Pulling the Trigger in Atypical Hemolytic Uremic Syndrome

Abstract

In the past 15 years, our understanding of the molecular mechanisms that predispose to atypical hemolytic uremic syndrome (aHUS) has increased dramatically.1 A series of studies established that dysregulation of the alternative complement pathway plays a significant role in the pathogenesis of disease in the majority of patients.1,2 Mutations in both complement regulators (factor H, factor I, and membrane co-factor protein) and activators (C3 and factor B) have been described in both familial and sporadic forms. In addition, factor H autoantibodies, which impair the activity of factor H, and mutations in the gene encoding thrombomodulin are now known.3,4 More than one family member is affected in approximately 10% of patients with aHUS. The study of such families reveals a higher prevalence of the aforementioned mutations and indicates that not every individual who carries a mutation manifests the disease.5 The rate of nonpenetrance is approximately 50%, and it has been shown that naturally occurring variability in single-nucleotide polymorphisms and haplotype blocks of the CFH and CD46 genes encoding factor H and membrane co-factor protein, respectively, increase susceptibility to disease. Moreover, multiple concurrent factors such as single-nucleotide …