Targeting complement in atypical hemolytic and uremic syndrome: development and current status of eculizumab and ravulizumab

Abstract

Until 2009, atypical hemolytic uremic syndrome (aHUS), a disease mediated by complement-induced endothelial activation, had a poor renal prognosis, with common progression to kidney failure and frequent recurrence after kidney transplantation, condemning often young patients to lifelong dialysis. Initially developed for paroxysmal nocturnal hemoglobinuria, anti-C5 monoclonal antibodies – eculizumab and later ravulizumab – were rapidly evaluated for the management of atypical HUS. Clinical development was based on uncontrolled studies, but with effects on microangiopathy and renal function recovery that were clearly more favorable than the spontaneous course of the disease. Nowadays, the use of anti-C5 monoclonal antibodies is recommended as first-line therapy for thrombotic microangiopathy associated with atypical HUS and for relapse prevention, particularly in the context of kidney transplantation, in both adults and children. Ravulizumab appears to have the same efficacy as eculizumab while allowing injections to be spaced every 8 weeks instead of every 2. Finally, the most feared adverse effect of these treatments is meningococcal infection, whose frequency is fortunately low thanks to prophylactic vaccination strategies and antibiotic prevention.