What is Hepatorenal Syndrome (HRS)?

Hepatorenal Syndrome (HRS) Definition

Hepatorenal syndrome is a specific form of functional renal failure that develops in patients with cirrhosis and ascites, characterized by renal vasoconstriction and decreased glomerular filtration rate without structural kidney damage, occurring in the setting of advanced liver disease with hemodynamic alterations and systemic inflammation. 1, 2

Core Pathophysiological Features

HRS represents a unique type of kidney dysfunction driven by multiple interconnected mechanisms:

• Splanchnic arterial vasodilation is the primary initiating event, causing reduction in effective arterial blood volume and decreased mean arterial pressure, leading to a hyperdynamic circulatory state 3, 4
• Renal vasoconstriction occurs as a compensatory response through activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), resulting in severe reduction in renal blood flow and GFR 3, 2
• Systemic inflammation plays a critical role beyond traditional hemodynamic mechanisms, with inflammatory signals affecting proximal tubular cells and contributing to metabolic dysfunction 3, 5
• Cirrhotic cardiomyopathy impairs the heart's ability to increase cardiac output sufficiently to compensate for vasodilation 3, 2

Updated Classification System

The International Club of Ascites has modernized HRS terminology to align with acute kidney injury frameworks:

• HRS-AKI (formerly Type 1 HRS) represents rapid, progressive renal impairment defined as an increase in serum creatinine ≥0.3 mg/dL within 48 hours or ≥50% from baseline, without requiring the previous threshold of 1.5 mg/dL 1, 2
• HRS-NAKI or HRS-CKD (formerly Type 2 HRS) features stable or slowly progressive renal impairment with a more chronic course 3, 2
• The removal of the 1.5 mg/dL creatinine threshold allows for earlier treatment initiation, which is associated with better outcomes 2

Diagnostic Criteria

HRS-AKI diagnosis requires meeting all of the following criteria established by the International Club of Ascites:

• Presence of cirrhosis with ascites as the underlying condition 2
• AKI criteria met using International Club of Ascites-AKI staging 2
• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g/day) 1, 2
• Absence of shock at time of diagnosis 2, 6
• No current or recent nephrotoxic drug exposure including NSAIDs, aminoglycosides, or iodinated contrast media 2
• No evidence of structural kidney injury: proteinuria <500 mg/day, microhematuria <50 RBCs per high power field, and normal renal ultrasonography 2

AKI Staging in HRS Context

The American Association for the Study of Liver Diseases recommends specific staging:

• Stage 1: Creatinine increase ≥0.3 mg/dL up to 2-fold of baseline 2
• Stage 2: Creatinine increase between 2-fold and 3-fold of baseline 2
• Stage 3: Creatinine increase >3-fold of baseline or creatinine >4 mg/dL with acute increase ≥0.3 mg/dL, or initiation of renal replacement therapy 2

Differential Diagnosis Considerations

HRS accounts for only 15-43% of AKI cases in cirrhotic patients, making differentiation from other causes essential 2:

• Hypovolemia represents 27-50% of AKI cases in cirrhosis 2
• Acute tubular necrosis (ATN) accounts for 14-35% of cases 2
• Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL), KIM-1, IL-18, and L-FABP may help differentiate HRS from ATN, though this remains an area of active investigation 2, 4

Clinical Significance and Prognosis

• Median survival of untreated HRS-AKI is approximately 1 month, making this one of the most severe complications of cirrhosis 1, 2
• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important precipitating factors, with HRS developing in approximately 30% of patients with SBP 2
• High MELD scores and HRS-AKI are associated with extremely poor prognosis without intervention 2

Treatment Principles

Terlipressin combined with albumin is the first-line pharmacological treatment for HRS-AKI, with FDA approval based on the CONFIRM trial showing 29.1% achieved verified HRS reversal versus 15.8% with placebo 6:

• Initial dosing: 1 mg terlipressin (0.85 mg terlipressin base) IV every 6 hours plus albumin 1 g/kg on day 1, then 40 g/day 7, 6
• Dose escalation to 2 mg every 4-6 hours if serum creatinine does not decrease by at least 25% after 3 days 7
• Liver transplantation remains the only definitive cure, with vasoconstrictors serving as a bridge to transplantation 2, 7

Prevention Strategies

• Albumin infusion with antibiotics when treating spontaneous bacterial peritonitis reduces HRS risk and improves survival 2, 7
• Norfloxacin 400 mg/day reduces HRS incidence in advanced cirrhosis 3, 7
• Pentoxifylline 400 mg three times daily may prevent HRS in severe alcoholic hepatitis 3, 7