How is hepatorenal syndrome diagnosed and what is the first‑line management in an adult with cirrhosis who develops an acute rise in serum creatinine (greater than 1.5 mg/dL) and oliguria without volume depletion, shock, nephrotoxic exposure, or intrinsic kidney disease?

Hepatorenal Syndrome: Diagnosis and First-Line Management

Diagnostic Confirmation

Hepatorenal syndrome-AKI (HRS-AKI) is diagnosed when a cirrhotic patient with ascites develops acute kidney injury (serum creatinine ≥0.3 mg/dL increase within 48 hours or ≥50% from baseline) that fails to improve after two consecutive days of diuretic withdrawal and albumin expansion (1 g/kg, maximum 100 g), in the absence of shock, nephrotoxic drugs, or structural kidney disease. 1

The diagnostic criteria require ALL of the following:

• Cirrhosis with ascites 2
• Serum creatinine >1.5 mg/dL (or AKI stage ≥2 by ICA-AKI criteria) 1, 2
• No improvement after 2 days of diuretic withdrawal plus albumin 1 g/kg (maximum 100 g/day) 3, 2
• Absence of shock 3, 2
• No current or recent nephrotoxic drug exposure (NSAIDs, aminoglycosides, contrast media) 2
• Absence of structural kidney disease: proteinuria <500 mg/day, microhematuria <50 RBCs/HPF, normal renal ultrasound 3, 2

Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis (SBP), which precipitates HRS in approximately 30% of cases and requires specific antibiotic treatment plus albumin. 1, 4

Critical Pitfall to Avoid

Do not wait for creatinine to reach the old threshold of 2.5 mg/dL before diagnosing HRS-AKI—the fixed 1.5 mg/dL cutoff has been abandoned because it delays diagnosis and worsens outcomes. 2 Use the dynamic AKI criteria (≥0.3 mg/dL increase within 48 hours) to enable earlier treatment. 1, 2

---

First-Line Management: Terlipressin Plus Albumin

The first-line pharmacological treatment for HRS-AKI is terlipressin plus albumin, which reverses HRS in 64–76% of patients compared to only 28–29% with alternative regimens. 1

Dosing Protocol

Initial regimen:

• Terlipressin: 1 mg IV bolus every 4–6 hours 1
• Albumin: 1 g/kg (maximum 100 g) on day 1, then 20–40 g/day 1

Dose escalation: If serum creatinine has not decreased ≥25% by day 3–4, increase terlipressin to 2 mg IV every 4 hours (maximum 12 mg/day). 1

Alternative continuous infusion: Terlipressin 2 mg/day by continuous IV infusion reduces adverse events compared to bolus dosing. 1

Treatment duration: Continue until serum creatinine ≤1.5 mg/dL (complete response) or for a maximum of 14 days. 1 Median time to response is 14 days, shorter in patients with lower baseline creatinine. 1

Contraindications

Terlipressin is absolutely contraindicated in patients with active coronary, peripheral, or mesenteric ischemia. 1 Obtain a baseline electrocardiogram before initiating therapy. 1, 2

---

Alternative Vasoconstrictor Regimens

Second-Line: Norepinephrine Plus Albumin

When terlipressin is unavailable or contraindicated, norepinephrine 0.5–3 mg/hour continuous IV infusion plus albumin is equally effective but requires ICU-level monitoring with central venous access. 1

• Starting dose: 0.5 mg/hour IV, titrate every 4 hours by 0.5 mg/hour to raise mean arterial pressure (MAP) by 10–15 mmHg 1
• Maximum dose: 3 mg/hour 1
• Critical safety note: Peripheral administration of norepinephrine risks tissue necrosis; central venous access is mandatory. 1

Third-Line: Midodrine Plus Octreotide Plus Albumin

In settings where terlipressin and norepinephrine are unavailable, use:

• Midodrine: 7.5–12.5 mg orally three times daily 1
• Octreotide: 100–200 µg subcutaneously three times daily 1
• Albumin: 10–20 g IV daily for up to 20 days 1

This regimen achieves HRS reversal in only 28–29% of cases and should be reserved for resource-limited settings. 1 It can be administered outside the ICU and even at home. 3, 1

---

Monitoring During Treatment

Check the following parameters regularly:

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

Response Criteria

• Complete response: Serum creatinine ≤1.5 mg/dL on two measurements ≥2 hours apart 1
• Partial response: Creatinine decrease ≥25% but still >1.5 mg/dL 1

---

Predictors of Treatment Success

Favorable response is more likely with:

• Baseline creatinine <3 mg/dL 1
• Bilirubin <10 mg/dL 1
• MAP increase ≥5 mmHg during therapy 1
• Lower MELD score and Child-Pugh <13 1
• Younger age 1

Treatment failure is predicted by:

• Baseline creatinine >3 mg/dL 1
• Severe systemic inflammation (multiple organ failures) 1
• Severe cholestasis (bilirubin >10 mg/dL) 1

---

Definitive Treatment: Liver Transplantation

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

---

Prevention Strategies

To prevent HRS development:

• In spontaneous bacterial peritonitis: Give albumin 1.5 g/kg at diagnosis, then 1 g/kg on day 3; this reduces HRS incidence from 30% to 10% and mortality from 29% to 10%. 1
• After gastrointestinal bleeding: Provide antibiotic prophylaxis for 7 days 1
• After large-volume paracentesis (>5 L): Administer IV albumin 6–8 g per liter of ascitic fluid removed to prevent post-paracentesis circulatory dysfunction 1
• In advanced cirrhosis with low ascitic fluid protein: Norfloxacin 400 mg/day reduces HRS incidence 1

---

Critical Clinical Pitfalls

1. Do not delay vasoconstrictor therapy waiting for higher creatinine thresholds—early initiation improves outcomes, especially before progression to higher ACLF grades. 1

2. Do not omit albumin—it is essential for volume expansion and anti-inflammatory effects; vasoconstrictors alone are insufficient. 1

3. Do not persist with ineffective therapy—if creatinine fails to decrease ≥25% after 3–4 days despite dose escalation, consider alternative vasoconstrictors, renal replacement therapy, or expedited transplantation. 1

4. Do not overlook precipitating factors—always rule out and treat SBP, gastrointestinal bleeding, and discontinue all nephrotoxic drugs (NSAIDs, aminoglycosides, contrast). 1, 2

5. Do not use diuretics in HRS-AKI—they worsen renal perfusion and should be withdrawn immediately. 1