What is the treatment for hepatorenal syndrome?

Treatment of Hepatorenal Syndrome

Terlipressin plus albumin is the first-line pharmacological treatment for hepatorenal syndrome, with an initial dose of 1 mg IV every 4-6 hours combined with albumin 1 g/kg on day 1 (maximum 100 g) followed by 20-40 g/day, while liver transplantation remains the only definitive curative treatment. 1, 2

Diagnostic Confirmation Before Treatment

Before initiating therapy, you must confirm the diagnosis by meeting all criteria: cirrhosis with ascites, serum creatinine >1.5 mg/dL, no improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin (1 g/kg), absence of shock, no nephrotoxic drug exposure, and absence of structural kidney disease (proteinuria <0.5 g/day, <50 RBCs/HPF on urinalysis, normal renal ultrasound). 1

Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis, which precipitates HRS in a significant proportion of cases and requires specific treatment with antibiotics plus albumin. 1, 3

First-Line Pharmacological Treatment: Terlipressin Plus Albumin

Start terlipressin at 1 mg IV every 4-6 hours plus albumin 1 g/kg (maximum 100 g) on day 1, followed by albumin 20-40 g/day. 4, 1 The FDA has approved terlipressin (TERLIVAZ) specifically to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function, though patients with serum creatinine >5 mg/dL are unlikely to benefit. 2

Dose Escalation Protocol

If serum creatinine does not decrease by at least 25% from baseline at day 3, increase terlipressin stepwise to a maximum of 2 mg IV every 4 hours. 4, 1 Continue treatment until serum creatinine decreases below 1.5 mg/dL (typically to 1-1.2 mg/dL) or for a maximum of 14 days. 4, 1

Monitoring and Response Assessment

Check serum creatinine every 2-3 days to assess response. 1, 3 Complete response is defined as serum creatinine ≤1.5 mg/dL on two occasions, while partial response is a ≥25% decrease in creatinine but still >1.5 mg/dL. 1 Predictors of favorable response include baseline serum bilirubin <10 mg/dL and an increase in mean arterial pressure >5 mmHg at day 3 of treatment. 4

Discontinue albumin if anasarca develops (indicating severe volume overload), but continue vasoconstrictors. 1, 5

Efficacy and Safety

Terlipressin plus albumin achieves reversal of HRS in 40-50% of patients, significantly superior to albumin alone. 4, 1 Cardiovascular or ischemic complications occur in approximately 12% of patients, requiring permanent withdrawal in only a minority of cases. 4 Most studies excluded patients with severe cardiovascular or ischemic conditions, so exercise caution in these populations. 4

Alternative Treatments When Terlipressin Is Unavailable

Option A: Norepinephrine Plus Albumin (ICU Required)

Norepinephrine 0.5-3 mg/hour IV continuous infusion plus albumin 20-40 g/day is an effective alternative but requires ICU admission with central venous access and continuous hemodynamic monitoring. 4, 1, 5 Titrate norepinephrine to increase mean arterial pressure by 15 mmHg. 4, 1 This regimen has shown an 83% success rate in reversing type 1 HRS in pilot studies. 1, 3

Critical pitfall: Never attempt peripheral administration of norepinephrine as it risks tissue necrosis—central venous access is mandatory. 1

Option B: Midodrine Plus Octreotide Plus Albumin (Can Be Given Outside ICU)

Start midodrine 7.5 mg orally three times daily, titrated up to a maximum of 12.5 mg three times daily, plus octreotide 100-200 μg subcutaneously three times daily, plus albumin 10-20 g IV daily for up to 20 days. 4, 1, 3 This combination can be administered outside the ICU and even at home, making it practical when ICU beds are unavailable. 1, 3

Important caveat: Never use octreotide as monotherapy—it requires midodrine to be effective, as two studies have definitively shown octreotide alone provides no benefit. 3 The evidence for this combination is weaker than for terlipressin or norepinephrine, with smaller patient numbers reported. 4

Definitive Treatment: Liver Transplantation

Liver transplantation is the only curative treatment for both type 1 and type 2 HRS, with post-transplant survival rates of approximately 65% in type 1 HRS. 1, 3 Patients with type 1 HRS should receive expedited referral for transplantation. 1, 3 Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes. 1

Critical consideration: Even if serum creatinine improves with vasoconstrictor therapy and MELD score decreases, this should not change the decision to perform liver transplantation, as prognosis after recovering from HRS remains poor without transplant. 1

Adjunctive and Alternative Therapies

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS has been reported to improve renal function in type 1 HRS, but applicability is very limited because many patients have contraindications. 4 More studies are needed before recommending TIPS as standard treatment. 4 TIPS has also shown benefit in type 2 HRS for improving renal function and controlling ascites. 4, 1

Renal Replacement Therapy

Renal replacement therapy (hemodialysis or continuous venovenous hemofiltration) may be useful only as a bridge to liver transplantation in patients who do not respond to vasoconstrictor therapy and fulfill criteria for renal support. 4, 1 There is insufficient evidence to recommend artificial liver support systems in clinical practice. 4

Prevention Strategies

Administer albumin 1.5 g/kg at diagnosis of spontaneous bacterial peritonitis, followed by 1 g/kg on day 3, to reduce HRS incidence from 30% to 10% and mortality from 29% to 10%. 1, 3 This is particularly important in patients with high bilirubin (≥4 mg/dL) or high creatinine (≥1 mg/dL). 3

Norfloxacin 400 mg/day reduces the incidence of HRS in advanced cirrhosis. 4, 1 Pentoxifylline 400 mg three times daily prevents HRS development in patients with severe alcoholic hepatitis. 4, 1

Type 2 HRS Considerations

Terlipressin is also associated with improvement of renal function in type 2 HRS, though there is more limited information on its use in these patients. 4 The main clinical manifestation of type 2 HRS is refractory ascites with a more stable course and median survival of 6 months. 1

Critical Pitfalls to Avoid

• Do not use terlipressin in patients with serum creatinine >5 mg/dL—they are unlikely to benefit. 2
• Exclude patients with known severe cardiovascular or ischemic conditions from terlipressin therapy due to increased risk of complications. 4
• The effectiveness of terlipressin in HRS with concomitant sepsis is unknown, as most trials excluded these patients. 4
• Monitor closely for cardiovascular or ischemic complications, which occur in ~12% of patients on terlipressin. 4
• Avoid nephrotoxic drugs and withdraw diuretics in patients at high risk for HRS. 1