Atypical haemolytic uraemic syndrome (HUS)

Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated

• the endothelial damage caused by thrombotic microangiopathy (TMA) can result in life-threatening manifestations of the disease, including kidney failure and extrarenal tissue damage
• prior to the availability of targeted treatment with complement C5 inhibitors, the prognosis of aHUS both in pediatric and adult patients was poor- around 29% of children required dialysis or died within 1 year and 48% reached chronic kidney disease (CKD) stage 5 or death at 3 years despite plasma therapy
• subdivision of this disease is possible, including recognition of those with anti-factor H autoantibodies (a subgroup which accounts for about 10% of paediatric aHUS)
  • definition of aHUS has been broadened to include other rare forms of HUS including diacylglycerol kinase E and Cobalamin C deficiency, as well as HUS with no clear precipitant
• diagnosis
  • based on the presence of thrombocytopenia, microangiopathic haemolysis, and kidney injury and the exclusion of other forms of HUS or thrombotic thrombocytopenic purpura (TTP)

NICE state (2):

• Ravulizumab is recommended, within its marketing authorisation, as an option for treating atypical haemolytic uraemic syndrome (aHUS) in people weighing 10 kg or more:
  • who have not had a complement inhibitor before or
  • whose disease has responded to at least 3 months of eculizumab treatment

Notes:

• ravulizumab
  • is a humanized monoclonal antibody (mAb) engineered from eculizumab to target the same complement C5 epitope while decreasing drug clearance and reducing the required frequency of infusions
  • incorporates selective amino acid modifications to both increase the dissociation rate of the mAb:C5 complex in the acidic early endosome at pH 6.0 and enhance the efficiency of neonatal Fc receptor-mediated antibody recycling, leading to an extended duration of terminal complement inhibition
  • has a mean terminal elimination half-life that is over 4 times greater than that of eculizumab (about 51.8 days vs. about 11 days) and offers a reduced dosing frequency of 4-8 weeks vs. every 2-3 weeks, depending on bodyweight
• eculizumab
  • has proved highly effective in children with aHUS
  • however, treatment regimen involves frequent intravenous infusions (every 2 weeks in patients weighing >10 kg), which can be particularly burdensome for pediatric patients and caregivers (1)

Reference:

• Tanaka K, Adams B, Aris AM, Fujita N, Ogawa M, Ortiz S, Vallee M, Greenbaum LA. The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab. Pediatr Nephrol. 2021 Apr;36(4):889-898
• NICE (June 2021). Ravulizumab for treating atypical haemolytic uraemic syndrome