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, in the absence of intrinsic renal disease or structural kidney damage.

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 

  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)
  1. Intense renal vasoconstriction
  2. ↓ 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-NonAKI(No Structural Kidney Disease)

  • HRS-Acute Kidney Dysfunction : GFR reduction for <3 months,Does NOT meet AKI criteria,eGFR <60 mL/min/1.73 m²
  • HRS-CKD: GFR reduction ≥3 months+eGFR: <60 mL/min/1.73 m²
  • 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
  1. No response after 48 hours of:
    • Diuretic withdrawal
    • Plasma volume expansion with albumin 1 g/kg/day (max 100 g/day)
  1. Absence of shock
  2. No nephrotoxic drugs
  3. No structural kidney disease
    • Proteinuria <500 mg/day
    • <50 RBCs/HPF
    • Normal renal ultrasound

Differential Diagnosis 

Feature

HRS

Prerenal AKI

Kidney structure

Normal

Normal

Urine sediment

Bland

Bland

FeNa

<0.2%

<1%

Urine Na

<10 mEq/L

<20 mEq/L

Response to fluids

No

Yes

Albumin challenge

No improvement

Improves

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 

Terlipressin + Albumin (Drug of choice)

A. Intermittent Bolus Regimen 

  • Initial:
    • 0.5–1 mg IV every 4–6 hours
  • Escalation:
    • If no response after 2–3 days:
      → Increase stepwise to 2 mg IV every 4–6 hours
  • Max dose:
    • 12 mg/day


B. Continuous Infusion (Preferred in ICU – Better Safety Profile)

  • Start:
    • 2 mg/day continuous IV infusion
  • Titrate:
    • Increase every 24–48 hr based on response
    • Max:
      • 12 mg/day

 Advantages:

  • More stable plasma levels
  • Less ischemic complications


Treatment Goals

  • ↓ Serum creatinine to:
    • <1.5 mg/dL OR
    • ≥50% reduction


Duration of Therapy

  • Usually:
    • 7–14 days
  • Stop earlier if:
    • Complete response achieved
  • Stop if:
    • No response after 4–7 days at max dose

 Response Definitions 

Response Type

Criteria

Complete response

Creatinine <1.5 mg/dL

Partial response

≥50% decrease but >1.5

No response

<50% decrease

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