In a patient with advanced cirrhosis and ascites, what are the diagnostic criteria for hepatorenal syndrome and the recommended first‑line therapy?

Hepatorenal Syndrome: Diagnostic Criteria and First-Line Therapy

In patients with advanced cirrhosis and ascites, hepatorenal syndrome (HRS-AKI) is diagnosed when serum creatinine rises to ≥1.5 mg/dL (or meets AKI stage ≥2 criteria) without improvement after two consecutive days of diuretic withdrawal and albumin volume expansion (1 g/kg up to 100 g), in the absence of shock, nephrotoxic drugs, or structural kidney disease; first-line therapy is 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, with dose escalation to 2 mg every 4 hours if creatinine fails to decrease ≥25% by day 3–4. 1, 2, 3

Diagnostic Criteria (All Must Be Present)

The International Club of Ascites revised diagnostic criteria require the following elements 1, 4:

• Cirrhosis with ascites – HRS occurs exclusively in patients with decompensated cirrhosis and ascites 1, 2
• Acute kidney injury stage ≥2 – Serum creatinine >1.5 mg/dL OR increase ≥0.3 mg/dL within 48 hours OR increase to 2–3× baseline 1, 4
• Failed volume challenge – No sustained improvement after at least 2 consecutive days of diuretic withdrawal AND plasma volume expansion with albumin 1 g/kg (maximum 100 g) 1, 2
• Absence of shock – No ongoing hemodynamic instability 1, 4
• No nephrotoxic drug exposure – Current or recent use excluded 1, 4
• Absence of structural kidney disease – Proteinuria <500 mg/day, no microhematuria (>50 RBCs/HPF), and normal renal ultrasonography 1, 2

Critical Diagnostic Step

Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis (SBP), which precipitates HRS in a significant proportion of cases and requires specific antibiotic treatment. 2, 4

Classification of HRS

Two distinct types exist with different prognoses 1, 2, 4:

• Type 1 HRS (HRS-AKI) – Rapidly progressive renal failure with doubling of serum creatinine to >2.5 mg/dL or 50% reduction in creatinine clearance to <20 mL/min within 2 weeks; median survival approximately 1 month without treatment 1, 2, 4
• Type 2 HRS (HRS-NAKI) – More stable or slowly progressive renal dysfunction, often associated with refractory ascites; better prognosis than Type 1 1, 2, 4

First-Line Pharmacologic Treatment: Terlipressin + Albumin

The European Association for the Study of the Liver and FDA-approved regimen establishes terlipressin as first-line therapy 1, 2, 3:

Initial Dosing Protocol

• Terlipressin: 1 mg IV bolus every 4–6 hours (equivalent to 0.85 mg terlipressin acetate) 2, 3
• Albumin: 1 g/kg body weight (maximum 100 g) on day 1, then 20–40 g/day thereafter 1, 2, 5
• Duration: Continue until serum creatinine ≤1.5 mg/dL on two consecutive measurements ≥2 hours apart, or maximum 14 days 2, 3

Dose Escalation Strategy

If serum creatinine has not decreased ≥25% by day 3–4, increase terlipressin to 2 mg IV every 4 hours (maximum 12 mg/day). 2, 3 If creatinine remains at or above baseline on day 4, discontinue treatment 3.

Alternative Continuous Infusion

Terlipressin 2 mg/day by continuous IV infusion reduces adverse events compared with bolus dosing while maintaining equivalent efficacy 2.

Efficacy Data

The CONFIRM trial demonstrated that 29% of terlipressin-treated patients achieved verified HRS reversal (two consecutive creatinine values ≤1.5 mg/dL) compared with 16% receiving placebo (p=0.012) 3. Durability of response without renal replacement therapy to day 30 was 32% versus 16% (p=0.003) 3.

Absolute Contraindications to Terlipressin

Terlipressin is absolutely contraindicated in patients with active coronary, peripheral, or mesenteric ischemia. 2 Obtain baseline electrocardiogram before initiation 2. Common ischemic adverse effects include angina, arrhythmias, and digital ischemia 2.

Alternative Vasoconstrictor Regimens

Second-Line: Norepinephrine + Albumin

When terlipressin is unavailable or contraindicated 1, 2:

• Norepinephrine: 0.5–3 mg/hour continuous IV infusion, titrated every 4 hours to increase mean arterial pressure (MAP) by 10–15 mmHg 1, 2
• Albumin: 20–40 g/day 2
• Requirements: ICU-level monitoring with central venous access mandatory; peripheral administration risks tissue necrosis 2
• Efficacy: 83% success rate in pilot studies 2

Third-Line: Midodrine + Octreotide + Albumin

Reserved for settings where terlipressin and norepinephrine are unavailable 2, 5:

• Midodrine: 7.5–12.5 mg orally three times daily 2, 5
• Octreotide: 100–200 μg subcutaneously three times daily 2, 5
• Albumin: 10–20 g IV daily for up to 20 days 2, 5
• Efficacy: Only 28–29% HRS reversal rate versus 64–76% with terlipressin 2
• Advantage: Can be administered outside ICU and even at home 2, 5

Important caveat: Octreotide should never be used as monotherapy; it requires midodrine to be effective 2.

Monitoring Parameters During Treatment

Essential monitoring includes 1, 2:

• Serum creatinine every 2–3 days to assess renal response
• Mean arterial pressure – target increase of 10–15 mmHg above baseline
• Heart rate – expect decrease of approximately 10 beats/min with terlipressin 2
• Central venous pressure when available to guide fluid balance and prevent overload 1, 2
• Urine output and serum sodium – should increase with effective treatment 2
• Vigilant monitoring for pulmonary edema, especially in patients with underlying cardiac dysfunction or cirrhotic cardiomyopathy 1, 2

Response Definitions

• Complete response: Serum creatinine ≤1.5 mg/dL on two occasions ≥2 hours apart 2, 3
• Partial response: Regression of AKI stage with creatinine decrease ≥25% but still >1.5 mg/dL 1, 2
• Median time to response: 14 days, shorter in patients with lower baseline creatinine 2

Predictors of Treatment Response

Favorable response is more likely with 2:

• Baseline creatinine <3 mg/dL
• Bilirubin <10 mg/dL
• MAP increase ≥5 mmHg during therapy
• Lower MELD score and Child-Pugh <13
• Younger age

Prevention Strategies

Spontaneous Bacterial Peritonitis Prophylaxis

Albumin 1.5 g/kg at SBP diagnosis, then 1 g/kg on day 3, reduces HRS incidence from 30% to 10% and mortality from 29% to 10%. 2, 5, 4 This is the single most effective HRS prevention strategy 2.

Additional Prevention Measures

• Norfloxacin 400 mg/day in patients with advanced cirrhosis and low ascitic fluid protein (<1.5 g/dL) 2, 4
• Antibiotic prophylaxis for 7 days after gastrointestinal bleeding 2
• Albumin 6–8 g per liter of ascitic fluid removed when >5 L paracentesis performed, to prevent post-paracentesis circulatory dysfunction 2
• Pentoxifylline 400 mg three times daily to prevent HRS in severe alcoholic hepatitis 2, 4

Definitive Treatment: Liver Transplantation

Liver transplantation is the only curative treatment for HRS, with post-transplant survival rates of approximately 65% in Type 1 HRS. 1, 2, 4 Expedited referral for transplantation should occur immediately upon HRS-AKI diagnosis 2, 4. Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes 2.

Adjunctive Therapies

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS is more applicable in Type 2 HRS due to more stable clinical condition; it improves both renal function and ascites control 2. Contraindications include severe hepatic dysfunction (bilirubin >5 mg/dL), high MELD score, significant renal dysfunction, cardiac failure, or clinically significant hepatic encephalopathy 2.

Renal Replacement Therapy

Initiate RRT only as a bridge to liver transplantation in patients unresponsive to vasoconstrictors, based on clinical indications such as refractory electrolyte disturbances, volume overload, or symptomatic azotemia 1, 2. Continuous venovenous hemofiltration causes less hypotension than intermittent hemodialysis 1.

Critical Pitfalls to Avoid

• Do not delay treatment – early initiation of vasoconstrictors after HRS-AKI diagnosis improves outcomes, especially before progression to higher ACLF grades 2
• Do not omit albumin – albumin is essential for volume expansion and anti-inflammatory effects; vasoconstrictors alone are ineffective 2, 5
• Do not persist with ineffective therapy – if creatinine fails to decrease ≥25% after 3–4 days despite dose escalation, consider alternative vasoconstrictors, RRT, or transplantation 2, 3
• Do not overlook precipitating factors – always rule out and treat SBP, gastrointestinal bleeding, and discontinue nephrotoxic drugs 2
• Do not use fixed albumin dosing without volume assessment – individualize albumin doses to avoid both under-resuscitation and pulmonary edema 2