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Epidemiology, Pathophysiology, and Management of Hepatorenal Syndrome

  • Ahmed Adel Amin
    Affiliations
    University College London Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK

    Assiut University Hospital, Internal Medicine Department, Assiut University, Assiut, Egypt
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  • Eman Ibrahim Alabsawy
    Affiliations
    University College London Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK

    Tropical Medicine Department, Alexandria University Hospital, Alexandria, Egypt
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  • Rajiv Jalan
    Affiliations
    University College London Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK
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  • Andrew Davenport
    Correspondence
    Address reprint requests to Andrew Davenport, MD, University College London Centre for Nephrology, Division of Medicine, Royal Free Hospital, University College London Medical School, Rowland Hill St, London NW3 2PF, UK.
    Affiliations
    University College London Centre for Nephrology, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK
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      Summary: Acute kidney injury (AKI) is a common presentation in patients with advanced cirrhosis hospitalized with acute decompensation. A new revised classification now divides AKI in cirrhotic patients into two broad subgroups: hepatorenal syndrome AKI (HRS AKI) and non–hepatorenal syndrome AKI (non-HRS AKI). HRS AKI represents the end-stage complication of decompensated cirrhosis with severe portal hypertension and is characterized by worsening of renal function in the absence of prerenal azotemia, nephrotoxicity, and intrinsic renal disease. Non-HRS AKI may be caused by prerenal hypoperfusion, bile acid nephropathy, nephrotoxicity, or acute parenchymal insult. There have been several mechanisms proposed to explain the pathophysiology of HRS AKI and non-HRS AKI, and a number of biomarkers have been suggested to aid in differentiation between these types of AKI and to act as prognostic indicators. The standard of care clinical management for patients with HRS AKI is to exclude other etiologies of AKI, followed by volume expansion with human albumin solution and then the introduction of vasopressors. However, some 40% of patients treated for HRS AKI fail to respond. In this review, we discuss the current and recent data about classification, pathophysiology, and management of AKI in general, with specific insight about the treatment of HRS AKI.

      Keywords

      Renal dysfunction is a common finding in patients with advanced liver disease with cirrhosis and portal hypertension admitted to the hospital, and is associated with increased morbidity and mortality. Typically, the cause of renal dysfunction is multifactorial and, as such, specific management strategies are limited because the exact mechanisms have not been fully elucidated. Within the spectrum of acute renal dysfunction in patients with cirrhosis, hepatorenal syndrome (HRS) carries the most ominous prognosis because it usually denotes a background of severe portal hypertension and circulatory dysfunction. HRS acute kidney injury (AKI) accounts for approximately 11% of AKI in hospitalized cirrhotic patients with refractory ascites, and is associated with high mortality.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      • Weil D
      • Levesque E
      • McPhail M
      • et al.
      Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis.
      In advanced cirrhosis, portal hypertension results in a profound hemodynamic derangement, which in turn leads to marked splanchnic vasodilation. This causes activation of both the renin-angiotensin-aldosterone system and the sympathetic nervous system, leading to intense renal vasoconstriction, which then plays a major role in the pathogenesis of HRS AKI.
      • Gines P
      • Guevara M
      • Arroyo V
      • Rodes J
      Hepatorenal syndrome.
      • El-Naggar MM
      • Khalil el-SA
      • El-Daker MA
      • Salama MF
      Bacterial DNA and its consequences in patients with cirrhosis and culture-negative, non-neutrocytic ascites.
      In addition, advanced portal hypertension leads to greater shear stress in the splanchnic vessels, increasing bacterial translocation from the bowel,
      • El-Naggar MM
      • Khalil el-SA
      • El-Daker MA
      • Salama MF
      Bacterial DNA and its consequences in patients with cirrhosis and culture-negative, non-neutrocytic ascites.
      which is associated with increased generation of nitric oxide (NO) and prostacyclins. These potent splanchnic vasodilators cause pooling of blood and decrease the effective circulating systemic blood volume.
      • Solé C
      • Solà E
      • Morales-Ruiz M
      • et al.
      Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis.
      Initially, these effects are compensated by hyperdynamic circulation with increased cardiac output, resulting from an increase in both stroke volume and heart rate, but as the severity of the underlying liver disease progresses, then cardiac output does not increase sufficiently to compensate for the degree of vasodilation.
      • Krag A
      • Bendtsen F
      • Henriksen JH
      • Møller S
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      • Schneider AW
      • Kalk JF
      • Klein CP
      Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis.
      Historically, most patients admitted with renal dysfunction in the context of chronic liver disease and ascites without evidence of intrinsic renal disease were considered to have HRS AKI until proven otherwise. In addition, the classification of HRS historically was subdivided into two types: type 1 when the deterioration in renal function occurred over days to weeks, and type 2 when deterioration occurred over months.
      • Salerno F
      • Gerbes A
      • Ginès P
      • Wong F
      • Arroyo V
      Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.
      This classification now has been abandoned because it does not accurately reflect the clinical scenario. A newer classification has been proposed by the International Club of Ascites (ICA), which divides patients with cirrhosis and AKI into distinct subgroups according to the underlying pathology.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      • Wong F
      • Nadim MK
      • Kellum JA
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      Causes of AKI in cirrhotic patients other than HRS AKI are identified in the new classification and include prerenal causes, bile acid nephropathy, and acute tubular injury.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      This type of AKI collectively is referred to as non-HRS AKI. This term is different from HRS AKI, which defines a functional type of AKI in the setting of normal renal parenchyma.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Chronic kidney disease represents a term that includes any cause that structurally affects the renal parenchyma, including glomerulopathies and interstitial renal disease, and causes associated with comorbid diseases such as diabetes mellitus and hypertension.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.
      Patients with cirrhosis may suffer episodes of acute hepatic decompensation, and acute-on-chronic liver failure (ACLF) is a recently recognized clinical entity that occurs in patients with acute hepatic decompensation. ACLF is characterized by multiple organ failures and is associated with increased short-term mortality.
      • Moreau R
      • Jalan R
      • Gines P
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      • Jalan R
      • Yurdaydin C
      • Bajaj JS
      • et al.
      Toward an improved definition of acute-on-chronic liver failure.
      AKI is an important factor that defines ACLF and it is considered one of its major components, however, the pathophysiologic mechanisms of AKI in ACLF have not been fully elucidated because patients may have non-HRS AKI or HRS AKI.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.
      Currently, therapeutic options for HRS AKI remain supportive and are only a bridge to liver transplantation. Despite the recent advances in scientific research in this field, the optimum management for patients with HRS AKI remains to be established, and a better understanding of the different pathophysiologic mechanisms of HRS and non-HRS AKI is required.
      • Boyer TD
      • Sanyal AJ
      • Wong F
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      • Wong F
      • Pappas SC
      • Boyer TD
      • et al.
      Terlipressin improves renal function and reverses hepatorenal syndrome in patients with systemic inflammatory response syndrome.
      In this review, we discuss the recent updates in the pathogenesis, diagnosis, and management of HRS AKI in the setting of the new definitions and classification of AKI.

      EPIDEMIOLOGY

      AKI occurs in 25% to 50% of cirrhotic patients admitted to the hospital after an episode of acute decompensation.
      • Piano S
      • Rosi S
      • Maresio G
      • et al.
      Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
      AKI is either prerenal, renal parenchymal, or obstructive in origin. Prerenal causes include hypovolemia and HRS AKI, and together they account for 60% to 70% of all causes of AKI,
      • Garcia-Tsao G
      • Parikh CR
      • Viola A
      Acute kidney injury in cirrhosis.
      with HRS AKI accounting for 11% to 20% of all causes of AKI.
      • Garcia-Tsao G
      • Parikh CR
      • Viola A
      Acute kidney injury in cirrhosis.
      • Fang J-T
      • Tsai M-H
      • Tian Y-C
      • et al.
      Outcome predictors and new score of critically ill cirrhotic patients with acute renal failure.
      Intrinsic renal causes account for approximately 30% of all causes of AKI in cirrhotic patients, and include ischemic injury and acute tubular necrosis, acute glomerulonephritis, and acute interstitial nephritis, whereas postrenal (obstructive) causes are relatively uncommon (<1%).
      • Garcia-Tsao G
      • Parikh CR
      • Viola A
      Acute kidney injury in cirrhosis.
      • Hartleb M
      • Gutkowski K
      Kidneys in chronic liver diseases.
      AKI is associated with an increased risk of mortality because 2% to 31% of hospitalized cirrhotic patients with AKI do not survive their admission.
      • Belcher JM
      • Garcia-Tsao G
      • Sanyal AJ
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      • Scott RA
      • Austin AS
      • Kolhe N V
      • McIntyre CW
      • Selby NM
      Acute kidney injury is independently associated with death in patients with cirrhosis.
      One- and 12-month mortality rates reported in these patients are 58% and 63%, respectively.
      • Fede G
      • D'Amico G
      • Arvaniti V
      • et al.
      Renal failure and cirrhosis: a systematic review of mortality and prognosis.
      Even those who survive their hospital admission are more prone to complications of cirrhosis, including ascites and hepatic encephalopathy.
      • Belcher JM
      • Garcia-Tsao G
      • Sanyal AJ
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      • D'Amico G
      • Garcia-Tsao G
      • Pagliaro L
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.

      DEFINITION AND CLASSIFICATION

      HRS now is described as a more homogeneous condition with specific diagnostic features.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.
      Historically, HRS was classified into 2 types: type 1 HRS, which was defined as rapid deterioration in kidney function over the course of 2 weeks with a serum creatinine level greater than 2.5 mg/dL, and type 2 HRS, which was characterized by a progressive slower course of moderate renal failure and serum creatinine concentrations between 1.5 and 2.5 mg/dL.
      • Salerno F
      • Gerbes A
      • Ginès P
      • Wong F
      • Arroyo V
      Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.
      The main problem with this older classification was that it relied predominantly on serum creatinine concentrations as the sole factor to classify HRS into types 1 and 2, irrespective of the underlying pathology or etiology. Serum creatinine does not accurately reflect the severity of renal impairment in cirrhotic patients because it is affected by several factors including assay interference with bilirubin, reduced hepatic creatine synthesis, muscle wasting, and malnutrition.
      • Francoz C
      • Glotz D
      • Moreau R
      • Durand F
      The evaluation of renal function and disease in patients with cirrhosis.
      In 2007, the Acute Kidney Injury Network proposed a new definition of AKI,
      • Mehta RL
      • Kellum JA
      • Shah S V
      • et al.
      Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury.
      which then was supported by both the Acute Dialysis Quality Initiative and the ICA in 2011.
      • Wong F
      • Nadim MK
      • Kellum JA
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      The Acute Kidney Injury Network's new definition of AKI allowed the use of any increase of the absolute values of serum creatinine from baseline by as little as 0.3 mg/dL (26.5 mmol/L), or any increase of serum creatinine by 50% above the baseline within a 48-hour period (Table 1).
      • Wong F
      • Nadim MK
      • Kellum JA
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      This definition was supported by observational data linking AKI stage severity and patient survival.
      • Piano S
      • Rosi S
      • Maresio G
      • et al.
      Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
      • Belcher JM
      • Garcia-Tsao G
      • Sanyal AJ
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      ,
      • Tsien CD
      • Rabie R
      • Wong F
      Acute kidney injury in decompensated cirrhosis.
      • Fagundes C
      • Barreto R
      • Guevara M
      • et al.
      A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.
      Table 1International Club of Ascites Definition and Staging of AKI in Patients With Cirrhosis
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      • Wong F
      • Nadim MK
      • Kellum JA
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      Definition of AKI
       Increase in serum creatinine ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; or a percentage increase in serum creatinine ≥50% frombaseline that is known, or presumed, to have occurred within the prior 7 days
      Stages of AKI
       Stage 1Increase in serum creatinine ≥0.3 mg/dL (26.5 mmol/L) or an increase in serum creatinine ≥1.5-fold to 2-fold from baseline
       Stage 2Increase in serum creatinine >2-fold to 3-fold from baseline
       Stage 3Increase in serum creatinine >3-fold from baseline or ≥4.0 mg/dL (353.6 mmol/L) with an acute increase ≥0.3 mg/dL(26.5 mmol/L) or initiation of renal replacement therapy
      Recently, the ICA proposed a new definition and diagnostic criteria for HRS AKI, and the older subclassifications of type 1 and type 2 and the time limit of 2 weeks to diagnose type 1 HRS were removed.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      In addition, the limiting threshold of a serum creatinine concentration of 2.5 mg/dL, which was the cornerstone for diagnosing HRS, was removed.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      According to this newer definition, HRS AKI now is defined as worsening kidney function in patients with advanced cirrhosis that meets the ICA-AKI criteria (Table 2); failing to respond to volume expansion with albumin; the absence of recent exposure to nephrotoxic agents (such as aminoglycosides, nonsteroidal anti-inflammatories, or contrast media); and no evidence of shock or signs of structural kidney disease (defined as proteinuria <500 mg/d, hematuria <50 red blood cells per high-power field, and normal renal ultrasonographic findings).
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Table 2ICA Diagnostic Criteria of HRS AKI
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Diagnosis of cirrhosis and ascites
      Diagnosis of AKI according to ICA AKI diagnostic criteria
      No response at 48 hours of plasma volume expansion usingalbumin 1 g/kg of body weight and withdrawal of diuretics
      Absence of shock
      No current or recent use of nephrotoxic drugs
      No macroscopic signs of structural kidney injury defined as follows:
       Absence of proteinuria (<500 mg/d)
       Absence of microhematuria (<50 RBCs per high-power field)
       Normal renal ultrasonography
      Abbreviation: RBC, red blood cells.
      This newer classification describes a new phenotypic classification of AKI HRS in cirrhotic patients based on pathophysiologic characteristics. Non-HRS AKI now describes other causes of AKI in cirrhotic patients other than HRS AKI, including bile salt nephropathy, prerenal hypovolemia caused by bleeding, excessive diuretic use, or any excessive fluid loss, acute tubular injury, acute tubular necrosis, and AKI caused by intrinsic renal causes such as acute interstitial nephritis.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.

      PATHOPHYSIOLOGY OF HRS AKI

      There have been several pathophysiological explanations proposed as to why HRS AKI occurs in patients with advanced cirrhosis and portal hypertension.

      Splanchnic Vasodilation

      The classic and traditional hypothesis for the development of HRS AKI is a reduction in kidney function caused by severe systemic vasodilation and subsequent renal vasoconstriction. Increasing portal hypertension and shear stress on the portal blood vessels causes the endothelium to produce several locally acting vasodilators such as NO and prostanoids.
      • Martin P-Y
      • Ginès P
      • Schrier RW
      Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis.
      • Gines P
      Schrier R
      , Ginès P. Renal failure in cirrhosis.
      These vasodilators act locally on the splanchnic vasculature causing intense vasodilation. In turn, the subsequent decrease in the effective mean arterial blood pressure leads to activation of the renin-angiotensin-aldosterone axis, and visceral sympathetic nervous system, to increase cardiac output and heart rate to compensate for this hemodynamic compromise.
      • Gines P
      Schrier R
      , Ginès P. Renal failure in cirrhosis.
      In addition, increased vasopressin release and local endothelin secretion contribute to reduced intraglomerular blood flow. Progression of liver disease results in further splanchnic vasodilation and renal vasoconstriction leading to functional renal impairment (Fig. 1). Aldosterone and vasopressin cause both sodium and water retention, which further worsen ascites.
      • Solà E
      • Ginès P
      Renal and circulatory dysfunction in cirrhosis: current management and future perspectives.
      • Kastelan S
      • Ljubicic N
      • Kastelan Z
      • Ostojic R
      • Uravic M
      The role of duplex-doppler ultrasonography in the diagnosis of renal dysfunction and hepatorenal syndrome in patients with liver cirrhosis.
      Evidence that HRS AKI is a functional disorder rather than a structural disease includes the success of cadaveric transplantation of kidneys donated from these patients,
      • Koppel MH
      • Coburn JW
      • Mims MM
      • Goldstein H
      • Boyle JD
      • Rubini ME
      Transplantation of cadaveric kidneys from patients with hepatorenal syndrome—evidence for the functional nature of renal failure in advanced liver disease.
      post-mortem examination,
      • Koppel MH
      • Coburn JW
      • Mims MM
      • Goldstein H
      • Boyle JD
      • Rubini ME
      Transplantation of cadaveric kidneys from patients with hepatorenal syndrome—evidence for the functional nature of renal failure in advanced liver disease.
      and resolution of HRS AKI after liver transplantation.
      • Iwatsuki S
      • Popovtzer MM
      • Corman JL
      • et al.
      Recovery from “hepatorenal syndrome” after orthotopic liver transplantation.
      The current clinical management of HRS AKI targets splanchnic vasodilation and effective volume depletion by using splanchnic vasoconstrictors and albumin. However, this treatment strategy—although improving renal function in the majority of patients

      Kalambokis GN, Tsiakas I, Christaki M, et al. Systemic hemodynamic response to terlipressin predicts development of hepatorenal syndrome and survival in advanced cirrhosis. Eur J Gastroenterol Hepatol. 2018;30:659-67.

      • Salerno F
      • Navickis RJ
      • Wilkes MM
      Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.
      —still is unable to reverse HRS AKI in approximately 40% of cases.
      • Fabrizi F
      • Dixit V
      • Martin P
      Meta-analysis: terlipressin therapy for the hepatorenal syndrome.
      This indicates that patients have either been misclassified as having non-HRS AKI or that other mechanisms are involved.
      Figure 1.
      Figure 1Pathophysiological basis of hepatorenal syndrome. Abbreviation: RAAS, renin-angiotensin-aldosterone system.

      Cardiac Dysfunction

      Cirrhotic cardiomyopathy, a term describing the abnormalities detected in the cardiac response and function of cirrhotic patients, can affect as many as 50% of patients.
      • Krag A
      • Bendtsen F
      • Henriksen JH
      • Møller S
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      It is marked by the abnormal response to both physiologic and pathologic stresses, with patients having a relatively low cardiac output for the degree of systemic vasodilation. Low cardiac output states in patients with cirrhosis and refractory ascites are found to be a predictor of HRS AKI and are associated with worse prognosis. β-blockers prescribed to patients with ascites have been reported to cause further deterioration in renal function in patients with HRS AKI,
      • Sersté T
      • Melot C
      • Francoz C
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      • Mandorfer M
      • Bota S
      • Schwabl P
      • et al.
      Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      most probably because of their hypotensive effects.

      Adrenal Insufficiency

      Adrenal insufficiency is reported to affect approximately 25% of patients with decompensated cirrhosis.
      • Acevedo J
      • Fernández J
      • Prado V
      • et al.
      Relative adrenal insufficiency in decompensated cirrhosis: relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death.
      It causes further deleterious effects on the heart by down-regulating β-adrenergic receptors and modulating the effects of catecholamines on myocardial contraction and vascular responsiveness.
      • Theocharidou E
      • Krag A
      • Bendtsen F
      • Møller S
      • Burroughs AK
      Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis.
      These effects add to the hemodynamic compromise of patients with decompensated cirrhosis.

      Inflammation

      Systemic inflammation is a key factor that predisposes to AKI in advanced cirrhotic patients, especially in association with ACLF.
      • Weichselbaum L
      • Gustot T
      The organs in acute-on-chronic liver failure.
      Inflammation is more likely to cause non-HRS AKI rather than HRS AKI. Mortality rates are more than twice as high in patients with cirrhosis and renal failure who have a systemic inflammatory response than those without.
      • Thabut D
      • Massard J
      • Gangloff A
      • et al.
      Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.
      Observational studies from patients with AKI and cirrhosis have reported that those patients with spontaneous bacterial peritonitis (SBP) had higher circulating levels of proinflammatory cytokines (including interleukin 6 and tumor necrosis factor-α) compared with those without SBP.
      • Navasa M
      • Follo A
      • Filella X
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.

      PATHOPHYSIOLOGY OF NON-HRS AKI

      Non-HRS AKI encompasses all of the other causes of AKI in the setting of decompensated cirrhosis other than HRS AKI. This includes prerenal causes that lead to hypovolemia, such as excess diuretic use, upper gastrointestinal bleeding, and any other causes of severe fluid loss, the toxic effects of bile acids on the renal tubules, and other intrinsic renal causes such as acute tubular injury and necrosis (ATN) and acute interstitial nephritis.
      Systemic inflammation and bacterial translocation have been proposed as one of the crucial mechanisms leading to non-HRS AKI in patients with advanced cirrhosis. Systemic and local intrarenal inflammation have been described recently and suggested to be a key factor for the development of AKI in the setting of ACLF. AKI in patients with ACLF is a heterogeneous disorder initiated by multiple factors including infection, and is associated with varying degrees of systemic inflammation, which leads to multi-organ failure.
      • Nadim MK
      • Kellum JA
      • Davenport A
      • et al.
      Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      In the Chronic Liver Failure Acute on-Chronic Liver Failure in Cirrhosis Consortium study, patients with renal failure (as defined by a serum creatinine concentration ≥2 mg/dL) had 20% mortality and mortality was significantly greater with other organ failures.
      • Moreau R
      • Jalan R
      • Gines P
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Patients are more likely to have non-HRS AKI than HRS AKI with higher organ failure scores (chronic liver Failure organ failure), increasing serum bilirubin concentrations, and nonresolving infections because these patients are more likely to fail to respond to supportive treatment with albumin and terlipressin.
      • Rodríguez E
      • Elia C
      • Solà E
      • et al.
      Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
      • Barreto R
      • Fagundes C
      • Guevara M
      • et al.
      Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival.
      In a recent study, various markers of systemic inflammation including 29 serum cytokines and nonmercaptalbumin 2 were measured in both ACLF and non-ACLF cirrhotic patients, and they were markedly and significantly increased in ACLF patients.
      • Clària J
      • Stauber RE
      • Coenraad MJ
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      Interestingly, the severity renal dysfunction was associated with increasing markers of inflammation (interleukin 6, interleukin 8, and human nonmercaptalbumin 2), but not with plasma renin or copeptin concentration.
      • Clària J
      • Stauber RE
      • Coenraad MJ
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      These findings suggest that AKI in cirrhotic patients is associated with systemic inflammation, especially in those with ACLF, rather than the more traditional hemodynamic dysfunction hypothesis of HRS AKI.
      In a retrospective study, renal biopsy specimens from 65 cirrhotic patients with unexplained renal dysfunction, defined as a serum creatinine level greater than 1.5 mg/dL, with no hematuria or proteinuria and with a normal ultrasound scan, were studied. Twenty-eight percent of these patients were found to have structural changes on their renal biopsy specimens, including chronic tubulointerstitial injury, glomerular injury, and vascular injury. These findings are of particular importance because they show that patients who may appear to have functional renal impairment also may have underlying parenchymal lesions.
      • Trawale JM
      • Paradis V
      • Rautou PE
      • et al.
      The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
      Another finding was the increased renal tubular expression of Toll-like receptor 4 and caspase-3 in the biopsy specimens from 5 patients with non-HRS AKI and ACLF, whereas biopsy specimens from patients with ACLF and HRS AKI did not show these local inflammatory changes in the renal tubules.
      • Trawale JM
      • Paradis V
      • Rautou PE
      • et al.
      The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
      This suggests that non-HRS AKI, unlike HRS AKI, is associated with an acute tubular injury, as evidenced by tubular cell death and increased Toll-like receptor 4 expression. These data have been reproduced in animal experiments by administering endotoxin to bile-ligated rat models of cirrhosis.
      • Shah N
      • Dhar D
      • El Zahraa Mohammed F
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      Gut bacterial translocation increases systemic proinflammatory cytokines and lipopolysaccharides, which can directly cause renal tubular cell apoptosis through the caspase-mediated pathway.
      • Jo SK
      • Cha DR
      • Cho WY
      • et al.
      Inflammatory cytokines and lipopolysaccharide induce fas-mediated apoptosis in renal tubular cells.
      This renal tubular injury can be attenuated markedly by the administration of norfloxacin before endotoxin exposure in animal models of cirrhosis.
      • Shah N
      • Dhar D
      • El Zahraa Mohammed F
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      In patients with cirrhosis, the use of norfloxacin as primary prophylaxis for SBP was found not only to delay the onset of HRS AKI, but also to improve 1-year survival.
      • Fernández J
      • Navasa M
      • Planas R
      • et al.
      Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
      Rifaximin also has been reported to reduce the incidence of AKI, including HRS AKI.
      • Dong T
      • Aronsohn A
      • Gautham Reddy K
      • Te HS
      Rifaximin decreases the incidence and severity of acute kidney injury and hepatorenal syndrome in cirrhosis.
      In a retrospective analysis of data from 4 cohorts of patients treated for HRS AKI, the ACLF grade was the major determinant of response to terlipressin and albumin, with reduced response with higher grades. In addition, patient survival was lower with increasing ACLF grade independently of the response to treatment.
      • Piano S
      • Schmidt HH
      • Ariza X
      • et al.
      Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome.
      Bile acids have been found to play a role in the pathogenesis of AKI through their direct toxic effects on the renal tubules.
      • Van Slambrouck CM
      • Salem F
      • Meehan SM
      • Chang A
      Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.
      Tubular bile acid casts have been found in renal biopsy specimens of patients with HRS AKI,
      • Van Slambrouck CM
      • Salem F
      • Meehan SM
      • Chang A
      Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.
      which may be a contributing factor to the development of AKI in patients with cirrhosis. Because bile acids accumulate in patients with increased serum bilirubin concentrations, this potentially may explain the link between higher bilirubin concentrations and worse outcomes and reduced responsiveness to terlipressin therapy in HRS AKI patients.
      • Barreto R
      • Fagundes C
      • Guevara M
      • et al.
      Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival.
      This hypothesis is supported by animal data, which showed that the use of nor-ursodeoxycholic acid, which increases bile acid clearance in the gut, may help decrease renal injury in rat models of cirrhosis.
      • Krones E
      • Eller K
      • Pollheimer MJ
      • et al.
      Norursodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice.
      Even though HRS AKI and non-HRS AKI have different pathogenic mechanisms, and are considered different subtypes of AKI, they also have overlapping characteristics. The fact that only 40% of patients with HRS AKI respond to treatment with terlipressin and albumin, and that this unresponsiveness increases with time, raises the possibility that even if HRS AKI was diagnosed correctly, then with persistent renal ischemia HRS AKI then may evolve with time to non-HRS AKI, because ongoing renal ischemia will lead to inflammatory changes within the renal interstitium and tubular cell death. Despite an initial response, 80% of patients with HRS AKI die within 3 months, and patients who develop HRS AKI for more than 6 weeks typically fail to recover residual renal function even with liver transplantation.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.
      It should be noted that in patients with chronic comorbid conditions, such as diabetes mellitus and systemic hypertension, as well as patients with nonalcoholic fatty liver disease and chronic viral hepatitis B or C, or other glomerular or interstitial nephropathies, may have some degree of established parenchymal renal injury irrespective of the degree of liver dysfunction.
      • Mehta G
      • Mookerjee RP
      • Sharma V
      • Jalan R
      Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure.
      Patients with chronic kidney disease are much more susceptible to developing AKI when exposed to any acute renal compromise.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.

      BIOMARKERS IN AKI

      Early treatment of AKI is crucial for determining outcome, and therefore it is important to differentiate HRS AKI from non-HRS AKI. Biomarkers have been used for both identifying etiology and determining prognosis. In some cases, biomarkers can be used to determine which patients are suitable for specific therapies.
      Serum creatinine concentration has been used to diagnose and assess the severity of AKI in routine clinical practice. However, serum creatinine is determined not only by renal function, but also by dietary protein intake, muscle mass and activity, and nonrenal clearance.
      • Davenport A
      • Agrawal B
      • Wright G
      • et al.
      Can non-invasive measurements aid clinical assessment of volume in patients with cirrhosis?.
      Moreover, most patients with advanced decompensated cirrhosis have ascites and fluid overload, which also affects the accurate measurement of serum creatinine concentration.
      • Ostermann M
      • Joannidis M
      Acute kidney injury 2016: diagnosis and diagnostic workup.
      High bilirubin levels also may affect the accuracy of serum creatinine in plasma samples owing to spectral effects and reacting with the assay reagents, leading to a lowering of the laboratory-reported serum creatinine concentration.
      • Cobbaert CM
      • Baadenhuijsen H
      • Weykamp CW
      Prime time for enzymatic creatinine methods in pediatrics.
      Therefore, alternative enzymatic methods to measure creatinine in patients with high bilirubin levels are preferred to the colorimetric assays. However, in most countries, enzymatic creatinine measurements are more expensive than the standard colorimetric Jaffe-based picric acid methods and may not be routinely available in all centers.
      A fractional excretion of urinary sodium (FENa) of less than 1% has been widely used to differentiate patients with prerenal AKI, but patients with HRS AKI also may have reduced FENa. Although it has been suggested that a very low FENa of <0.1% may be supportive of a diagnosis of prerenal AKI in patients with cirrhosis, it must be remembered that not only does the ability to concentrate urinary sodium fall with age, but that urinary sodium excretion also can be affected by diuretics and sepsis, and as such the diagnostic value of FENa in routine clinical practice has limited value.
      • Carvounis CP
      • Nisar S
      • Guro-Razuman S
      Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure.
      There has been renewed interest in measuring the fractional excretion of urea as a marker to differentiate between renal hypoperfusion and tubular injury.
      • Patidar KR
      • Kang L
      • Bajaj JS
      • Carl D
      • Sanyal AJ
      Fractional excretion of urea: a simple tool for the differential diagnosis of acute kidney injury in cirrhosis.
      Urea is filtered by the glomeruli and then reabsorbed in the proximal renal tubules and concentrated in the inner medulla to generate a concentration gradient,
      • Fenton RA
      • Knepper MA
      Urea and renal function in the 21st century: insights from knockout mice.
      so any renal hypoperfusion should decrease its fractional excretion, whereas any tubular injury should cause an increase in its fractional excretion. Because diuretics predominantly affect the ascending loop of Henle and distal tubule, urea is less affected by the action of diuretics.
      • Carvounis CP
      • Nisar S
      • Guro-Razuman S
      Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure.
      In a recent cohort study performed on 50 patients with cirrhosis and ascites admitted with AKI, fractional excretion of urea was found to be a promising tool to differentiate AKI of different causes, including HRS, prerenal azotemia, and tubular injury.
      • Patidar KR
      • Kang L
      • Bajaj JS
      • Carl D
      • Sanyal AJ
      Fractional excretion of urea: a simple tool for the differential diagnosis of acute kidney injury in cirrhosis.
      Recently, several different studies suggested measuring serum cystatin C as an alternative to serum creatinine for assessing renal function and, more importantly, predicting prognosis. Cystatin C is secreted from all nucleated cells in the body and freely passes through the glomeruli, and was thought to be removed exclusively by the kidney.
      • Stevens LA
      • Coresh J
      • Greene T
      • Levey AS
      Assessing kidney function—measured and estimated glomerular filtration rate.
      A recent observational study that included 350 patients with cirrhosis and ascites reported that serum cystatin C was an independent predictor of mortality and HRS when compared with serum creatinine.
      • Seo YS
      • Park SY
      • Kim MY
      • et al.
      Serum cystatin C level: an excellent predictor of mortality in patients with cirrhotic ascites.
      However, cystatin C is increased in inflammatory conditions, and older studies have noted a progressive increase between patients with Child-Turcotte-Pugh grades from A to C, and it is unclear whether nonrenal clearance of cystatin C is altered in patients with advanced cirrhosis. Cystatin C concentrations are reported to vary over the course of the day, and can be affected by age, drugs, comorbidity, and other factors including smoking. There has now been standardization of cystatin C assays, increasing the reliability of measurements. Although increased cystatin C is of prognostic value, it has not yet been shown to be superior to creatinine in assessing renal function.
      Serum neutrophil gelatinase-associated lipocalin (NGAL) has been the most widely investigated marker among the newer biomarkers. NGAL is synthesized predominantly in the liver, but also is expressed by the renal tubules after an inflammatory insult, be it ischemic, toxic, or infective. Although some studies have suggested that it differentiates HRS AKI, prerenal azotemia, and acute intrinsic kidney disease, the main limitation is the significant overlap of NGAL values in different types of AKI, and urinary NGAL is increased with urinary tract infections.
      • Belcher JM
      • Sanyal AJ
      • Peixoto AJ
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      Similarly, other urinary biomarkers, such as interleukin 18, kidney injury molecule-1, hepatic fatty acid binding protein, insulin-like growth hormone 1, and tissue inhibitor of metalloproteinase 2, have not been shown to clearly separate AKI HRS and non-HRS AKI.
      In a recent study, high levels of circulating microRNA-21 and low levels of microRNA 146a and 210 were observed in both ATN and HRS AKI patients compared with controls, with a statistically significant difference between ATN and HRS. These preliminary results suggest that different microRNAs potentially could be used to differentiate between ATN and HRS, but such preliminary observational reports require further evaluation.
      • Watany MM
      • Hagag RY
      • Okda HI
      Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: a pilot study.

      TREATMENT

      Early diagnosis and rapid medical treatment is crucial in HRS because AKI HRS may progress to nonreversible HRS AKI. The standard of care in the management of HRS is based on the understanding of the hemodynamic dysfunction, which underpins its pathogenesis. Patients suffering from cirrhosis, ascites, and AKI should be managed according to ICA recommendations.
      • Angeli P
      • Ginès P
      • Wong F
      • et al.
      Erratum: diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Optimized biomarkers to differentiate HRS AKI from structural kidney injury and renal function algorithms may help to refine management.
      • Kalafateli M
      • Wickham F
      • Burniston M
      • et al.
      Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: the royal free hospital cirrhosis glomerular filtration rate.

      Volume Expansion and RemovingNephrotoxic Agents

      Any potential nephrotoxic drugs (ie, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, antibiotics, and so forth) ideally should be minimized or stopped, and any element of hypovolemia corrected (Fig. 2).
      • Piano S
      • Tonon M
      • Angeli P
      Management of ascites and hepatorenal syndrome.
      Intravascular volume assessment is an initial key step to ensure that hypovolemia is managed adequately. Accurate volume assessment in cirrhotic patients with their hyperdynamic circulation and decreased systemic vascular resistance and ascites is challenging.
      • Davenport A
      • Sheikh MF
      • Lamb E
      • Agarwal B
      • Jalan R
      Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit?.
      Unfortunately, monitoring central venous pressure has a limited role because it correlates poorly with the intravascular response to fluid challenges. In addition, the presence of ascites leads to increased central venous pressure without a correspondingly high ventricular preload.
      • Marik PE
      • Baram M
      • Vahid B
      Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.
      Figure 2.
      Figure 2Management of different stages of AKI in cirrhosis. NSAIDs, nonsteroidal anti-inflammatory drugs. *Dose of albumin = 1 g/kg/d for 2 days. **Albumin should be continued at a dose of 20 to 40 g/d.
      A meta-analysis of 38 reports comparing the use of hydroxyethyl starch, crystalloids, albumin, and gelatin in intensive care patients with AKI showed that volume resuscitation with albumin in comparison with crystalloids does not reduce mortality, whereas hydroxyethyl starch was associated with a significantly increased risk of AKI and mortality.
      • Zarychanski R
      • Abou-Setta AM
      • Turgeon AF
      • et al.
      Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis.
      Although another study showed no significant difference in 90-day mortality after resuscitation with 6% hydroxyethyl starch or saline, patients resuscitated with 6% hydroxyethyl starch were more likely to require renal replacement therapy, and, as such, clinical guidelines recommend avoidance of synthetic starches in patients with cirrhosis.
      • Myburgh JA
      • Finfer S
      • Bellomo R
      • et al.
      Hydroxyethyl starch or saline for fluid resuscitation in intensive care.

      Vasoconstrictors and Albumin

      Clinical guidelines recommend using vasoconstrictors in combination with albumin as the first-line treatment for HRS AKI
      • Colle I
      • Laterre P-F
      Hepatorenal syndrome: the clinical impact of vasoactive therapy.
      to counteract splanchnic arterial vasodilation.
      • Arroyo V
      • Garcia-Martinez R
      • Salvatella X
      Human serum albumin, systemic inflammation, and cirrhosis.
      The goal of using albumin is to combat the hemodynamic dysfunction by antagonizing the decreased effective circulating volume and increasing the mean arterial pressure.
      The most commonly used vasoconstrictors are norepinephrine, vasopressin analogues (terlipressin), somatostatin analogues (octreotide), and midodrine.
      • Ginès P
      • Angeli P
      • Lenz K
      • et al.
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      The original studies were performed with vasopressin, but because of ischemic side effects, other analogues were developed. Terlipressin is the most extensively studied vasopressor in this group,
      • Gifford FJ
      • Morling JR
      • Fallowfield JA
      Systematic review with meta-analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1.
      and now is considered as the first line of treatment of choice in treating HRS AKI patients in Europe. This is because it has a greater affinity for vasopressin 1 receptors in the splanchnic bed compared with vasopressin 2 receptors in the kidneys, thus predominantly exerting its vasoconstrictor effects on the splanchnic viscera without causing equal renal vasoconstriction.
      • Gifford FJ
      • Morling JR
      • Fallowfield JA
      Systematic review with meta-analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1.
      Even so, terlipressin is a powerful vasoconstrictor and can cause ischemia, so should not be used in patients with symptomatic ischemic heart disease, peripheral vascular disease, or recent stroke. Although vasopressin is available in the United States, terlipressin, which was developed more than 20 years ago to have greater vasopressin 1 specificity,
      • Bernadich C
      • Bandi JC
      • Melin P
      • Bosch J
      Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension.
      is not currently approved by the Food and Drug Administration for use in the United States or Canada because some recent large randomized controlled trials failed to show a clear benefit for terlipressin in treating HRS type 1.
      • Papaluca T
      • Gow P
      Terlipressin: current and emerging indications in chronic liver disease.
      Numerous studies and meta-analyses have been conducted to investigate the use of different vasopressors and albumin in managing HRS-AKI (Table 3).
      • Sanyal AJ
      • Boyer TD
      • Frederick RT
      • 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.
      • Facciorusso A
      • Chandar AK
      • Murad MH
      • et al.
      Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
      A network meta-analysis including 16 randomized controlled clinical trials of patients with HRS reported that the combinations of terlipressin and albumin, and noradrenaline and albumin, were more effective than albumin therapy alone to achieve a complete reversal of HRS, as defined by a reduction in serum creatinine concentration to less than 1.5 mg/d, whereas the combinations of octreotide and albumin, or midodrine and albumin, failed to show any beneficial effects compared with albumin alone.
      • Sridharan K
      • Sivaramakrishnan G
      Vasoactive agents for hepatorenal syndrome: a mixed treatment comparison network meta-analysis and trial sequential analysis of randomized clinical trials.
      However, there were no significant differences between these different regimens in terms of HRS AKI recurrence, other adverse events, or mortality, in keeping with previous meta-analyses.
      • Sridharan K
      • Sivaramakrishnan G
      Vasoactive agents for hepatorenal syndrome: a mixed treatment comparison network meta-analysis and trial sequential analysis of randomized clinical trials.
      Table 3Characteristics of Randomized Controlled Trials of Albumin and Vasoconstrictors for Treatment of HRS
      StudyIntervention GroupControl GroupConcomitant TherapyEnd PointsOutcomes
      Terlipressin versus placebo or control studies
       Solanki et al,
      • Solanki P
      • Chawla A
      • Garg R
      • Gupta R
      • Jain M
      • Sarin SK
      Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial.
      2003
      Terlipressin 1 mg every 12 h for 15 days; n = 12Placebo for 15 days; n = 12Albumin 20 g/d intravenously; dopamine ≤4 µg/min for the first 24-48 h; fresh-frozen plasma until central venous pressure reaches the normal range15-day mortality, HRS reversal; and incidence of side effectsTerlipressin group showed significant improvement in urine output, creatinine clearance, serum creatinine, and overall survival, and all survivors had reversal of HRS
       Neri et al,
      • Neri S
      • Pulvirenti D
      • Malaguarnera M
      • et al.
      Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome.
      2008
      Terlipressin 1 mg every 8 h for 5 days followed by 0.5 mg every 8 h for 14 days; n = 26Albumin alone for 15 days, n = 26Albumin 1 g/kg on the first day followed by 20-40 g/d1- and 3-month mortality; HRS reversal; and incidence of side effectsPatients from terlipressin group showed a significant improvement in renal function and probability of survival
       Sanyal et al,
      • Sanyal AJ
      • Boyer T
      • Garcia-Tsao G
      • et al.
      A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.
      2008
      Terlipressin 1 mg/6 h up to 2 mg/6 h × 14 days; n = 56Placebo for 14 days; n = 56Albumin 100 g on day 1 followed by 25 g/d2- and 6-month mortality; HRS reversal; HRS recurrence; and incidence of side effectsTerlipressin was superior to placebo for HRS reversal (34% versus 13%)
       Martin-Llahi et al,
      • Martín-Llahí M
      • Pépin MN
      • Guevara M
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      2008
      Terlipressin 1 mg every 4 h up to 2 mg every 4 h for 15 days; n = 17Albumin alone for 15 days; n = 18Albumin 1 g/kg on the first day followed by 40 g/d albumin3-month mortality; HRS reversal; HRS recurrence; and incidence of side effectsTerlipressin was superior to placebo for HRS reversal (43.5% versus 8.7%)
       Zafar et al,
      • Zafar S
      • Haque I
      • Tayyab G
      • Khan G
      • Chaudry N
      Role of terlipressin and albumin combination versus albumin alone in hepatorenal syndrome.
      2012
      Terlipressin 1 mg every 4 h for 7-10 days; n = 25Albumin alone for 7-10 days; n = 25Albumin 1 g/kg followed by 20-40 g/d3-month mortality and HRS reversalTerlipressin was superior to placebo for HRS reversal (40% versus 8%)
       Boyer et al,
      • Boyer TD
      • Sanyal AJ
      • Wong F
      • et al.
      Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.
      2016
      Terlipressin 1 mg every 6 h up to 2 mg every 6 h for 14 days; n = 97Placebo for 14 days; n = 99Albumin 20-40 g/d3-month mortality; HRS reversal; HRS recurrence; and incidence of side effectsHRS reversal was achieved in 23.7% in terlipressin group versus 15.2% in placebo group
      Noradrenaline versus terlipressin studies
       Alessandria et al,
      • Alessandria C
      • Ottobrelli A
      • Debernardi-Venon W
      • et al.
      Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.
      2007
      Noradrenaline 0.1 µg/kg/min up to 0.7 µg/kg/min until HRS reversal or for a maximum of 14 days; n = 5Terlipressin 1 mg every 4 h up to 2 mg every 4 h for 28 days until HRS reversal or for a maximum of 14 days; n = 4Albumin 40-80 g/d1-, 3-, and 6-month mortality; HRS reversal; HRS recurrence; and incidence of side effects of albuminReversal of HRS was observed in 7 of the 10 patients (70%) treated with noradrenalin and in 10 of the 12 patients (83%) treated with terlipressin
       Ghosh et al,
      • Ghosh S
      • Choudhary NS
      • Sharma AK
      • et al.
      Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study.
      2013
      Noradrenaline (dose and duration not reported); n = 30Terlipressin (dose and duration not reported); n = 30Albumin (dose not reported)3-month mortality; HRS reversal; and HRS recurrenceReversal of HRS was observed in 53% treated with noradrenaline versus 57% treated with terlipressin
       Sharma et al,
      • Sharma P
      • Kumar A
      • Shrama BC
      • Sarin SK
      An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      2008
      Noradrenaline 0.5 mg/h up to 3 mg/h for 15 days; n = 20Terlipressin 0.5 mg every 6 h up to 2 mg every 6 h for 15 days; n = 20Albumin 20-40 g/d15-day mortality; HRS reversal; and incidence of side effectsEach group achieved 50% HRS reversal
       Singh et al,
      • Singh V
      • Ghosh S
      • Singh B
      • et al.
      Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
      2012
      Noradrenaline 0.5 mg/h up to 3 mg/h until HRS reversal or a maximum of 14 days; n = 23Terlipressin 0.5 mg/6 h up to 2 mg every 6 h until HRS reversal or for a maximum of 14 days; n = 23Albumin 20 g/d1-month mortality; HRS reversal; HRS recurrence; and incidence of side effectsHRS reversal could be achieved in 39.1% in terlipressin group versus 43.4% in patients in noradrenaline group
      Midodrine plus octreotide versus terlipressin studies
       Cavallin et al,
      • Cavallin M
      • Kamath PS
      • Merli M
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      2015
      Midodrine 7.5 mg/8 h up to 12.5 mg/8 h orally plus octreotide 100 µg/8 h up to 200 µg/8 h subcutaneously until HRS reversal or a maximum of 14 days (with albumin); n = 22Terlipressin 3 mg/24 h up to 12 mg/24 h until HRS reversal or a maximum of 14 d (with albumin); n = 27Albumin 1 g/kg on first day followed by 20-40 g/d1- and 3-month mortality; HRS reversal; incidence of side effectsSignificantly higher rate of recovery of renal function in terlipressin group (70.4% versus 28.6%)
      Dopamine plus furosemide versus terlipressin studies
       Srivastava et al,
      • Srivastava S
      • Shalimar
      • Vishnubhatla S
      • et al.
      Randomized controlled trial comparing the efficacy of terlipressin and albumin with a combination of concurrent dopamine, furosemide, and albumin in hepatorenal syndrome.
      2015
      Dopamine 2 µg/kg/min plus furosemide 0.01 mg/kg/h for 5 days; n = 20Terlipressin 0.5 mg every 6 h for 5 days; n = 20Albumin 20 g/d; cefotaxime 2 g intravenously every 8 h and lactulose1-month mortality and incidence of side effectsIn HRS-I, significant improvement in renal function at the end of 5 days increased in both treatment groups
      Midodrine plus octreotide versus noradrenaline studies
      Tavakkoli,
      • Tavakkoli H
      • Yazdanpanah K
      • Mansourian M
      Noradrenalin versus the combination of midodrine and octreotide in patients with hepatorenal syndrome: randomized clinical trial.


      2011–2012;

      2012
      Midodrine orally 5 mg 3 times/d up to 15 mg 3 times/d plus octreotide subcutaneously 100 μg every 8 h up to 200 μg every 8 h until HRS reversal or for a maximum of 15 days; n = 9Noradrenaline 0.1 µg/kg/min up to 0.7 µg/kg/min until HRS reversal or a maximum of 15 days; n = 6

      albumin
      Albumin 20-60 g/d3-month mortality; HRS reversal; HRS recurrence; and incidence of side effectsHRS reversal was observed in 73% treated with noradrenalin versus 75% treated with midodrine-octreotide
      Abbreviations: HRS-1, hepato-renal syndrome 1.
      Comparator studies have suggested that norepinephrine is an attractive alternative to terlipressin in the treatment of HRS AKI, and may be associated with fewer adverse events,
      • Weil D
      • Levesque E
      • McPhail M
      • et al.
      Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis.
      • Zheng J-N
      • Han Y-J
      • Zou T-T
      • et al.
      Comparative efficacy of vasoconstrictor therapies for type 1 hepatorenal syndrome: a network meta-analysis.
      ,
      • Nanda A
      • Reddy R
      • Safraz H
      • Salameh H
      • Singal AK
      Pharmacological therapies for hepatorenal syndrome.
      whereas other studies showed that administering terlipressin by a continuous infusion instead of four intermittent boluses is better tolerated.
      • Gifford FJ
      • Morling JR
      • Fallowfield JA
      Systematic review with meta-analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1.
      • Fabrizi F
      • Aghemo A
      • Messa P
      Hepatorenal syndrome and novel advances in its management.
      A recent prospective study explored the safety and efficacy of a continuous terlipressin infusion at 2 mg/d versus bolus dosing starting at 0.5 mg, administered four times a day in patients with HRS AKI, and reported significantly fewer adverse events in the continuous infusion group in comparison with intermittent bolus administration.
      • Cavallin M
      • Piano S
      • Romano A
      • et al.
      Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study.
      In preliminary studies, terlipressin has been given to outpatients as a continuous infusion at 2 mg/d and has been reported to be safe, well tolerated, and an effective option for the treatment of HRS AKI as a bridge to transplant.
      • Robertson M
      • Majumdar A
      • Garrett K
      • Rumler G
      • Gow P
      • Testro A
      Continuous outpatient terlipressin infusion for hepatorenal syndrome as a bridge to successful liver transplantation.
      • Vasudevan A
      • Ardalan Z
      • Gow P
      • Angus P
      • Testro A
      Efficacy of outpatient continuous terlipressin infusions for hepatorenal syndrome.
      There are data supporting the efficacy of human albumin solution in the treatment of HRS AKI.
      • Valerio C
      • Theocharidou E
      • Davenport A
      • Agarwal B
      Human albumin solution for patients with cirrhosis and acute on chronic liver failure: beyond simple volume expansion.
      The optimal dose of albumin used for HRS AKI treatment remains to be established, and the doses administered vary between reports. However, a recent meta-analysis including 19 clinical studies showed that the most important factor in predicting a successful response to albumin therapy appears to be the cumulative dose.
      • Salerno F
      • Navickis RJ
      • Wilkes MM
      Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.
      This meta-analysis observed a dose-response relationship between the amount of infused albumin and survival, with significantly improved survival with increasing 100-gram increments, and expected 30-day survival rates among patients receiving cumulative albumin doses of 200, 400, and 600 g were 43.2%, 51.4%, and 59.0%, respectively, independent of treatment duration, vasoconstrictor type, or mean arterial pressure.
      • Salerno F
      • Navickis RJ
      • Wilkes MM
      Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.
      Moreover, volume expansion using albumin for patients with SBP after large-volume paracentesis, and with antibiotic prophylaxis in advanced cirrhosis with low ascitic fluid protein, has been reported to prevent HRS-AKI.
      • Valerio C
      • Theocharidou E
      • Davenport A
      • Agarwal B
      Human albumin solution for patients with cirrhosis and acute on chronic liver failure: beyond simple volume expansion.
      • Acevedo JG
      • Cramp ME
      Hepatorenal syndrome: update on diagnosis and therapy.
      Albumin not only has a role in maintaining plasma oncotic pressure, and carrying trace elements and hormones, but also plays a major role in terms of detoxification. Fluid replacement with albumin has theoretical advantages over crystalloids in terms of its anti-inflammatory and antioxidant properties.
      • Valerio C
      • Theocharidou E
      • Davenport A
      • Agarwal B
      Human albumin solution for patients with cirrhosis and acute on chronic liver failure: beyond simple volume expansion.

      Ascitic drainage

      AKI resulting from abdominal compartment syndrome is well recognized when intra-abdominal pressure typically exceeds 18 mm Hg,
      • Acevedo JG
      • Cramp ME
      Hepatorenal syndrome: update on diagnosis and therapy.
      although AKI can develop with lower pressures.
      • Shear W
      • Rosner MH
      Acute kidney dysfunction secondary to the abdominal compartment syndrome.
      In patients with cirrhosis, paracentesis is recommended for symptomatic relief.
      • Piano S
      • Tonon M
      • Angeli P
      Management of ascites and hepatorenal syndrome.
      However, simple drainage of ascites can result in hypotension and ischemic kidney injury, and, as such, replacement with albumin is recommended for drainage of 5 L or more. Uncontrolled studies have reported an improvement in renal function in patients with HRS AKI after paracentesis for increased intra-abdominal pressure, with a reduction in intrarenal pressure with improved diastolic perfusion, shown with color Doppler ultrasound.
      • Dalfino L
      • Tullo L
      • Donadio I
      • et al.
      Intra-abdominal hypertension and acute renal failure in critically ill patients.
      However, simply removing ascitic fluid, but maintaining intra-abdominal pressure, did not improve renal function,
      • Umgelter A
      • Reindl W
      • Franzen M
      • Lenhardt C
      • Huber W
      • Schmid RM
      Renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites.
      and, as such, most clinicians wait until ascites are tense or symptomatic before attempting drainage.
      • Savino JA
      • Cerabona T
      • Agarwal N
      • et al.
      Manipulation of ascitic fluid pressure in cirrhotics to optimize hemodynamic and renal function.
      • Davenport A
      • Ahmad J
      • Al-Khafaji A
      • Kellum JA
      • Genyk YS
      • Nadim MK
      Medical management of hepatorenal syndrome.
      Liver transplantation (LT) is the best and most definitive treatment option for HRS AKI by curing end-stage liver disease and subsequently reversing HRS AKI.
      • Boyer TD
      • Sanyal AJ
      • Garcia-Tsao G
      • et al.
      Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.
      The overall 1- and 5-year survival rates after LT in the setting of pretransplantation AKI have been reported as 77% and 69%, respectively.
      • Ruiz R
      • Barri YM
      • Jennings LW
      • et al.
      Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT).
      Pretransplantation renal function has been shown to be an important predictor of renal dysfunction after LT, with a shorter duration of HRS AKI (<4 wk), with better outcomes and greater renal recovery.
      • Wong F
      • Leung W
      • Al Beshir M
      • Marquez M
      • Renner EL
      Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
      However, if the AKI episode persisted for longer than 6 weeks, then patients were less likely to recover renal function, and as such should be considered for combined liver-kidney transplantation.
      • Nadim MK
      • Kellum JA
      • Davenport A
      • et al.
      Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      A recent retrospective observational study from Japan reported that preoperative renal dysfunction with a cut-off glomerular filtration rate of less than 40 mL/min/1.73 m2 at admission was an independent risk factor for 1-year survival for living-related transplant recipients, and the postoperative 1-, 3-, and 5-year survival rate was significantly lower in patients with preoperative HRS AKI than in patients without HRS.
      • Okamura Y
      • Hata K
      • Inamoto O
      • et al.
      Influence of hepatorenal syndrome on outcome of living donor liver transplantation: a single-center experience in 357 patients.
      Although LT is the ideal option, it is not available for all patients in all countries.

      Renal Replacement Therapy

      The effect of renal replacement therapy (RRT) remains controversial in the management of HRS AKI, with similar short-term (30 d) and long-term (180 d) survival compared with non–RRT-treated patients, suggesting that routine use of RRT may not be beneficial in HRS.
      • Zhang Z
      • Maddukuri G
      • Jaipaul N
      • Cai CX
      Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus albumin.
      The Acute Dialysis Quality Initiative group recommended renal support for patients with HRS AKI only if there was an acute potentially reversible event, or liver transplantation planned, because of the lack of any evidence for a major survival benefit for RRT in HRS AKI, and that without an easily reversible precipitant or potential liver transplant, 3-month survival is marginal at best.
      • Trawale JM
      • Paradis V
      • Rautou PE
      • et al.
      The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.
      • Okamura Y
      • Hata K
      • Inamoto O
      • et al.
      Influence of hepatorenal syndrome on outcome of living donor liver transplantation: a single-center experience in 357 patients.
      Transjugular intrahepatic portosystemic shunting (TIPS) is also an option for treatment of HRS AKI, especially in patients failing to respond to pharmacologic treatment, or with frequent relapses. TIPS increases the effective renal blood flow by decreasing portal pressure and redistributing regional vascular resistance.
      • Rossle M
      TIPS: 25 years later.
      TIPS has been shown to reduce the potent renal vasoconstrictor endothelin-1, and reduce intrarenal pressure and increase diastolic blood flow.
      • Umgelter A
      • Reindl W
      • Geisler F
      • Saugel B
      • Huber W
      • Berger H
      • et al.
      Effects of TIPS on global end-diastolic volume and cardiac output and renal resistive index in ICU patients with advanced alcoholic cirrhosis.
      A meta-analysis reported on the efficacy and safety of TIPS for the treatment of HRS AKI and showed that serum creatinine, sodium, blood urea nitrogen, urinary sodium excretion, and urine volume significantly improved after TIPS. However, the higher incidence of hepatic encephalopathy limits the standard use of TIPS as a routine therapeutic option for HRS.
      • Song T
      • Rössle M
      • He F
      • Liu F
      • Guo X
      • Qi X
      Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: a systematic review and meta-analysis.

      Experimental Agents

      There is a clinical need to develop agents to reverse HRS AKI. Serelaxin (a recombinant human relaxin-2) is a peptide with vasoprotective properties, has been studied in rat models of cirrhosis, and has shown an increase in renal perfusion by reducing renal vascular resistance.
      • Snowdon VK
      • Lachlan NJ
      • Hoy AM
      • et al.
      Serelaxin as a potential treatment for renal dysfunction in cirrhosis: preclinical evaluation and results of a randomized phase 2 trial.
      Studies to compare intravenous serelaxin infusion with terlipressin intravenous bolus in cirrhotic patients with renal impairment have shown that serelaxin infusion increased the total renal arterial blood flow by 65% from baseline, and was safe and well tolerated, with no adverse effects related to systemic blood pressure or hepatic perfusion, whereas there was no significant change in renal arterial blood flow with terlipressin.
      • Snowdon VK
      • Lachlan NJ
      • Hoy AM
      • et al.
      Serelaxin as a potential treatment for renal dysfunction in cirrhosis: preclinical evaluation and results of a randomized phase 2 trial.
      Nebivolol is a third-generation nonselective vasodilator β-blocker and has been studied in D-galactosamine–induced HRS in rats, where it was reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties, with renoprotective and hepatoprotective effects. This potentially makes nebivolol a promising drug with a possible effect in the prevention of HRS AKI or as an add-on medication in patients with known HRS.
      • Atwa A
      • Hegazy R
      • Mohsen R
      • Yassin N
      • Kenawy S
      Protective effects of the third generation vasodilatory βeta - blocker nebivolol against D-galactosamine - induced hepatorenal syndrome in rats.
      Pentoxifylline has been advocated for the treatment of alcoholic hepatitis, and potentially can reduce inflammation by decreasing proinflammatory cytokines, such as tumor necrosis α. A preliminary, randomized, placebo-controlled, clinical trial studied the safety of adding pentoxifylline to albumin with midodrine and octreotide in the treatment of HRS-1 and was shown to be safe, but further large-scale prospective studies are needed to validate the efficacy of pentoxifylline.
      • Stine JG
      • Wang J
      • Cornella SL
      • et al.
      Treatment of type-1 hepatorenal syndrome with pentoxifylline: a randomized placebo controlled clinical trial.
      Rifaximin has been shown to reduce the incidence of HRS AKI, and additional studies have investigated the effect of administration to patients with cirrhosis and ascites, and these have shown that the overall blood urea nitrogen and serum creatinine concentrations were statistically significantly lower in the rifaximin group compared with the control group who received standard medical care.
      • Ibrahim ES
      • Alsebaey A
      • Zaghla H
      • Moawad Abdelmageed S
      • Gameel K
      • Abdelsameea E
      Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.
      Rifaximin also may decrease the plasma concentrations of interleukin 6, tumor necrosis factor-α, and endotoxins, which play a crucial role in the development of SBP and HRS AKI.
      • Kang DJ
      • Kakiyama G
      • Betrapally NS
      • Herzog J
      • Nittono H
      • Hylemon PB
      • et al.
      Rifaximin exerts beneficial effects independent of its ability to alter microbiota composition.

      CONCLUSIONS

      In conclusion, the change in the classification of AKI and further advances in understanding the pathophysiological basis of this syndrome is likely to lead to newer therapies for this terrible complication of cirrhosis, which is associated with high mortality rates.

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