CHRISMED Journal of Health and Research

: 2020  |  Volume : 7  |  Issue : 2  |  Page : 83--89

Hepatorenal syndrome: A review into changing definition, diagnostic criteria, pathophysiology, and management

Vishal Bodh, Brij Sharma, Rajesh Sharma 
 Department of Gastroenterology, IGMC, Shimla, Himachal Pradesh, India

Correspondence Address:
Vishal Bodh
Department of Gastroenterology, IGMC, Shimla, Himachal Pradesh


Hepatorenal syndrome (HRS) is a form of kidney function impairment that characteristically occurs in patients with cirrhosis. The diagnostic criteria for this syndrome have been revised throughout the years, with recent revisions aimed at improving earlier diagnosis and treatment. HRS definition has been updated recently by the International Club of Ascites in accordance with Kidney Disease Improving Global Outcomes acute kidney injury (AKI) classification. Recent changes in terminology have led to acute or Type I HRS being referred to as AKI-HRS and chronic or Type II HRS as chronic kidney disease (CKD)-HRS. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of HRS has been highlighted in recent years. The current standard of care for the management of HRS involves the use of vasoconstrictor therapy and volume expansion with albumin. All patients do not respond to treatment, and even in those who respond, early mortality rates are very high in the absence of liver transplantation (LT). LT is the only curative treatment of HRS.

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Bodh V, Sharma B, Sharma R. Hepatorenal syndrome: A review into changing definition, diagnostic criteria, pathophysiology, and management.CHRISMED J Health Res 2020;7:83-89

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Bodh V, Sharma B, Sharma R. Hepatorenal syndrome: A review into changing definition, diagnostic criteria, pathophysiology, and management. CHRISMED J Health Res [serial online] 2020 [cited 2020 Nov 30 ];7:83-89
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Conventionally, renal failure in patients with cirrhosis was defined more than 30 years ago by increase in serum creatinine (SCr) value ≥1.5 mg/dl because this value was considered an index of glomerular filtration rate (GFR) ≤40 ml/min.[1] Beyond the well-known types of renal dysfunction that can occur in the general population, patients with cirrhosis may develop a specific type of renal dysfunction called hepatorenal syndrome (HRS).[2] HRS has been defined as renal dysfunction that occurs in a patient with chronic liver disease and advanced hepatic failure and portal hypertension because of reduced renal perfusion due to hemodynamic alterations in arterial circulation, as well as overactivity of the endogenous vasoactive systems.[1],[3] In 2007, the International Club of Ascites classified HRS into types 1 and 2 (HRS-1 and HRS-2).[3] HRS-1 is characterized by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterized by acute renal failure (ARF) while HRS-2 is mainly characterized by refractory ascites.

Recently, the term ARF has been replaced by acute kidney injury (AKI), and new concepts, definitions, and diagnostic criteria have been developed and validated by nephrologists for renal dysfunction in noncirrhotic patients.[4],[5],[6] These new criteria were also proposed and applied in the diagnoses of AKI in patients with cirrhosis. A recent consensus guideline has been published by the International Ascites Club (IAC) for the Diagnosis of AKI in patients with cirrhosis, which now align with the Kidney Disease Improving Global Outcomes (KDIGO) AKI classification.[7] Furthermore, the diagnostic criteria for Type I HRS were revised in light of new classification of AKI, which now corresponds to HRS-AKI.[7],[8] 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-non-AKI (NAKI) (i.e., NAKI).[9] In recent years, it is increasingly recognized that HRS is not a purely “functional” entity with hemodynamic derangements, but systemic inflammation, oxidative stress, and bile salt-related tubular damage may contribute significantly to its development.[10] 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.

The classification, nomenclature, diagnostic criteria, and theories about pathology of HRS have evolved over the years since the first traditional classification of HRS-1 and HRS-2 was described, so the aim of this review is to provide an update on the definition, diagnostic criteria, pathophysiology, and treatment of HRS.

 Definitions and Diagnostic Criteria of Hepatorenal Syndrome

The diagnostic criteria of HRS have been revised many times. The definition came from IAC in 1996, was based on major and minor criteria to characterize the occurrence of renal failure in cirrhotic patients [Table 1].[1]{Table 1}

These criteria were subsequently revised in 2007 to improve accuracy and applicability [Table 1],[3] where minor criteria were excluded. Ongoing bacterial infection without septic shock was no longer an exclusion criterion. A creatinine clearance criterion was also removed, and preference was given to albumin rather than saline for plasma volume expansion.[3]

Type 1 HRS is a rapidly progressive renal impairment defined by doubling of the SCr to a level >2.5 mg/dL or >226 μmol/L in <2 weeks.[3] Type 2 HRS is a moderate renal impairment (SCr >1.5 mg/dL and up to 2.5 mg/dL or >133 and up to 226 μmol/L) with a steady progressive course that evolves over weeks to months.[3]

The IAC diagnostic criteria use fixed value of SCr to define AKI. In clinical practice, SCr is influenced by body weight, race, age, and gender. The use of SCr in patients with cirrhosis is also affected by (1) decreased formation of creatinine from creatinine in muscles, secondary to muscle wasting,[11] (2) increased renal tubular secretion of creatinine,[12] (3) the increased volume of distribution in cirrhosis that may dilute SCr, and (4) interference with assays for SCr by elevated bilirubin.[13]

As a consequence, the measurement of SCr in patients with cirrhosis overestimates GFR or kidney function, and also fixed threshold does not take into account the dynamic changes in SCr that occur in the preceding days or weeks, which are needed to distinguish between acute and chronic kidney injury.[14]

In the meantime, a panel of experts proposed KDIGO criteria[6] for defining AKI in noncirrhotic patients. KDIGO guidelines define AKI as any of the following: (1) increase in SCr by ≥0.3 mg/dl (≥26.5 mmol/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.

In recent IAC consensus [Table 2],[7] the definition of AKI in cirrhosis was modified to align with KDIGO criteria with few modifications. KDIGO urinary output criteria was not considered by IAC consensus because (a) cirrhotic patients are frequently oliguric with avid sodium retention, despite a relatively normal GFR,[15] (b) they may have an increased urine output (UO) because of diuretics, and (c) on a regular ward, urine collection is often inaccurate.[7] Baseline SCr used in the KDIGO criteria included an SCr value dated within the last week before admission, and when not available, baseline SCr can be calculated by inversely applying the formulas that are used to calculate the estimated GFR, considering normal values of GFR of 75 ml/min.[6] While an imputed SCr is accepted in the general population, it cannot be used in patients with cirrhosis.[16] Therefore, it has been proposed that not only the value obtained in the last 7 days but also that within the last 3 months be considered as a baseline value of SCr in patients with cirrhosis [Table 2].{Table 2}

The main differences between the new criteria and the conventional criteria are as follows: (1) an absolute increase in SCr is considered; (2) the threshold of SCr ≥1.5 mg/dL is abandoned; and (3) a staging system of AKI, based on a change in SCr over a slightly longer time frame, arbitrarily set at 1-week to enable assessment for progression of stage as well as a regression of stage [Table 2].

As per the 2015 IAC consensus definition of AKI in patients with cirrhosis,[7] the traditional nomenclature and definition of HRS and HRS-1 revised. Because HRS-1 is a form of AKI, it was renamed as HRS-AKI and be defined based on changes in SCr. The only change that was introduced was the removal of the fixed cutoff value of SCr from the diagnostic criteria of HRS, while all the remaining criteria are maintained [Table 1].[7]

However, these criteria do not rule out the possibility of renal parenchymal damage.[17] Thus, all the experts agreed on the potential role of new urinary biomarkers such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin (IL)-18, and liver fatty acid-binding protein may be useful in the differential diagnosis of AKI in patients with cirrhosis.[18],[19] More recently, it was observed that adding the UO diagnostic criteria of AKI to the assessment of critically ill patients with chronic liver disease improved the identification of patients with AKI, and patients identified based on UO criteria without SCr elevation had a significantly higher mortality.[20] Hence, based on these findings, Angeli et al.'s in their position paper have proposed new diagnostic criteria for HRS AKI and included UO and urine biomarkers (if available) [Table 3].[10] Recent EASL guideline[9] have also suggested that UO criteria can be applied in patients with cirrhosis who has a bladder catheter.{Table 3}

The recent EASL guidelines on “management of decompensated cirrhosis” propose HRS-2 be referred to as HRS-NAKI (i.e., NAKI).[9] KDIGO guidelines define chronic kidney disease (CKD) as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for >90 days and acute kidney disease (AKD) as AKI or as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for <90 days.[6] As HRS-2 was poorly defined and assumed more chronic abnormalities in SCr without a definite timeline, Angeli et al.'s in their position, study have proposed that the diagnosis of HRS-NAKI be made either in the context of CKD, in patient with cirrhosis and GFR <60 ml/min/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 <90 days [Table 4].[10]{Table 4}

 Pathology and Pathophysiology of Hepatorenal Syndrome

Regarding the pathophysiology of HRS, the main hypothesis in the last 20 years had been the “splanchnic arterial vasodilatation theory.”[21] 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 vasodilatation and inadequate cardiac output.[22],[23],[24],[25] The favorable response of half of the patients with HRS to the administration of systemic vasoconstrictors plus intravenous (iv) albumin has been considered proof of this pathophysiological mechanism.[25],[26]

A new theory has also been proposed regarding HRS recently based on the pathophysiology of decompensated cirrhosis.[27] It is now recognized that HRS not only involves circulatory dysfunction but also systemic inflammation. Bacterial translocation is the main mechanism by which portal hypertension induces the circulatory dysfunction characteristic of HRS.[28] Bacterial translocation leads to monocyte activation by pathogen-associated molecular patterns (PAMPs) such as endotoxins and bacterial DNA. Monocyte activation results in the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha, IL-6, and IL-1b.[29] These cytokines have been associated with impairment of renal function in patients with cirrhosis, as well as in patients with acute on chronic liver failure and acute liver failure.[30] In clinical[31] and experimental studies[32] it has been shown that renal tubular toll-like receptor 4 may be up regulated, which is associated with the development of florid renal dysfunction, tubular damage, and apoptosis.

Moving from the concept that AKI and HRS-AKI are often precipitated by a bacterial infection, the new hypothesis on the pathogenesis of sepsis-induced AKI should also be considered.[33],[34],[35] This theory proposes that a synergic interplay of inflammation and microvascular dysfunction is responsible for the amplification of the signal that PAMPs and damage-associated molecular pattern exert on proximal epithelial tubular cells. The recognition of this signal and its subsequent spread to all the other proximal tubular epithelial cells cause a mitochondria-mediated metabolic downregulation and reprioritization of cell functions to favor survival processes above all else.[36] The sacrificed functions include the absorption on the lumen side of sodium and chloride. The consequent increases of sodium chloride delivery to the macula densa triggers further intrarenal activation of the Renin Angiotensin Aldosterone System (RAAS) and thus lower GFR. Finally, severe cholestasis may further impair renal function by worsening inflammation and/or macrocirculatory dysfunction, or by promoting bile salt-related direct tubular damage.[37],[38] Thus the pathophysiology of AKI, and particular of HRS-AKI, in patients with decompensated cirrhosis seems more complex than as was previously hypothesized.


In patients with liver diseases and renal dysfunction, the first step to be addressed in the diagnostic process is to establish if the patient has a CKD, AKD, or AKI as well as an overlap between these diagnostic categories.[9] Once AKI is diagnosed based on KDIGO criteria, cause should be investigated, and start management immediately. Irrespective of the stage, diuretics should be discontinued. Similarly, even if there are controversial data, beta-blockers should be stopped.[39] Other precipitating factors of AKI should be identified and treated, including screening and treatment of infection, volume expansion when appropriate, and discontinuation of all nephrotoxic drugs, such as vasodilators or nonsteroidal anti-inflammatory drugs.[7] Volume replacement should be used in accordance with the cause and the severity of fluid loss. Patients with diarrhea or excessive diuresis should be treated with crystalloids, while patients with acute gastrointestinal bleeding should be given packed red blood cells to maintain hemoglobin level between 7 and 9 g/dl.[40] In patients with AKI and tense ascites, therapeutic paracentesis should be associated with albumin infusion since it improves renal function.[41] In case of no obvious cause, 20% albumin solution at the dose of 1 g of albumin/kg of body weight (with a maximum of 100 g of albumin) for 2 consecutive days should be given.[9]

When HRS-AKI is diagnosed, a specific pharmacological treatment in the form of vasoconstrictors and albumin is recommended in all patients.[9] Terlipressin plus albumin should be considered as the first-line therapeutic option for the treatment of HRS-AKI.[9] Telipressin can be used by iv boluses at the initial dose of 1 mg every 4-6 h. However, giving terlipressin by continuous iv infusion at initial dose of 2 mg/day makes it possible to reduce the global daily dose of the drug and thus, the rate of its adverse effects. In case of nonresponse (decrease in SCr <25% from the peak value), after 2 days, the dose of terlipressin should be increased in a stepwise manner to a maximum of 12 mg/day. Adding albumin to terlipressin is more effective than terlipressin alone. One possible explanation is that albumin by increasing intravascular volume may counteract the decrease in cardiac output associated with HRS.[23] In addition to this, antioxidant and anti-inflammatory properties of albumin may have a beneficial effect in HRS patient.[42] Albumin solution (20%) should be used at the dose 20–40 g/day. Ideally, apart from routinely monitoring patients with HRS-AKI, the serial measurement of central venous pressure or other measures of assessing central blood volume can help to prevent circulatory overload by optimizing the fluid balance and helping to titrate the dose of albumin.

Other vasoconstrictive drugs include iv noradrenaline and oral midodrine plus subcutaneous or iv octretide, both in combination with albumin. Noradrenaline, given by continuous iv infusion at the dose of 0.5–3 mg/h, has been proven to be as effective as terlipressin regarding the increase in mean arterial pressure, the reversal of renal impairment and 1-month survival.[43],[44],[45],[46] However, the number of patients treated with noradrenaline remains too small to definitively confirm its efficacy. In contrast to terlipressin, the use of noradrenaline always requires a central venous line and intensive care unit stay. The combination midodrine plus octreotide, used in countries where terlipressin is not yet available,[47] has been shown to be much less effective than terlipressin in the treatment of Type 1 HRS in a recent randomized controlled trial.[48]

According to the new definition of HRS-AKI, complete response to the treatment should be defined by a final SCr within 0.3 mg/dl (26.5 mmol/L) from the baseline value, while partial response should be defined by the regression of AKI stage to a final SCr ≥0.3 mg/dl (26.5 mol/L) from the baseline value. Adverse events related to terlipressin or noradrenaline include ischemic and cardiovascular events. Thus, a careful clinical screening including electrocardiogram is recommended before starting the treatment. According to the type and severity of side effects, the treatment should be modified or discontinued.

Recurrent HRS in responders, after the end of the treatment, has been reported in up to 20% of cases. Retreatment is usually effective, however, in some cases, continuous recurrence occurs; thus, a long-term treatment with terlipressin plus albumin and a long-term hospitalization are required.[49]

Terlipressin plus albumin is also effective in the treatment of HRS outside the criteria of AKI (HRS-NAKI), formerly known as HRS type II. Unfortunately, recurrence after the withdrawal of the treatment is the norm, and controversial data exist on the impact of the treatment on long-term clinical outcome, particularly from the perspective of liver transplantation (LT). As such, vasoconstrictors and albumin are not recommended in this clinical scenario.[9]

There are insufficient data to advocate transjugular intrahepatic port systemic stenting (TIPS) in HRS-AKI, but it could be suggested in selected patients with HRS-NAKI. TIPS has been studied in patients with Type 2 HRS[50] and in the management of refractory ascites, frequently associated with Type 2 HRS. In these patients, TIPS has been shown to improve renal function.[51]

LT is the best therapeutic option for patients with HRS regardless of the response to drug therapy. The decision to initiate renal replacement therapy should be based on the individual severity of illness. The indication for liver-kidney transplantation remains controversial. This procedure should be considered in patients with significant CKD or with sustained AKI, including HRS-AKI with no response to drug therapy.


The approach to HRS in patients with cirrhosis is witnessing significant changes, with better understanding of the underlying pathophysiological mechanisms. Newer changes in definitions of syndrome, is not only allowing better categorization of the patient into different categories of HRS, as well as allowing earlier identification and earlier institution of pharmacotherapy when it is most effective.

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Conflicts of interest

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