What is the treatment for hepato-renal syndrome (HRS) in a patient with impaired renal function and liver disease?

Treatment of Hepatorenal Syndrome

Terlipressin plus albumin is the first-line treatment for HRS-AKI and should be initiated immediately upon diagnosis, starting with terlipressin 1 mg IV every 4-6 hours (or 2 mg/day by continuous infusion) combined with albumin 1 g/kg on day 1 (maximum 100 g), followed by 20-40 g/day. 1, 2, 3

Initial Management Approach

Immediate Actions for HRS-AKI (Type 1 HRS)

• Withdraw all diuretics immediately and discontinue nephrotoxic medications including NSAIDs and aminoglycosides, as these worsen renal perfusion 1, 4

• Initiate volume expansion with albumin at 1 g/kg body weight (maximum 100 g) on day 1, then 20-40 g/day thereafter, even before confirming HRS diagnosis 1, 2

• Screen for and treat infections aggressively, particularly spontaneous bacterial peritonitis, as bacterial infections are the most important precipitating factor for HRS 2, 5

• Perform electrocardiogram before starting vasoconstrictors to screen for cardiovascular contraindications, as ischemic and cardiovascular events are potential adverse effects 1

First-Line Pharmacologic Treatment

Terlipressin Plus Albumin Protocol

Dosing regimen:

• Start terlipressin at 1 mg IV bolus every 4-6 hours, OR 2 mg/day by continuous IV infusion (continuous infusion reduces total daily dose and adverse effects) 1, 2, 3

• Administer albumin 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day 1, 2

• On day 3-4, assess response: If serum creatinine has not decreased by ≥25% from peak value, increase terlipressin in stepwise manner to maximum of 12 mg/day (or 2 mg every 4 hours) 1, 2, 3

• Continue treatment until: Serum creatinine decreases to ≤1.5 mg/dL on two consecutive measurements at least 2 hours apart, OR for maximum of 14 days 1, 2, 3

• Discontinue if: No response by day 4, or serum creatinine remains at or above baseline 3

Evidence of efficacy: The FDA-approved CONFIRM trial demonstrated that 29.1% of patients achieved verified HRS reversal with terlipressin versus 15.8% with placebo (p=0.012), with durability of response in 31.7% versus 15.8% (p=0.003) 3

Alternative Vasoconstrictors (When Terlipressin Unavailable)

In North America where terlipressin is not available:

• Norepinephrine has been shown equivalent to terlipressin, though requires ICU monitoring 1, 2

• Midodrine plus octreotide plus albumin: Start midodrine 7.5 mg orally three times daily and octreotide 100-200 μg subcutaneously three times daily, combined with albumin 1, 2

Important caveat: Meta-analyses show vasoconstrictors with albumin reduce mortality compared to no intervention (RR 0.82,95% CI 0.70-0.96, p<0.01), regardless of agent used 6

Management of HRS-NAKI (Type 2 HRS)

• Vasoconstrictors and albumin are NOT routinely recommended for Type 2 HRS outside the context of AKI, as recurrence after treatment withdrawal is the norm and controversial data exists on long-term clinical outcomes 1

• TIPS may be considered for Type 2 HRS patients with refractory ascites, as it improves renal function and ascites control in more stable patients compared to Type 1 HRS 1, 2

• TIPS is generally contraindicated in Type 1 HRS due to severe liver failure, high risk of hepatic encephalopathy, and potential unmasking of cirrhotic cardiomyopathy 1

Renal Replacement Therapy

Indications for RRT in HRS:

• Non-responders to vasoconstrictors 1
• Severe and/or refractory electrolyte or acid-base imbalance 1
• Severe or refractory volume overload 1
• Symptomatic azotemia 1

Technical considerations:

• Continuous renal replacement therapy (CRRT) is preferred over intermittent hemodialysis in hemodynamically unstable patients, providing greater cardiovascular stability and allowing slower correction of severe hyponatremia 1, 4

• Early RRT may improve survival based on data from acute liver failure and critically ill patients 1, 4

• RRT should not be limited to transplant candidates but based on individual severity of illness, with repeated risk stratification necessary 1

Definitive Treatment: Liver Transplantation

• Liver transplantation is the only curative treatment for HRS, addressing the underlying hepatic dysfunction driving the pathophysiology 2, 5

• Patients with Type 1 HRS should be given priority for transplantation due to high mortality while on the waiting list 2

• Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes 2

• Combined liver-kidney transplantation is NOT routinely superior to liver transplantation alone, except in patients who have been under prolonged renal support therapy (>12 weeks) 2

• HRS resolves in approximately 58% of patients post-liver transplant, with mean time to resolution of 21 days (range 4-110 days) 7

Management of Recurrent HRS

• In cases of HRS recurrence after treatment cessation, repeat the course of terlipressin plus albumin 1

• Long-term therapy with terlipressin and albumin can serve as a bridge to liver transplant in patients with recurrent HRS 6

Prevention Strategies

High-risk patients should receive:

• Norfloxacin 400 mg/day for secondary and primary spontaneous bacterial peritonitis prophylaxis, which reduces HRS incidence in advanced cirrhosis 1, 2, 5

• Albumin infusion during large-volume paracentesis (>5 L): 6-8 g/L of ascitic fluid removed 1

• Early recognition and treatment of spontaneous bacterial peritonitis with antibiotics PLUS IV albumin at 1.5 g/kg at diagnosis and 1 g/kg on day 3, which reduces HRS risk and improves survival 1, 2

• Pentoxifylline 400 mg three times daily prevents HRS development in patients with severe alcoholic hepatitis 2, 5

• Antibiotic prophylaxis for 7 days following gastrointestinal bleeding 1

Critical Pitfalls to Avoid

• Do NOT delay vasoconstrictor therapy waiting for creatinine to reach 2.5 mg/dL - the old Type 1 HRS criteria have been revised, and earlier treatment (AKI stage >1A) improves outcomes 1, 2, 5

• Do NOT use diuretics in HRS-AKI - they worsen renal perfusion 5

• Do NOT use vasoconstrictors in patients with shock, sepsis, or uncontrolled bacterial infection - these are contraindications 3

• Monitor closely for ischemic and cardiovascular adverse events during vasoconstrictor therapy, with readiness to modify or discontinue treatment based on severity of side effects 1

• Recognize that recovery of renal function occurs in less than 50% of patients even with terlipressin, and recovery may be partial even in defined full responders 6

• Pre-transplantation dialysis or long waiting period should NOT preclude transplantation in patients with HRS 7