What is hepatorenal syndrome and how is it managed?

Hepatorenal Syndrome: Definition and Management

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

Definition and Diagnostic Criteria

HRS is diagnosed based on the following criteria:

• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dL (133 μmol/L)
• No improvement in renal function (creatinine decreasing to <133 μmol/L) after:
  • At least 2 days of diuretic withdrawal
  • Volume expansion with albumin (1 g/kg/day up to 100 g/day)
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal renal disease as defined by:
  • Proteinuria <500 mg/day
  • No microhematuria (<50 red cells/high power field)
  • Normal renal ultrasonography 1, 2

Classification

HRS is classified into two types:

1. HRS-AKI (formerly Type 1): Characterized by rapid, progressive impairment in renal function with increase in serum creatinine ≥100% from baseline to a level >2.5 mg/dL in less than 2 weeks. Median survival without treatment is approximately 1 month. 1, 2

2. HRS-CKD (formerly Type 2): Features stable or slowly progressive renal impairment. This is a common cause of death in patients who do not die from other cirrhosis complications. 1, 2

Pathophysiology

Four key factors contribute to HRS development:

1. Splanchnic vasodilation: Causes reduced effective arterial blood volume and decreased mean arterial pressure

2. Activation of sympathetic nervous system and renin-angiotensin-aldosterone system: Results in renal vasoconstriction and altered renal autoregulation

3. Impaired cardiac function: Due to cirrhotic cardiomyopathy, leading to inadequate compensatory increase in cardiac output

4. Increased synthesis of vasoactive mediators: Affecting renal blood flow and glomerular microcirculation 1

Recent evidence highlights the role of systemic inflammation in HRS pathophysiology, particularly in the context of bacterial infections 3, 4.

Risk Factors and Prognosis

• Major risk factor: Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), which triggers HRS in approximately 30% of cases
• Prognosis: Poor, with median survival of approximately 3 months for all HRS patients
• Mortality: Particularly high for untreated HRS-AKI (Type 1) at approximately 1 month 1, 2

Management

General Measures

1. Early diagnosis: Critical for improving outcomes
2. Close monitoring: Patients with HRS-AKI should be monitored in an intensive care setting
3. Parameters to monitor: Urine output, fluid balance, arterial pressure, and central venous pressure 1

Pharmacological Treatment

First-line therapy: Vasoconstrictors combined with albumin 1, 5

• Terlipressin plus albumin: Most effective option where available, with high response rates
• Norepinephrine plus albumin: Alternative in ICU settings (83% success rate in reversing Type 1 HRS)
• Midodrine and octreotide plus albumin: Option that can be administered outside ICU settings
  • Midodrine: Titrated up to 12.5 mg orally three times daily
  • Octreotide: Target dose 200 μg subcutaneously three times daily
  • Albumin: 10-20 g IV daily for 20 days 1

Renal Replacement Therapy

• Hemodialysis or continuous venovenous hemofiltration/hemodialysis may be used to control azotemia and maintain electrolyte balance before liver transplantation
• Continuous venovenous methods cause less hypotension but require continuous nursing support 1

Definitive Treatment

Liver transplantation is the definitive treatment for HRS 1, 3, 4

• Some patients may require simultaneous liver-kidney transplantation if significant kidney damage is present
• Patients with HRS-AKI should receive expedited referral for liver transplantation 1

Common Pitfalls and Caveats

1. Diagnostic challenges: Differentiating HRS from acute tubular necrosis can be difficult; biomarkers like urine NGAL may help 2, 4

2. Treatment timing: Delaying treatment worsens outcomes; higher baseline serum creatinine predicts poorer response to vasoconstrictors 1, 5

3. Monitoring complications: Patients on vasoconstrictors require close monitoring for adverse effects

4. NSBB considerations: Patients with refractory ascites on non-selective beta-blockers should be monitored closely for hypotension or worsening renal function 1

5. Transplant prioritization: Patients who respond to vasoconstrictor therapy may have reduced MELD scores, potentially affecting transplant prioritization 5