Management of Hepatorenal Syndrome (HRS)

Pathophysiology (Brief Overview)

Fig. Proposed pathophysiology of HRS - Sleisenger & Fordtran's Gastrointestinal and Liver Disease

Classification

Diagnostic Criteria (ICA 2019)

1. Cirrhosis, acute liver failure, or acute-on-chronic liver failure (ACLF) with ascites
2. AKI: serum creatinine rise ≥0.3 mg/dL within 48 h, OR ≥50% from baseline within 7 days; or urine output ≤0.5 mL/kg/h for ≥6 h
3. No full or partial response after at least 2 days of diuretic withdrawal + albumin (1 g/kg/day, max 100 g/day)
4. Absence of shock
5. No current or recent nephrotoxic drugs (NSAIDs, aminoglycosides, contrast)
6. No parenchymal kidney disease (proteinuria >500 mg/day, microhematuria >50 RBC/hpf, abnormal renal US)
7. FENa <0.2% (highly predictive if <0.1%)

• Comprehensive Clinical Nephrology, 7th Ed., Box 76.2

Prevention

• Over-diuresis (stepwise approach: spironolactone 100 mg/day → max 400 mg/day; furosemide added → max 160 mg/day)
• Large-volume paracentesis without albumin replacement (give albumin 8 g per liter of ascites removed)
• NSAIDs, ACEIs, ARBs, aminoglycosides, IV contrast
• GI bleeding (use beta-blockers, band ligation for varices)
• Cautious use of beta-blockers in refractory ascites (reduce MAP and GFR)

• SBP: Give IV albumin 1.5 g/kg on day 1 + 1.0 g/kg on day 3 to prevent HRS in patients with SBP - reduces risk of renal failure and improves survival
• Severe alcoholic hepatitis: Pentoxifylline has been used
• High-risk patients with low ascites protein (<1 g/L) + advanced liver dysfunction: long-term antibiotic prophylaxis (ciprofloxacin 500 mg/day or rifaximin 600 mg BID)
• Harrison's 22E; Sleisenger & Fordtran's; Comprehensive Clinical Nephrology 7th Ed.

Treatment

Step 1: Immediate Measures (all patients)

• Stop all diuretics, NSAIDs, ACEIs, ARBs, lactulose (if contributing to volume depletion)
• Treat underlying precipitants (infection, GI bleed)
• Volume expansion: IV albumin 1 g/kg/day (max 100 g/day) for 48 h - if no improvement, HRS is confirmed

Step 2: Pharmacological (Vasoconstrictors + Albumin)

First-Line: Terlipressin + Albumin (preferred globally; FDA-approved in USA 2022)

• Comprehensive Clinical Nephrology 7th Ed., Box 76.3; Goldman-Cecil Medicine

Second-Line: Norepinephrine + Albumin (ICU setting)

Third-Line (especially when terlipressin unavailable): Midodrine + Octreotide + Albumin

Per Harrison's 22E (2025): Midodrine + octreotide + albumin are now third line behind terlipressin (first) and norepinephrine (second).

Alternative: Vasopressin + Albumin (less commonly used)

• IV infusion starting at 0.01 U/min, titrating up to 0.8 U/min to achieve MAP increase ≥10 mmHg; max 11 days

Step 3: Renal Replacement Therapy (RRT)

• Indicated if pharmacotherapy fails and the patient develops uremia, severe hyperkalemia, acidosis, or fluid overload
• Not definitive - used as bridge to transplantation
• Patients requiring hemodialysis carry a 1.77x higher post-transplant mortality vs. those who do not need dialysis

Step 4: Transjugular Intrahepatic Portosystemic Shunt (TIPS)

• Best evidence for Type 2 HRS (HRS-CKD) / diuretic-resistant ascites
• Benefits: reduces portal pressure, improves serum creatinine, increases sodium excretion, improves neurohumoral responses
• Pilot studies in Type 1 HRS show some benefit, especially when combined with midodrine + octreotide + albumin followed by TIPS
• Limitations: Risk of worsening hepatic function (worsening hepatic encephalopathy) in decompensated cirrhosis; not suitable for high MELD score patients

Step 5: Liver Transplantation (Definitive Treatment)

• The only treatment with potential to reverse both liver dysfunction and HRS
• Any patient with HRS should be immediately evaluated for transplant and prioritized on the waiting list
• Outcomes:
  • HRS reverses in 83% after liver transplantation (systematic review of 20 studies)
  • 3-year survival ~60% (vs. 70-80% for non-HRS transplant patients)
  • Up to 35% of HRS patients require long-term RRT post-transplant
  • Pre-transplant dialysis is an independent predictor of worse survival (RR 1.77)
• Simultaneous liver-kidney transplantation (SLK) may be considered in appropriate candidates with prolonged renal failure
• Medical therapy (vasoconstrictors) serves as a bridge to transplantation

Step 6: Experimental / Salvage Options

• Extracorporeal albumin dialysis (MARS - Molecular Adsorbent Recirculating System): Experimental; mixed results in small trials; may reduce creatinine and improve survival in some patients; not effective as salvage after vasoconstrictor failure in HRS-AKI
• ET receptor antagonists (e.g., tezosentan): Studied but found to worsen renal function in HRS; not used clinically

Summary Algorithm

HRS suspected (AKI in cirrhosis with ascites)
        ↓
Stop diuretics, NSAIDs, ACEIs/ARBs
Albumin challenge: 1 g/kg/day × 2 days
Treat infections, GI bleeding
        ↓
No response → Confirm HRS-AKI diagnosis
        ↓
Vasoconstrictor + Albumin:
  1st: Terlipressin (0.5-2 mg IV q4-6h) + Albumin
  2nd: Norepinephrine (ICU) + Albumin
  3rd: Midodrine + Octreotide + Albumin
        ↓
Evaluate for LIVER TRANSPLANTATION (all patients)
        ↓
If failing / uremia → RRT as bridge
TIPS: consider for HRS-CKD or as bridge

Prognosis

• Without treatment, median survival HRS-AKI: ~2 weeks; HRS-CKD: ~4-6 months
• Reversal of HRS is associated with improved survival regardless of modality used
• Patients who do not achieve creatinine reversal within 14 days of vasoconstrictor therapy have very poor outcomes

• Harrison's Principles of Internal Medicine 22E (2025), McGraw-Hill
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Saunders
• Comprehensive Clinical Nephrology, 7th Edition, Elsevier
• Goldman-Cecil Medicine International Edition