What is the treatment for Hepatorenal Syndrome (HRS)?

Treatment of Hepatorenal Syndrome (HRS)

The first-line treatment for hepatorenal syndrome is terlipressin plus albumin, which reverses HRS in approximately 40-70% of patients and improves short-term survival. 1, 2

Initial Management and Diagnosis

Before initiating specific HRS therapy, you must:

• Perform diagnostic paracentesis to exclude spontaneous bacterial peritonitis, which can precipitate HRS 1, 3
• Withdraw all diuretics immediately upon diagnosis of acute kidney injury 1
• Stop nephrotoxic drugs including NSAIDs and aminoglycosides 1
• Consider withholding non-selective beta-blockers, particularly in hypotensive patients 1
• Administer albumin 1 g/kg (maximum 100 g) on day 1 for volume expansion to exclude volume-responsive AKI before diagnosing HRS 1

First-Line Pharmacologic Treatment: Terlipressin Plus Albumin

Terlipressin Dosing Protocol

Start terlipressin at 1 mg IV every 4-6 hours (or 0.85 mg of the FDA-approved formulation) 1, 2:

• If serum creatinine does not decrease by ≥25% by day 3, increase to 2 mg every 4-6 hours (maximum dose) 1
• Continue treatment until serum creatinine falls below 1.5 mg/dL (typically 1.0-1.2 mg/dL) 1
• Maximum treatment duration is 14 days, though median time to response is 14 days 1
• If serum creatinine remains at or above baseline after 4 days at maximum dose, discontinue therapy 1, 2

Alternative Terlipressin Administration

Continuous IV infusion of terlipressin (starting at 2 mg/day, increased to maximum 12 mg/day) is equally effective as bolus dosing but causes fewer ischemic side effects 1. This method provides more stable portal pressure reduction 1.

Albumin Dosing with Terlipressin

Administer 20% albumin at 1 g/kg on day 1 (maximum 100 g), followed by 40-50 g/day throughout treatment 1:

• Albumin improves efficacy by increasing cardiac output and providing antioxidant/anti-inflammatory effects 1
• The combination of terlipressin plus albumin is significantly more effective than terlipressin alone (77% vs 25% response rate) 4
• Monitor for volume overload and pulmonary edema, especially with prolonged albumin infusion 1

Expected Response and Monitoring

Response is characterized by progressive reduction in serum creatinine, increased arterial pressure (>5 mmHg by day 3), increased urine output, and rising serum sodium 1:

• Predictors of good response include: serum bilirubin <10 mg/dL, lower baseline creatinine, and mean arterial pressure increase >5 mmHg at day 3 1
• The CONFIRM trial demonstrated 29.1% achieved verified HRS reversal vs 15.8% with placebo (p=0.012) 2
• Recurrence after treatment withdrawal is uncommon (approximately 17%) and retreatment is generally effective 1, 4

Side Effects of Terlipressin

Cardiovascular and ischemic complications occur in approximately 12% of patients 1:

• Abdominal pain or intestinal ischemia
• Digital or skin ischemia
• Cardiac ischemia or arrhythmias
• Pulmonary edema from albumin
• Most studies excluded patients with severe cardiovascular disease 1

Second-Line Treatment: Norepinephrine Plus Albumin

When terlipressin is unavailable or contraindicated, norepinephrine plus albumin is an equally effective alternative 1, 5:

Norepinephrine Dosing Protocol

• Start at 0.5 mg/hour as continuous IV infusion (requires ICU setting) 1, 5
• Increase by 0.5 mg/hour every 4 hours to maximum 3 mg/hour 1, 5
• Goal: increase mean arterial pressure by at least 10 mmHg or urine output >200 mL/4 hours 1, 5
• Administer albumin to maintain central venous pressure 4-10 mmHg 1

Meta-analyses show no significant difference between terlipressin+albumin and norepinephrine+albumin in HRS reversal or relapse rates 1, 5. Success rates with norepinephrine reach 83% in some studies 5, 3.

Third-Line Treatment: Midodrine Plus Octreotide Plus Albumin

This combination is significantly less effective than terlipressin or norepinephrine and should only be used when neither is available 1:

Dosing Protocol

• Midodrine: start 7.5 mg orally three times daily, titrate to maximum 12.5 mg three times daily 1, 6
• Octreotide: 100-200 μg subcutaneously three times daily 1, 3
• Albumin: 20-40 g/day IV for up to 20 days 3

Terlipressin achieved 70.4% response rate vs 28.6% with midodrine/octreotide in head-to-head comparison (p=0.01) 6. This combination works more slowly and has limited supporting evidence 1, 5.

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS has been reported to improve renal function in type 1 HRS but cannot be recommended as standard therapy due to insufficient evidence and limited applicability 1, 3:

• High rates of contraindications in HRS patients (advanced liver failure, encephalopathy)
• Very limited data from small uncontrolled studies
• May be considered in highly selected cases

Renal Replacement Therapy (RRT)

RRT should not be used as first-line therapy but only as a bridge to liver transplantation in patients unresponsive to vasoconstrictors 1, 7:

• Continuous RRT is preferred over intermittent hemodialysis in cirrhotic patients 1
• Initiate RRT for: severe acidosis, hyperkalemia, severe hyponatremia unresponsive to medical management, or progressive volume overload 1
• Prognosis with RRT is very poor unless integrated into transplant plan 1

Liver Transplantation

Liver transplantation is the definitive treatment for HRS with approximately 65% survival in type 1 HRS patients 3, 7:

• Expedited referral for transplantation is recommended for all HRS patients 3
• Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes 3
• Even if creatinine improves with treatment, transplant decision should not change as prognosis remains poor 3

Prevention of HRS

In high-risk populations, preventive strategies include:

• Norfloxacin 400 mg/day reduces HRS incidence in advanced cirrhosis 1, 3
• Pentoxifylline 400 mg three times daily prevents HRS in severe alcoholic hepatitis 1, 3
• Albumin with antibiotics for spontaneous bacterial peritonitis reduces HRS risk 1

Type 2 HRS Management

Terlipressin plus albumin also improves renal function in type 2 HRS, though evidence is more limited 1:

• TIPS may be particularly beneficial for type 2 HRS with refractory ascites 3
• Median survival is 6 months without treatment 8
• Liver transplantation remains definitive therapy 3

Critical Pitfalls to Avoid

• Do not delay vasoconstrictor therapy - higher baseline creatinine predicts treatment failure 1, 9
• Do not use vasoconstrictors without albumin - combination therapy is significantly more effective 4
• Do not continue ineffective therapy beyond 4 days at maximum dose - increases adverse effects without benefit 1, 9
• Do not use RRT as first-line therapy - reserve for bridge to transplant only 7
• Do not assume HRS is purely functional - ATN may coexist, consider urinary NGAL to differentiate 1
• Monitor closely for ischemic complications with terlipressin, especially cardiovascular events 1