aHUS: a disorder with many risk factors

Abstract

In this issue of Blood, Moore and colleagues demonstrate that the presence of anti–factor H autoantibodies in aHUS may be associated with the deletion of the CFHR1 gene. In addition, Moore et al provide data further supporting the model that the concurrence of multiple risk factors influences the onset of aHUS.

Intense research in recent years has demonstrated that atypical hemolytic uremic syndrome (aHUS), a rare but devastating disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, is associated with mutations and polymorphisms in various components and regulators of the complement alternative pathway (AP) including factor H, factor I, membrane cofactor protein (MCP), factor B, and C3. Mutations altering the C3b/polyanions-binding site located at the C-terminal region of factor H, specifically impairing the capacity of this complement regulator to protect host cells, are the prototypical genetic risk factor associated with aHUS.1 In addition to the genetic alterations in complement proteins, it has been shown that 5% to 10% of aHUS patients present anti–factor H (anti-fH) autoantibodies and that these autoantibodies have functional consequences similar to those caused by the prototypical mutations in the C-terminal region of factor H.2,3 On the basis of these genetic and functional data, it is well established that aHUS is a disease of complement dysregulation. Accordingly, it is believed that in persons carrying the aHUS-associated mutations or developing anti-fH autoantibodies, conditions that trigger complement activation, resulting in deposition and amplification of C3b on the kidney microvasculature endothelial cells, cannot be controlled. This culminates in tissue damage and destruction