What is the definition of hepatorenal syndrome?

Definition of Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is renal failure occurring in patients with advanced liver disease in the absence of any identifiable cause of kidney dysfunction—it is fundamentally a diagnosis of exclusion. 1

Diagnostic Criteria

The diagnosis requires meeting all of the following major criteria 1:

• Serum creatinine >1.5 mg/dL (133 μmol/L) 1
• Advanced chronic or acute liver failure with portal hypertension 1
• Absence of shock 1
• Absence of hypovolemia, defined as no sustained improvement in renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics) and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day 1
• No current or recent treatment with nephrotoxic drugs 1
• Absence of parenchymal renal disease, indicated by:
  • Proteinuria <0.5 g/day (or <500 mg/dL) 1
  • No microhematuria (<50 red blood cells per high-powered field) 1
  • Normal renal ultrasonography 1

Classification into Two Types

HRS is classified into two distinct clinical patterns based on the rapidity of renal function deterioration 1:

Type 1 HRS (HRS-AKI)

Characterized by rapid and progressive renal impairment with either 1:

• Doubling of initial serum creatinine to a level >2.5 mg/dL in less than 2 weeks, OR
• 50% reduction of initial 24-hour creatinine clearance to <20 mL/minute in less than 2 weeks, OR
• Increase in serum creatinine ≥100% from baseline to >2.5 mg/dL in less than 2 weeks 1

Prognosis: Median survival of approximately 1 month without treatment 1

Type 2 HRS (HRS-CKD)

Characterized by stable or slowly progressive renal impairment without the rapid deterioration seen in Type 1 1

Prognosis: Better than Type 1, with median survival of approximately 3-6 months 1

Pathophysiologic Basis

The definition reflects the underlying pathophysiology, which involves 1:

• Splanchnic vasodilation causing reduction in effective arterial blood volume and decreased mean arterial pressure 1
• Activation of vasoconstrictor systems (sympathetic nervous system and renin-angiotensin-aldosterone system) causing renal vasoconstriction 1
• Cirrhotic cardiomyopathy leading to relative impairment of compensatory cardiac output 1
• Systemic inflammation from bacterial translocation contributing to renal microcirculatory dysfunction 2, 3

Critical Diagnostic Considerations

The diagnosis is essentially one of exclusion—other causes of acute kidney injury must be ruled out before diagnosing HRS 1. The most important differential diagnoses include 1:

• Hypovolemia from gastrointestinal or renal fluid losses
• Sepsis-induced acute kidney injury
• Acute tubular necrosis
• Nephrotoxic drug exposure
• Parenchymal kidney disease

Common pitfall: The 2021 AASLD guidance emphasizes that HRS-AKI is no longer strictly a diagnosis of exclusion and may coexist with other forms of AKI such as acute tubular injury 1, 4. This represents an evolution from older definitions that required complete exclusion of all other causes.