What is hepatorenal syndrome?

What is Hepatorenal Syndrome Type 1 (HRS-AKI)?

Hepatorenal syndrome type 1, now termed HRS-AKI (hepatorenal syndrome-acute kidney injury), is a rapidly progressive functional kidney failure occurring in patients with advanced cirrhosis and ascites, characterized by a doubling of serum creatinine to >2.5 mg/dL within less than 2 weeks, without any structural kidney damage. 1

Core Definition and Pathophysiology

HRS-AKI represents a severe form of functional renal failure that develops specifically in the context of advanced liver disease. 1 The condition is fundamentally driven by:

• Splanchnic arterial vasodilation causing reduction in effective arterial blood volume and decreased mean arterial pressure, creating a hyperdynamic circulatory state 2
• Arterial underfilling that 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, preventing adequate cardiac output compensation for systemic vasodilation 1, 2
• Increased synthesis of vasoactive mediators including cysteinyl leukotrienes, thromboxane A2, and endothelin-1, which further compromise renal blood flow and glomerular microcirculation 2

Current Diagnostic Criteria

The International Club of Ascites and American Association for the Study of Liver Diseases have established specific criteria that must ALL be met: 1

Required positive findings:

• Cirrhosis with ascites 1
• Serum creatinine >1.5 mg/dL 1
• AKI staging: Stage 1 (creatinine increase ≥0.3 mg/dL up to 2-fold baseline), Stage 2 (2-3 fold increase), or Stage 3 (>3-fold increase or >4 mg/dL with acute rise ≥0.3 mg/dL or initiation of dialysis) 1

Required exclusions (must be absent):

• No improvement after 2 consecutive days of diuretic withdrawal AND plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g/day) 1
• No shock 1
• No current or recent nephrotoxic drug use (NSAIDs, aminoglycosides, iodinated contrast) 1
• No proteinuria >500 mg/day 1
• No microhematuria >50 RBCs per high power field 1
• Normal renal ultrasonography 1

Clinical Significance and Prognosis

HRS-AKI carries an extremely poor prognosis with median survival of approximately 1 month if untreated. 1 This represents one of the most lethal complications of cirrhosis, with mortality approaching 90% at three months. 3

Key epidemiologic points:

• HRS accounts for 15-43% of all AKI cases in cirrhotic patients 1
• Approximately 40% of cirrhotic patients will develop HRS during their disease course 4
• Bacterial infections, particularly spontaneous bacterial peritonitis (SBP), are the most important precipitating factors, with HRS developing in approximately 30% of SBP cases 1, 2

Distinction from Type 2 HRS (HRS-CKD)

Type 2 HRS, now termed HRS-CKD (chronic kidney disease), differs fundamentally from HRS-AKI: 1

• Features stable or slowly progressive renal impairment with a more chronic course 1
• Main clinical manifestation is refractory ascites rather than acute deterioration 5
• Median survival of 6 months (versus 1 month for HRS-AKI) 5

Critical Differential Diagnosis

The most important clinical challenge is distinguishing HRS-AKI from acute tubular necrosis (ATN), as both present with AKI in cirrhotic patients but require different management approaches. 1

Other common causes of AKI in cirrhosis include:

• Hypovolemia (27-50% of cases) 1
• Acute tubular necrosis (14-35% of cases) 1

Urinary biomarkers, particularly neutrophil gelatinase-associated lipocalin (NGAL), along with KIM-1, IL-18, and L-FABP, can help differentiate HRS from ATN, though these are not yet universally available. 1, 6

Evolution of Diagnostic Criteria

A critical update: the previous requirement for serum creatinine to double to >2.5 mg/dL within 2 weeks has been removed from current guidelines. 1 This change reflects recognition that earlier diagnosis and treatment lead to better outcomes, and waiting for such severe deterioration delays potentially life-saving therapy. 1

Treatment Implications

Terlipressin plus albumin is the first-line pharmacological treatment, with liver transplantation remaining the only definitive cure. 7 The response rate to terlipressin is only 40-50%, underscoring the severity of this condition. 5, 6

Prevention is paramount: albumin infusion with antibiotics when treating SBP can prevent HRS development. 1, 7