What are the diagnosis and treatment options for Hepatorenal Syndrome (HRS), including differentiating between Type 1 and Type 2 HRS?

Diagnosis and Treatment of Hepatorenal Syndrome (HRS)

Hepatorenal syndrome (HRS) is now classified into HRS-AKI (formerly Type 1) and HRS-CKD (formerly Type 2), with terlipressin plus albumin being the first-line treatment for HRS-AKI due to its proven efficacy in improving renal function and survival. 1

Diagnostic Criteria for HRS

HRS-AKI (formerly Type 1 HRS)

• Characterized by rapidly progressive renal dysfunction
• Diagnostic criteria include 2, 1:
  • Diagnosis of cirrhosis and ascites
  • AKI according to ICA-AKI criteria:
    • Stage 1: Increase in serum creatinine ≥0.3 mg/dL or up to 2-fold from baseline
    • Stage 2: Increase in serum creatinine 2-3 fold from baseline
    • Stage 3: Increase in serum creatinine >3-fold from baseline, or creatinine >4 mg/dL with acute increase ≥0.3 mg/dL, or initiation of RRT
  • No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg)
  • Absence of shock
  • No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, contrast media)
  • No macroscopic signs of structural kidney injury:
    • Absence of proteinuria (>500 mg/day)
    • Absence of microhematuria (>50 RBCs per high power field)
    • Normal findings on renal ultrasonography

HRS-CKD (formerly Type 2 HRS)

• Characterized by stable or slowly progressive renal dysfunction
• Often associated with refractory ascites
• Develops over weeks to months without obvious precipitating event 3, 4

Pathophysiology

HRS develops due to 1, 5:

• Splanchnic arterial vasodilation leading to decreased effective arterial blood volume
• Activation of sympathetic nervous system and renin-angiotensin-aldosterone system
• Renal vasoconstriction resulting in decreased renal blood flow
• Systemic inflammation (particularly important in HRS-AKI)
• Bacterial infections (especially spontaneous bacterial peritonitis) are major precipitating factors

Treatment Algorithm

First-Line Treatment for HRS-AKI

1. Vasoconstrictor plus Albumin 1, 6

   • Terlipressin plus albumin is the most effective combination:
     • Terlipressin: Start at 1 mg IV every 4-6 hours
     • If serum creatinine doesn't decrease by at least 25% after 3 days, increase dose to maximum 2 mg every 4-6 hours
     • Albumin: 1 g/kg on day 1, followed by 20-40 g/day
   • Response rate: 40-50% of patients
   • FDA-approved based on CONFIRM trial showing 29.1% achieved verified HRS reversal vs 15.8% with placebo 6

2. Alternative Vasoconstrictors (if terlipressin unavailable)

   • Norepinephrine plus albumin (in ICU setting) 1
   • Midodrine + octreotide + albumin:
     • Midodrine: Titrate up to 12.5 mg orally three times daily
     • Octreotide: 200 μg subcutaneously three times daily
     • Albumin: 10-20 g/day IV for up to 20 days

Treatment Monitoring

• Monitor serum creatinine, arterial pressure, urine output, and serum sodium
• Watch for cardiovascular or ischemic complications (occur in ~12% of patients on terlipressin)
• Continue albumin therapy at 20-40 g/day IV
• Hold diuretics and beta-blockers until renal function improves 1

Predictors of Treatment Response

• Lower baseline serum creatinine (<5.0 mg/dL)
• Serum bilirubin <10 mg/dL before treatment
• Increase in mean arterial pressure >5 mm Hg at day 3 of treatment 1

Definitive Treatment

• Liver transplantation is the only curative treatment for HRS
• Expedited referral for transplantation should be considered for all patients with cirrhosis, ascites, and HRS
• Simultaneous liver-kidney transplantation for patients with significant kidney damage 1

Bridge to Transplantation

• Continuous renal replacement therapy (RRT) may be used as a bridge to liver transplantation in non-responders to vasoconstrictors
• Transjugular Intrahepatic Portosystemic Shunt (TIPS) may be considered in selected patients with partial response to medical therapy, but is contraindicated in severe liver failure or significant encephalopathy 1

Prevention of HRS

• Norfloxacin (400 mg/day) reduces incidence of HRS in advanced cirrhosis
• Pentoxifylline (400 mg three times daily) may prevent HRS development in severe alcoholic hepatitis
• Treatment of spontaneous bacterial peritonitis with albumin plus antibiotics reduces risk of HRS development 1

Important Clinical Considerations

• Early treatment initiation is crucial as higher serum creatinine at treatment start correlates with lower probability of response 2
• The rigid serum creatinine cut-off value of >2.5 mg/dL from old diagnostic criteria has been removed to allow earlier treatment 2
• Median time to response with terlipressin treatment is 14 days, shorter in patients with lower baseline serum creatinine 1
• Prognosis remains poor despite treatment, with median survival of approximately 3 months for all HRS patients; untreated HRS-AKI has median survival of approximately 1 month 1

HRS diagnosis and management requires prompt recognition, exclusion of other causes of renal dysfunction, and timely initiation of appropriate therapy to improve outcomes in this severe complication of advanced liver disease.