What is the treatment approach for a patient with hepatorenal syndrome, particularly those with advanced liver disease and cirrhosis?

Treatment of Hepatorenal Syndrome

Terlipressin plus albumin is the first-line pharmacological treatment for hepatorenal syndrome type 1 (HRS-AKI), with liver transplantation being the only definitive cure. 1, 2

Diagnostic Confirmation Before Treatment

Before initiating therapy, confirm the diagnosis by meeting all of the following criteria: 1

• Cirrhosis with ascites and serum creatinine >1.5 mg/dL
• No improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin (1 g/kg for 2 days)
• Absence of shock, nephrotoxic drug exposure, and structural kidney disease (proteinuria <0.5 g/day, <50 RBCs/HPF, normal renal ultrasound)
• Perform diagnostic paracentesis to exclude spontaneous bacterial peritonitis, which precipitates HRS in a significant proportion of cases 1, 3

The International Club of Ascites now uses AKI staging: 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) 1

First-Line Treatment: Terlipressin Plus Albumin

Start terlipressin 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. 1, 3 This combination achieves reversal of HRS in 64-76% of patients. 1

Terlipressin Dosing Protocol

• Initial dose: 1 mg IV every 4-6 hours 1
• Dose escalation: If serum creatinine doesn't decrease by at least 25% after 3 days, increase stepwise to maximum 2 mg every 4 hours 1
• Duration: Continue until complete response (creatinine ≤1.5 mg/dL on two occasions) or maximum 14 days 1
• FDA limitation: Patients with serum creatinine >5 mg/dL are unlikely to benefit 2

Albumin Administration

• Day 1: 1 g/kg body weight (maximum 100 g) 1, 3
• Subsequent days: 20-40 g/day IV 1, 3
• Critical prerequisite: Withdraw all diuretics for at least 2 consecutive days before starting 3
• Never use albumin alone—it must be combined with vasoconstrictors 3
• Discontinue albumin if anasarca develops, but continue vasoconstrictors 1

Monitoring During Terlipressin Treatment

• Check serum creatinine every 2-3 days to assess response 1
• Expect heart rate decrease of approximately 10 beats/minute 1
• Monitor for mean arterial pressure increase of 16.2 mmHg (maximum effect at 1.2-2 hours post-dose) 2
• Watch for complications: cardiac/intestinal ischemia, pulmonary edema, distal necrosis 1
• Central venous pressure monitoring is ideal to guide fluid management 1

Alternative Treatment Options

When Terlipressin is Unavailable: Midodrine + Octreotide + Albumin

This combination can be administered outside the ICU and even at home. 1, 3

• Midodrine: Start 7.5 mg orally three times daily, titrate up to maximum 12.5 mg three times daily 1, 3
• Octreotide: 200 μg subcutaneously three times daily 1
• Albumin: 10-20 g IV daily for up to 20 days 1, 3
• Important caveat: Never use octreotide as monotherapy—it requires midodrine to be effective 3

ICU-Based Alternative: Norepinephrine + Albumin

Norepinephrine requires ICU admission with central venous access. 1, 3

• Dose: 0.5-3.0 mg/hour IV continuous infusion 1
• Goal: Increase mean arterial pressure by 15 mmHg 1
• Success rate: 83% in reversing type 1 HRS 1
• Critical warning: Attempting peripheral administration risks tissue necrosis—central access is mandatory 1
• Requires continuous hemodynamic monitoring 1

Type 2 HRS (HRS-CKD) Management

For patients with more stable, chronic kidney dysfunction: 1

• Transjugular intrahepatic portosystemic shunt (TIPS) is more applicable in type 2 HRS than type 1 HRS due to the more stable clinical condition 1
• TIPS improves both renal function and ascites control 1

Definitive Treatment: Liver Transplantation

Liver transplantation is the only curative treatment for both type 1 and type 2 HRS. 1, 3

• Expedited referral is recommended for patients with type 1 HRS 1
• Post-transplant survival rates: Approximately 65% in type 1 HRS 1
• Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes 1
• HRS reverses in approximately 75% of patients after liver transplantation alone (without combined liver-kidney transplant) 1
• Important consideration: The reduction in serum creatinine after treatment should not change the decision to perform liver transplantation, since prognosis after recovering from HRS is still poor 1

Renal Replacement Therapy

Consider continuous venovenous hemofiltration/hemodialysis only as a bridge to liver transplantation in selected patients with type 1 HRS who are unresponsive to vasoconstrictors. 1 This is based on limited evidence and should not be routine. 1

Prevention Strategies

Prevention During Spontaneous Bacterial Peritonitis

Albumin 1.5 g/kg at diagnosis of SBP, then 1 g/kg on day 3 reduces HRS incidence from 30% to 10% and mortality from 29% to 10%. 1, 3 Patients with high bilirubin (≥4 mg/dL) or high creatinine (≥1 mg/dL) are at highest risk and benefit most. 3

Prophylaxis in Advanced Cirrhosis

• Norfloxacin 400 mg/day reduces HRS incidence in advanced cirrhosis 1, 3
• Pentoxifylline 400 mg three times daily for 4 weeks prevents HRS development in patients with severe alcoholic hepatitis 1, 3
• Avoid nephrotoxic drugs in all patients with advanced cirrhosis 1

Common Pitfalls and How to Avoid Them

• Do not exceed 100 g albumin on day 1—higher doses are associated with worse outcomes due to fluid overload 3
• Do not use hydroxyethyl starch or other artificial colloids as albumin substitutes—they are associated with harm in patients at risk of AKI 3
• Distinguish HRS from acute tubular necrosis (ATN)—this is challenging but critical, as vasoconstrictors are not justified for ATN 4, 5
• Manage patients in ICU or semi-ICU settings for optimal monitoring 1
• Do not delay transplant evaluation—median survival of untreated type 1 HRS is approximately 1 month 3