What is hepatorenal syndrome?

Definition of Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a functional renal failure that occurs in patients with advanced liver cirrhosis and ascites, characterized by reduced renal blood flow and glomerular filtration rate in the absence of structural kidney damage, resulting from circulatory and hemodynamic alterations of advanced cirrhosis. 1, 2

Diagnostic Criteria

The International Club of Ascites and major liver associations define HRS based on the following criteria:

• Presence of cirrhosis with ascites 1
• Acute kidney injury according to ICA-AKI criteria 1
• No improvement in serum creatinine after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg body weight) 1, 2
• Absence of shock 1, 2
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media) 1, 2
• Absence of signs of structural kidney injury:
  • No proteinuria (>500 mg/day) 1, 2
  • No microhematuria (>50 red blood cells per high power field) 1, 2
  • Normal findings on renal ultrasonography 1, 2

Classification

HRS is classified into two types:

• HRS-AKI (formerly Type 1 HRS): Characterized by rapid, progressive renal impairment with serum creatinine increasing ≥100% to >2.5 mg/dL in less than 2 weeks 3, 2
• HRS-CKD (formerly Type 2 HRS): Features stable or less progressive impairment in renal function with a more chronic course 3, 2

Pathophysiology

The development of HRS involves several key mechanisms:

• Splanchnic arterial vasodilation leading to reduced effective arterial blood volume and decreased mean arterial pressure 3
• Portal hypertension contributing to increased sinusoidal pressure and lymph formation 3
• Arterial underfilling triggering activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), causing renal vasoconstriction 1, 3
• Impaired cardiac function due to cirrhotic cardiomyopathy leading to inadequate cardiac output to compensate for vasodilation 1, 3
• Increased synthesis of vasoactive mediators affecting renal blood flow and glomerular microcirculation 1, 3
• Inflammatory signals affecting proximal tubular epithelial cells, leading to mitochondria-mediated metabolic downregulation 3

Risk Factors and Prognosis

• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors for HRS development 1, 3
• HRS develops in approximately 30% of patients with SBP 1
• Prognosis is poor, with median survival of untreated HRS-AKI approximately 1 month 1, 2
• HRS accounts for 15-43% of AKI cases in cirrhotic patients 1

Treatment Options

• First-line treatment for HRS-AKI is terlipressin plus albumin 2
• Alternative treatments include midodrine plus octreotide plus albumin, or norepinephrine plus albumin 2
• Liver transplantation is the definitive treatment for both types of HRS 1, 2

Prevention Strategies

• Albumin infusion with antibiotics when treating spontaneous bacterial peritonitis 1, 2
• Norfloxacin (400 mg/day) can reduce HRS incidence in advanced cirrhosis 2
• Pentoxifylline (400 mg three times daily) can prevent HRS in severe alcoholic hepatitis 2
• Avoiding nephrotoxic drugs in patients with advanced cirrhosis 2

Clinical Pearls and Pitfalls

• Early diagnosis is critical as HRS carries high mortality 1
• Differential diagnosis is crucial as HRS requires specific treatment different from other causes of AKI in cirrhosis 4
• Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) may help differentiate HRS from acute tubular necrosis 1
• Other common causes of AKI in cirrhotic patients include hypovolemia (27-50%) and acute tubular necrosis (14-35%) 1