Haemolytic Uraemic Syndrome

OVERVIEW

• Haemolytic uraemic syndrome (HUS) is a clinically similar condition to TTP
• in HUS (unlike TTP): renal failure > neurological symptoms
• typical and atypical forms

HUS VERSUS TTP

• TTP has predominantly neurological features, in HUS renal failure predominates.
• TTP has a distinct molecular pathogenesis – most cases either have inherited ADAMTS13 mutations or acquired antibodies against ADAMST13 (a von Willebrand’s Factor-cleaving metalloproteinase).
• TTP and aHUS can coexist!

TYPES OF HUS

Diarrhoea-associated (D+ HUS)

• >90% of HUS cases
• caused by preceding infection with a verocytotoxin-producing bacteria, typically E.coli O157:H7

Non-diarrhoeal/ atypical (D- or aHUS)

• rare
• possibly familial
• only about 50% of those with the genetic predisposition develop aHUS
• poorer prognosis
• often results from complement dysregulation — 50% involve complement regulatory genes: factor H, membrane cofactor protein (MCP) and factor I

TRIGGERS

D+ HUS

• verocytotoxin-producing bacteria, typically E.coli O157:H7

aHUS

• Streptococcus pneumoniae (40%) (also known as P-HUS, a subtype of aHUS)
• Pregnancy (term or post-partum)
• Drugs – quinine, mitomycin, ciclosporin, tacrolimus, ticlopidine, caboplatinum, gemcitabine
• Transplantation – renal, haematological stem cell transplantation
• HIV
• Combined methylmalonic aciduria and homocystinuria (a vitamin B12 metabolism disorder)

P-HUS

• occurs because S. pneumoniae has a neuraminidase that removes N-acetylneuraminic acid from cell-surface glycoproteins
• this  exposes the normally hidden T antigen (Thomsen-Friedenreich antigen) on red blood cells, platelets, and glomeruli
• Anti-T immunoglobulin M (IgM) in the serum reacts with the antigen causing hemolysis, thrombocytopenia and renal damage

CLINICAL FEATURES

• childhood: bloody diarrhoea post E.coli infection
• adulthood: same but also HIV, antiphospholipid syndrome, malignant hypertension
• bone transplant
• CMV infection

Classic pentad: (FAT R/N)

• fever
• anaemia (microangiopathic haemolytic)
• thrombocytopenia
• renal problems (88% have renal problems, 15% haematuria) – more likely in HUS
• neurological problems (headaches, confusion, seizures) – more likely in TTP

INVESTIGATIONS

-> microangiopathic haemolytic anaemia, ARF, thrombocytopenia

• low platelets
• low Hb with polychromasia, schistocytes and spherocytes
• increased reticulocytes
• reduced haptoglobins
• increased LDH
• unconjugated hyperbilirubinaemia with urinary urobilinogen
• variable neutrophilia
• increased urea and creatinine levels (greater in HUS)

Renal biopsy (may be contra-indicated by thrombocytopenia) — histological findings include:

• Thrombotic microangiopathy with swollen glomerular endothelial cells and red cells and platelets in the capillaries
• Accumulation of fibrin-like material in the subendothelial space resulting in thickened capillary walls
• Thrombi in the glomerular capillaries and arterioles
• There may be acute cortical necrosis involving both glomeruli and convoluted tubules

Other tests to confirm aHUS and identify the underlying cause include:

• genetic testing
• C3 levels are low in Factor H and I deficiency
• FDP/ D-dimer is high but the coagulation profile is otherwise normal.

MANAGEMENT

Supportive care and monitoring are the mainstays:

• antibiotics may worsen toxin production
• platelets are contra-indicated
• plasmapheresis if unsure
• seek and treat the underlying cause and any complications

Specific therapies

• Plasma exchange and plasma infusion
  • Efficacy is uncertain given the absence of any randomised controlled trials in aHUS
  • Mortality has decreased from 50% to 25% since their introduction to clinical practice
  • Avoided in S. pneumoniaeassociated HUS (P-HUS) because anti-T IgM in the administered plasma may exacerbate the disease.
• There is no good evidence for:
  • Steroids
  • Heparin
  • Aspirin
  • Antioxidants

General treatment of acute renal failure

• Fluid restriction and diuretics
• Anti-hypertensives
• Avoidance of nephrotoxins where possible
• RRT if necessary

References and Links

LITFL

• Pediatric Perplexity 002 — Hemolysis and renal failure in a toddler (Atypical HUS)

Journal articles

• Amirlak I, Amirlak B. Haemolytic uraemic syndrome: an overview. Nephrology(Carlton). 2006 Jun;11(3):213-8. PMID: 16756634.