What is the step‑by‑step diagnostic approach to hepatorenal syndrome (HRS) acute kidney injury (AKI) in a patient with advanced cirrhosis and ascites?

Diagnostic Formulation of HRS-AKI

The diagnosis of HRS-AKI requires a systematic exclusion process: first confirm AKI by ICA-AKI criteria, then remove all reversible causes and perform a 48-hour albumin trial, and finally verify absence of structural kidney disease—only when all other causes are excluded and the patient fails to respond to volume expansion can HRS-AKI be diagnosed. 1

Step 1: Establish Baseline Creatinine and Confirm AKI

• Use the last serum creatinine value within 3 months prior to admission as your baseline reference point. 2
• Diagnose AKI when serum creatinine rises ≥0.3 mg/dL within 48 hours OR increases ≥50% (1.5-fold) from baseline within 7 days. 1, 3
• If no prior creatinine is available and the admission value is ≥1.5 mg/dL, use clinical judgment to identify a clear precipitating event (e.g., GI bleeding, infection); if present, assume AKI and use the admission value as baseline for subsequent monitoring. 2
• Do NOT use MDRD or CKD-EPI equations to estimate baseline creatinine in cirrhotic patients with ascites—these formulas are highly inaccurate and will misclassify >75% of patients. 2, 1

Step 2: Stage the AKI Severity

• Stage 1A: Creatinine rise ≥0.3 mg/dL or 1.5–2× baseline, with peak creatinine <1.5 mg/dL. 1
• Stage 1B: Creatinine rise ≥0.3 mg/dL or 1.5–2× baseline, with peak creatinine ≥1.5 mg/dL. 1
• Stage 2: Creatinine >2–3× baseline. 1, 3
• Stage 3: Creatinine >3× baseline OR ≥4.0 mg/dL with acute rise ≥0.3 mg/dL OR initiation of dialysis. 1, 3

Step 3: Immediate Risk-Factor Removal (All AKI Stages)

• Discontinue all diuretics immediately (complete cessation for Stage 2–3; dose reduction acceptable for Stage 1). 2, 1
• Stop all nephrotoxic agents: NSAIDs, aminoglycosides, ACE-inhibitors, ARBs, other vasodilators, and iodinated contrast. 2, 1
• Identify and treat bacterial infections aggressively—infection is the most common precipitant of HRS-AKI. 2, 1
• Assess for hypovolemia: look for recent large-volume paracentesis without albumin replacement, GI bleeding, or excessive diuretic use. 2, 4

Step 4: Perform the Mandatory 48-Hour Albumin Trial

• Administer intravenous albumin 1 g/kg body weight (maximum 100 g) on day 1, followed by 20–40 g on day 2. 2, 1
• Re-measure serum creatinine at 48 hours to determine response. 2, 1
• If creatinine returns to within 0.3 mg/dL of baseline, the patient had volume-responsive AKI, NOT HRS-AKI; continue close monitoring. 2
• If creatinine does not improve after 48 hours, proceed to verify HRS-AKI diagnostic criteria. 2, 1

Step 5: Confirm All Six HRS-AKI Diagnostic Criteria

HRS-AKI can only be diagnosed when all six of the following are present: 1, 4

1. Cirrhosis with ascites documented clinically or by imaging. 1
2. AKI Stage 2 or 3 (or Stage 1B that progresses despite initial management). 1
3. No improvement in creatinine after 2 consecutive days of diuretic withdrawal and albumin volume expansion (as described in Step 4). 1, 4
4. Absence of shock (no vasopressor requirement for hypotension). 1, 4
5. No current or recent exposure to nephrotoxic drugs (verified by medication review). 1, 4
6. No macroscopic structural kidney injury: proteinuria <500 mg/day, microhematuria <50 RBC/HPF, and normal renal ultrasound (no hydronephrosis, masses, or cortical thinning). 1, 4

Step 6: Adjunctive Diagnostic Tools (Optional)

• Fractional excretion of urea (FEUrea) <28% has 75% sensitivity and 83% specificity for HRS versus other AKI causes; FEUrea is superior to fractional excretion of sodium (FENa) in cirrhosis. 3
• Urinary biomarkers (NGAL, KIM-1, IL-18, L-FABP) may help differentiate HRS-AKI from acute tubular necrosis but are not yet standard of care or required for diagnosis. 1

Common Pitfalls to Avoid

• Do not diagnose HRS-AKI in Stage 1A patients (peak creatinine <1.5 mg/dL)—these patients rarely meet full criteria and should not receive vasoconstrictors. 1
• Do not skip the 48-hour albumin trial—failure to respond to volume expansion is a mandatory diagnostic criterion. 1, 4
• Do not assume ascites equals adequate intravascular volume—cirrhotic patients have reduced effective arterial blood volume despite total body fluid overload. 4
• Do not rely on urine output alone—serum creatinine is the primary diagnostic marker per ICA-AKI criteria. 1, 3
• Do not delay evaluation for liver transplantation—HRS-AKI is a diagnosis-of-exclusion emergency, and transplant is the only definitive cure. 1