What is the recommended treatment for hepatorenal syndrome in an adult with cirrhosis and acute kidney injury?

Treatment of Hepatorenal Syndrome in Adults with Cirrhosis and Acute Kidney Injury

For adults with cirrhosis and hepatorenal syndrome-AKI (HRS-AKI), treatment consists of immediate diuretic withdrawal, intravenous albumin (1 g/kg up to 100 g/day for 2 days), followed by vasoconstrictors (terlipressin or norepinephrine) plus albumin (20-40 g/day) for Stage 2 or greater AKI, with liver transplantation being the definitive cure. 1

Initial Management: First 48 Hours

Immediate Risk Factor Removal

• Discontinue all diuretics immediately upon diagnosis of AKI in cirrhotic patients 1
• Withdraw all nephrotoxic medications including NSAIDs, aminoglycosides, ACE inhibitors, ARBs, and iodinated contrast 1
• Treat any bacterial infections promptly with appropriate antibiotics, as infection is the most common precipitant of HRS-AKI 1

Volume Expansion Trial

• Administer intravenous albumin at 1 g/kg body weight (maximum 100 g) on day 1, followed by 20-40 g on day 2 1
• This albumin trial serves to exclude volume-responsive AKI and is mandatory before diagnosing HRS-AKI 1
• Reassess serum creatinine after 48 hours to determine response 1

Critical caveat: Recent evidence suggests that fixed-dose albumin in unselected cirrhotic patients with AKI may cause harm via volume overload and pulmonary edema. 2 Therefore, assess volume status carefully before albumin administration, particularly in patients with signs of fluid overload.

Vasoconstrictor Therapy: When and How

Indications for Vasoconstrictors

Initiate vasoconstrictors plus albumin when:

• Patient has Stage 2 or Stage 3 AKI (serum creatinine >2× baseline or >3× baseline, respectively) 1, 3
• No improvement in creatinine after the 48-hour albumin trial 1
• Patient meets full diagnostic criteria for HRS-AKI 1

Do NOT initiate vasoconstrictors for:

• Stage 1A AKI (peak creatinine <1.5 mg/dL) due to uncertain benefit and increased adverse events 1, 3
• Patients with ACLF Grade 3 (acute-on-chronic liver failure with ≥3 organ failures) 1
• Patients with active coronary, peripheral, or mesenteric ischemia 4
• Patients with hypoxia (SpO₂ <90%) until oxygenation improves 4

First-Line Vasoconstrictor: Terlipressin

Terlipressin is the preferred first-line agent when available and without contraindications. 1, 5, 6

Dosing regimen:

• Days 1-3: Terlipressin 0.85 mg (1 mg) IV every 6 hours 1, 4
• Day 4: Assess serum creatinine response:
  • If creatinine decreased ≥30% from baseline: continue 0.85 mg every 6 hours 4
  • If creatinine decreased <30%: increase to 1.7 mg (2 mg) every 6 hours 4
  • If creatinine at or above baseline: discontinue terlipressin 4
• Continue until 24 hours after two consecutive creatinine values ≤1.5 mg/dL at least 2 hours apart, or for a maximum of 14 days 1, 4
• Administer with albumin 20-40 g/day throughout treatment 1

Alternative dosing: Continuous infusion of terlipressin 2-12 mg/24 hours IV may be equally effective with lower daily doses and fewer adverse events compared to bolus dosing 1

Mandatory monitoring with terlipressin:

• Continuous pulse oximetry throughout treatment; discontinue if SpO₂ drops below 90% 4
• Monitor for respiratory failure, which is the most serious adverse reaction and can be fatal 4
• Patients with volume overload are at highest risk for respiratory failure 4
• Monitor for ischemic events (cardiac, peripheral, mesenteric) that may require dose interruption 4

Alternative Vasoconstrictor: Norepinephrine

Norepinephrine is an effective alternative to terlipressin and may be preferred in certain situations. 1

When to use norepinephrine:

• Patient is already in shock requiring vasopressor support 1
• Patient has central venous access (norepinephrine requires central line; terlipressin can be given peripherally) 1
• Terlipressin is unavailable or contraindicated 1
• Patient is in the intensive care unit where continuous monitoring is available 2

Evidence: A meta-analysis found no difference in HRS reversal or relapse rates between terlipressin plus albumin versus norepinephrine plus albumin, though patient numbers remain small 1

Avoid Midodrine/Octreotide

The combination of midodrine and octreotide is less effective than terlipressin or norepinephrine and should largely be abandoned. 1, 2, 5

• Octreotide alone is ineffective for HRS 1
• The midodrine/octreotide combination shows inferior outcomes compared to other vasoconstrictors 1

Renal Replacement Therapy

Indications for RRT in HRS-AKI:

• Patients who have failed pharmacotherapy (vasoconstrictors plus albumin) 1
• Patients who are listed or being considered for liver transplantation 1
• Absolute indications: refractory hyperkalemia, severe volume overload causing pulmonary edema, intractable metabolic acidosis, or uremic complications 7

Important considerations:

• RRT should not be used as first-line therapy for HRS-AKI 8
• Patients requiring pretransplant RRT for >6 weeks should be considered for simultaneous liver-kidney transplant 1
• Intraoperative RRT during liver transplant shows no difference in postoperative outcomes 1

Liver Transplantation: The Definitive Treatment

Liver transplantation is the only definitive cure for HRS-AKI. 1, 6, 8

Key transplant considerations:

• All patients with HRS-AKI who are potential transplant candidates should be referred for evaluation without delay 1
• Response to vasoconstrictor therapy improves post-transplant outcomes, with fewer patients needing RRT and developing chronic kidney disease at 1 year post-transplant 1
• Patients who are non-responders to pharmacotherapy and are not transplant candidates should be referred for palliative care 1

Diagnostic Criteria for HRS-AKI

To ensure appropriate treatment, confirm the diagnosis using these criteria (all must be met): 1

• Cirrhosis with ascites
• AKI Stage 2 or 3 (serum creatinine >2× baseline)
• No response after 2 consecutive days of diuretic withdrawal and albumin volume expansion
• Absence of shock
• No current or recent nephrotoxic drug exposure
• Absence of structural kidney disease (proteinuria <500 mg/day, microhematuria <50 RBC/HPF, normal renal ultrasound)

Important update: HRS-AKI is not a diagnosis of exclusion—it may coexist with acute tubular injury or develop in patients with pre-existing chronic kidney disease. 2 The newest guidelines recommend determining HRS-AKI diagnosis within 24 hours to allow prompt initiation of effective therapy. 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Delaying vasoconstrictor therapy

• Recent data show that effective treatment of HRS-AKI requires rapid diagnosis and prompt intervention 2
• Do not wait beyond 48 hours if albumin trial fails and patient meets HRS-AKI criteria 2

Pitfall 2: Using vasoconstrictors in Stage 1A AKI

• Most experts have concerns about early vasoconstrictor use in patients with peak creatinine <1.5 mg/dL 1, 3
• Risk of adverse events may outweigh uncertain benefits 3

Pitfall 3: Administering fixed-dose albumin without volume assessment

• Indiscriminate albumin administration can cause volume overload, pulmonary edema, and respiratory failure 2
• Assess for signs of fluid overload before and during albumin therapy 2

Pitfall 4: Continuing terlipressin despite hypoxia

• Terlipressin carries a black box warning for serious or fatal respiratory failure 4
• Discontinue immediately if SpO₂ falls below 90% 4
• Never initiate in patients already hypoxic 4

Pitfall 5: Using midodrine/octreotide as first-line therapy

• This combination lacks efficacy compared to terlipressin or norepinephrine 2, 5
• Should be abandoned in favor of more effective vasoconstrictors 2