What is hepatorenal syndrome?

Hepatorenal Syndrome: Definition and Management

Hepatorenal syndrome (HRS) is a specific form of kidney dysfunction that occurs in patients with advanced liver disease, characterized by renal failure in the absence of identifiable kidney pathology, resulting from circulatory and hemodynamic alterations of advanced cirrhosis, aggravated by systemic inflammation. 1, 2, 3

Definition and Diagnostic Criteria

HRS is diagnosed based on the following criteria:

• Serum creatinine >1.5 mg/dL (133 μmol/L)
• Absence of shock
• No hypovolemia (no improvement in renal function after diuretic withdrawal and albumin administration)
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal renal disease (proteinuria <0.5 g/day, no microhematuria, normal renal ultrasound) 1

Classification

HRS has been reclassified by the International Club of Ascites into:

1. HRS-AKI (formerly Type 1): Rapid, progressive impairment in renal function

   • Increase in serum creatinine ≥0.3 mg/dL within 48 hours or ≥50% from baseline
   • No longer requires a final creatinine threshold of 1.5 mg/dL, allowing earlier treatment 1, 2

2. HRS-NAKI (formerly Type 2): Stable or less progressive renal impairment 1

Pathophysiology

Four key mechanisms contribute to HRS development:

1. Splanchnic vasodilation leading to reduced effective arterial blood volume and decreased mean arterial pressure
2. Activation of sympathetic nervous system and renin-angiotensin-aldosterone system causing renal vasoconstriction
3. Impaired cardiac function due to cirrhotic cardiomyopathy
4. Increased synthesis of vasoactive mediators affecting renal blood flow 1

Newer understanding includes the critical role of systemic inflammation in HRS pathophysiology 1, 3

Risk Factors and Prognosis

• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors
• HRS develops in approximately 30% of patients with SBP
• Prognosis is poor with median survival of only 3 months for all HRS patients
• Untreated type 1 HRS has median survival of approximately 1 month 1, 2

Management

First-Line Treatment

• Terlipressin plus albumin is the first-line treatment for HRS-AKI:
  • Initial dose: 1 mg IV every 4-6 hours
  • Can be increased to 2 mg every 4-6 hours (maximum 12 mg/day) if serum creatinine decreases <25% after 2 days
  • Albumin: 1.5 g/kg on day 1, followed by 1 g/kg on day 3 2

Alternative Treatments

• Norepinephrine plus albumin: 0.5-3 mg/hour continuous infusion (requires ICU setting)
• Midodrine + octreotide + albumin: Midodrine up to 12.5 mg orally three times daily, octreotide 200 μg subcutaneously three times daily, albumin 10-20 g/day IV 2

Monitoring and Treatment Duration

• Daily serum creatinine checks
• Monitor blood pressure, heart rate, and urine output
• Continue treatment until serum creatinine decreases below 1.5 mg/dL or for maximum 14 days
• Watch for ischemic complications with vasoconstrictors 2

Definitive Treatment

• Liver transplantation is the only curative treatment for HRS
• Consider expedited referral for all patients with cirrhosis, ascites, and HRS
• Simultaneous liver-kidney transplantation may be needed for patients with significant kidney damage 2

Special Considerations

• TIPS (Transjugular Intrahepatic Portosystemic Shunt) may be considered in selected patients who partially respond to medical therapy
• Renal Replacement Therapy can serve as a bridge to liver transplantation in non-responders to vasoconstrictors 2

Common Pitfalls and Caveats

1. Delayed diagnosis: The new HRS-AKI definition eliminates the need for a minimum creatinine threshold, allowing earlier treatment initiation 4

2. Differential diagnosis challenges: Distinguishing HRS from acute tubular necrosis can be difficult; kidney biomarkers may be helpful 3, 5

3. Treatment response assessment: Complete response is defined as final serum creatinine within 0.3 mg/dL from baseline; partial response is regression of AKI stage with final serum creatinine ≥0.3 mg/dL from baseline 2

4. Relapse risk: Despite treatment, relapse is common without liver transplantation 2

5. Prioritization for transplantation: Patients who respond to treatment may have reduced MELD/MELD-Na scores, potentially extending their waiting time for transplantation 4