What is the treatment for Hepato-Renal Syndrome (HRS)?

Treatment of Hepatorenal Syndrome

Terlipressin plus albumin is the first-line pharmacological treatment for hepatorenal syndrome, with liver transplantation being the definitive cure. 1, 2, 3, 4, 5

Immediate Management Approach

Diagnostic Confirmation Before Treatment

• Exclude other causes of acute kidney injury including hypovolemia, shock, nephrotoxic drugs, and parenchymal renal disease before initiating HRS-specific therapy 1
• Perform diagnostic paracentesis to rule out spontaneous bacterial peritonitis, which precipitates HRS in approximately 30% of cases 1, 3, 4
• Confirm serum creatinine >1.5 mg/dL (133 μmol/L) with no improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin 1, 4

First-Line Pharmacological Treatment: Terlipressin + Albumin

This combination achieves HRS reversal in 64-76% of patients and is superior to albumin alone. 4, 5

Dosing Protocol

• Terlipressin: Start at 1 mg IV bolus every 4-6 hours 1, 2, 3, 4, 5
• Albumin: 1 g/kg (maximum 100 g) on day 1, followed by 20-40 g/day thereafter 1, 2, 3, 4
• Dose escalation: If serum creatinine does not decrease by at least 25-30% by day 3-4, increase terlipressin to 2 mg every 4 hours (maximum dose) 1, 2, 5
• Treatment duration: Continue until serum creatinine decreases below 1.5 mg/dL or for maximum 14 days 1, 2, 3, 4
• Discontinuation criteria: Stop treatment if serum creatinine remains at or above baseline on day 4 5

Expected Response

• Median time to response is approximately 14 days, with shorter response times in patients with lower baseline creatinine 1, 2
• Response characterized by progressive reduction in serum creatinine, increased arterial pressure, increased urine volume, and increased serum sodium 1, 2
• Complete response defined as two consecutive creatinine values ≤1.5 mg/dL obtained at least 2 hours apart 4, 5

Alternative Vasoconstrictor Regimens

When terlipressin is unavailable (as it was in the United States until recently), alternative vasoconstrictors can be used, though evidence is less robust. 1, 2, 3, 4

Midodrine + Octreotide + Albumin

• Midodrine: Start at 7.5 mg orally three times daily, titrate up to 12.5-15 mg three times daily 2, 3, 4
• Octreotide: 100-200 μg subcutaneously three times daily 2, 3, 4
• Albumin: 10-20 g IV daily for up to 20 days 2, 3, 4
• This combination can be administered outside ICU settings and has shown improved survival in observational studies, though evidence is based on smaller patient numbers 1, 6

Norepinephrine + Albumin

• Norepinephrine: 0.5-3 mg/hour continuous IV infusion, titrated to increase mean arterial pressure by 15 mmHg 1, 2, 3, 4
• Requires ICU-level monitoring with central venous access due to risk of tissue necrosis with peripheral administration 4
• Success rate of 83% reported in pilot studies, comparable to terlipressin 4
• Albumin: 20-40 g/day 4

Monitoring During Treatment

Essential Parameters

• Monitor urine output, fluid balance, arterial pressure, and vital signs carefully 1
• Central venous pressure monitoring is ideal to guide fluid management and prevent volume overload 1, 2
• Check serum creatinine every 2-3 days 4
• Patients should be managed in ICU or semi-ICU settings 1

Predictors of Good Response

• Serum bilirubin <10 mg/dL before treatment 2
• Increase in mean arterial pressure >5 mmHg at day 3 of treatment 2
• Lower baseline serum creatinine 1, 2

Complications to Monitor

• Ischemic complications with terlipressin: arrhythmia, angina, splanchnic ischemia, digital ischemia 2
• Pulmonary edema from albumin administration 4
• Cardiac/intestinal ischemia 4

Definitive Treatment: Liver Transplantation

Liver transplantation is the definitive treatment for both type 1 and type 2 HRS, with survival rates of approximately 65%. 1, 3, 4

• Patients with type 1 HRS should receive expedited priority for transplantation due to high mortality (median survival 1 month without treatment) while on the waiting list 1, 3, 4
• Treatment of HRS with vasoconstrictors before transplantation may improve post-transplant outcomes 1, 3, 4
• Combined liver-kidney transplantation offers no advantage over liver transplantation alone, except in patients who have been under prolonged renal support therapy (>12 weeks) 3

Adjunctive and Alternative Therapies

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

• TIPS may improve renal function in selected patients with HRS, particularly type 2 HRS 1, 3, 4
• Applicability is very limited because many patients have contraindications (coagulopathy, encephalopathy, cardiac dysfunction) 1
• More applicable in type 2 HRS than type 1 HRS due to more stable clinical condition 3
• Insufficient data to support TIPS as first-line treatment for type 1 HRS 1

Renal Replacement Therapy

• Should not be used as first-line therapy for HRS 7
• May be useful as a bridge to liver transplantation in patients who do not respond to vasoconstrictor therapy and fulfill criteria for renal support 1, 2, 3
• Continuous renal replacement therapy is preferable to intermittent hemodialysis in hemodynamically unstable patients 2
• Confers extremely poor short-term prognosis when used in HRS-AKI 8

Prevention Strategies

High-Risk Patients

• Norfloxacin 400 mg/day reduces the incidence of HRS in advanced cirrhosis 1, 3, 4
• Albumin infusion (1.5 g/kg at diagnosis, then 1 g/kg on day 3) plus antibiotics for spontaneous bacterial peritonitis reduces HRS incidence from 30% to 10% and mortality from 29% to 10% 1, 3, 4

Severe Alcoholic Hepatitis

• Pentoxifylline 400 mg three times daily for 4 weeks prevents HRS development in patients with severe alcoholic hepatitis 1, 3, 4

Type-Specific Considerations

Type 1 HRS (HRS-AKI)

• Characterized by rapid progression with serum creatinine doubling to >2.5 mg/dL within 2 weeks 3
• Median survival without treatment is approximately 1 month 1, 3
• Requires urgent treatment with vasoconstrictors plus albumin 1, 2, 3
• Terlipressin achieves reversal in 40-50% of patients 1, 9

Type 2 HRS

• More stable course with moderate renal dysfunction and median survival of 6 months 9
• Main clinical manifestation is refractory ascites 9
• Same vasoconstrictor regimens can be applied, though urgency is less acute 3
• TIPS may be more applicable in type 2 HRS 3

Critical Pitfalls to Avoid

• Never delay treatment while waiting for complete diagnostic workup if HRS is strongly suspected—early intervention improves outcomes 2
• Avoid nephrotoxic drugs (NSAIDs, aminoglycosides, contrast agents) in all patients with cirrhosis and ascites 4
• Do not use triple combination of ACE inhibitors, ARBs, and aldosterone antagonists due to hyperkalemia risk 2
• Attempting peripheral administration of norepinephrine risks tissue necrosis—always use central access 4
• Discontinue diuretics during HRS treatment to avoid further renal hypoperfusion 1
• Do not withhold liver transplantation even if HRS reverses with medical therapy, as prognosis remains poor without transplantation 4