What is Hepatorenal Syndrome (HRS) and how is it managed?

What is Hepatorenal Syndrome (HRS) and How to Manage It

Definition and Pathophysiology

Hepatorenal syndrome is a functional renal failure that develops in patients with advanced cirrhosis and ascites, characterized by marked impairment of kidney function due to severe circulatory dysfunction, splanchnic vasodilation, and systemic inflammation. 1, 2

The pathophysiology involves four key mechanisms 3:

• Splanchnic vasodilation triggering activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, causing renal vasoconstriction 4
• Impaired cardiac function from cirrhotic cardiomyopathy, leading to inadequate compensatory cardiac output 4
• Increased synthesis of vasoactive mediators (cysteinyl leukotrienes, thromboxane A2, endothelin-1) affecting renal blood flow 3
• Systemic inflammation and bacterial translocation aggravating hemodynamic alterations 2

Classification

Two types exist 1, 4:

• Type 1 HRS (HRS-AKI): Rapid, progressive renal impairment with doubling of creatinine to >2.5 mg/dL or 50% reduction in creatinine clearance to <20 mL/min within 2 weeks 4
• Type 2 HRS (HRS-CKD): More stable, chronic course with moderate renal dysfunction 4

The prognosis is dismal—median survival of untreated type 1 HRS is approximately 1 month, with overall HRS survival around 3 months. 3, 4

Diagnostic Criteria

The International Club of Ascites requires ALL of the following criteria to diagnose HRS 1, 4:

1. Cirrhosis with ascites 1
2. AKI defined by ICA-AKI staging criteria 4:
   • 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
3. No improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin 1 g/kg (maximum 100 g) 1, 4
4. Absence of shock 1
5. No current or recent nephrotoxic drug use (NSAIDs, aminoglycosides, contrast media) 1
6. No evidence of structural kidney disease: proteinuria <500 mg/day, microhematuria <50 RBCs/HPF, normal renal ultrasound 1, 4

Critical Diagnostic Pitfall

Do not wait for creatinine to reach 1.5 mg/dL before considering HRS—the fixed threshold has been abandoned because it delays diagnosis and signifies severely reduced GFR. 4 Use the dynamic AKI criteria instead, as earlier treatment leads to better outcomes 4.

Always perform diagnostic paracentesis to exclude spontaneous bacterial peritonitis (SBP), which precipitates HRS in approximately 30% of cases. 1, 5

Consider renal biopsy if proteinuria, microhematuria, or abnormal kidney size is present to evaluate for parenchymal disease and guide combined liver-kidney transplant decisions 4.

Management Algorithm

First-Line Treatment: Terlipressin Plus Albumin

Terlipressin plus albumin is the first-line pharmacological treatment for type 1 HRS (HRS-AKI). 1

Dosing protocol 3, 1:

• Terlipressin: Start 1 mg IV every 4-6 hours
• Increase to 2 mg every 4 hours if serum creatinine does not decrease by at least 25% after 3 days
• Albumin: 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day 1
• Continue treatment until serum creatinine decreases below 1.5 mg/dL (133 μmol/L), typically to 1-1.2 mg/dL (88-106 μmol/L) 3
• Median time to response is 14 days 3

Terlipressin achieves reversal of HRS in 40-50% of patients, significantly superior to albumin alone (64-76% vs albumin alone). 3, 1, 6

Recent data show terlipressin by continuous IV infusion is better tolerated than boluses with equal efficacy 6.

Alternative Treatment Options (When Terlipressin Unavailable)

Midodrine plus octreotide plus albumin 1:

• 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
• Can be administered outside ICU and even at home 1

Norepinephrine plus albumin (requires ICU setting) 1:

• Dosing: 0.5-3.0 mg/hour IV, titrated to increase mean arterial pressure by 15 mmHg 1
• Success rate of 83% reported in pilot studies 1
• Requires central venous access—attempting peripheral administration risks tissue necrosis 1
• Equally effective as terlipressin in reversing HRS 7

Monitoring and Duration

Monitor in ICU or semi-ICU setting with 3, 1:

• Urine output, fluid balance, arterial pressure
• Central venous pressure (ideally) to guide fluid management 3
• Serum creatinine every 2-3 days 1

Response definitions 1:

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

Treatment duration 1:

• Until complete response or maximum 14 days for terlipressin
• 10-20 days for alternatives
• Discontinue albumin if anasarca develops, but continue vasoconstrictors 1

Watch for complications: cardiac/intestinal ischemia, pulmonary edema, distal necrosis with terlipressin 1

Predictors of Response

Predictors of response to terlipressin 6, 8:

• Lower baseline serum creatinine and bilirubin
• Increase in blood pressure during treatment
• Younger age (independent predictor)
• Absence of systemic inflammatory response syndrome

Predictors of mortality 8:

• Age, bilirubin, creatinine increase after diagnostic volume expansion
• Mortality rate 97% among patients with at least two negative predictors

Definitive Treatment: Liver Transplantation

Liver transplantation is the definitive treatment for both type 1 and type 2 HRS, with expedited referral recommended for patients with type 1 HRS. 1, 5

Post-transplant survival rates are approximately 65% in type 1 HRS. 1, 5

Treatment of HRS before transplantation with vasoconstrictors may improve post-transplant outcomes. 1 However, the reduction in serum creatinine and MELD score after treatment should not change the decision to perform liver transplantation, as prognosis after recovering from HRS remains poor 1.

Combined liver-kidney transplantation is recommended for patients with 7:

• Prolonged history of AKI
• Underlying chronic kidney disease
• Hereditary renal conditions

Renal Replacement Therapy

Renal replacement therapy (continuous venovenous hemofiltration/hemodialysis) may be considered only as a bridge to liver transplantation in selected patients unresponsive to vasoconstrictors. 1, 7

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS has been reported effective in type 1 HRS in uncontrolled studies and improves renal function and ascites control in type 2 HRS. 1 However, more evidence is needed before routine recommendation 1.

Prevention Strategies

The most effective prevention strategies are 1, 5:

1. For SBP prevention and treatment:

   • Albumin 1.5 g/kg at diagnosis of SBP, then 1 g/kg on day 3 reduces HRS incidence from 30% to 10% and mortality from 29% to 10% 1
   • Norfloxacin 400 mg/day to reduce HRS incidence in advanced cirrhosis 1, 5

2. For severe alcoholic hepatitis:

   • Pentoxifylline 400 mg three times daily to prevent HRS development 1, 5

3. General measures 5:

   • Avoid nephrotoxic drugs and diuretics in high-risk patients
   • Volume expansion with albumin after large volume paracentesis 6

Risk Factors

Bacterial infections, particularly SBP, are the most important risk factor for HRS development. 3, 4, 5 HRS develops in approximately 30% of patients with SBP 3, 4.

High MELD scores and type 1 HRS are associated with very poor prognosis 3, 5.

Differential Diagnosis

HRS accounts for 15-43% of AKI cases in cirrhotic patients, while other common causes include 4:

• Hypovolemia (27-50% of cases)
• Acute tubular necrosis (14-35% of cases)

Biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) may help differentiate HRS from acute tubular necrosis. 4, 6 Other useful biomarkers include KIM-1, IL-18, and L-FABP 4.