What are the types of hepatorenal syndrome (HRS) and their management?

Hepatorenal Syndrome Types

Classification System

Hepatorenal syndrome is classified into two distinct types: HRS-AKI (formerly Type 1 HRS) characterized by rapid, progressive renal impairment, and HRS-CKD (formerly Type 2 HRS) featuring stable or slowly progressive chronic kidney dysfunction. 1

HRS-AKI (Type 1 HRS)

• Defined by rapid deterioration of renal function with serum creatinine increasing ≥100% to >2.5 mg/dL in less than 2 weeks, though modern criteria now use dynamic AKI staging rather than fixed thresholds 1

• Carries extremely poor prognosis with median survival of approximately 1 month if untreated, making it a medical emergency requiring immediate intervention 2, 1

• Often precipitated by bacterial infections, particularly spontaneous bacterial peritonitis (SBP), which triggers HRS development in approximately 30% of cases 1, 3

• Requires AKI staging according to International Club of Ascites criteria: Stage 1 (creatinine increase ≥0.3 mg/dL or 1.5-2x baseline), Stage 2 (2-3x baseline), Stage 3 (>3x baseline or >4 mg/dL with acute increase ≥0.3 mg/dL or initiation of renal replacement therapy) 2, 1

HRS-CKD (Type 2 HRS)

• Characterized by moderate, stable or slowly progressive renal impairment with a more chronic course and median survival of approximately 6 months 1, 4

• Main clinical manifestation is refractory ascites rather than acute kidney failure, distinguishing it from the acute presentation of HRS-AKI 4, 5

• Serum creatinine remains moderately elevated above 1.5 mg/dL but stays relatively stable over longer periods without the rapid doubling seen in HRS-AKI 5

Diagnostic Criteria (Applicable to Both Types)

All of the following must be present for HRS diagnosis according to the International Club of Ascites 2, 1:

• Cirrhosis with ascites as the underlying condition 1

• No improvement after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight (maximum 100 g on day 1) 2, 1

• Absence of shock at time of diagnosis 2, 1

• No current or recent nephrotoxic drug exposure (NSAIDs, aminoglycosides, iodinated contrast media) 2, 1

• No evidence of structural kidney injury: proteinuria <500 mg/day, microhematuria <50 RBCs per high power field, and normal renal ultrasonography 2, 1

Critical Evolution in Classification

• The fixed serum creatinine threshold of >1.5 mg/dL has been abandoned because it delays diagnosis and signifies severely reduced GFR; newer criteria emphasize dynamic creatinine changes allowing earlier detection and treatment 1

• Earlier treatment leads to better outcomes, making the shift to dynamic AKI criteria clinically crucial given the 1-month median survival of untreated HRS-AKI 1

• HRS is no longer considered purely "functional"—systemic inflammation, oxidative stress, and bile salt-related tubular damage contribute significantly, explaining why some patients fail to respond to vasoconstrictors 6

Management Differences by Type

HRS-AKI (Type 1) Treatment

• Terlipressin plus albumin is first-line therapy: start with 1 mg IV every 4-6 hours plus albumin 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day 2, 7

• Dose escalation on Day 4: increase to 2 mg every 4 hours if serum creatinine doesn't decrease by at least 25-30% after 3 days 2, 7

• Achieves HRS reversal in 29.1% of patients (verified reversal defined as two consecutive creatinine values ≤1.5 mg/dL at least 2 hours apart) compared to 15.8% with placebo 7

• Alternative regimen where terlipressin unavailable: midodrine (titrated to 12.5 mg PO TID) plus octreotide (200 μg SC TID) plus albumin (10-20 g IV daily for up to 20 days) 2

• Norepinephrine plus albumin is another option requiring ICU setting, with goal to increase mean arterial pressure by 15 mmHg 2

• Expedited liver transplantation referral is mandatory as this is the definitive treatment, with post-transplant survival approximately 65% 2, 3

HRS-CKD (Type 2) Treatment

• TIPS (transjugular intrahepatic portosystemic shunt) is particularly effective for improving renal function and controlling refractory ascites in Type 2 HRS 2

• Vasoconstrictor therapy may be used but the urgency is less than with HRS-AKI given the more stable clinical course 2

• Liver transplantation remains definitive treatment for both types, though Type 2 patients may have more time for optimization 2, 3

Prevention Strategies

• Albumin with antibiotics for SBP: 1.5 g/kg at diagnosis, then 1 g/kg on day 3 reduces HRS incidence from 30% to 10% and mortality from 29% to 10% 2

• Norfloxacin 400 mg/day reduces HRS incidence in advanced cirrhosis 2, 3

• Pentoxifylline 400 mg TID prevents HRS development in severe alcoholic hepatitis 2, 3

Common Pitfalls to Avoid

• Do not wait for creatinine to reach 1.5 mg/dL before considering HRS—use dynamic AKI criteria instead for earlier intervention 1

• Do not rely on urine output as a diagnostic criterion in cirrhotic patients with ascites 1

• Do not discontinue treatment on Day 4 if creatinine is at or above baseline—this indicates treatment failure and alternative strategies are needed 7

• 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

• Recognize that HRS reversal may be partial—recovery of renal function occurs in less than 50% of patients even with optimal terlipressin therapy 4