Defining treatment duration in atypical hemolytic uremic syndrome in adults: a clinical and pathological approach

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) that is driven by uncontrolled activation of the alternative complement pathway, classically in the context of a genetic or autoimmune complement abnormality. Initial guidelines suggested lifelong treatment with the C5 inhibitor eculizumab, which until recently was the only therapy approved by the US Food and Drug Administration and European Medicines Agency for aHUS. However, multicenter observational studies provide compelling evidence that discontinuation of eculizumab, with careful monitoring for recurrence of renal injury, is an option for some patients. Although relapse occurs in 20% to 35% of patients with aHUS after a median of 3 months (range, 1-30 months) following eculizumab cessation, ostensibly irrespective of initial treatment duration, successful rescue with reinstitution of drug has been described in small cohorts if relapse is promptly recognized and eculizumab is immediately re-started. Rates of off-treatment TMA are higher in children than in adults; they are also elevated in those with a personal or family history of aHUS, certain complement mutations or anti-complement factor H autoantibodies, a renal allograft, or extrarenal manifestations of aHUS. Given the complex and unpredictable nature of aHUS, prospective trials defining the optimal treatment duration in diverse settings are required. In the interim, this review-which excludes pediatric patients and hematopoietic stem cell transplant recipients-suggests that eculizumab may be discontinued in some groups of patients; discontinuation should be undertaken on a case-by-case basis and with careful monitoring, following 6 to 12 months of treatment for aHUS that encompasses at least 3 months of normalization of renal function or stabilization of chronic renal disease.