Hepatorenal Syndrome: Diagnostic Criteria and First-Line Management
Diagnostic Criteria
Hepatorenal syndrome (HRS-AKI) is diagnosed when ALL of the following criteria are met in a patient with cirrhosis and ascites: AKI defined by serum creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% from baseline, no improvement after 2 consecutive days of diuretic withdrawal and albumin expansion (1 g/kg, maximum 100 g), absence of shock, no current or recent nephrotoxic drug use (NSAIDs, aminoglycosides, contrast media), and absence of structural kidney injury (proteinuria <500 mg/day, <50 RBCs per high-power field, normal renal ultrasound). 1
AKI Staging System
The International Club of Ascites recommends staging AKI according to creatinine changes rather than waiting for absolute thresholds: 1
- Stage 1: Creatinine increase ≥0.3 mg/dL or 1.5-2× baseline
- Stage 2: Creatinine 2-3× baseline
- Stage 3: Creatinine >3× baseline or >4 mg/dL with acute increase ≥0.3 mg/dL, or initiation of renal replacement therapy
Critical Evolution from Old Criteria
The fixed threshold of serum creatinine >1.5 mg/dL has been abandoned because it delays diagnosis and signifies severely reduced GFR—the newer dynamic criteria allow earlier detection and treatment, which directly improves outcomes. 1 The median survival of untreated type 1 HRS is only approximately 1 month, making early recognition life-saving. 1
Essential Differential Diagnosis Steps
Before confirming HRS, you must exclude other common causes of AKI in cirrhosis: 1
- Hypovolemia (27-50% of AKI cases): responds to volume expansion alone
- Acute tubular necrosis (14-35% of cases): involves structural kidney damage
- Spontaneous bacterial peritonitis: perform diagnostic paracentesis immediately in all patients with ascites and AKI 2
Urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) can differentiate HRS from acute tubular necrosis, with a cutoff of 220 μg/g creatinine showing 88% sensitivity and 85% specificity. 1
First-Line Management
Terlipressin plus albumin is the first-line pharmacological treatment for HRS-AKI, with the goal of bridging patients to liver transplantation—the only definitive cure. 1, 2
Terlipressin Plus Albumin Protocol
Initial dosing: 2
- Terlipressin: 1 mg IV bolus every 4-6 hours
- Albumin: 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day
Dose escalation: 2
- If serum creatinine has NOT decreased ≥25% by day 3-4, increase terlipressin to 2 mg IV every 4 hours (maximum 12 mg/day)
- Continuous infusion alternative: 2 mg/day by continuous IV infusion reduces adverse events compared to bolus dosing 2
Treatment duration and response criteria: 2
- Continue until creatinine ≤1.5 mg/dL or for maximum 14 days
- Complete response: two consecutive creatinine values ≤1.5 mg/dL taken ≥2 hours apart
- Median time to response is 14 days 2
Predictors of favorable response: baseline creatinine <3 mg/dL, bilirubin <10 mg/dL, MAP increase ≥5 mmHg during therapy, lower MELD score and Child-Pugh <13, and younger age 2
Absolute Contraindications to Terlipressin
Terlipressin is absolutely contraindicated in patients with active coronary, peripheral, or mesenteric ischemia. 2 Obtain a baseline electrocardiogram before initiation. 2 Common ischemic adverse effects include angina, arrhythmias, and digital ischemia. 2 The FDA specifically warns against use in any known ischemic condition. 2
Alternative Vasoconstrictor Regimens
When terlipressin is unavailable or contraindicated: 2
Norepinephrine plus albumin (equally effective to terlipressin): 1, 2
- Start at 0.5 mg/hour continuous IV infusion
- Titrate every 4 hours by 0.5 mg/hour up to maximum 3 mg/hour
- Goal: increase MAP by 10-15 mmHg
- Requires central venous access and ICU-level monitoring—peripheral administration risks tissue necrosis 2
Midodrine plus octreotide plus albumin (substantially lower efficacy): 2
- Midodrine 7.5-12.5 mg orally three times daily
- Octreotide 100-200 μg subcutaneously three times daily
- Albumin 10-20 g IV daily for up to 20 days
- Preferred in patients with ischemic heart disease because octreotide offers the safest cardiovascular profile 2
Monitoring During Vasoconstrictor Therapy
Check the following parameters: 2
- Serum creatinine every 2-3 days
- Mean arterial pressure: target increase of 10-15 mmHg
- Heart rate: expect decrease of ~10 beats/minute with terlipressin 2
- Central venous pressure (when available) to guide fluid balance
- Urine output and serum sodium: should rise with effective treatment 2
- Vigilantly watch for pulmonary edema, especially in patients with underlying cardiac dysfunction 2
Prevention Strategies
Albumin administration with antibiotics during spontaneous bacterial peritonitis is the most effective HRS prevention strategy: 2
- Give albumin 1.5 g/kg at SBP diagnosis, then 1 g/kg on day 3
- This reduces HRS incidence from ~30% to ~10% and mortality from ~29% to ~10% 2
Additional prevention measures: 1, 2
- Albumin 6-8 g per liter of ascitic fluid removed during large-volume paracentesis (when >5 L)
- Antibiotic prophylaxis for 7 days after gastrointestinal bleeding
- Norfloxacin 400 mg/day in patients with advanced cirrhosis and low ascitic fluid protein
Transjugular Intrahepatic Portosystemic Shunt (TIPS)
TIPS is more suitable for Type 2 HRS (HRS-NAKI/chronic HRS) because patients are clinically more stable; it improves both renal function and ascites control. 2 Small studies suggest TIPS may benefit Type 1 HRS, but its use is limited by advanced liver failure. 2
Contraindications to TIPS: bilirubin >5 mg/dL, high MELD score, significant renal dysfunction, cardiac failure, or clinically significant hepatic encephalopathy 2
Renal Replacement Therapy
Initiate RRT based on clinical indications (refractory electrolyte/acid-base disturbances, refractory volume overload, symptomatic azotemia, or worsening renal function despite vasoconstrictors), primarily as a bridge to liver transplantation. 2 Continuous venovenous hemofiltration is preferred over intermittent dialysis in hemodynamically unstable patients. 1 Outcomes in critically ill cirrhotic patients requiring RRT remain poor with high mortality. 2
Liver Transplantation
Liver transplantation is the only curative treatment for HRS, addressing the underlying hepatic dysfunction that drives the entire pathophysiological process. 3 Expedited referral is recommended for all patients with Type 1 HRS. 1, 2 Survival rates are approximately 65% in Type 1 HRS after transplantation. 1 Treatment with vasoconstrictors before transplantation may improve post-transplant outcomes. 2
Critical Clinical 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 wait for creatinine to reach 1.5 mg/dL or 2.5 mg/dL—use the dynamic AKI criteria instead. 1
Do not omit albumin: Albumin is essential for volume expansion and anti-inflammatory effects, not just vasoconstrictors alone. 2
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
Do not use diuretics in HRS-AKI: They worsen renal perfusion. 1
Do not overlook precipitating factors: Always rule out and treat SBP, gastrointestinal bleeding, and discontinue nephrotoxic drugs. 2 Bacterial infections, particularly SBP, are the most important risk factor—HRS develops in approximately 30% of patients with SBP. 1