What is hepatorenal syndrome?

Hepatorenal Syndrome: Definition and Clinical Implications

Hepatorenal syndrome (HRS) is a unique form of kidney dysfunction characterized by functional impairment of the kidneys due to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, in the absence of structural kidney damage. 1, 2

Pathophysiology

• Splanchnic arterial vasodilation is the primary event that reduces effective arterial blood volume and decreases mean arterial pressure, leading to a hyperdynamic circulatory state 3
• Portal hypertension contributes to increased sinusoidal pressure and lymph formation 3
• Arterial underfilling triggers activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), causing renal vasoconstriction 4, 3
• Impaired cardiac function due to cirrhotic cardiomyopathy leads to inadequate cardiac output to compensate for vasodilation 4, 3
• Increased synthesis of vasoactive mediators (cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, endothelin-1) affects renal blood flow and glomerular microcirculation 4, 3
• Systemic inflammation and bacterial translocation aggravate these hemodynamic alterations 5

Classification

• Type 1 HRS (now termed HRS-AKI): Characterized by rapid, progressive renal impairment with serum creatinine increasing ≥100% to >2.5 mg/dl in less than 2 weeks 4, 1
• Type 2 HRS (now termed HRS-CKD): Features stable or less progressive impairment in renal function with a more chronic course 4, 2

Diagnostic Criteria

Current diagnostic criteria for HRS include:

• Presence of cirrhosis with ascites 1, 2
• Serum creatinine >1.5 mg/dL 2
• No improvement of serum creatinine after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg body weight, maximum 100 g/day) 4, 1
• Absence of shock 1, 2
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media) 4, 1
• Absence of parenchymal renal disease as indicated by:
  • No proteinuria (>500 mg/day) 4, 1
  • No microhematuria (>50 red blood cells per high power field) 4, 1
  • Normal findings on renal ultrasonography 4, 1

Risk Factors and Prognosis

• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors for HRS development 4, 1
• HRS develops in approximately 30% of patients with SBP 4
• Prognosis is poor, with median survival of untreated type 1 HRS approximately 1 month 4, 2
• High MELD scores and type 1 HRS are associated with very poor prognosis 4

Treatment Approaches

• Liver transplantation is the definitive treatment for both types of HRS 2, 6
• Pharmacological therapy with vasoconstrictors plus albumin is the first-line treatment for HRS-AKI:
  • Terlipressin plus albumin is the most effective combination (initial dose 1 mg IV every 4-6 hours) 2, 6
  • Alternative treatments include midodrine plus octreotide plus albumin, or norepinephrine plus albumin 2
• Renal replacement therapy should not be used as first-line therapy but may serve as a bridge to liver transplantation 7

Prevention Strategies

• Albumin infusion with antibiotics when treating spontaneous bacterial peritonitis 4, 2
• Norfloxacin (400 mg/day) in advanced cirrhosis 2
• Pentoxifylline (400 mg three times daily) in severe alcoholic hepatitis 2
• Avoiding nephrotoxic drugs in patients with advanced cirrhosis 2

Clinical Pitfalls and Challenges

• Differential diagnosis between HRS-AKI and acute tubular necrosis can be challenging 5
• Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) may help differentiate HRS from acute tubular necrosis 1
• Early diagnosis is critical as delayed treatment worsens outcomes 1
• Response to vasoconstrictors with reduction in serum creatinine is associated with improved survival, though overall survival benefit remains limited 8