What is hepatorenal syndrome?

What is Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a functional kidney failure that develops in patients with advanced cirrhosis and ascites, characterized by renal vasoconstriction without structural kidney damage, triggered by severe splanchnic arterial vasodilation and circulatory dysfunction. 1

Core Pathophysiology

HRS results from a cascade of hemodynamic derangements that begin in the splanchnic circulation and ultimately devastate renal perfusion:

• Splanchnic arterial vasodilation is the primary event, causing reduction in effective arterial blood volume and decreased mean arterial pressure despite a hyperdynamic circulatory state 2
• Portal hypertension from cirrhosis increases sinusoidal pressure and triggers the release of vasodilatory substances into the systemic circulation 2
• Arterial underfilling activates compensatory mechanisms including the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), which paradoxically cause intense renal vasoconstriction 1, 2
• Cirrhotic cardiomyopathy impairs the heart's ability to increase cardiac output sufficiently to compensate for the systemic vasodilation 2
• Inflammatory signals and bacterial translocation exert effects on renal tubular cells, leading to mitochondrial dysfunction and metabolic downregulation 2
• Vasoactive mediators including cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1 further compromise renal blood flow and glomerular microcirculation 2

The kidneys themselves remain structurally intact—this is purely functional renal failure that can reverse with liver transplantation 3, 4.

Clinical Classification

The nomenclature has evolved to align with standard kidney injury terminology:

• Type 1 HRS (now HRS-AKI) features rapid, progressive renal impairment with serum creatinine increasing ≥100% to >2.5 mg/dL in less than 2 weeks, carrying a median survival of approximately 1 month without treatment 1, 3
• Type 2 HRS (now HRS-CKD) presents with stable or slowly progressive renal impairment over a more chronic course, with median survival of approximately 6 months 2, 5

The fixed creatinine threshold of >1.5 mg/dL has been abandoned because it delays diagnosis—newer criteria emphasize dynamic changes allowing earlier detection and treatment. 1

Diagnostic Criteria

The International Club of Ascites requires ALL of the following elements for HRS diagnosis 1, 3:

• Cirrhosis with ascites 1
• Acute kidney injury defined by ICA-AKI criteria (Stage 1: creatinine increase ≥0.3 mg/dL up to 2-fold baseline; Stage 2: 2-3-fold increase; Stage 3: >3-fold increase or >4 mg/dL with acute increase ≥0.3 mg/dL or initiation of dialysis) 1, 3
• No improvement in serum creatinine after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g/day) 1, 3
• Absence of shock 1, 3
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media) 1, 3
• Absence of proteinuria (>500 mg/day) and microhematuria (>50 RBCs per high power field) 1, 3
• Normal findings on renal ultrasonography 1, 3

Differential Diagnosis

HRS accounts for only 15-43% of AKI cases in cirrhotic patients 1:

• Hypovolemia causes 27-50% of AKI cases 1
• Acute tubular necrosis (ATN) causes 14-35% of AKI cases 1
• Urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), KIM-1, IL-18, and L-FABP may help differentiate HRS from ATN 1, 6

Critical Pitfalls to Avoid

• 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
• Consider renal biopsy if proteinuria, microhematuria, or abnormal kidney size is present to evaluate for parenchymal disease 1

Risk Factors and Triggers

• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important risk factors—HRS develops in approximately 30% of patients with SBP 1, 3
• High MELD scores predict increased HRS risk 1
• Severe cholestasis and hepatocellular carcinoma with vascular invasion can exacerbate the pathophysiology 2

Prognosis

HRS carries a grim prognosis with median survival of untreated type 1 HRS approximately 1 month. 1, 3 The mortality rate approaches 90% at three months after diagnosis without treatment 7. Early diagnosis and treatment are critical as earlier intervention leads to better outcomes 1.

Treatment Approach

Terlipressin plus albumin is the first-line pharmacologic treatment, with a starting dose of 0.5-1 mg IV every 4-6 hours, increasing gradually to a maximum of 2 mg every 4 hours if serum creatinine does not decrease by at least 25% after 3 days 3. However, this reverses HRS in only 40-50% of patients 5, 6.

• Norepinephrine plus albumin is an equally effective alternative to terlipressin and may be administered outside ICU settings with close monitoring 2, 3
• Terlipressin in continuous IV infusion is better tolerated than IV boluses with the same efficacy 6
• Liver transplantation is the only curative treatment, addressing the underlying hepatic dysfunction that drives the entire pathophysiological process 2, 3, 4
• Renal replacement therapy should not be used as first-line therapy 4, 5

Prevention Strategies

• Albumin infusion with antibiotics when treating spontaneous bacterial peritonitis helps prevent HRS 1, 3
• Norfloxacin 400 mg/day reduces HRS incidence in advanced cirrhosis 2, 3
• Pentoxifylline 400 mg three times daily prevents HRS in severe alcoholic hepatitis 2, 3
• Avoiding nephrotoxic drugs in patients with advanced cirrhosis is essential 3