What are the diagnosis and treatment options for a patient with advanced liver disease, such as cirrhosis, presenting with rapidly progressive impaired renal function, suspected to have Hepatorenal Syndrome (HRS)?

Hepatorenal Syndrome: Diagnosis and Treatment

Diagnostic Criteria

HRS-AKI should be diagnosed when a patient with cirrhosis and ascites develops acute kidney injury (creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% from baseline) that fails to improve after 2 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

Essential Diagnostic Requirements

The diagnosis requires ALL of the following criteria 2, 1:

• Cirrhosis with ascites - the fundamental prerequisite 1
• AKI by ICA-AKI criteria - creatinine increase ≥0.3 mg/dL within 48 hours OR ≥50% increase from baseline 2, 1
• No response to volume challenge - no improvement after 2 days of diuretic withdrawal plus albumin 1 g/kg (maximum 100 g on day 1) 2, 1
• Absence of shock - hemodynamic stability required 1
• No nephrotoxic drug exposure - exclude NSAIDs, aminoglycosides, contrast media 1
• No structural kidney injury - proteinuria <500 mg/day, microhematuria <50 RBCs/HPF, normal renal ultrasound 1

AKI Staging for Treatment Planning

Stage the severity to guide urgency 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 dialysis

Critical Diagnostic Pitfall

Do not wait for creatinine to reach 1.5 mg/dL or 2.5 mg/dL before diagnosing HRS-AKI. The old fixed threshold criteria have been abandoned because they delay treatment and worsen outcomes. 1 The new dynamic criteria allow earlier intervention when it is most effective. 2

Differential Diagnosis

HRS-AKI accounts for only 15-43% of AKI in cirrhosis 1. Other common causes include:

• Hypovolemia (27-50% of cases) - responds to volume expansion 2, 1
• Acute tubular necrosis (14-35% of cases) - structural kidney damage 2, 1
• Spontaneous bacterial peritonitis - perform diagnostic paracentesis in all cases 3

Urinary neutrophil gelatinase-associated lipocalin (NGAL) can differentiate HRS from ATN, with cutoff values of 220 μg/g creatinine showing 88% sensitivity and 85% specificity. 1, 3 Other biomarkers (KIM-1, IL-18, L-FABP) may also help distinguish structural from functional kidney injury. 1

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Treatment Algorithm

Step 1: Immediate Actions Upon Diagnosis

Start vasoconstrictor therapy plus albumin immediately upon confirming HRS-AKI diagnosis - do not delay. 2, 3

• Withdraw all diuretics - they worsen renal perfusion 3
• Perform diagnostic paracentesis - rule out spontaneous bacterial peritonitis, which precipitates HRS in 30% of cases 1, 3
• Initiate urgent liver transplant evaluation - all HRS-AKI patients should be considered given high short-term mortality even in treatment responders 3

Step 2: First-Line Pharmacological Treatment

Terlipressin plus albumin is the first-line treatment for HRS-AKI. 2, 3, 4

Terlipressin Dosing Protocol 3, 4:

• Initial dose: 1 mg IV every 4-6 hours (or 2 mg/day continuous infusion)
• Albumin: 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day
• Day 4 assessment: If creatinine has NOT decreased by ≥25%, increase terlipressin to 2 mg every 4 hours
• Discontinue if: Creatinine at or above baseline on Day 4
• Maximum duration: 14 days

Response Criteria 3:

• Complete response: Creatinine ≤1.5 mg/dL on two occasions at least 2 hours apart
• Partial response: Creatinine decrease ≥25% but still >1.5 mg/dL

Terlipressin achieves HRS reversal in 64-76% of patients, significantly superior to albumin alone. 3 In the CONFIRM trial, 29.1% of terlipressin-treated patients achieved verified HRS reversal versus 15.8% with placebo (p=0.012). 4

Step 3: Alternative Vasoconstrictors

If Terlipressin Unavailable (e.g., United States):

Midodrine plus octreotide plus albumin 3:

• Midodrine: Titrate up to 12.5 mg orally three times daily
• Octreotide: 200 μg subcutaneously three times daily
• Albumin: 10-20 g IV daily for up to 20 days
• Limitation: Based only on pilot studies with weaker evidence 3

If ICU Setting Available:

Norepinephrine plus albumin 3:

• Norepinephrine: 0.5-3.0 mg/hour IV continuous infusion
• Goal: Increase mean arterial pressure by 15 mmHg
• Albumin: 20-40 g/day
• Success rate: 83% in pilot studies, equally effective as terlipressin 2, 3
• Critical requirement: Central venous access mandatory - peripheral administration risks tissue necrosis 3

Step 4: Monitoring During Treatment

Monitor every 2-3 days 3:

• Serum creatinine - primary efficacy marker
• Mean arterial pressure - should increase by ~15 mmHg
• Heart rate - expect decrease of ~10 beats/minute with terlipressin 3
• Urine output - should increase with response
• Serum sodium - should increase with effective treatment 3
• Central venous pressure (ideally) - guide fluid management, prevent volume overload 3

Watch for complications 3:

• Cardiac/intestinal ischemia with terlipressin
• Pulmonary edema from albumin - discontinue albumin if anasarca develops, but continue vasoconstrictors 3
• Distal necrosis with terlipressin

Step 5: Renal Replacement Therapy

Use RRT only as a bridge to liver transplantation in patients unresponsive to vasoconstrictors with worsening renal function, electrolyte disturbances, or volume overload. 3

• Continuous RRT preferred over intermittent dialysis in hemodynamically unstable patients 3
• RRT should NOT be used as first-line therapy 5

Step 6: Definitive Treatment

Liver transplantation is the only curative treatment for HRS-AKI. 2, 3

• Expedited referral recommended for all type 1 HRS patients 3
• Survival after transplant: Approximately 65% in HRS-AKI patients 3
• Pre-transplant vasoconstrictor treatment may improve post-transplant outcomes 3
• HRS reverses in approximately 75% of patients after liver transplantation alone (without combined liver-kidney transplant) 3

Important consideration: Even if creatinine improves with vasoconstrictors and MELD score decreases, this should NOT change the decision to proceed with liver transplantation, as prognosis after recovering from HRS remains poor. 3

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Prevention Strategies

Primary Prevention in High-Risk Patients

Albumin with antibiotics for spontaneous bacterial peritonitis 3:

• 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% 3

Norfloxacin prophylaxis 2, 3:

• 400 mg/day in patients with advanced cirrhosis and low ascitic fluid protein
• Reduces HRS incidence 2, 3

Pentoxifylline in severe alcoholic hepatitis 3:

• 400 mg three times daily for 4 weeks
• Prevents HRS development 3

Albumin after large-volume paracentesis 6:

• Prevents post-paracentesis circulatory dysfunction

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Pathophysiology Context

Understanding the mechanism helps avoid treatment errors 1, 7:

• Splanchnic vasodilation causes effective arterial underfilling despite total volume expansion 1, 7
• Compensatory vasoconstriction (sympathetic nervous system, RAAS activation) leads to intense renal vasoconstriction 1, 7
• Bacterial translocation from increased gut permeability worsens systemic inflammation 7
• Infections (especially SBP) are the most common precipitant, inducing further vasodilation and cytokine release 1, 7

Critical insight: Despite being termed "functional" renal failure, severe or repeated episodes can cause structural kidney damage over time, challenging the traditional view of complete reversibility. 1, 7

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Prognosis

Untreated type 1 HRS has a median survival of approximately 1 month. 1 Even with treatment, mortality remains high, emphasizing the need for:

• Early diagnosis using dynamic AKI criteria 1
• Immediate vasoconstrictor therapy 3
• Urgent transplant evaluation 3
• Aggressive prevention in high-risk patients 3