What is hepatorenal syndrome?

Definition of Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a functional renal failure that occurs in patients with cirrhosis and ascites, characterized by severe impairment of kidney function due to renal vasoconstriction in the absence of structural kidney abnormalities. 1, 2

Diagnostic Criteria

The International Club of Ascites and major liver associations define HRS by the following criteria:

• Presence of cirrhosis with ascites 1
• Acute kidney injury according to the International Club of Ascites-AKI criteria 1
• No improvement of serum creatinine after 2 consecutive days of:
  • Diuretic withdrawal
  • Plasma volume expansion with albumin (1 g/kg body weight) 1, 3
• Absence of shock 1, 3
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media) 1, 3
• Absence of signs of structural kidney injury, indicated by:
  • No significant proteinuria (<500 mg/day)
  • No microhematuria (<50 red blood cells per high power field)
  • Normal findings on renal ultrasonography 1, 3

Classification

HRS is classified into two main types:

• HRS-AKI (formerly Type 1 HRS): Rapidly progressive renal impairment with serum creatinine increasing ≥100% to >2.5 mg/dL in less than 2 weeks 4, 3
• HRS-CKD (formerly Type 2 HRS): Stable or less progressive impairment in renal function with a more chronic course 4, 3

Pathophysiology

The pathophysiological mechanisms of HRS include:

• Splanchnic arterial vasodilation leading to reduced effective arterial blood volume and decreased mean arterial pressure 4, 2
• Portal hypertension contributing to increased sinusoidal pressure and lymph formation 4
• Arterial underfilling triggering activation of:
  • Sympathetic nervous system
  • Renin-angiotensin-aldosterone system (RAAS), causing renal vasoconstriction 1, 4
• Impaired cardiac function due to cirrhotic cardiomyopathy leading to inadequate cardiac output 4
• Increased synthesis of vasoactive mediators affecting renal blood flow 4
• Systemic inflammation and bacterial translocation exacerbating circulatory dysfunction 5

Clinical Significance and Prognosis

• HRS accounts for 15-43% of AKI cases in cirrhotic patients 1
• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors for HRS development 4
• HRS develops in approximately 30% of patients with SBP 4
• Prognosis is poor, with median survival of untreated HRS-AKI approximately 1 month 1, 3

AKI Staging in HRS

The American Association for the Study of Liver Diseases recommends AKI staging as follows:

• Stage 1: Increase of creatinine ≥0.3 mg/dL up to 2-fold of baseline
• Stage 2: Increase in creatinine between 2-fold and 3-fold of baseline
• Stage 3: Increase in creatinine >3-fold of baseline or creatinine >4 mg/dL with an acute increase ≥0.3 mg/dL or initiation of renal replacement therapy 1, 3

Differential Diagnosis

• Other common causes of AKI in cirrhotic patients include:
  • Hypovolemia (27-50% of cases)
  • Acute tubular necrosis (14-35% of cases) 1
• Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) may help differentiate HRS from acute tubular necrosis 1

Treatment Approach

• First-line treatment for HRS-AKI is vasoconstrictors (terlipressin) plus albumin 1, 3
• Liver transplantation remains the definitive treatment for HRS 1, 3, 2
• Prevention strategies include albumin infusion with antibiotics when treating spontaneous bacterial peritonitis 1, 3

Common Pitfalls in HRS Diagnosis

• Failing to exclude other causes of AKI in cirrhosis (pre-renal azotemia, acute tubular necrosis) 5
• Not allowing sufficient time for albumin challenge (full 48 hours) before diagnosing HRS 1
• Missing underlying structural kidney disease that may mimic HRS 1
• Overlooking the presence of nephrotoxic medications that could be causing or contributing to kidney injury 3