What is the pathophysiology of hepatorenal syndrome (HRS) and how is it diagnosed?

Pathophysiology of Hepatorenal Syndrome

Hepatorenal syndrome develops through a cascade of hemodynamic collapse triggered by splanchnic arterial vasodilation and systemic inflammation, leading to intense renal vasoconstriction despite preserved kidney structure. 1

Primary Hemodynamic Mechanisms

The pathophysiology centers on portal hypertension causing splanchnic arterial vasodilation, which creates a hyperdynamic circulatory state with decreased effective arterial blood volume and reduced mean arterial pressure. 2, 1 This arterial underfilling triggers compensatory activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), causing intense renal vasoconstriction and shifting the renal autoregulatory curve. 2, 1

• Increased sinusoidal hydrostatic pressure from portal hypertension drives lymph formation and ascites development, contributing directly to the circulatory dysfunction. 1
• Cirrhotic cardiomyopathy impairs cardiac contractility, preventing adequate cardiac output compensation for systemic vasodilation and worsening renal hypoperfusion. 2, 1
• The severity of diastolic dysfunction correlates with survival: approximately 95% survival without dysfunction, 79% with grade I dysfunction, and only 39% with grade II dysfunction. 1

Inflammatory and Molecular Mechanisms

The modern understanding has shifted from purely hemodynamic dysfunction to recognize systemic inflammation as a direct contributor to HRS. 2 Pro-inflammatory cytokines and chemokines exert direct effects on proximal tubular epithelial cells, causing mitochondria-mediated metabolic downregulation and reprioritization of cell functions away from sodium-chloride absorption. 2 This increases sodium chloride delivery to the macula densa, triggering intrarenal RAAS activation and further lowering GFR. 2

• Bacterial translocation from increased gut permeability due to portal hypertension contributes to systemic inflammation and worsens splanchnic vasodilation. 1
• Increased synthesis of vasoactive mediators—including cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1—affects renal blood flow and glomerular microcirculation. 1
• Severe cholestasis may further impair renal function by worsening inflammation and macrocirculatory dysfunction. 2

Structural Kidney Damage

Despite HRS being classified as "functional" renal failure, severe or repeated episodes of renal hypoperfusion can lead to structural kidney damage over time, exposing kidneys to direct hemodynamic injury. 1 This challenges the traditional view of HRS as purely reversible and has implications for combined liver-kidney transplantation decisions. 1

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Diagnosis of Hepatorenal Syndrome

HRS-AKI is diagnosed when a patient with cirrhosis and ascites develops AKI that fails to improve after 2 consecutive days of diuretic withdrawal and albumin expansion (1 g/kg, maximum 100 g), in the absence of shock, nephrotoxic drugs, or structural kidney disease. 1

Diagnostic Criteria (All Must Be Present)

• Cirrhosis with ascites is required for HRS diagnosis. 1
• AKI defined by ICA-AKI criteria: Stage 1 = creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% from baseline; Stage 2 = 2-3× baseline; Stage 3 = >3× baseline or >4 mg/dL with acute increase ≥0.3 mg/dL or initiation of renal replacement therapy. 1
• No improvement after volume challenge: No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g/day). 1
• Absence of shock is necessary. 1
• No current or recent nephrotoxic drug use (NSAIDs, aminoglycosides, iodinated contrast media). 1
• No evidence of structural kidney injury: proteinuria <500 mg/day, microhematuria <50 red blood cells per high power field, and normal renal ultrasonography. 1

Critical Evolution from Old Criteria

The fixed threshold of serum creatinine >1.5 mg/dL has been abandoned because it delays diagnosis and signifies severely reduced GFR. 1 The newer criteria emphasize dynamic changes in creatinine rather than absolute values, allowing earlier detection and treatment. 1 Earlier treatment leads to better outcomes, as median survival of untreated type 1 HRS is only approximately 1 month. 1

Differential Diagnosis

HRS accounts for only 15-43% of AKI cases in cirrhotic patients, making differential diagnosis crucial. 1

• Hypovolemia (27-50% of cases) responds to volume expansion. 1
• Acute tubular necrosis (14-35% of cases) involves structural kidney damage. 1
• Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) with cutoff values of 220 μg/g creatinine show 88% sensitivity and 85% specificity for differentiating HRS from acute tubular necrosis. 1, 3
• Other biomarkers (KIM-1, IL-18, L-FABP) may also help differentiate HRS from acute tubular necrosis. 1

Essential Diagnostic Steps

• Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis (SBP), which precipitates HRS in approximately 30% of cases. 1, 3
• Obtain baseline electrocardiogram before starting vasoconstrictor therapy to screen for cardiac contraindications. 2, 3
• Consider renal biopsy if proteinuria, microhematuria, or abnormal kidney size is present to evaluate for parenchymal disease and guide combined liver-kidney transplant decisions. 1

Common Diagnostic Pitfalls

• Do not wait for creatinine to reach 1.5 mg/dL before considering HRS—use the dynamic AKI criteria instead. 1
• Do not rely on urine output as a diagnostic criterion in cirrhotic patients with ascites. 1
• Do not delay treatment waiting for creatinine to reach 2.5 mg/dL; the old type 1 HRS criteria have been revised, and earlier treatment improves outcomes. 3

Risk Factors and Clinical Context

• Bacterial infections, particularly SBP, are the most important risk factor—HRS develops in approximately 30% of patients with SBP. 1
• High MELD scores and type 1 HRS carry very poor prognosis with median survival of approximately 3 months overall and 1 month for untreated type 1 HRS. 1
• Volume depletion from aggressive diuretic use, large-volume paracentesis without albumin replacement, or gastrointestinal bleeding can precipitate HRS. 1