HepatoRenal Syndrome

Hepatorenal Syndrome (HRS)

Definition

Hepatorenal syndrome (HRS) is a functional, potentially reversible acute kidney injury (AKI) occurring in patients with advanced cirrhosis and portal hypertension, characterized by marked renal vasoconstriction and severely reduced GFR, in the absence of intrinsic renal disease or structural kidney damage.

Key concept for exams:
HRS is not due to tubular necrosis or glomerular pathology—the kidneys are structurally normal.

Epidemiology & Clinical Context

• Occurs in advanced decompensated cirrhosis (often Child-Pugh C)
• Common settings:
  • Refractory ascites
  • Spontaneous bacterial peritonitis (SBP)
  • Large-volume paracentesis without albumin
  • GI bleeding
  • Severe alcoholic hepatitis
• Incidence:
  • ~20–40% of cirrhotics with ascites over time
• Prognosis: Very poor without treatment or transplantation

Pathophysiology 

HRS results from extreme circulatory dysfunction in cirrhosis.

Stepwise Mechanism

1. Portal hypertension → ↑ shear stress
2. ↑ Splanchnic vasodilators (NO, CO, prostacyclin)
3. Splanchnic arterial vasodilation
4. ↓ Effective arterial blood volume
5. Compensatory activation of:
   • RAAS
   • Sympathetic nervous system
   • Arginine vasopressin (ADH)

6. Intense renal vasoconstriction
7. ↓ Renal blood flow → ↓ GFR → AKI

Important Points

• Cardiac output may initially be high (hyperdynamic circulation)
• Renal hypoperfusion is functional, not structural
• Tubules remain intact → bland urine sediment

Updated Classification 

HRS-AKI (replaces old Type 1 HRS)

• Rapid rise in creatinine
• Defined using ICA-AKI criteria
• Most common and most lethal form

HRS-NAKI

• HRS-AKD: GFR reduction for <3 months
• HRS-CKD: GFR reduction ≥3 months
• Seen with long-standing refractory ascites

Old terminology 

• Type 1 HRS → Rapidly progressive renal failure
• Type 2 HRS → Slowly progressive renal dysfunction with refractory ascites

Diagnostic Criteria (ICA 2015 / AASLD / EASL)

All must be present

1. Cirrhosis with ascites
2. AKI defined by ICA criteria
   • ↑ serum creatinine ≥0.3 mg/dL in 48 h
     OR
   • ≥50% increase from baseline in 7 days

3. No response after 48 hours of:

1. • Diuretic withdrawal
   • Plasma volume expansion with albumin 1 g/kg/day (max 100 g/day)

4. Absence of shock
5. No nephrotoxic drugs
6. No structural kidney disease

1. • Proteinuria <500 mg/day
   • <50 RBCs/HPF
   • Normal renal ultrasound

Differential Diagnosis 

Clinical Features

• Oliguria
• Rising serum creatinine
• Dilutional hyponatremia
• Hypotension (often)
• Refractory ascites
• No hematuria or proteinuria
• Often precipitated by:
  • SBP
  • GI bleed
  • Excess diuretics
  • Sepsis

Investigations

• Serum creatinine (trend is critical)
• Urine sodium, FeNa (supportive)
• Urinalysis (bland)
• Renal ultrasound (normal size, no obstruction)
• Exclude infection (blood, urine, ascitic fluid cultures)
• LFTs, INR, MELD score

Management 

1. General Measures

• Stop diuretics
• Stop nephrotoxins (NSAIDs, ACEI/ARB)
• Treat precipitating factors:
  • SBP → antibiotics + albumin
  • GI bleed → early control
• Optimize MAP (≥65 mmHg)

2. Plasma Expansion

• Albumin
  • 1 g/kg/day (max 100 g/day) for 2 days
  • Then 20–40 g/day during vasoconstrictor therapy

3. Vasoconstrictor Therapy (Cornerstone)

Terlipressin + Albumin (Drug of choice)

• IV bolus or infusion
• Mechanism:
  • Splanchnic vasoconstriction
  • ↑ Effective arterial volume
  • ↓ Renal vasoconstriction
• Response:
  • ↓ Serum creatinine
• Adverse effects:
  • Ischemia
  • Arrhythmias
  • Respiratory failure (important ICU point)

Alternatives

• Norepinephrine (ICU)
  • Comparable efficacy to terlipressin
• Midodrine + Octreotide
  • Less effective
  • Used where terlipressin unavailable

4. Renal Replacement Therapy (RRT)

• Bridge to liver transplantation
• Indications same as other AKI:
  • Refractory hyperkalemia
  • Severe acidosis
  • Volume overload
  • Uremic complications
• Poor long-term survival without transplant

5. Definitive Therapy – Liver Transplantation

• Only curative treatment
• Renal function often recovers post-transplant
• Prolonged HRS → risk of irreversible kidney injury → may require combined liver-kidney transplant

Prevention

• Albumin during SBP (1.5 g/kg day 1, 1 g/kg day 3)
• Albumin after large-volume paracentesis (>5 L)
• Early treatment of infections
• Avoid nephrotoxins
• Careful diuretic dosing

Prognosis

• Untreated HRS-AKI:
  • Median survival: weeks
• With vasoconstrictors:
  • Reversal in ~40–50%
• Best outcomes with early diagnosis and transplantation