Hepatorenal syndrome

  • Development of renal failure in patients with severe liver disease (acute or chronic)
    • In the absence of any other identifiable cause of renal pathology
Risk Factors 
  • Strong
    • Advanced cirrhosis
    • Ascites
    • Alcoholic hepatitis
    • Acute liver failure
    • Hyponatraemia
    • High plasma renin activity (PRA)
    • Spontaneous bacterial peritonitis
  • Weak
    • Large volume paracentesis
    • GI bleeding
Differential diagnosis
  • The probability of developing HRS in patients with cirrhosis is approximately 40% in 5 years
  • It occurs in 4% of patients admitted with decompensated cirrhosis
  • HRS may develop spontaneously in patients with cirrhosis
    • No objective criteria for a precipitating event other than progressive liver failure
  • May also develop in other chronic liver diseases associated with severe liver failure and portal hypertension
    • Alcoholic hepatitis 
    • Acute liver failure
  • Cirrhosis is most commonly a result of infectious hepatitis or chronic alcoholism
  • Independent predictive factors of HRS occurrence are:
    • Low serum sodium concentration 
    • High plasma renin activity
Clinical features
  • Key features:
    • Advanced cirrhosis (common)
    • Jaundice (common)
    • Ascites (common)
  • Other diagnostic factors
    • Moderate lowering of BP (common)
    • Peripheral oedema (common)
    • Hepatosplenomegaly (common)
    • Spider angioma (common)
    • Oliguria (uncommon)
    • Bruising (uncommon)
    • Petechiae (uncommon)
    • Palmar erythema (uncommon)
    • Scratch marks (uncommon)
    • Gynaecomastia (uncommon)
    • Encephalopathy (uncommon)
    • Pruritus (uncommon)
    • Confusion (uncommon)
    • Drowsiness (uncommon)
  • Four primary factors are involved in the pathophysiology of HRS:
    • Systemic vasodilation 
      • Leads to a moderate lowering of blood pressure
    • Activation of the sympathetic nervous system 
      • Leads to renal vasoconstriction and altered renal autoregulation
      • Causes renal blood flow to be much more dependent on mean arterial pressure
    • Relative impairment of cardiac function
      • Although cardiac output may increase, it cannot increase adequately to maintain blood pressure
      • In cirrhosis, this is termed cirrhotic cardiomyopathy
    • Increased formation of renal vasoconstrictors
      • Thromboxane A2, F2-isoprostanes, endothelin-1, cysteinyl-leukotrienes
      • Their exact role in the pathogenesis of HRS is unclear
  • Creatinine
    • Rapid deterioration in patients with type 1 HRS
    • Slower course (deteriorating over several months) in type 2 HRS
  • Urea
    • May be artificially decreased because of reduced hepatic synthesis of urea 
    • May be increased if GI haemorrhage
  • Electrolytes
    • Low sodium due to chronic liver disease
    • Potassium increases as renal failure progresses
  • FBC
    • Anaemia and thrombocytopenia due to chronic liver disease
    • An elevated WBC count is suggestive of the presence of an infection
      • May be responsible for the worsening renal function
  • LFTs
    • Transaminases, gamma-GT, and Alk phos may be normal or elevated in chronic liver disease
    • Low albumin is an indication of impaired liver function
  • Coagulation study
    • Indication of impaired liver function
  • Diagnostic paracentesis and culture of ascitic fluid
    • Elevated WBC suggests spontaneous bacterial peritonitis, which commonly precipitates HRS
  • Blood culture
    • Positive culture suggests sepsis
  • Urinalysis and culture
    • Presence of WBC and organisms indicates a possible infective cause of worsening renal function
    • Presence of RBC and red cell casts suggests an intrinsic renal cause of the renal failure
      • e.g. glomerulonephritis
    • Urinary sodium is low in HRS 
      • Due to preserved tubular function and activation of sodium-retaining systems
      • Should not be used as a major criterion to differentiate between HRS and acute tubular necrosis
  • CXR
    • CXR is performed to exclude sepsis

a) conservative
  • Supportive therapy
    • Patients should have their fluid status, urine output, and serum electrolytes monitored closely
    • In particular, patients should be prevented from developing severe hyponatraemia
      • But rapid correction of hyponatraemia is avoided 
        • May lead to demyelination syndrome and increased ascites formation
    • If tense, symptomatic ascites is present, paracentesis may temporarily improve renal function
    • If severe electrolyte disturbances, volume overload, or metabolic acidosis is present:
      • Patients are considered for continuous haemofiltration
      • However, limitations such as hypotension make it difficult in this patient group
    • Immunisation with influenza and pneumococcal vaccines is important
      • These patients are immunocompromised
b) medical 
  • Terlipressin 
    • Terlipressin (a vasopressin analogue) plus albumin is the first-line therapeutic approach for type 1 HRS
    • It may prolong short-term survival, and reverse type 1 HRS
    • Treatment should target a serum creatinine of <133 micromol/L (<1.5 mg/dL)
  • Fluid bolus
    • If renal failure is due to hypovolaemia, it will improve after fluid bolus
    • No improvement will occur in patients with HRS
  • Antibiotics
    • Broad-spectrum non-nephrotoxic antibiotics such as ceftriaxone should be commenced 
    • Continue until results of cultures are known
    • Negative cultures and persisting renal impairment indicate HRS
  • Albumin
    • Combined treatment with albumin and antibiotics reduces the incidence of renal impairment and death
  • Pentoxifylline
    • Improves short-term survival in patients with severe alcoholic hepatitis
    • Appears to be related to a decreased risk of developing HRS
  • Octreotide + midodrine + albumin
    • Midodrine is a vasoconstrictor, while octreotide inhibits release of endogenous vasodilators
    • These drugs work synergistically to improve renal haemodynamics
    • Usually only used as a bridging therapy until liver transplantation is available
c) surgical
  • Transjugular intrahepatic portosystemic shunt
    • Used in patients without severe liver failure in whom vasoconstrictors have failed to improve renal function
      • High serum bilirubin, Childs-Pugh score >12, severe hepatic encephalopathy
    • Functions as a side-to-side portocaval shunt and serves to relieve portal hypertension
    • Performed under analgesia 
    • Placement of a self-expandable metal stent between a hepatic vein and the intrahepatic portion of the portal vein
      • Uses a transjugular approach
    • Usually only used as a bridging therapy until liver transplantation is available
  • Liver transplantation
    • Liver transplantation is the only definitive treatment of HRS
    • The decision for transplantation of a limited resource is complex and involves severity of illness and likely prognosis
    • Patients with severe co-morbidities are not candidates for a liver transplant
    • e.g. CAD or heart failure, advanced age, alcoholism, and infection
  • Prognosis for patients with HRS is poor
    • Type 1 HRS has a hospital survival of less than 10%, and median survival time is 2 weeks
    • Type 2 HRS has a median survival time of around 6 months
  • The severity of underlying liver disease is a factor in the ability to recover from the renal failure
  • The 1-year survival for type 2 HRS is 38.5%
  • In patients with HRS, the 5-year survival following liver transplant is around 60%
    • This is significantly lower than in patients without HRS (68%)