What is the treatment for a patient with Type 1 Hepatorenal Syndrome (HRS)?

Treatment of Type 1 Hepatorenal Syndrome

Patients with Type 1 HRS should receive terlipressin plus intravenous albumin as first-line therapy, starting at 1 mg IV every 4-6 hours with albumin 1 g/kg (maximum 100 g) on day 1, followed by 20-40 g/day, escalating terlipressin to 2 mg every 4-6 hours if serum creatinine does not decrease by at least 25-30% after 3-4 days. 1, 2

Initial Management and Diagnosis Confirmation

Before initiating vasoconstrictor therapy, several critical steps must be completed:

• Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis, which precipitates HRS in approximately 30% of cases and requires specific antibiotic treatment 1, 3
• Withdraw all diuretics and provide volume expansion with albumin 1 g/kg for 2 consecutive days to exclude prerenal azotemia 1
• Exclude structural kidney disease by confirming proteinuria <0.5 g/day, microhematuria <50 RBCs/HPF, and normal renal ultrasound 1, 3
• Discontinue all nephrotoxic medications including NSAIDs, aminoglycosides, and contrast agents 1

First-Line Pharmacologic Treatment: Terlipressin Plus Albumin

Dosing Protocol

Terlipressin administration:

• Start at 1 mg IV bolus every 4-6 hours (or 2 mg/day continuous infusion in Europe) 1
• On Day 3-4, assess response: if serum creatinine has not decreased by ≥25-30% from baseline, increase to 2 mg IV every 4-6 hours (maximum 12 mg/day) 1, 2
• Continue treatment until serum creatinine decreases to ≤1.5 mg/dL or for maximum 14 days 1, 2
• Continuous IV infusion may reduce adverse effects compared to bolus dosing while maintaining similar efficacy 1

Albumin co-administration:

• Day 1: 1 g/kg IV (maximum 100 g) 1, 2
• Subsequent days: 20-40 g/day IV as clinically indicated 1

Evidence for Efficacy

The FDA-approved 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 in 31.7% versus 15.8% (p=0.003) 2. Meta-analyses show terlipressin plus albumin achieves HRS reversal in 40-50% of patients overall 1, 4.

Monitoring and Response Assessment

• Check serum creatinine every 2-3 days to assess response 1, 3
• Monitor mean arterial pressure (expect increase of ~16 mmHg) and heart rate (expect decrease of ~10 beats/minute) 2, 3
• Complete response: Two consecutive serum creatinine values ≤1.5 mg/dL at least 2 hours apart 1, 2
• Partial response: Decrease in serum creatinine ≥25% but still >1.5 mg/dL 1
• Median time to response is 14 days, shorter in patients with lower baseline creatinine 1, 3

Important Predictors of Response

• Baseline serum creatinine <3 mg/dL predicts significantly better outcomes (49.2% reversal rate versus 9.1% with creatinine ≥5 mg/dL) 5
• Serum bilirubin <10 mg/dL and increase in MAP ≥5 mmHg by day 3 are associated with higher probability of response 1, 6
• Each 1 mg/dL reduction in creatinine reduces mortality risk by 27%, even with partial response 6

Adverse Events and Contraindications

• Perform baseline ECG before starting terlipressin to screen for cardiovascular disease 1
• Common adverse events include: ischemic complications (cardiac, intestinal, digital), respiratory side effects, and bradycardia 1, 7, 4
• Contraindications: active coronary artery disease, severe peripheral vascular disease, uncontrolled arrhythmias 1
• Monitor closely for ischemic events; reduce dose or discontinue if severe adverse effects occur 1

Alternative Vasoconstrictor Options

Norepinephrine Plus Albumin (When Terlipressin Unavailable or Fails)

Norepinephrine is equally effective to terlipressin with HRS reversal rates of 39-70% and should be used when terlipressin is unavailable or contraindicated 7, 6:

• Dosing: 0.5-3.0 mg/hour continuous IV infusion (or 5-10 μg/min), titrated to increase MAP by 10-15 mmHg 1, 7
• Requires ICU-level monitoring with central venous access (peripheral administration risks tissue necrosis) 3, 7
• Combine with albumin using the same protocol as with terlipressin 1, 7
• Meta-analyses show no significant difference between norepinephrine and terlipressin in HRS reversal or relapse rates 7

Midodrine Plus Octreotide Plus Albumin (Least Preferred)

This combination is significantly less effective than terlipressin or norepinephrine and should only be used when neither is available 3, 7:

• Midodrine: titrate up to 12.5 mg orally three times daily 1, 3
• Octreotide: 200 μg subcutaneously three times daily (or continuous infusion) 1, 3
• Albumin: 10-20 g IV daily for up to 20 days 3
• This regimen works more slowly and has lower efficacy than other vasoconstrictors 7

Management of Non-Responders

If serum creatinine does not decrease by ≥25% after 3-4 days at initial terlipressin dose 6:

1. Escalate terlipressin to 2 mg every 4-6 hours (maximum 12 mg/day) 1, 6
2. Verify adequate albumin administration (1 g/kg day 1, then 20-40 g/day) 6
3. If still no response after dose escalation, switch to norepinephrine 0.5-3.0 mg/hour IV 1, 6
4. Consider renal replacement therapy as bridge to transplantation in complete non-responders 1, 3

Adjunctive and Alternative Therapies

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

• TIPS may be considered in HRS-1 patients with lower MELD scores who have adequate liver function 1
• TIPS decreases portal hypertension and improves renal perfusion by reducing vasoconstrictor mediators 1
• Applicability is limited because most HRS-1 patients have severe liver failure that contraindicates TIPS 1
• More applicable in Type 2 HRS due to more stable clinical condition 3

Renal Replacement Therapy

• Initiate RRT for standard indications: severe/refractory electrolyte or acid-base imbalance, refractory volume overload, symptomatic azotemia 1
• Consider RRT as bridge to liver transplantation in vasoconstrictor non-responders 1, 3
• Continuous RRT (CRRT) is preferred over hemodialysis for better hemodynamic stability and slower correction of hyponatremia 1
• Early RRT may improve survival based on data from critically ill patients 1

Definitive Treatment: Liver Transplantation

• Liver transplantation is the only curative treatment for HRS-1 1, 3, 7
• Expedited transplant evaluation is mandatory for all HRS-1 patients 3
• Post-transplant survival is approximately 65% in HRS-1 patients 1, 3
• Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes 3, 7
• HRS reverses in approximately 75% of patients after liver transplantation alone without combined liver-kidney transplant 3
• Even if HRS reverses with medical therapy, proceed with transplantation as long-term prognosis remains poor 3

Prevention Strategies

Prevention of HRS in High-Risk Patients

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

Critical Pitfalls to Avoid

• Do not delay treatment waiting for creatinine to rise further - early treatment with lower baseline creatinine (<3 mg/dL) yields significantly better outcomes 5
• Do not administer norepinephrine peripherally - requires central venous access to avoid tissue necrosis 3, 7
• Do not use midodrine/octreotide as first-line when terlipressin or norepinephrine are available - significantly inferior efficacy 7
• Do not withhold albumin - vasoconstrictors alone are less effective 1
• Monitor for volume overload carefully - albumin administration carries risk of pulmonary edema in patients with cirrhosis 1
• Do not continue treatment beyond 14 days without response - reassess and consider alternative strategies 1, 2