What are the causes of hepatorenal syndrome?

Causes of Hepatorenal Syndrome

Primary Underlying Mechanism

Hepatorenal syndrome develops from a cascade of hemodynamic disturbances initiated by portal hypertension in cirrhotic patients, leading to splanchnic arterial vasodilation, effective arterial underfilling, and compensatory renal vasoconstriction. 1, 2

The pathophysiology centers on four interconnected mechanisms:

• Portal hypertension creates both structural (fibrosis, nodules, vascular occlusion) and dynamic (increased vascular tone) changes that raise resistance to portal blood flow, triggering splanchnic vasodilation 1
• Splanchnic arterial vasodilation reduces effective arterial blood volume despite total plasma volume expansion, creating a paradoxical state where the body perceives volume depletion 1, 3, 2
• Compensatory vasoconstrictor activation occurs through the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), causing intense renal vasoconstriction and sodium/water retention 1, 3, 2
• Cirrhotic cardiomyopathy impairs cardiac contractility, limiting the ability to augment cardiac output sufficiently to compensate for systemic vasodilation, thereby worsening renal hypoperfusion 4, 1, 3

Major Precipitating Factors

HRS does not occur spontaneously but requires specific triggers in patients with advanced cirrhosis:

Bacterial Infections (Most Important)

• Spontaneous bacterial peritonitis (SBP) is the single most important precipitant—HRS develops in approximately 30% of patients with SBP 1, 5
• Bacterial infections induce further splanchnic vasodilation and worsen circulatory dysfunction 1
• Increased gut permeability from portal hypertension allows bacterial translocation, contributing to systemic inflammation 1, 3

Volume Depletion

• Aggressive diuretic use without adequate monitoring 1
• Large-volume paracentesis without albumin replacement (>5 liters removed) 5
• Gastrointestinal bleeding causing acute volume loss 1

Acute Deterioration in Liver Function

• Any acute worsening of hepatic function can tip the balance toward HRS 1
• Severe cholestasis from tumor involvement (in hepatocellular carcinoma patients) may further impair renal function 3

Advanced Pathophysiological Contributors

Systemic Inflammation

• Bacterial products and induced cytokines worsen splanchnic and systemic vasodilation, increasing circulatory dysfunction 3, 2
• Inflammatory signals exert direct effects on proximal tubular cells, leading to mitochondria-mediated metabolic downregulation 3
• Bacterial products can alter renal peritubular microcirculation, cause direct kidney damage, and induce oxidative stress affecting cellular metabolism and apoptosis 3

Vasoactive Mediators

• Increased synthesis of cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1 affects renal blood flow and glomerular microcirculation 3
• These mediators contribute to the intense renal vasoconstriction characteristic of HRS 1

Increased Sinusoidal Pressure

• Portal hypertension increases sinusoidal hydrostatic pressure, driving lymph formation and contributing directly to ascites development 3
• This creates a vicious cycle of worsening hemodynamic dysfunction 1

Clinical Context and Risk Factors

HRS occurs exclusively in patients with cirrhosis and ascites—it cannot develop without these two prerequisites 1, 5. The condition typically appears in advanced decompensated cirrhosis with:

• High MELD scores 1
• Refractory ascites (particularly in Type 2 HRS) 5
• Systemic hypotension and hyponatremia 5
• Reduced cardiac output as a manifestation of cirrhotic cardiomyopathy 4

Diastolic Dysfunction as a Prognostic Factor

• Presence of diastolic dysfunction is associated with higher mortality: 95% survival without dysfunction, 79% with grade I dysfunction, and 39% with grade II dysfunction 4
• Reduced cardiac output predisposes patients to acute kidney injury—including HRS—following infections such as SBP 4

Important Clinical Pitfall

Despite being classified as "functional" renal failure, severe and/or repeated episodes of renal hypoperfusion can lead to structural kidney damage over time, exposing patients to direct hemodynamic injury that challenges the traditional view of HRS as purely reversible 1, 3. This underscores the critical importance of early recognition and treatment of precipitating factors, particularly bacterial infections.