Causes of Hepatorenal Syndrome
Hepatorenal syndrome develops from the combination of advanced cirrhosis with portal hypertension causing splanchnic vasodilation, which leads to effective arterial underfilling and compensatory renal vasoconstriction, often precipitated by bacterial infections or other acute insults. 1, 2
Primary Underlying Mechanism
The fundamental cause is cirrhosis with portal hypertension, which creates a cascade of hemodynamic disturbances 1:
- Splanchnic arterial vasodilation is the primary event, causing reduction in effective arterial blood volume despite total plasma volume expansion 1, 3
- Increased sinusoidal hydrostatic pressure from portal hypertension drives lymph formation and ascites development 1, 3
- Effective arterial underfilling triggers activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), leading to intense renal vasoconstriction 1, 2
- Impaired cardiac function from cirrhotic cardiomyopathy prevents adequate compensation for the vasodilation 2, 3
Major Precipitating Factors
While cirrhosis creates the substrate, specific triggers commonly precipitate HRS 1, 2:
Bacterial Infections (Most Important)
- Spontaneous bacterial peritonitis (SBP) is the single most important precipitant, causing HRS in approximately 30% of cases 2, 4
- Bacterial products and cytokines induce further splanchnic vasodilation, worsening circulatory dysfunction 1
- Bacterial products directly alter renal peritubular microcirculation and cause oxidative stress 1
Volume Depletion
- Aggressive diuretic use without adequate monitoring 1
- Large-volume paracentesis without albumin replacement 1
- Gastrointestinal bleeding causing hypovolemia 1
Nephrotoxic Insults
- NSAIDs are particularly dangerous in cirrhotic patients 2
- Aminoglycosides and other nephrotoxic antibiotics 2
- Iodinated contrast media 2
Other Precipitants
- Severe alcoholic hepatitis 4
- Hepatocellular carcinoma with vascular invasion or severe cholestasis 3
- Any acute deterioration in liver function 1
Advanced Pathophysiological Contributors
Beyond the primary hemodynamic mechanisms, additional factors contribute 3, 5:
- Systemic inflammation is increasingly recognized as a key feature, with inflammatory signals affecting proximal tubular cells and causing mitochondrial dysfunction 3, 5
- Increased synthesis of vasoactive mediators including cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1 affects renal blood flow 3
- Increased gut permeability from portal hypertension allows bacterial translocation, contributing to systemic inflammation 1
Important Clinical Context
HRS accounts for only 15-43% of AKI cases in cirrhotic patients—other common causes include hypovolemia (27-50%) and acute tubular necrosis (14-35%) 2. This is a critical pitfall: not all kidney injury in cirrhosis is HRS, and distinguishing these entities is essential because vasoconstrictors are not indicated for ATN 5, 6.
Despite being classified as "functional" renal failure, severe or repeated episodes of renal hypoperfusion can lead to structural kidney damage over time, exposing patients to direct hemodynamic injury 1, 3. This challenges the traditional view of HRS as purely reversible and suggests HRS and ATN may represent a continuum rather than distinct entities 5, 6.