • a)
        Absolute increase in sCr ≥0.3 mg/dl within 48 h
        and/or
      • b)
        Urinary output ≤ 0.5 ml/kg B.W. ≥6 h
        the evaluation of this parameter requires a urinary catheter.
        or
      • c)
        Percent increase in sCr ≥50% using the last available value of outpatient sCr within 3 months as the baseline value
      HRS-2
      Fulfillment of all the new International Ascites Club criteria for the diagnosis of HRS (Box 1).
      HRS-NAKIHRS-AKD
      • a)
        eGFR <60 ml/min per 1.73 m2 for <3 months in the absence of other (structural) causes
      • b)
        Percent increase in sCr <50% using the last available value of outpatient sCr within 3 months as the baseline value
      HRS-CKD
      • a)
        eGFR <60 ml/min per 1.73 m2 for ≥3 months in the absence of other (structural) causes
      AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRS, hepatorenal syndrome; sCr, serum creatinine.
      # Fulfillment of all the new International Ascites Club criteria for the diagnosis of HRS (Box 1).
      * the evaluation of this parameter requires a urinary catheter.
      Approximately 20–30% of AKI cases in patients with cirrhosis develop prior to hospital admission.
      • Rosi S.
      • Piano S.
      • Frigo A.C.
      • Morando F.
      • Fasolato S.
      • Cavallin M.
      • et al.
      New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?.
      In order to make a prompt diagnosis of AKI on admission to the hospital, the consensus definition of AKI defines baseline sCr as the lowest sCr obtained within the prior 3 months,
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      choosing the most recent measurement during that period if available (Fig. 1). This will avoid a diagnostic delay of at least 2 days. While recognising that outpatient sCr values may show significant variation and that the choice of the most appropriate sCr value may be a clinician’s judgment call, it would still be better than imputing the baseline sCr. The imputation method recommended by KDIGO consists of the inverse application of the Modification of Diet in Renal Disease (MDRD)-6 variable equation, which assumes a baseline glomerular filtration rate (GFR) of 75 ml/min per 1.73 m2.
      • Rosi S.
      • Piano S.
      • Frigo A.C.
      • Morando F.
      • Fasolato S.
      • Cavallin M.
      • et al.
      New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?.
      This approach cannot be used in patients with cirrhosis because any creatinine-based formula will overestimate the true GFR,
      • Rosi S.
      • Piano S.
      • Frigo A.C.
      • Morando F.
      • Fasolato S.
      • Cavallin M.
      • et al.
      New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?.
      • Francoz C.
      • Prié D.
      • Abdelrazek W.
      • Moreau R.
      • Mandot A.
      • Belghiti J.
      • et al.
      Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score.
      • Francoz C.
      • Nadim M.K.
      • Baron A.
      • Prié D.
      • Antoine C.
      • Belghiti J.
      • et al.
      Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations.
      reducing the probability of detecting AKI upon admission.
      • Rosi S.
      • Piano S.
      • Frigo A.C.
      • Morando F.
      • Fasolato S.
      • Cavallin M.
      • et al.
      New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?.
      The second step in the diagnostic process of AKI in cirrhosis is the differential diagnosis among the different AKI phenotypes, namely, acute tubular necrosis AKI (ATN-AKI), prerenal AKI, HRS-AKI and post-renal AKI. Because most prerenal-AKI cases can be resolved by plasma volume expansion and because post-renal AKI is rare, the real clinical challenge is to differentiate between HRS-AKI and ATN-AKI. The diagnostic limitation is that sCr is a marker of kidney filtration, not injury, and, thus, cannot distinguish functional from structural aetiologies of AKI. Tubular injury biomarkers reflect frank structural injury and, thus, when appearing in consort with an acute drop in GFR, should indicate the drop is attributable to structural damage.
      • Francoz C.
      • Nadim M.K.
      • Durand F.
      Kidney biomarkers in cirrhosis.
      Among the most promising are urinary biomarkers, interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver type fatty acid-binding protein (L-FABP) and neutrophil gelatinase-associated lipocalin (NGAL).
      • Belcher J.M.
      • Edelstein C.L.
      • Parikh C.R.
      Clinical applications of biomarkers for acute kidney injury.
      Urinary values of NGAL, IL-18, KIM-1, L-FABP, and albumin, were found to be significantly higher in patients with ATN than in those without ATN.
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      Comparing the three distinct diagnoses, all biomarkers were significantly elevated in ATN-AKI relative to prerenal AKI, but only NGAL, IL-18, and albumin were statistically higher in ATN compared with HRS and no injury markers distinguished prerenal AKI from HRS. Nevertheless, the presence of increased levels of some tubular biomarkers in patients with HRS-AKI may suggest that there is a continuum from HRS to ATN.
      • Ariza X.
      • Solà E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      Across the majority of studies
      • Verna E.C.
      • Brown R.S.
      • Farrand E.
      • Pichardo E.M.
      • Forster C.S.
      • Sola-Del Valle D.A.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • et al.
      Urinary neutrophil gelatinase- associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      • Ariza X.
      • Solà E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      levels of NGAL, the most investigated biomarker, have been remarkably consistent in patients diagnosed with HRS, raising the possibility of NGAL as an objective test to distinguish primarily functional AKI from structural AKI in patients with cirrhosis
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      and guide decisions regarding vasoconstrictor therapy.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      More specifically, the cut-off with the best predictive accuracy for ATN diagnosis was found to be 220 μg/g of creatinine.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      Most patients with ATN-AKI (86%) had values of urinary NGAL above this threshold, whereas the majority of patients with HRS-AKI or prerenal AKI (88% and 93%, respectively) had values below it.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      However, none of these studies included a gold standard (histology) for the diagnosis of ATN and thus, a diagnosis of ATN remains difficult to establish in patients with cirrhosis and AKI; indeed, HRS and ATN may be considered a continuum rather than two distinct entities.
      While NGAL and other biomarkers of structural injury hold great promise for distinguishing between HRS from ATN, the test is not clinically available in much of the world. Thus, clinically available tests that make this distinction are lacking. The diagnosis of HRS is a clinical one and often one of exclusion. It is possible that a frequently utilised test in AKI, the fractional excretion of sodium (FENa), may assist with this differential diagnosis. In many settings of AKI, fractional excretion of sodium FENa is useful for distinguishing functional from structural disease. In functional AKI, such as with prerenal azotemia, tubules are structurally intact and sodium avid due to renal hypoperfusion, thus FENa is low, below 1%. With structural aetiologies such as ATN, tubular injury limits sodium reabsorption and FENa increases, typically by >2–3%. Due to the physiology of cirrhotic circulation, virtually all patients with advanced cirrhosis have chronic renal hypoperfusion and have an FENa <1%, even in the absence of AKI. As sodium avidity is pronounced in advanced cirrhosis, even patients with ATN typically have an FENa <1%. Thus, the test has historically been considered unhelpful in distinguishing HRS from ATN.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      However, in several studies the FENa in patients diagnosed with HRS was around 0.2% and, in each study, significantly lower than in patients with ATN. While the values for ATN varied across studies based on diagnostic definitions, it appears that FENa, with a new lower cut-off of 0.2% may in fact be clinically useful for distinguishing HRS from ATN.
      • Diamond J.R.
      • Yoburn D.C.
      Nonoligouric acute renal failure associated with a low fractional excretion of sodium.
      Fractional excretion of urea
      • Patidar K.R.
      • Kang L.
      • Bajaj J.S.
      • Carl D.
      • Sanyal A.J.
      Fractional excretion of urea: a simple tool for the differential diagnosis of acute kidney injury in cirrhosis.
      and albuminuria
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      have been also proposed as tools for the differential diagnosis of AKI in patients with cirrhosis.

       Acute and chronic kidney disease

      KDIGO guidelines define CKD as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for >90 days,
      KDIGO criteria Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group
      KDIGO clinical practice guideline for acute kidney injury.
      and AKD, as AKI or as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for <90 days.
      KDIGO criteria Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group
      KDIGO clinical practice guideline for acute kidney injury.
      Because HRS-2 was poorly defined and just assumed more chronic abnormalities in sCr
      • Wong F.
      • Nadim M.K.
      • Kellum J.A.
      • Salerno F.
      • Bellomo R.
      • Gerbes A.
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      without a definite timeline, arriving at a new more granular definition of HRS-2 is more complicated. Recently, in the European Association for the Study of the Liver guidelines on the “management of decompensated cirrhosis” it was proposed that HRS-2 should be referred to as HRS-NAKI (i.e. non-AKI).

      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69: 406–460.

      We propose that the diagnosis of HRS-NAKI be made in the context of CKD, or AKD that does not meet the criteria for AKI and lasts for <90 days.
      We propose that the diagnosis of HRS-NAKI be made either in the context of CKD, that is, in a patient with cirrhosis and a GFR <60 ml/min per 1.73 m2 for >3 months (HRS-CKD) in whom other causes have been excluded, or in the context of AKD, defined as a renal dysfunction that does not meet criteria for AKI and lasts for less than 90 days (Table 1, Fig. 2).
      Figure thumbnail gr2
      Fig. 2Criteria for the diagnosis of HRS-NAKI based on the time of initial presentation (T0). #Fulfillment of all the new ICA criteria for the diagnosis of HRS. AKD, acute kidney disease; CKD, chronic kidney disease; ICA, International Club of Ascites; HRS, hepatorenal syndrome; sCr, serum creatinine; NAKI, non-acute kidney injury.
      Although, recently the Acute Disease Quality Initiative (ADQI) proposed considering AKI and AKD as a continuum, where AKI is considered to have evolved to AKD when it persists for ≥7 days after the precipitating event,
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      we think that this paradigm cannot be applied to HRS because: a) the duration of treatment of HRS-AKI with vasoconstrictors plus albumin could be extended for more than 7 days and up to 2 weeks and b) the course of patients with HRS-AKI whose sCr decreases but not to baseline would appear to be different than that of patients who met the previous definition of HRS-2. These issues require more investigation. In the meantime, for research purposes, persistent HRS-AKI despite adequate treatment should be considered clinically and pathophysiologically distinct from HRS-NAKI.
      Although there may be inaccuracies in the definition of HRS-NAKI since it includes the use of eGFR, it would facilitate a diagnosis of HRS-AKI superimposed on HRS-CKD or HRS-AKD, unlike the previous HRS-1 or HRS-2 nomenclature. Importantly, the new nomenclature may enable clinicians’ to define the presence of HRS-AKI superimposed on CKD in a patient with structural damage of the kidney, as evidenced by abnormal biopsy, renal ultrasonography or by significant proteinuria (i.e. diabetic nephropathy). This need is pressing given the increasing rate of cirrhosis due to non-alcoholic steatohepatitis that is characterised by the presence of comorbidities, such as diabetes mellitus and arterial hypertension, that may lead to structural CKD. Although further diagnostic and prognostic studies are necessary in this context, the criteria for HRS-AKI (Box 1), except for criterion 6, would still apply to patients with underlying structural kidney disease. In the context of the new definition of HRS-AKI on CKD we have provided different clinical settings: HRS-AKI on HRS-CKD, in which there would be no evidence of chronic structural damage, and, on an individual basis, HRS-AKI on CKD in which there would be evidence of chronic structural damage (i.e. chronic proteinuria and/or abnormal renal ultrasonography) but with a high suspicion of HRS-AKI.
      It should be highlighted that the limited information on several pathophysiological and clinical aspects of HRS still limits the delineation of the new definitions and classification. Therefore, the new HRS definitions and classifications should be validated in future prospective studies. Nevertheless, these new definitions will be immediately useful in the design of clinical trials on diagnosis, pathophysiology and the clinical management of this severe complication.

      What is new in the pathophysiology of hepatorenal syndrome?

      According to the new theory on the development of decompensation and OFs in patients with cirrhosis, it is now recognised that HRS not only involves circulatory dysfunction but also systemic inflammation (Fig. 3). Looking at the heat-map highlighting the levels of the different biomarkers of systemic inflammation in patients with cirrhosis and AD, three different patterns were recently observed, according to three clinical phenotypes: cirrhosis with AD-1 defined as patients without any single OF, with sCr <1.5 mg/dl (133 µmol/L) and without hepatic encephalopathy (HE); cirrhosis with AD-2 defined as patients with sCr >1.5 mg/dl (133 µmol/L), but <2 mg/dl (177 µmol/L) and/or mild to moderate HE without any associated single non-renal or non-cerebral OF; and cirrhosis with AD-3 defined as patients with a single non-renal OF, with an sCr <1.5 mg/dl (133 µmol/L). Although patterns were different, all patients exhibitedat least partial activation of systemic inflammation. In addition, those with the most extensive baseline systemic inflammation had the highest risk of ACLF development and death.
      • Trebicka J.
      • Amoros A.
      • Pitarch C.
      • Titos E.
      • Alcaraz-Quiles J.
      • Schierwagen R.
      • et al.
      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      Translating these alterations to the pathogenesis of renal dysfunction in patients with cirrhosis, it should be recognised that the systemic inflammation associated with AKI, and in particular HRS-AKI, is frequently due to pathological bacterial translocation or an overt bacterial infection.
      • Trebicka J.
      • Amoros A.
      • Pitarch C.
      • Titos E.
      • Alcaraz-Quiles J.
      • Schierwagen R.
      • et al.
      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      Bacterial translocation is the main mechanism by which portal hypertension induces the circulatory dysfunction characteristic of HRS and is the main mechanism involved in the pathogenesis of spontaneous bacterial peritonitis and other infections in patients with cirrhosis.
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in liver cirrhosis.
      Bacterial translocation leads to monocyte activation by PAMPs such as endotoxins and bacterial DNA. Monocyte activation results in the release of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β).
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      These cytokines have been associated with impairment of renal function in patients with cirrhosis, as well as in patients with ACLF and acute liver failure (ALF).
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      • Maiwall R.
      • Chandel S.S.
      • Wani Z.
      • Kumar S.
      • Sarin S.K.
      SIRS at admission is a predictor of AKI development and mortality in hospitalized patients with severe alcoholic hepatitis.
      In both clinical
      • Shah N.
      • Mohamed F.E.
      • Jover-Cobos M.
      • Macnaughtan J.
      • Davies N.
      • Moreau R.
      • et al.
      Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
      and experimental studies,
      • Shah N.
      • Dhar D.
      • El Zahraa Mohammed F.
      • Habtesion A.
      • Davies N.A.
      • Jover-Cobos M.
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      it has been shown that renal tubular toll-like receptor 4 (TLR4) may be upregulated, which is associated with the development of florid renal dysfunction, tubular damage and apoptosis. Although the mechanism of tubular TLR4 upregulation is not entirely clear, it likely results from bacterial translocation. Experimentally, significant tubular damage has been detected in rats with cirrhosis following administration of a sub-lethal dose of lipopolysaccharide.
      • Shah N.
      • Dhar D.
      • El Zahraa Mohammed F.
      • Habtesion A.
      • Davies N.A.
      • Jover-Cobos M.
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      Specifically, the presence of vacuolar degeneration with accompanying tubular cell sloughing was present, indicating tubular apoptosis. In order to better understand the mechanism by which bacterial products and proinflammatory cytokines, which filter at the glomerular level, interact with tubular function, one suggestion is to consider the possible overlap in the pathogenetic mechanisms of HRS-AKI and sepsis-induced AKI.
      • Gomez H.
      • Ince C.
      • De Backer D.
      • Pickkers P.
      • Payen D.
      • Hotchkiss J.
      • et al.
      A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.
      Thus, interplay of inflammation and microvascular dysfunction characterizes and amplifies the signal that PAMPs and DAMPs exert on epithelial cells of the proximal tubule. The recognition of this signal and its subsequent extension to all other proximal tubule epithelial cells causes mitochondria-mediated metabolic downregulation and reprioritisation of cell functions favouring survival processes above all others. Functions that are thereby sacrificed include the absorption on the luminal side of sodium and chloride. The increased delivery of sodium chloride to the macula densa triggers further intrarenal activation of the renin–angiotensin system and thus lowers the GFR. Finally, cholestasis that can be present in several patients with HRS-AKI may further impair renal function by worsening inflammation and/or macrovascular dysfunction, or by promoting bile salt-related direct tubular damage.
      • Ficket P.
      • Krones E.
      • Pollheimer M.J.
      • Thueringer A.
      • Moustafa T.
      • Silbert D.
      • et al.
      Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice.
      • Van Slambrouck C.M.
      • Salem F.
      • Meehan S.M.
      • Chang A.
      Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.
      Figure thumbnail gr3
      Fig. 3New pathopshysiological hypothesis of acute decompensation and development of organ dysfunction in patients with cirrhosis. ROS, reactive oxygen species.
      All these features (Fig. 4), which can develop even in the absence of circulatory dysfunction and thus of renal hypoperfusion, suggest that the pathophysiology of HRS-AKI can deviate from what has been traditionally accepted for more than 20 years. This may explain the progressive lack of response to vasoconstrictors observed in patients with ACLF as the number of OFs increases.
      • Piano S.
      • Schmidt H.H.
      • Ariza X.
      • Amoros A.
      • Romano A.
      • Hüsing-Kabar A.
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
      New insights into the pathophysiology of HRS must be considered in relation to their potential impact on pharmacological treatment.
      Figure thumbnail gr4
      Fig. 4Mechanisms of renal injury potentially involved in HRS-AKI in patients with cirrhosis. AKI, acute kidney injury; HRS, hepatorenal syndrome.

      What is new in the pathology of hepatorenal syndrome?

      The functional nature of renal dysfunction in HRS, based on the assumed absence of renal parenchymal damage, has been substantiated mainly based on the following: a) renal dysfunction in cirrhosis usually occurs in the absence of significant renal histological changes as seen in post-mortem examinations, b) classical images of HRS showing extreme but reversible renal vasoconstriction, c) reversibility of renal dysfunction by liver transplant alone and d) the ability to use kidneys from patients with HRS as grafts for renal transplantation.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      Accordingly, risk factors for renal parenchymal damage (septic shock, treatment with nephrotoxic drugs) or evidence of such damage (significant proteinuria, haematuria, abnormal renal ultrasonography) should be excluded before the diagnosis of HRS can be established.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      • Salerno F.
      • Gerbes A.
      • Gines P.
      • et al.
      Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
      However, the absence of renal parenchymal damage in HRS has never been definitively proven. In fact, the need to exclude parenchymal damage in HRS appears to be questionable in light of two recent lines of evidence:
      The first line of evidence derives from studies analyzing renal biopsies of patients with cirrhosis and renal dysfunction, which demonstrates a discrepancy between renal histological findings and clinical presentation in patients with cirrhosis. The absence of significant proteinuria and haematuria did not rule out the presence of renal lesions.
      • Trawalé J.M.
      • Paradis V.
      • Rautou P.E.
      • Francoz C.
      • Escolano S.
      • Sallée M.
      • et al.
      The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
      • Wadei H.M.
      • Geiger X.J.
      • Cortese C.
      • Mai M.L.
      • Kramer D.J.
      • Rosser B.G.
      • et al.
      Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy.
      Specifically, in one of these studies, among 18 of the patients with a previous diagnosis of CKD based on an sCr >1.5 mg/d (133 µmol), but with proteinuria <500 mg/day and no haematuria, thus with a possible diagnosis of HRS-CKD, renal histology revealed chronic tubular interstitial injury in 13, acute tubular interstitial injury in 12, glomerular injury in 10, and vascular injury in 12.
      • Trawalé J.M.
      • Paradis V.
      • Rautou P.E.
      • Francoz C.
      • Escolano S.
      • Sallée M.
      • et al.
      The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
      The second line of evidence emerged from studies investigating novel biomarkers of tubular damage that could be used to make the differential diagnosis between the different phenotypes of AKI, particularly between HRS and ATN. These studies show, as previously discussed, that high levels of multiple biomarkers in the urine, particularly NGAL, are indicative of the presence of ATN.
      • Belcher J.M.
      • Edelstein C.L.
      • Parikh C.R.
      Clinical applications of biomarkers for acute kidney injury.
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      • Verna E.C.
      • Brown R.S.
      • Farrand E.
      • Pichardo E.M.
      • Forster C.S.
      • Sola-Del Valle D.A.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • et al.
      Urinary neutrophil gelatinase- associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      • Ariza X.
      • Solà E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      However, they also demonstrate that in HRS, as defined in Box 1, these biomarkers are also increased, albeit not as in patients with ATN but more than in patients with prerenal AKI.
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      • Ariza X.
      • Solà E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      Figure thumbnail gr5
      Box 1. New diagnostic criteria for HRS-AKI*The evaluation of this parameter requires a urinary catheter. **This criterion would not be included in cases of known pre-existing structural chronic kidney disease (e.g. diabetic or hypertensive nephropathy). AKI, acute kidney injury; FENa, fractional excretion of sodium; HRS, hepatorenal syndrome; ICA, International Club of Ascites.
      Based on this evidence, the idea that HRS is purely a “functional” renal failure appears unsustainable. Instead, HRS appears to include a spectrum of kidney injury, which can be predominantly functional or associated with some degree of parenchymal damage, a concept that may have therapeutic and prognostic implications.
      We propose defining HRS based on renal dysfunction in patients with liver disease (cirrhosis with ascites, ALF, or ACLF).
      We propose defining HRS based on one of the possible phenotypes of renal dysfunction in patients with liver disease (cirrhosis, ACLF or ALF). In these patients, HRS is often precipitated by hepatic (i.e. alcohol abuse, drugs) and/or extrahepatic (i.e. bacterial infections and/or bacterial translocation) events. The pathogenesis of HRS is complex, including: macrovascular dysfunction (systemic vasodilatation, inadequate cardiac output), microvascular dysfunction, danger/inflammation signals from either pathogen- (PAMPs) or tissue-associated (DAMPs) molecular patterns, and direct tubular damage. The nature of HRS can be predominantly functional or associated with some degree of parenchymal damage in a continuous spectrum of kidney injury.

      What is new in the treatment of hepatorenal syndrome?

      The management of AKI should be started immediately once a diagnosis has been made and the cause of AKI identified. In patients taking diuretics and/or β-blockers these should be discontinued. In addition, drugs that could be associated with AKI such as vasodilators, non-steroidal anti-inflammatory drugs and other nephrotoxic drugs should be immediately stopped. Volume replacement should be used in accordance with the cause and severity of fluid losses. When HRS-AKI is diagnosed, a specific pharmacological treatment should start as soon as possible. There is no doubt about this approach since several randomised studies have shown that vasoconstrictors
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      • Ortega R
      • Gines P
      • Uriz J
      • Cardenas A
      • Calahorra B
      • De Las Heras D
      • et al.
      Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
      • Martin-Llahi M.
      • Pepin M.N.
      • Guevara M.
      • Díaz F.
      • Torre A.
      • Monescillo A.
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      • Rodríguez E.
      • Elia C.
      • Solà E.
      • Barreto R.
      • Graupera I.
      • Andrealli A.
      • et al.
      Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      • Boyer T.D.
      • Sanyal A.J.
      • Wong F.
      • Frederick R.T.
      • Lake J.R.
      • O'Leary J.G.
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      • Cavallin M.
      • Piano S.
      • Romano A.
      • Fasolato S.
      • Frigo A.C.
      • Benetti G.
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
      • Angeli P.
      • Volpin R.
      • Gerunda G.
      • Craighero R.
      • Roner P.
      • Merenda R.
      • et al.
      Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.
      • Singh V.
      • Ghosh S.
      • Singh B.
      • Kumar P.
      • Sharma N.
      • Bhalla A.
      • et al.
      Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
      • Sharma P.
      • Kumar A.
      • Shrama B.C.
      • Sarin S.K.
      An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      • Esrailian E.
      • Pantangco E.R.
      • Kyulo N.L.
      • Hu K.Q.
      • Runyon B.A.
      Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome.
      particularly terlipressin plus albumin,
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      • Moreau R
      • Durand F.
      • Poynard T.
      • Duhamel C.
      • Cervoni J.P.
      • Ichai P.
      • et al.
      Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a restrospective multicenter study.
      • Ortega R
      • Gines P
      • Uriz J
      • Cardenas A
      • Calahorra B
      • De Las Heras D
      • et al.
      Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
      • Martin-Llahi M.
      • Pepin M.N.
      • Guevara M.
      • Díaz F.
      • Torre A.
      • Monescillo A.
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      • Rodríguez E.
      • Elia C.
      • Solà E.
      • Barreto R.
      • Graupera I.
      • Andrealli A.
      • et al.
      Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      • Boyer T.D.
      • Sanyal A.J.
      • Wong F.
      • Frederick R.T.
      • Lake J.R.
      • O'Leary J.G.
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      • Cavallin M.
      • Piano S.
      • Romano A.
      • Fasolato S.
      • Frigo A.C.
      • Benetti G.
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
      • Singh V.
      • Ghosh S.
      • Singh B.
      • Kumar P.
      • Sharma N.
      • Bhalla A.
      • et al.
      Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
      • Sharma P.
      • Kumar A.
      • Shrama B.C.
      • Sarin S.K.
      An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      have significantly improved renal function in patients with HRS-1. Moreover, patients who responded to treatment with terlipressin plus albumin showed better survival than non-responders to treatment;
      • Rodríguez E.
      • Elia C.
      • Solà E.
      • Barreto R.
      • Graupera I.
      • Andrealli A.
      • et al.
      Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      moreover, in three meta-analyses of randomised trials, the use of terlipressin was associated with a significant improvement in short-term survival in all patients.
      • Allegretti A.S.
      • Israelsen M.
      • Krag A.
      • Jovani M.
      • Goldin A.H.
      • Schulman A.R.
      • et al.
      Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome.
      • Gluud L.L.
      • Christensen K.
      • Christensen E.
      • Krag A.
      Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
      • Facciorusso A.
      • Chandar A.K.
      • Murad M.H.
      • Prokop L.J.
      • Muscatiello N.
      • Kamath P.S.
      • et al.
      Comparative effi cacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
      However, it should be noted that all these studies were performed in patients with HRS-1, defined according to the old classification of ICA, that is, a baseline sCr >2.5 mg/dl. Finding that a higher baseline value of sCr is definitively an independent predictor of no response to the vasoconstrictor treatment
      • Piano S.
      • Schmidt H.H.
      • Ariza X.
      • Amoros A.
      • Romano A.
      • Hüsing-Kabar A.
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Blei A.
      • Carl D.
      • Bexon A.S.
      • Teuber P.
      • et al.
      Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.
      was one of the main reasons that led the ICA to introduce the new definition of “HRS-AKI” (Box 1). According to the new definition, a final cut-off value of sCr is no longer needed to make the diagnosis of HRS-AKI and to start its pharmacological treatment.
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
      Although a positive impact of the new definition on the rate of response to the pharmacological treatment is expected, it should be confirmed by further studies.
      Another factor that may have a deep impact on the response to the pharmacological treatment of HRS-AKI is the complexity of the pathophysiology, as previously described, with the potential development of some degree of renal parenchymal damage. The possibility of structural damage should be strongly factored in when evaluating the lack of response or, even, a partial response to pharmacological treatment in patients with HRS-AKI. Factors that can affect the response to treatment have recently been split into two categories, those related to the therapeutic agents used and those which are independent from them.
      • Ginès P.
      • Solà E.
      • Angeli P.
      • Wong F.
      • Nadim M.K.
      • Kamath P.S.
      Hepatorenal syndrome.

       Factors independent of the agents used

      The rationale behind the introduction of vasoconstrictors in the treatment of HRS-1 was based on the previous theory of splanchnic arterial vasodilatation. Accordingly, terlipressin was introduced to counteract splanchnic arterial vasodilation
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      while albumin was introduced to further improve effective circulating volume and to improve cardiac contractility.
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      • Fernández J.
      • Monteagudo J.
      • Bargallo X.
      • Jiménez W.
      • Bosch J.
      • Arroyo V.
      • et al.
      A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.
      • Bortoluzzi A.
      • Ceolotto G.
      • Gola E.
      • Sticca A.
      • Bova S.
      • Morando F.
      • et al.
      Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      However, according to recent developments in the pathophysiology of HRS, two main questions arise. Firstly, to what extent does the presence of systemic inflammation and oxidative stress affect the rate of response to vasoconstrictors plus albumin? Secondly, to what extent does the presence of some degree of parenchymal damage limit the efficacy of treatment in patients with HRS. With regard to the first question, it has been observed that in patients with ACLF the number of OFs, which correlate with the degree of systemic inflammation, affects the response of HRS-AKI to medical treatment.
      • Piano S.
      • Schmidt H.H.
      • Ariza X.
      • Amoros A.
      • Romano A.
      • Hüsing-Kabar A.
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
      Regarding the second question, although a high urinary level of NGAL is an independent predictor of AKI progression, no difference in NGAL levels was found in patients with HRS-1 between responders and non-responders to terlipressin and albumin.
      • Huelin P.
      • Solà E.
      • Elia C.
      • Solé C.
      • Risso A.
      • Moreira R.
      • et al.
      Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
      Finally, among the factors that are not related to therapeutic agents, the pretreatment level of sCr should also be considered, as previously discussed.
      • Amathieu R.
      • Al-Khafaji A.
      • Sileanu F.E.
      • Foldes E.
      • DeSensi R.
      • Hilmi I.
      • et al.
      Significance of oliguria in critically ill patients with chronic liver disease.
      • Piano S.
      • Schmidt H.H.
      • Ariza X.
      • Amoros A.
      • Romano A.
      • Hüsing-Kabar A.
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.

       Factors related to the agents used

       Type of vasoconstrictor

      Three types of vasoconstrictors are currently available for the treatment of HRS: terlipressin, noradrenaline and the combination of midodrine + octreotide. Terlipressin is the most investigated vasoconstrictor in this field. Two pilot studies,
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      • Moreau R
      • Durand F.
      • Poynard T.
      • Duhamel C.
      • Cervoni J.P.
      • Ichai P.
      • et al.
      Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a restrospective multicenter study.
      as well as three randomised controlled trials,
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      • Martin-Llahi M.
      • Pepin M.N.
      • Guevara M.
      • Díaz F.
      • Torre A.
      • Monescillo A.
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      • Boyer T.D.
      • Sanyal A.J.
      • Wong F.
      • Frederick R.T.
      • Lake J.R.
      • O'Leary J.G.
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      have demonstrated that the combination of terlipressin plus albumin is more effective than albumin alone in the treatment of HRS. Terlipressin can be administered both as intravenous boluses (starting from 0.5–1 mg every 4–6 h to a maximum dose of 2 mg every 4 h)
      • Sanyal A.J.
      • Boyer T.D.
      • Frederick R.T.
      • Wong F.
      • Rossaro L.
      • Araya V.
      • et al.
      Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
      • Martin-Llahi M.
      • Pepin M.N.
      • Guevara M.
      • Díaz F.
      • Torre A.
      • Monescillo A.
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      • Boyer T.D.
      • Sanyal A.J.
      • Wong F.
      • Frederick R.T.
      • Lake J.R.
      • O'Leary J.G.
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      and as continuous intravenous infusions (starting from 2 mg/day to maximum dose of 12 mg/day).
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      • Cavallin M.
      • Piano S.
      • Romano A.
      • Fasolato S.
      • Frigo A.C.
      • Benetti G.
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
      The latter administration has been associated with a significantly lower incidence of severe side effects which include persistent diarrhea, abdominal ischemia, peripheral ischemia, angina pectoris, and circulatory overload.
      • Cavallin M.
      • Piano S.
      • Romano A.
      • Fasolato S.
      • Frigo A.C.
      • Benetti G.
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
      These findings are probably consistent with the short-term effect (3–4 h) of terlipressin on portal pressure.
      • Escorsell A.
      • Bandi J.C.
      • Moitinho E.
      • Feu F.
      • García-Pagan J.C.
      • Bosch J.
      • et al.
      Time profile of the haemodynamic effects of terlipressin in portal hypertension.
      Thus, careful clinical screening is recommended before starting treatment, with close monitoring of patients continued for the duration of treatment. The dose of terlipressin should be increased in a stepwise manner if sCr does not decrease by at least 25% after 3 days of treatment. Albumin should be administered at the dose of 20–40 g/day. The treatment with vasoconstrictors plus albumin should be continued until sCr reaches a final value within 0.3 mg of the patient’s baseline sCr. In patients with no response or partial response, the treatment should be discontinued within 14 days. In the last two randomised controlled clinical trials the percentage of patients with HRS-1 who showed a complete response to terlipressin plus albumin, defined as a reduction of sCr >50% to a final value <1.5 mg/dl (133 µmol/L) was 55.5%.
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      • Cavallin M.
      • Piano S.
      • Romano A.
      • Fasolato S.
      • Frigo A.C.
      • Benetti G.
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
      After discontinuation, a recurrence of HRS may be observed in less than 20% of patients with HRS-1 and retreatment is usually effective.
      Conversely, despite higher rates of response to terlipressin and albumin, in patients with type 2 HRS, recurrence of HRS is quite common.
      • Alessandria C.
      • Ottobrelli A.
      • Debernardi-Venon W.
      • Todros L.
      • Cerenzia M.T.
      • Martini S.
      • et al.
      Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.
      In addition, a recent case-control study did not show any difference in terms of post liver transplantation (LT) outcomes in patients treated or not with terlipressin.
      • Rodriguez E.
      • Henrique Pereira G.
      • Solà E.
      • Elia C.
      • Barreto R.
      • Pose E.
      • et al.
      Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: effects on kidney function and transplantation outcomes.
      For these reasons, HRS-2, now termed HRS-NAKI, cannot be considered an indication for the use of terlipressin plus albumin even in patients who are on the waiting list for LT. Terlipressin has not been approved for use in the United States.
      Midodrine (an α1-agonist drug) combined with octreotide (a somatostatin analogue), together with albumin infusion has been shown to be effective in treating HRS-1.
      • Angeli P.
      • Volpin R.
      • Gerunda G.
      • Craighero R.
      • Roner P.
      • Merenda R.
      • et al.
      Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.
      • Esrailian E.
      • Pantangco E.R.
      • Kyulo N.L.
      • Hu K.Q.
      • Runyon B.A.
      Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome.
      However, in a small, single center, randomised controlled trial, the combination of terlipressin plus albumin was shown to be significantly more effective than the combination of midodrine plus octreotide and albumin in the treatment of HRS (improvement of renal function in 70 vs. 29%, respectively; p = 0.01).
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      The administration of norepinephrine (administered at a dose of 0.5–3 mg/hour) plus albumin has been investigated in the treatment of HRS. In patients with HRS-1, noradrenaline was shown to be as effective as terlipressin in the treatment of HRS in two small controlled clinical trials
      • Singh V.
      • Ghosh S.
      • Singh B.
      • Kumar P.
      • Sharma N.
      • Bhalla A.
      • et al.
      Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
      • Sharma P.
      • Kumar A.
      • Shrama B.C.
      • Sarin S.K.
      An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      and in a recent prospective study.
      • Gupta K.
      • Rani P.
      • Rohatgi A.
      • Verma M.
      • Handa S.
      • Dalal K.
      • et al.
      Noradrenaline for reverting hepatorenal syndrome: a prospective, observational, single-center study.
      However, in a recent randomised trial, terlipressin was shown to be more effective than noradrenaline in the treatment of HRS in patients with ACLF;
      • Arora V.
      • Maiwall R.
      • Rajan V.
      • Jindal A.
      • Muralikrishna Shasthry S.
      • et al.
      Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure.
      this is probably related to the fact that noradrenaline, unlike terlipressin, has no effect on portal pressure
      • Massicotte L.
      • Perrault M.A.
      • Denault A.Y.
      • Klinck J.R.
      • Beaulieu D.
      • Roy J.D.
      • et al.
      Effects of phlebotomy and phenylephrine infusion on portal venous pressure and systemic hemodynamics during liver transplantation.
      or on the expression of inducible NOS.
      • Moreau R
      • Barrière E
      • Tazi KA
      • Lardeux B
      • Dargère D
      • Urbanowicz W
      • et al.
      Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis..
      Despite these limitations, the use of norepinephrine for the treatment of HRS is tempting because it is a cheaper than terlipressin, although it should be administered through a central venous line and under continuous monitoring, so it cannot be used outside intensive care units. Therefore, further studies are needed to determine the feasibility of norepinephrine.

       Dose of albumin

      Albumin is crucial for the effectiveness of the treatment of HRS. In the only study in which terlipressin was used alone in the treatment of HRS, it was much less effective than when it was used together with albumin.
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      One possible explanation is that a fall in cardiac output (CO), which is a crucial event in the pathophysiology of HRS,
      • Ruiz del Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Gines P.
      • Moreira V.
      • et al.
      Circulatory function and hepato-renal syndrome.
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Møller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      could be exacerbated by the effect of terlipressin.
      • Narahara Y.
      • Kanazawa H.
      • Taki Y.
      • Kimura Y.
      • Atsukawa M.
      • Katakura T.
      • et al.
      Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis.
      In contrast, albumin is capable of maintaining or increasing the CO even in the most advanced phases of liver disease.
      • Brinch K.
      • Møller S.
      • Bendtsen F.
      • Becker U.
      • Henriksen J.H.
      Plasma volume expansion by albumin in cirrhosis. Relation to blood volume distribution, arterial compliance and severity of disease.
      To date, albumin has been given at a dose of 20–40 g/day and managed only according to the level of central venous pressure in order to avoid circulatory overload. Now, there is increasing experimental
      • Bortoluzzi A.
      • Ceolotto G.
      • Gola E.
      • Sticca A.
      • Bova S.
      • Morando F.
      • et al.
      Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.
      and clinical
      • Fernández J.
      • Monteagudo J.
      • Bargallo X.
      • Jiménez W.
      • Bosch J.
      • Arroyo V.
      • et al.
      A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      evidence that the increase in systemic vascular resistance and CO due to albumin are mainly related to the non-oncotic properties of the molecule and particularly to its capacity to exert anti-oxidant and anti-inflammatory actions. The role and details of these actions go beyond the scope of this manuscript, nevertheless, it is important to highlight two concepts. The first is that when albumin is used alone, the dose needed to obtain and to maintain an effective improvement of the cardio circulatory function as well as an anti-inflammatory effect is quite high (1.5 g/kg of bodyweight/week).
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      Up to now, this dose has never been usedin patients with HRS-AKI, thus its efficacy and safety should be proved in RCTs. The second is that while exerting its non-oncotic actions, the molecule of albumin goes through post-transitional changes that consume its biological potential.
      • Domenicali M.
      • Baldassarre M.
      • Giannone F.A.
      • Naldi M.
      • Mastroroberto M.
      • Biselli M.
      • et al.
      Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis.
      Thus, either the pretreatment concentration of endogenous effective albumin or the dose of exogenous effective albumin administered could be future targets for the optimisation of treatment responses in HRS.

      What is new in the perspective of liver transplantation in patients with hepatorenal syndrome?

      LT represents the optimal treatment for patients with HRS-AKI regardless of their response to pharmacological treatment.
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Regenstein F.
      • Rossaro L.
      • Appenrodt B.
      • et al.
      Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.
      However three main points deserve further investigation: a) to what extent renal failure is reversible after LT, b) when should a simultaneous liver kidney transplantation (SLK) be considered in non-responders to pharmacological treatment and c) how to ascribe the correct priority on the waiting list to responders to pharmacological treatment. Regarding the first and the second points, which are strongly related, several studies have shown that mean sCr after LT is higher in patients transplanted for HRS than for patients without HRS, thus re-proposing the question about the real nature of HRS.
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Regenstein F.
      • Rossaro L.
      • Appenrodt B.
      • et al.
      Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.
      • Wong F.
      • Leung W.
      • Al Beshir M.
      • Marquez M.
      • Renner E.L.
      Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
      The introduction of model for end-stage liver disease (MELD) score-based allocation in 2002 coincided with a dramatic increase in the number of SLK transplants, representing 10% of all liver transplants in 2017 in the United States.
      • Formica R.N.
      • Aeder M.
      • Boyle G.
      • Kucheryavaya A.
      • Stewart D.
      • Hirose R.
      • et al.
      Simultaneous liver-kidney allocation policy: a proposal to optimize appropriate utilization of scarce resources.
      The decision to perform SLK vs. LT alone, with a possible kidney transplant after the LT,
      • Ruiz R.
      • Barri Y.M.
      • Jennings L.W.
      • Chinnakotla S.
      • Goldstein R.M.
      • Levy M.F.
      • et al.
      Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT).
      is driven not only by concerns relating to increased mortality post-transplant, but also to the lack of renal recovery which is felt to contribute to increased mortality. Currently in the United States, a listing policy for SLK now exists based on prior consensus recommendations
      • Eason J.D.
      • Gonwa T.A.
      • Davis C.L.
      • Sung R.S.
      • Gerber D.
      • Bloom R.D.
      Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK).
      • Davis C.L.
      • Feng S.
      • Sung R.
      • Wong F.
      • Goodrich N.P.
      • Melton L.B.
      • et al.
      Simultaneous liver-kidney transplantation: evaluation to decision making.
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      and includes elements such as duration of AKI, need for dialysis, and evidence of CKD. Factors that may impact the recovery of renal function after LT such as age, comorbidities or aetiology of AKI are currently not included in the criteria. However, renal recovery and patient survival 1 and 5 years after liver transplant are significantly worse for patients with renal dysfunction secondary to ATN in comparison to patients with HRS.
      • Nadim M.K.
      • Genyk Y.S.
      • Tokin C.
      • Fieber J.
      • Ananthapanyasut W.
      • Ye W.
      • et al.
      Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome.
      Prediction of renal recovery and the extent of that recovery following LT is a challenge which has plagued the transplant community, as the relative contributions of pre-existing comorbidities, unrecognised intrinsic renal disease, perioperative events, and post-transplant immunosuppression, to renal dysfunction after LT are difficult to delineate.
      Regarding the third point, in order to optimize the results of pharmacological treatment in patients with HRS-AKI, responders should receive the right priority in the waiting list, taking into account not only the specific value of HRS per se on 3-month mortality beyond the MELD score,
      • Alessandria C.
      • Ozdogan O.
      • Guevara M.
      • Restuccia T.
      • Jiménez W.
      • Arroyo V.
      • et al.
      MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.
      but also considering that lowering sCr can reduce the baseline MELD score and thus, delay the timing of LT. This paradoxical effect of treatment in the responders can be avoided either by continuing to consider the baseline MELD, or by considering the pharmacological treatment of HRS as dialysis in the calculation of the MELD score, according to the type of response.
      • Angeli P.
      • Gines P.
      Hepatorenal syndrome, MELD score and liver transplantation: an evolving issue with relevant implications for clinical practice.

      Conclusions

      Renal dysfunction is a common complication in patients with cirrhosis, ACLF, and ALF. This review proposes a new definition and overall a new classification for HRS that expands on the recent ICA consensus document. It should be highlighted that the new proposal is based on new data, which are quite interesting but still limited. Therefore, the new proposed definition and classification of HRS should be validated in future prospective studies. Nevertheless, they will be immediately useful in the design of clinical trials on the pathophysiology and the management of HRS in patients with liver disease.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      All the Authors designed, drafted and finalized the manuscript

      Supplementary data

      The following are the Supplementary data to this article:

      References

        • Ginès P.
        • Cárdenas A.
        • Schrier R.W.
        Liver disease and the kidney.
        in: Schrier R.W. Diseases of the kidney and urinary tract. 8th ed. Lippincott Williams & Wilkins, Philadelphia2007: 2179-2205
        • Tujios S.R.
        • Hynan L.S.
        • Vazquez M.A.
        • Larson A.M.
        • Seremba E.
        • Sanders C.M.
        • et al.
        Acute Liver Failure Study Group. risk factors and outcomes of acute kidney injury in patients with acute liver failure.
        Clin Gastroenterol Hepatol. 2015; 13: 352-359
        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144: 1426-1437
        • Arroyo V.
        • Gines P.
        • Gerbes A.L.
        • Dudley F.J.
        • Gentilini P.
        • Laffi G.
        • et al.
        Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
        Hepatology. 1996; 23: 164-176
        • Salerno F.
        • Gerbes A.
        • Gines P.
        • et al.
        Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis a consensus workshop of the International Ascites Club.
        Gut. 2007; 56: 1310-1318
        • KDIGO criteria Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group
        KDIGO clinical practice guideline for acute kidney injury.
        Kidney Int. 2012; 2: 1-138
        • Angeli P.
        • Gines P.
        • Wong F.
        • Bernardi M.
        • Boyer T.D.
        • Gerbes A.
        • et al.
        Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the ICA.
        J Hepatol. 2015; 62: 968-974
        • Moreau R.
        • Lebrec D.
        Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.
        Hepatology. 2003; 37: 233-243
        • Sort P.
        • Navasa M.
        • Arroyo V.
        • Aldeguer X.
        • Planas R.
        • Ruiz-del-Arbol L.
        • et al.
        Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
        N Engl J Med. 1999; 341: 403-409
        • Follo A.
        • Llovet J.M.
        • Navasa M.
        • Planas R.
        • Forns X.
        • Francitorra A.
        • et al.
        Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.
        Hepatology. 1994; 20: 1495-1501
        • Fasolato S.
        • Angeli P.
        • Dallagnese L.
        • Maresio G.
        • Zola E.
        • Mazza E.
        • et al.
        Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.
        Hepatology. 2007; 45: 223-229
        • Terra C.
        • Guevara M.
        • Torre A.
        • Gilabert R.
        • Fernandez J.
        • Martin-Llahi M.
        • et al.
        Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.
        Gastroenterology. 2005; 129: 1944-1953
        • Ginès A.
        • Fernández-Esparrach G.
        • Monescillo A.
        • Vila C.
        • Domènech E.
        • Abecasis R.
        • et al.
        Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
        Gastroenterology. 1996; 111: 1002-1010
        • Angeli P.
        • Fasolato S.
        • Mazza E.
        • Okolicsanyi L.
        • Maresio G.
        • Velo E.
        • et al.
        Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
        Gut. 2010; 59: 98-104
        • Akriviadis E.
        • Botla R.
        • Briggs W.
        • Han S.
        • Reynolds T.
        • Shakil O.
        Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.
        Gastroenterology. 2000; 119: 1637-1648
        • Leithead J.A.
        • Ferguson J.W.
        • Bates C.M.
        • Davidson J.S.
        • Lee A.
        • Bathgate A.J.
        • et al.
        The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure.
        Gut. 2009; 58: 443-449
        • Schrier R.W.
        • Arroyo V.
        • Bernardi M.
        • Epstein M.
        • Henriksen J.H.
        • Rodes J.
        Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
        Hepatology. 1988; 8: 1151-1157
        • Ruiz del Arbol L.
        • Monescillo A.
        • Arocena C.
        • Valer P.
        • Gines P.
        • Moreira V.
        • et al.
        Circulatory function and hepato-renal syndrome.
        Hepatology. 2005; 42: 439-447
        • Krag A.
        • Bendtsen F.
        • Henriksen J.H.
        • Møller S.
        Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
        Gut. 2010; 59: 105-110
        • Angeli P.
        • Merkel C.
        Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis.
        J Hepatol. 2008; 48: S93-S100
        • Sanyal A.J.
        • Boyer T.D.
        • Frederick R.T.
        • Wong F.
        • Rossaro L.
        • Araya V.
        • et al.
        Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.
        Aliment Pharmacol Ther. 2017; 45: 1390-1402
        • Allegretti A.S.
        • Israelsen M.
        • Krag A.
        • Jovani M.
        • Goldin A.H.
        • Schulman A.R.
        • et al.
        Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome.
        Cochrane Database Syst Rev. 2017; 6CD005162https://doi.org/10.1002/14651858.CD0
        • Piano S.
        • Rosi S.
        • Maresio G.
        • Fasolato S.
        • Cavallin M.
        • Romano A.
        • et al.
        Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
        J Hepatol. 2013; 59: 482-489
        • Wong F.
        • O'Leary J.G.
        • Reddy K.R.
        • Patton H.
        • Kamath P.S.
        • Fallon M.B.
        • et al.
        New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection.
        Gastroenterology. 2013; 145: 1280-1288
        • Fagundes C.
        • Barreto R.
        • Guevara M.
        • Garcia E.
        • Solà E.
        • Rodríguez E.
        • et al.
        A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.
        J Hepatol. 2013; 59: 474-481
        • Belcher J.M.
        • Garcia-Tsao G.
        • Sanyal A.J.
        • et al.
        Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
        Hepatology. 2013; 57: 753-762
        • Bajaj J.S.
        • O'Leary J.G.
        • Reddy K.R.
        • Wong F.
        • Biggins S.W.
        • Patton H.
        • et al.
        Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures.
        Hepatology. 2014; 60: 250-256
        • Bernardi M.
        • Moreau R.
        • Angeli P.
        • Schnabl B.
        • Arroyo V.
        Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis.
        J Hepatol. 2015; 63: 1272-1284
        • Clària J.
        • Stauber R.E.
        • Coenraad M.J.
        • Moreau R.
        • Jalan R.
        • Pavesi M.
        • et al.
        Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
        Hepatology. 2016; 64: 1249-1264
        • Trebicka J.
        • Amoros A.
        • Pitarch C.
        • Titos E.
        • Alcaraz-Quiles J.
        • Schierwagen R.
        • et al.
        Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
        Front Immunol. 2019; 10 (eCollection 2019): 476https://doi.org/10.3389/fimmu.2019.00476
        • Sayiner M.
        • Koenig A.
        • Henry L.
        • Younossi Z.M.
        Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world.
        Clin Liver Dis. 2016; 20: 205-214
        • Marengo A.
        • Jouness R.I.
        • Bugianesi E.
        Progression and natural history of nonalcoholic fatty liver disease in adults.
        Clin Liver Dis. 2016; 20: 313-324
        • Amathieu R.
        • Al-Khafaji A.
        • Sileanu F.E.
        • Foldes E.
        • DeSensi R.
        • Hilmi I.
        • et al.
        Significance of oliguria in critically ill patients with chronic liver disease.
        Hepatology. 2017; 66: 1592-1600
        • Piano S.
        • Schmidt H.H.
        • Ariza X.
        • Amoros A.
        • Romano A.
        • Hüsing-Kabar A.
        • et al.
        Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
        Clin Gastroenterol Hepatol. 2018; 16: 1792-1800
        • Boyer T.D.
        • Sanyal A.J.
        • Garcia-Tsao G.
        • Blei A.
        • Carl D.
        • Bexon A.S.
        • Teuber P.
        • et al.
        Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.
        J Hepatol. 2011; 55: 315-321
        • Rosi S.
        • Piano S.
        • Frigo A.C.
        • Morando F.
        • Fasolato S.
        • Cavallin M.
        • et al.
        New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?.
        Liver Int. 2015; 35: 2108-12014
        • Francoz C.
        • Prié D.
        • Abdelrazek W.
        • Moreau R.
        • Mandot A.
        • Belghiti J.
        • et al.
        Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score.
        Liver Transpl. 2010; 16: 1169-1177
        • Francoz C.
        • Nadim M.K.
        • Baron A.
        • Prié D.
        • Antoine C.
        • Belghiti J.
        • et al.
        Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations.
        Hepatology. 2014; 59: 1514-1521
        • Francoz C.
        • Nadim M.K.
        • Durand F.
        Kidney biomarkers in cirrhosis.
        J Hepatol. 2016; 65: 809-824
        • Belcher J.M.
        • Edelstein C.L.
        • Parikh C.R.
        Clinical applications of biomarkers for acute kidney injury.
        Am J Kidney Dis. 2011; 57: 930-940
        • Belcher J.M.
        • Sanyal A.J.
        • Peixoto A.J.
        • Perazella M.A.
        • Lim J.
        • Thiessen-Philbrook H.
        • et al.
        Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
        Hepatology. 2014; 60: 622-632
        • Verna E.C.
        • Brown R.S.
        • Farrand E.
        • Pichardo E.M.
        • Forster C.S.
        • Sola-Del Valle D.A.
        • et al.
        Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
        Dig Dis Sci. 2012; 57: 2362-3237
        • Fagundes C.
        • Pepin M.N.
        • Guevara M.
        • et al.
        Urinary neutrophil gelatinase- associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
        J Hepatol. 2012; 57: 267-273
        • Ariza X.
        • Solà E.
        • Elia C.
        • Barreto R.
        • Moreira R.
        • Morales-Ruiz M.
        • et al.
        Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
        PLoS ONE. 2015; 10e0128145https://doi.org/10.1371/journal.pone.0128145. eCollection 2015
        • Huelin P.
        • Solà E.
        • Elia C.
        • Solé C.
        • Risso A.
        • Moreira R.
        • et al.
        Neutrophil gelatinase‐associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study.
        Hepatology. 2019; ([Epub ahead of print])
        • Diamond J.R.
        • Yoburn D.C.
        Nonoligouric acute renal failure associated with a low fractional excretion of sodium.
        Ann Intern Med. 1982; 96: 597-600
        • Patidar K.R.
        • Kang L.
        • Bajaj J.S.
        • Carl D.
        • Sanyal A.J.
        Fractional excretion of urea: a simple tool for the differential diagnosis of acute kidney injury in cirrhosis.
        Hepatology. 2018; 68: 224-233
        • Chawla L.S.
        • Bellomo R.
        • Bihorac A.
        • Goldstein S.L.
        • Siew E.D.
        • Bagshaw S.M.
        • et al.
        Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
        Nat Rev Nephrol. 2017; 13: 241-257
        • Wong F.
        • Nadim M.K.
        • Kellum J.A.
        • Salerno F.
        • Bellomo R.
        • Gerbes A.
        • et al.
        Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
        Gut. 2011; 60: 702-709
      1. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69: 406–460.

        • Wiest R.
        • Lawson M.
        • Geuking M.
        Pathological bacterial translocation in liver cirrhosis.
        J Hepatol. 2014; 60: 197-209
        • Navasa M.
        • Follo A.
        • Filella X.
        • Jiménez W.
        • Francitorra A.
        • Planas R.
        • et al.
        Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
        Hepatology. 1998; 27: 1227-1232
        • Maiwall R.
        • Chandel S.S.
        • Wani Z.
        • Kumar S.
        • Sarin S.K.
        SIRS at admission is a predictor of AKI development and mortality in hospitalized patients with severe alcoholic hepatitis.
        Dig Dis Sci. 2016; 61: 920-929
        • Shah N.
        • Mohamed F.E.
        • Jover-Cobos M.
        • Macnaughtan J.
        • Davies N.
        • Moreau R.
        • et al.
        Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
        Liver Int. 2013; 33: 398-409
        • Shah N.
        • Dhar D.
        • El Zahraa Mohammed F.
        • Habtesion A.
        • Davies N.A.
        • Jover-Cobos M.
        • et al.
        Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
        J Hepatol. 2012; 56: 1047-1053
        • Gomez H.
        • Ince C.
        • De Backer D.
        • Pickkers P.
        • Payen D.
        • Hotchkiss J.
        • et al.
        A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.
        Shock. 2014; 41: 3-11
        • Ficket P.
        • Krones E.
        • Pollheimer M.J.
        • Thueringer A.
        • Moustafa T.
        • Silbert D.
        • et al.
        Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice.
        Hepatology. 2013; 58: 2056-2069
        • Van Slambrouck C.M.
        • Salem F.
        • Meehan S.M.
        • Chang A.
        Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.
        Kidney Int. 2013; 84: 192-197
        • Trawalé J.M.
        • Paradis V.
        • Rautou P.E.
        • Francoz C.
        • Escolano S.
        • Sallée M.
        • et al.
        The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
        Liver Int. 2010; 30: 725-732
        • Wadei H.M.
        • Geiger X.J.
        • Cortese C.
        • Mai M.L.
        • Kramer D.J.
        • Rosser B.G.
        • et al.
        Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy.
        Am J Transplant. 2008; 8: 2618-2626
        • Uriz J.
        • Ginès P.
        • Cárdenas A.
        • Sort P.
        • Jiménez W.
        • Salmerón J.M.
        • et al.
        Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
        J Hepatol. 2000; 33: 43-48
        • Moreau R
        • Durand F.
        • Poynard T.
        • Duhamel C.
        • Cervoni J.P.
        • Ichai P.
        • et al.
        Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a restrospective multicenter study.
        Gastroenterology. 2002; 4: 923-930
        • Ortega R
        • Gines P
        • Uriz J
        • Cardenas A
        • Calahorra B
        • De Las Heras D
        • et al.
        Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
        Hepatology. 2002; 36: 941-948
        • Martin-Llahi M.
        • Pepin M.N.
        • Guevara M.
        • Díaz F.
        • Torre A.
        • Monescillo A.
        • et al.
        Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
        Gastroenterology. 2008; 134: 1352-1359
        • Rodríguez E.
        • Elia C.
        • Solà E.
        • Barreto R.
        • Graupera I.
        • Andrealli A.
        • et al.
        Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
        J Hepatol. 2014; 60: 955-961
        • Cavallin M.
        • Kamath P.S.
        • Merli M.
        • Fasolato S.
        • Toniutto P.
        • Salerno F.
        • et al.
        Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
        Hepatology. 2015; 62: 567-574
        • Boyer T.D.
        • Sanyal A.J.
        • Wong F.
        • Frederick R.T.
        • Lake J.R.
        • O'Leary J.G.
        • et al.
        Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
        Gastroenterology. 2016; 150: 1579-1589
        • Cavallin M.
        • Piano S.
        • Romano A.
        • Fasolato S.
        • Frigo A.C.
        • Benetti G.
        • et al.
        Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.
        Hepatology. 2016; 63: 983-992
        • Angeli P.
        • Volpin R.
        • Gerunda G.
        • Craighero R.
        • Roner P.
        • Merenda R.
        • et al.
        Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.
        Hepatology. 1999; 29: 1690-1697
        • Singh V.
        • Ghosh S.
        • Singh B.
        • Kumar P.
        • Sharma N.
        • Bhalla A.
        • et al.
        Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
        J Hepatol. 2012; 56: 1293-1298
        • Sharma P.
        • Kumar A.
        • Shrama B.C.
        • Sarin S.K.
        An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
        Am J Gastroenterol. 2008; 103: 1689-1697
        • Esrailian E.
        • Pantangco E.R.
        • Kyulo N.L.
        • Hu K.Q.
        • Runyon B.A.
        Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome.
        Dig Dis Sci. 2007; 52: 742-748
        • Gluud L.L.
        • Christensen K.
        • Christensen E.
        • Krag A.
        Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
        Hepatology. 2010; 51: 576-584
        • Facciorusso A.
        • Chandar A.K.
        • Murad M.H.
        • Prokop L.J.
        • Muscatiello N.
        • Kamath P.S.
        • et al.
        Comparative effi cacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
        Lancet Gastroenterol Hepatol. 2017; 2: 94-102
        • Ginès P.
        • Solà E.
        • Angeli P.
        • Wong F.
        • Nadim M.K.
        • Kamath P.S.
        Hepatorenal syndrome.
        Nat Rev Dis Primers. 2018; 4: 23https://doi.org/10.1038/s41572-018-0022-7
        • Fernández J.
        • Monteagudo J.
        • Bargallo X.
        • Jiménez W.
        • Bosch J.
        • Arroyo V.
        • et al.
        A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.
        Hepatology. 2005; 42: 627-634
        • Bortoluzzi A.
        • Ceolotto G.
        • Gola E.
        • Sticca A.
        • Bova S.
        • Morando F.
        • et al.
        Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.
        Hepatology. 2013; 57: 266-276
        • Fernández J.
        • Clària J.
        • Amorós A.
        • Aguilar F.
        • Castro M.
        • Casulleras M.
        • et al.
        Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
        Gastroenterology. 2019; (pii: S0016-5085(19)33576-0 [Epub ahead of print])https://doi.org/10.1053/j.gastro.2019.03.021
        • Escorsell A.
        • Bandi J.C.
        • Moitinho E.
        • Feu F.
        • García-Pagan J.C.
        • Bosch J.
        • et al.
        Time profile of the haemodynamic effects of terlipressin in portal hypertension.
        J Hepatol. 1997; 26: 621-627
        • Alessandria C.
        • Ottobrelli A.
        • Debernardi-Venon W.
        • Todros L.
        • Cerenzia M.T.
        • Martini S.
        • et al.
        Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.
        J Hepatol. 2007; 47: 499-505
        • Rodriguez E.
        • Henrique Pereira G.
        • Solà E.
        • Elia C.
        • Barreto R.
        • Pose E.
        • et al.
        Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: effects on kidney function and transplantation outcomes.
        Liver Transpl. 2015; 21: 1347-1354
        • Gupta K.
        • Rani P.
        • Rohatgi A.
        • Verma M.
        • Handa S.
        • Dalal K.
        • et al.
        Noradrenaline for reverting hepatorenal syndrome: a prospective, observational, single-center study.
        Clin Exp Gastroenterol. 2018; 11: 317-324
        • Arora V.
        • Maiwall R.
        • Rajan V.
        • Jindal A.
        • Muralikrishna Shasthry S.
        • et al.
        Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure.
        Hepatology. 2018; ([Epub ahead of print])https://doi.org/10.1002/hep.30208
        • Massicotte L.
        • Perrault M.A.
        • Denault A.Y.
        • Klinck J.R.
        • Beaulieu D.
        • Roy J.D.
        • et al.
        Effects of phlebotomy and phenylephrine infusion on portal venous pressure and systemic hemodynamics during liver transplantation.
        Transplantation. 2010; 89: 920-927
        • Moreau R
        • Barrière E
        • Tazi KA
        • Lardeux B
        • Dargère D
        • Urbanowicz W
        • et al.
        Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis..
        Hepatology. 2002; 36: 1070-1078
        • Narahara Y.
        • Kanazawa H.
        • Taki Y.
        • Kimura Y.
        • Atsukawa M.
        • Katakura T.
        • et al.
        Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis.
        J Gastroenterol Hepatol. 2009; 24: 1791-1797
        • Brinch K.
        • Møller S.
        • Bendtsen F.
        • Becker U.
        • Henriksen J.H.
        Plasma volume expansion by albumin in cirrhosis. Relation to blood volume distribution, arterial compliance and severity of disease.
        J Hepatol. 2003; 39: 24-31
        • Domenicali M.
        • Baldassarre M.
        • Giannone F.A.
        • Naldi M.
        • Mastroroberto M.
        • Biselli M.
        • et al.
        Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis.
        Hepatology. 2014; 60: 1851-1860
        • Boyer T.D.
        • Sanyal A.J.
        • Garcia-Tsao G.
        • Regenstein F.
        • Rossaro L.
        • Appenrodt B.
        • et al.
        Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.
        Liver Transpl. 2011; 17: 1328-1332
        • Wong F.
        • Leung W.
        • Al Beshir M.
        • Marquez M.
        • Renner E.L.
        Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
        Liver Transpl. 2015; 21: 300-307
        • Formica R.N.
        • Aeder M.
        • Boyle G.
        • Kucheryavaya A.
        • Stewart D.
        • Hirose R.
        • et al.
        Simultaneous liver-kidney allocation policy: a proposal to optimize appropriate utilization of scarce resources.
        Am J Transplant. 2016; 16: 758-766
        • Ruiz R.
        • Barri Y.M.
        • Jennings L.W.
        • Chinnakotla S.
        • Goldstein R.M.
        • Levy M.F.
        • et al.
        Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT).
        Liver Transpl. 2007; 13: 838-843
        • Eason J.D.
        • Gonwa T.A.
        • Davis C.L.
        • Sung R.S.
        • Gerber D.
        • Bloom R.D.
        Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK).
        Am J Transplant. 2008; 8: 2243-2251
        • Davis C.L.
        • Feng S.
        • Sung R.
        • Wong F.
        • Goodrich N.P.
        • Melton L.B.
        • et al.
        Simultaneous liver-kidney transplantation: evaluation to decision making.
        Am J Transplant. 2007; 7: 1702-1709
        • Nadim M.K.
        • Sung R.S.
        • Davis C.L.
        • Andreoni K.A.
        • Biggins S.W.
        • Danovitch G.M.
        • et al.
        Simultaneous liver-kidney transplantation summit: current state and future directions.
        Am J Transplant. 2012; 12: 2901-2908
        • Nadim M.K.
        • Genyk Y.S.
        • Tokin C.
        • Fieber J.
        • Ananthapanyasut W.
        • Ye W.
        • et al.
        Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome.
        Liver Transpl. 2012; 18: 539-548
        • Alessandria C.
        • Ozdogan O.
        • Guevara M.
        • Restuccia T.
        • Jiménez W.
        • Arroyo V.
        • et al.
        MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.
        Hepatology. 2005; 41: 1282-1289
        • Angeli P.
        • Gines P.
        Hepatorenal syndrome, MELD score and liver transplantation: an evolving issue with relevant implications for clinical practice.
        J Hepatol. 2012; 57: 1135-1140

      Linked Article

      • Reply to: “Lack of evidence for a continuum between hepatorenal syndrome and acute tubular necrosis”
        Journal of HepatologyVol. 72Issue 3
        • Preview
          We thank Dr. Solé et al. for their letter. We particularly thank them for their comments agreeing on using the term HRS-AKI to define the acute type of HRS (formerly termed HRS-1) to avoid confusion with HRS-CKD, the more chronic form of HRS that still requires further characterization.
        • Full-Text
        • PDF
      • Lack of evidence for a continuum between hepatorenal syndrome and acute tubular necrosis
        Journal of HepatologyVol. 72Issue 3
        • Preview
          We read with great interest the review article “News in Pathophysiology, Definition, and Classification of Hepatorenal Syndrome: a step beyond the International Club of Ascites (ICA) Consensus document” by Angeli et al. published recently in Journal of Hepatology.1 The review discusses a number of important issues related to acute kidney injury (AKI) in cirrhosis and proposes modifications to the definition, classification, pathogenesis, and management of hepatorenal syndrome (HRS). HRS is a specific type of kidney impairment unique to patients with cirrhosis characterized by a sudden and severe impairment in kidney function in the absence of significant histological abnormalities in the kidneys.
        • Full-Text
        • PDF