What is Hepatorenal syndrome?

Hepatorenal Syndrome: Definition, Pathophysiology, and Management

Hepatorenal syndrome (HRS) is a serious form of renal failure that occurs in patients with advanced liver disease, characterized by functional impairment of the kidneys in the absence of identifiable kidney disease or other causes of renal failure. 1 This condition represents one of the most severe complications of cirrhosis with poor prognosis if left untreated.

Definition and Diagnostic Criteria

HRS is diagnosed based on the following criteria:

• Serum creatinine >1.5 mg/dL (133 μmol/L)
• Absence of shock
• Absence of hypovolemia (no improvement in renal function after at least 2 days of diuretic withdrawal and volume expansion with albumin at 1 g/kg/day up to 100 g)
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal renal disease (proteinuria <0.5 g/day, no microhematuria, normal renal ultrasonography) 1

Classification

HRS is classified into two distinct types:

1. Type 1 HRS (HRS-AKI): Characterized by rapid and progressive impairment in renal function with:

   • Increase in serum creatinine ≥100% from baseline to >2.5 mg/dL in less than 2 weeks 1
   • More recently defined as Stage 2 AKI (doubling of baseline serum creatinine) while fulfilling other HRS criteria 2
   • Extremely poor prognosis with median survival of approximately 1 month if untreated 1

2. Type 2 HRS: Features a stable or less progressive impairment in renal function

   • More recently referred to as HRS-chronic kidney disease 3
   • Better survival compared to type 1 HRS but still poor overall prognosis 1

Pathophysiology

Four key factors contribute to the development of HRS:

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

2. Activation of sympathetic nervous system and renin-angiotensin-aldosterone system: Leads to renal vasoconstriction and altered renal autoregulation, making renal blood flow highly sensitive to changes in mean arterial pressure

3. Impaired cardiac function: Cirrhotic cardiomyopathy results in inadequate compensatory increase in cardiac output in response to vasodilation

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

Recent understanding has expanded to include the role of inflammation alongside hemodynamic changes in the pathophysiology of HRS 2.

Risk Factors

The most significant risk factor for HRS is bacterial infection, particularly spontaneous bacterial peritonitis (SBP). Approximately 30% of patients who develop SBP will subsequently develop HRS 1. Other risk factors include:

• Advanced cirrhosis with ascites
• High MELD scores
• Gastrointestinal bleeding
• Large-volume paracentesis without albumin replacement

Management Approach

1. Early Diagnosis

• Monitor serum creatinine regularly in patients with cirrhosis and ascites
• Exclude other causes of renal failure (hypovolemia, shock, nephrotoxic drugs, parenchymal renal disease) 1
• Consider renal biopsy in cases with suspected parenchymal disease 1

2. Pharmacological Treatment for Type 1 HRS (HRS-AKI)

First-line treatment: Vasoconstrictor drugs combined with albumin infusion

• Terlipressin plus albumin: Most widely studied and effective option (not available in the US) 1, 4

  • Continuous infusion (2-12 mg/day) may have fewer adverse effects than bolus administration 5
  • Monitor for respiratory complications, especially in patients with pre-existing respiratory compromise 2

• Norepinephrine plus albumin: Equally effective as terlipressin in reversing HRS-1 1, 2

  • Traditionally requires ICU setting, though recent data suggest it may be administered outside ICU with close monitoring 2

• Midodrine and octreotide plus albumin: Available in the US

  • Midodrine: Titrated up to 12.5 mg orally three times daily
  • Octreotide: Target dose of 200 μg subcutaneously three times daily
  • Albumin: 10-20 g intravenous daily for up to 20 days 1
  • Can be administered outside the ICU and even at home 1

3. Renal Replacement Therapy

• Used as a bridge to liver transplantation
• Controls azotemia and maintains electrolyte balance
• Hypotension during hemodialysis is a common problem
• Continuous venovenous hemofiltration causes less hypotension but requires continuous involvement of dialysis staff 1
• Without transplantation, survival remains dismal 1

4. Definitive Treatment

• Liver transplantation: The definitive treatment for HRS 1, 3
• Combined liver-kidney transplantation: Consider for patients with prolonged AKI, underlying chronic kidney disease, or hereditary renal conditions 2

Prognosis

• Untreated type 1 HRS: Median survival approximately 1 month
• Overall median survival of all HRS patients: Approximately 3 months
• Response to vasoconstrictors with reduction in serum creatinine is associated with improved survival 2
• High MELD scores and type 1 HRS are associated with particularly poor prognosis 1

Important Considerations and Pitfalls

• Diagnostic delay: Early recognition is critical as treatment outcomes are better with earlier intervention
• MELD/MELD-Na scoring: Responding patients may have reduced MELD scores after treatment, potentially resulting in longer waiting times for transplantation. Consider using pre-treatment MELD values for transplant prioritization 5
• Preventive measures: Treatment of SBP with albumin infusion together with antibiotics reduces the risk of developing HRS and improves survival 1
• Biomarkers: Future developments in biomarkers and metabolomics may help identify at-risk patients earlier, allowing for more timely treatment 2, 3