How should acute kidney injury due to hepatorenal syndrome be managed in a patient with cirrhosis, portal hypertension, and ascites?

Management of Acute Kidney Injury Due to Hepatorenal Syndrome

Immediately withdraw all diuretics and nephrotoxic drugs, then administer intravenous albumin 1 g/kg/day (maximum 100 g) for 2 consecutive days; if serum creatinine fails to improve after 48 hours, initiate vasoconstrictors (terlipressin or norepinephrine) combined with continued albumin therapy. 1, 2

Initial Diagnostic Confirmation and Staging

Before initiating HRS-specific therapy, confirm the diagnosis meets ICA-AKI criteria and stage the severity 1:

• Stage 1: Creatinine increase ≥0.3 mg/dL within 48 hours OR ≥1.5-2× baseline 1, 3
  • Stage 1A: Peak creatinine <1.5 mg/dL 3
  • Stage 1B: Peak creatinine ≥1.5 mg/dL (higher mortality risk) 3
• Stage 2: Creatinine >2-3× baseline 1, 3
• Stage 3: Creatinine >3× baseline OR ≥4.0 mg/dL with acute increase ≥0.3 mg/dL OR need for dialysis 1, 3

HRS-AKI diagnostic criteria require: cirrhosis with ascites, AKI by ICA-AKI criteria, no response after 2 days of diuretic withdrawal and albumin expansion, absence of shock, no recent nephrotoxic drug exposure, and no macroscopic structural kidney injury (proteinuria >500 mg/day, microhematuria >50 RBCs/HPF, or abnormal renal ultrasound) 1, 4

Stepwise Management Algorithm

Step 1: Immediate Risk Factor Removal (All AKI Stages)

Within the first hours of AKI recognition 1, 2:

• Review and discontinue: NSAIDs, aminoglycosides, iodinated contrast, ACE inhibitors, ARBs, all vasodilators 1, 4
• Withdraw or reduce diuretics completely if Stage 2-3, or reduce dose if Stage 1 1, 2
• Screen for and treat infections aggressively: Perform diagnostic paracentesis if ascites present; treat spontaneous bacterial peritonitis with antibiotics PLUS albumin 1.5 g/kg on day 1 and 1 g/kg on day 3 2, 4

Step 2: Albumin-Based Volume Expansion Trial (48-Hour Window)

For all patients with Stage 1,2, or 3 AKI 1:

• Administer IV albumin: 1 g/kg bodyweight on day 1 (maximum 100 g), then 20-40 g/day on day 2 1, 2
• Reassess serum creatinine at 48 hours 1, 4
• If creatinine improves: Continue supportive care and monitor daily 2, 3
• If creatinine stable or worsens: Proceed to Step 3 (vasoconstrictor therapy) 1

Step 3: Vasoconstrictor Therapy for Confirmed HRS-AKI

Initiate vasoconstrictors immediately if no response to albumin after 48 hours 1, 2, 5:

Terlipressin Protocol (Preferred Agent)

• Starting dose: 1 mg IV bolus every 6 hours (equivalent to 0.85 mg terlipressin base) 6
• Continue albumin: 20-40 g/day throughout treatment 6, 5
• Day 4 assessment: If creatinine decreased <30% from baseline, increase to 2 mg every 6 hours 6
• Discontinue if: Creatinine at or above baseline on Day 4 6
• Treatment duration: Maximum 14 days or until creatinine ≤1.5 mg/dL on two consecutive measurements 6
• Response rate: 29-32% achieve verified HRS reversal (creatinine ≤1.5 mg/dL sustained for 10 days without dialysis) 6

Alternative: Norepinephrine

• Use when terlipressin unavailable or contraindicated 7, 5
• Continuous IV infusion: Start 0.5-3 mg/hour, titrate to increase MAP by 10 mmHg 5
• Combined with albumin: Same dosing as terlipressin protocol 5
• Note: Some evidence suggests faster response with terlipressin, but norepinephrine may have fewer adverse events 7

Step 4: Monitoring During Vasoconstrictor Therapy

Daily mandatory assessments 2, 3:

• Serum creatinine: Daily measurement 2, 3
• Urine output: Hourly monitoring in severe cases (Stage 2-3) with catheterization 2
• Hemodynamics: Continuous blood pressure and heart rate monitoring 2
• Electrolytes: Monitor for hyperkalemia >6.0 mEq/L requiring urgent intervention 2
• Respiratory status: Watch for pulmonary edema from albumin administration 6

Critical Pitfalls to Avoid

Do not delay treatment waiting for creatinine to reach 2.5 mg/dL - the old HRS-1 criteria requiring creatinine doubling to >2.5 mg/dL have been abandoned; treat based on ICA-AKI staging 4, 3

Do not assume ascites equals adequate renal perfusion - cirrhotic patients have effective hypovolemia despite total body fluid overload 4

Do not use eGFR equations - MDRD and CKD-EPI formulas are inaccurate in cirrhosis; use absolute creatinine values and ICA-AKI staging 1, 4

Do not overlook infection - present in 25-40% of AKI cases in cirrhosis and requires specific albumin therapy in addition to antibiotics for SBP 4

Avoid vasoconstrictors in Stage 1A (creatinine <1.5 mg/dL) - expert consensus recommends caution, as benefit unclear and adverse events possible 1

Adjunctive and Definitive Therapies

Transjugular intrahepatic portosystemic shunt (TIPS): May be considered as adjuvant therapy to improve renal blood flow, but cannot replace definitive treatment 7

Renal replacement therapy: Use only as bridge to transplantation in Stage 3 AKI unresponsive to vasoconstrictors; does not improve survival without transplantation 8, 9

Liver transplantation: The only curative treatment for HRS-AKI 7, 9, 5

• Combined liver-kidney transplantation (CLKT): Consider when AKI persists >4 weeks despite medical therapy or when chronic kidney disease coexists 7, 5
• Timing: Initiate transplant evaluation immediately upon HRS-AKI diagnosis, as 40-50% fail medical therapy 5, 10

Prognostic Considerations

Stage 1B, 2, and 3 AKI carry significantly higher short-term mortality than Stage 1A or no AKI 3, 9

Response to vasoconstrictors predicts survival: Factors determining responsiveness include timing of initiation, rise in mean arterial pressure, and degree of cholestasis 8, 5

Urinary biomarkers (NGAL, KIM-1, IL-18, L-FABP) may help differentiate HRS-AKI from acute tubular necrosis, though not yet standard of care 1, 4, 5