Treatment of Hepatorenal Syndrome
Initiate terlipressin 1 mg IV every 4-6 hours plus albumin 1 g/kg (maximum 100 g) on day 1, followed by 20-40 g/day, as first-line treatment for hepatorenal syndrome type 1 (HRS-AKI), with dose escalation to 2 mg every 4 hours if serum creatinine does not decrease by at least 25% after 3 days. 1, 2, 3
Diagnostic Confirmation Before Treatment
Before initiating therapy, confirm the diagnosis by ensuring all criteria are met: 2
- Cirrhosis with ascites
- Serum creatinine >1.5 mg/dL (or AKI stage 2-3)
- No improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin
- Absence of shock, nephrotoxic drug exposure, and structural kidney disease (proteinuria <0.5 g/day, <50 RBCs/HPF, normal renal ultrasound)
Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis, which precipitates HRS in a significant proportion of cases and requires specific antibiotic treatment plus albumin. 2
First-Line Pharmacological Treatment: Terlipressin Plus Albumin
Dosing Protocol
Start terlipressin 0.85 mg (equivalent to 1 mg terlipressin acetate) IV bolus every 4-6 hours, administered over 2 minutes. 1, 3
Administer albumin 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day thereafter. 1, 2
Dose Escalation Strategy
On day 3-4 of therapy, if serum creatinine has not decreased by at least 25-30% from baseline, increase terlipressin to 1.7 mg (equivalent to 2 mg terlipressin acetate) every 4 hours. 1, 3
If serum creatinine is at or above baseline on day 4, discontinue treatment as the patient is a non-responder. 3
Treatment Duration and Goals
Continue treatment until serum creatinine decreases to ≤1.5 mg/dL on two consecutive measurements at least 2 hours apart, or for a maximum of 14 days. 1, 3
The CONFIRM trial demonstrated that terlipressin achieved verified HRS reversal in 29.1% of patients versus 15.8% with placebo (p=0.012), with durability of reversal (without renal replacement therapy to day 30) in 31.7% versus 15.8% (p=0.003). 3
Monitoring Parameters
Monitor the following every 2-3 days: 2
- Serum creatinine
- Urine output and fluid balance
- Blood pressure (expect MAP increase of approximately 16 mmHg)
- Heart rate (expect decrease of approximately 10 beats/minute)
- Central venous pressure (ideally)
Watch for ischemic complications including cardiac ischemia/arrhythmia, splanchnic ischemia, and digital necrosis, which are the primary safety concerns with terlipressin. 4
Alternative Vasoconstrictor Regimens
Midodrine Plus Octreotide Plus Albumin
In regions where terlipressin is unavailable, use midodrine starting at 7.5 mg orally three times daily (titrate to 12.5-15 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. 1, 2
This combination can be administered outside the ICU and even at home, providing a practical alternative when terlipressin is not accessible. 2
Norepinephrine Plus Albumin
Norepinephrine 0.5-3 mg/hour IV continuous infusion plus albumin is an effective alternative, but requires ICU-level monitoring with central venous access and titration to increase MAP by 15 mmHg. 5, 1, 2
Never attempt peripheral administration of norepinephrine due to risk of tissue necrosis. 2
A pilot study reported an 83% success rate with norepinephrine, making it a reliable alternative when ICU monitoring is available. 2
Type 2 HRS Management
For type 2 HRS (stable or slowly progressive renal dysfunction with refractory ascites), the same vasoconstrictor regimens can be used, though the urgency is less acute than type 1 HRS. 1
Transjugular intrahepatic portosystemic shunt (TIPS) is more applicable in type 2 HRS than type 1 HRS due to the more stable clinical condition, and has been shown to improve both renal function and ascites control. 5, 1, 2
Renal Replacement Therapy
Consider renal replacement therapy only as a bridge to liver transplantation in patients who do not respond to vasoconstrictor therapy and fulfill criteria for renal support. 5, 2
Continuous venovenous hemofiltration is preferable to intermittent hemodialysis in hemodynamically unstable patients. 4
The duration of pretransplant dialysis is the only predictor of HRS non-reversal after liver transplantation, with a 6% increased risk of non-reversal for each additional day of dialysis. 6 This underscores the importance of timely liver transplantation rather than prolonged dialysis support.
Definitive Treatment: Liver Transplantation
Liver transplantation is the definitive treatment for both type 1 and type 2 HRS, with survival rates of approximately 65% in type 1 HRS. 5, 1, 2
Patients with type 1 HRS should receive expedited referral and priority for transplantation due to high mortality while on the waiting list (median survival approximately 2 weeks without treatment). 1, 2, 7
Treatment of HRS with vasoconstrictors before transplantation may improve post-transplant outcomes, and HRS reverses in approximately 75% of patients after liver transplantation alone (without combined liver-kidney transplant). 5, 2, 6
Combined liver-kidney transplantation offers no advantage over liver transplantation alone, except in patients who have been under prolonged renal support therapy (>12 weeks). 1
Prevention Strategies
In Advanced Cirrhosis
Administer norfloxacin 400 mg/day to reduce the incidence of HRS in patients with advanced cirrhosis. 5, 1, 2
In Spontaneous Bacterial Peritonitis
Give albumin 1.5 g/kg at diagnosis of spontaneous bacterial peritonitis, then 1 g/kg on day 3, which reduces HRS incidence from 30% to 10% and mortality from 29% to 10%. 2
In Severe Alcoholic Hepatitis
Administer pentoxifylline 400 mg three times daily for 4 weeks to prevent HRS development in patients with severe alcoholic hepatitis. 5, 1, 2
Important Clinical Pitfalls
Avoid nephrotoxic drugs (NSAIDs, aminoglycosides, contrast agents) and diuretics in patients at high risk for HRS. 2
Do not use the triple combination of ACE inhibitors, ARBs, and aldosterone antagonists due to severe hyperkalemia risk. 4
Predictors of good response to terlipressin include serum bilirubin <10 mg/dL before treatment and an increase in MAP >5 mmHg at day 3 of treatment. 4
The median time to response is approximately 14 days, with shorter response times in patients with lower baseline serum creatinine. 4
Even when HRS reverses with medical therapy, the prognosis remains poor without liver transplantation, so the reduction in MELD score after treatment should not change the decision to proceed with transplantation. 2