What is hepatorenal syndrome?

Hepatorenal Syndrome Definition

Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure, making it essentially a diagnosis of exclusion. 1

Diagnostic Criteria for Hepatorenal Syndrome

The diagnosis of HRS requires meeting all of the following criteria:

• Serum creatinine >1.5 mg/dl (133 μmol/L) 1
• Absence of shock 1
• Absence of hypovolemia, defined as no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal and volume expansion with albumin at 1 g/kg/day up to 100 g/day 1
• No current or recent treatment with nephrotoxic drugs 1
• Absence of parenchymal renal disease, defined by:
  • Proteinuria <0.5 g/day 1
  • No microhematuria (<50 red cells/high powered field) 1
  • Normal renal ultrasonography 1

Classification of Hepatorenal Syndrome

HRS is classified into two types:

• Type 1 HRS (HRS-AKI): Characterized by rapid and progressive impairment in renal function (increase in serum creatinine ≥100% compared to baseline to a level higher than 2.5 mg/dl in less than 2 weeks) 1
• Type 2 HRS (HRS-NAKI): Characterized by a stable or less progressive impairment in renal function 1

Recent guidelines have updated the terminology:

• Type 1 HRS is now termed HRS-acute kidney injury (HRS-AKI) 1, 2
• Type 2 HRS is now termed HRS-non-AKI (HRS-NAKI) or chronic kidney disease 1, 3

Pathophysiology of Hepatorenal Syndrome

Four key factors are involved in the pathogenesis of HRS:

1. Splanchnic vasodilation: Causes reduction in effective arterial blood volume and decreased mean arterial pressure 1, 4
2. Activation of sympathetic nervous system and renin-angiotensin-aldosterone system: Causes renal vasoconstriction and shifts the renal autoregulatory curve, making renal blood flow more sensitive to changes in mean arterial pressure 1, 4
3. Impaired cardiac function: Due to cirrhotic cardiomyopathy, leading to relative impairment of compensatory increase in cardiac output secondary to vasodilation 1, 4
4. Increased synthesis of vasoactive mediators: Affecting renal blood flow or glomerular microcirculation (cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1) 1, 4

Additional pathophysiological mechanisms include:

• Systemic inflammation 1, 2
• Bacterial translocation 3
• Nitric oxide dysfunction 2

Risk Factors and Prognosis

• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors for HRS 1, 4
• HRS develops in approximately 30% of patients who develop SBP 1
• Treatment of SBP with albumin infusion together with antibiotics reduces the risk of developing HRS and improves survival 1, 4
• Prognosis is poor, with average median survival of approximately 3 months for all patients with HRS 1
• High MELD scores and type 1 HRS are associated with very poor prognosis 1
• Median survival of untreated type 1 HRS is approximately 1 month 1, 4

Management Approach

Diagnosis and Monitoring

• Early diagnosis is crucial - exclude other causes of renal failure in cirrhosis (hypovolemia, shock, parenchymal renal diseases, nephrotoxic drugs) 1
• Suspect parenchymal renal diseases if significant proteinuria or microhematuria is present, or if renal ultrasonography shows abnormalities in kidney size 1
• Renal biopsy may be important in these patients to help plan further management, including potential need for combined liver and kidney transplantation 1
• For therapeutic purposes, HRS is usually diagnosed when serum creatinine increases to >133 μmol/L (1.5 mg/dl) 1
• Repeated measurement of serum creatinine helps in early identification of HRS 1

Treatment

• Liver transplantation is the definitive treatment for HRS 5, 2
• While awaiting transplantation, pharmacological therapy includes:
  • Vasoconstrictors plus albumin: First-line treatment to counteract splanchnic arterial vasodilation 1, 5, 2
  • Terlipressin plus albumin: Most effective vasoconstrictor therapy 5, 6
  • Midodrine plus octreotide plus albumin: Alternative where terlipressin is unavailable 5
  • Norepinephrine plus albumin: Another alternative, requiring ICU setting 5

Prevention

• Albumin infusion with therapeutic paracentesis can help prevent HRS development 4
• Antibiotic prophylaxis against spontaneous bacterial peritonitis reduces risk of developing HRS 4
• Prompt treatment of SBP with albumin and antibiotics reduces risk of developing HRS 4
• Avoidance of nephrotoxic medications (NSAIDs, ACE inhibitors, ARBs) 4

Important Considerations and Pitfalls

• Differential diagnosis between HRS and acute tubular necrosis can be challenging 2, 3
• Kidney biomarkers may be useful in differentiating between causes of AKI in cirrhosis 3
• Patients with type 1 HRS should be monitored carefully, ideally in an intensive care or semi-intensive care unit 1
• Parameters to monitor include urine output, fluid balance, arterial pressure, and standard vital signs 1
• Central venous pressure monitoring helps with fluid balance management to prevent volume overload 1
• Renal replacement therapy should not be used as first-line therapy but may be considered as a bridge to liver transplantation in selected patients 5, 7