What are the diagnostic criteria and treatment options for Hepatorenal Syndrome (HRS)?

Diagnosis of Hepatorenal Syndrome

Hepatorenal syndrome (HRS) should be diagnosed when a cirrhotic patient with ascites develops acute kidney injury (AKI) with serum creatinine >1.5 mg/dL that fails to improve after 2 consecutive days of diuretic withdrawal and albumin volume expansion (1 g/kg body weight), while excluding other causes of renal failure. 1, 2

Diagnostic Criteria

The diagnosis requires meeting ALL of the following criteria:

Essential Requirements

• Cirrhosis with ascites 1, 2
• AKI defined by International Club of Ascites-AKI criteria: increase in serum creatinine ≥0.3 mg/dL within 48 hours OR increase ≥50% from baseline within 7 days 1
• No response to volume expansion: Serum creatinine remains elevated after 2 consecutive days of diuretic withdrawal AND plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g/day) 3, 1

Exclusion Criteria (Must Rule Out)

• Absence of shock 1, 2
• No current or recent nephrotoxic drugs: NSAIDs, aminoglycosides, iodinated contrast media 3, 1
• No structural kidney injury:
  • Proteinuria <500 mg/day 3, 1
  • Microhematuria <50 red blood cells per high power field 3, 1
  • Normal renal ultrasonography 3, 1
• No hypovolemia or prerenal azotemia 3
• No parenchymal renal disease (consider renal biopsy if suspected) 3

AKI Staging in HRS

Stage the severity using the following criteria 1:

• Stage 1: Creatinine increase ≥0.3 mg/dL OR up to 2-fold from baseline
• Stage 2: Creatinine increase 2-fold to 3-fold from baseline
• Stage 3: Creatinine increase >3-fold from baseline OR creatinine >4 mg/dL with acute increase ≥0.3 mg/dL OR initiation of renal replacement therapy

Critical Diagnostic Updates

The outdated requirement of serum creatinine doubling to >2.5 mg/dL has been eliminated 1. This change reflects evidence that earlier treatment improves outcomes and that smaller acute changes in creatinine negatively affect survival 3. The median survival of untreated type 1 HRS is approximately 1 month, making rapid diagnosis essential 3, 1.

Differential Diagnosis

HRS accounts for only 15-43% of AKI cases in cirrhotic patients 1. You must actively exclude:

• Hypovolemia/prerenal azotemia (27-50% of cases): responds to volume expansion 1
• Acute tubular necrosis (14-35% of cases): may coexist with HRS 1, 4
• Drug-induced renal injury: particularly NSAIDs, aminoglycosides 5

Biomarkers can help differentiate HRS from ATN: urinary neutrophil gelatinase-associated lipocalin (NGAL), KIM-1, IL-18, and L-FABP may distinguish structural kidney injury from functional HRS 1.

Clinical Classification

Type 1 HRS (HRS-AKI)

• Rapidly progressive renal impairment: serum creatinine increases ≥100% to >2.5 mg/dL in <2 weeks 3, 2
• Extremely poor prognosis: median survival ~1 month without treatment 3, 1
• Requires intensive monitoring: urine output, fluid balance, arterial pressure, ideally central venous pressure 3
• Manage in ICU or semi-ICU setting 3

Type 2 HRS (HRS-CKD)

• Stable or slowly progressive renal dysfunction 3, 2
• Better survival than Type 1 but still poor overall prognosis 2

Risk Factors and Triggers

Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most critical risk factor 3, 1:

• HRS develops in ~30% of patients with SBP 3
• Infection precipitates HRS in 48% of cases 5
• GI bleeding precipitates HRS in 33% of cases 5
• Large-volume paracentesis without albumin in 27% of cases 5

High MELD scores predict worse outcomes 3.

Treatment Approach

First-Line Pharmacologic Therapy

Terlipressin plus albumin is the most effective treatment 3, 2, 6:

• Initial dose: 1 mg IV every 4-6 hours 3, 2
• Dose escalation: Increase to 2 mg every 4-6 hours if serum creatinine doesn't decrease by ≥25% after 3 days 3
• Continue until: Serum creatinine <1.5 mg/dL (typically 1.0-1.2 mg/dL) 3
• Median response time: 14 days 3
• Efficacy: 40-50% response rate 3, 7
• Albumin dosing: 1 g/kg on day 1 (maximum 100 g), then 40 g/day 3

Predictors of response to terlipressin 3:

• Serum bilirubin <10 mg/dL before treatment
• Mean arterial pressure increase >5 mmHg at day 3

Important safety consideration: Terlipressin causes cardiovascular/ischemic complications in ~12% of patients; exclude those with severe cardiovascular disease 3. Recent data indicate risk of potentially fatal respiratory failure requiring careful patient selection 4.

Alternative Therapies

• Norepinephrine plus albumin: Requires ICU setting, may be primary option for many ICU patients 2, 4
• Midodrine plus octreotide plus albumin: Should largely be abandoned due to lack of efficacy 2, 4

Definitive Treatment

Liver transplantation is the only definitive cure 1, 2:

• Post-transplant survival ~65% 2
• Expedited referral recommended for Type 1 HRS 2
• Consider combined liver-kidney transplant if structural kidney disease present 3

Prevention Strategies

Albumin infusion (1.5 g/kg at diagnosis, 1 g/kg on day 3) plus antibiotics when treating SBP reduces HRS risk and improves survival 3, 2.

Additional preventive measures 2:

• Norfloxacin 400 mg/day in advanced cirrhosis
• Pentoxifylline 400 mg three times daily in severe alcoholic hepatitis
• Avoid nephrotoxic drugs in advanced cirrhosis

Common Pitfalls

• Delaying diagnosis by waiting for creatinine >2.5 mg/dL: Use the updated AKI criteria immediately 1
• Administering fixed-dose albumin to all AKI patients: Recent data suggest harm from volume overload; assess volume status thoughtfully and diagnose HRS within 24 hours 4
• Assuming HRS is a diagnosis of exclusion: HRS may coexist with ATN or develop on background of CKD 4
• Using MELD score after treatment response: Use pre-treatment MELD for transplant prioritization, as responding patients have reduced scores but still need urgent transplant 8