aHUS caused by complement dysregulation: new therapies on the horizon

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disease that is caused by defective complement regulation in over 50% of cases. Mutations have been identified in genes encoding both complement regulators [complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), and membrane cofactor protein (MCP)], as well as complement activators [complement factor B (CFB) and C3]. More recently, mutations have also been identified in thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a. Inhibitory autoantibodies to CFH account for an additional 5-10% of cases and can occur in isolation or in association with mutations in CFH, CFI, CFHR 1, 3, 4, and MCP. Plasma therapies are considered the mainstay of therapy in aHUS secondary to defective complement regulation and may be administered as plasma infusions or plasma exchange. However, in certain cases, despite initiation of plasma therapy, renal function continues to deteriorate with progression to end-stage renal disease and renal transplantation. Recently, eculizumab, a humanized monoclonal antibody against C5, has been described as an effective therapeutic strategy in the management of refractory aHUS that has failed to respond to plasma therapy. Clinical trials are now underway to further evaluate the efficacy of eculizumab in the management of both plasma-sensitive and plasma-resistant aHUS.

Fig. 1

Activation and regulation of the alternative complement pathway. Complement factor H binds to the endothelial cell surface, C3b, and with membrane co-factor protein (MCP), acts as a co-factor for cleavage of C3b. This process is mediated by complement factor I. This presents the formation of C3bBb complex. Dissociation of the C3 convertase is also mediated by factor H. Thrombomodulin enhances factor-I- mediated cleavage of C3b in the presence of factor H and promotes activation of TAFIa (thrombin activatable fibrinolysis inhibitor), which degrades C3a and C5a. Ab antibody; CFB complement factor B; CFH complement factor H; CFI complement factor I; TM thrombomodulin; MCP membrane cofactor protein; TAFIa thrombin activatable fibrinolysis inhibitor; Thn thrombin

Fig. 2

Site of action of eculizumab. a Complement C5 is split by C5 convertase into C5a and C5b. C5a increases the permeability of blood vessels and attracts inflammatory cells by chemotaxis. C5b binds to other complement components (C6, C7, and C8). The C5b-8 complex is expanded with C9 to form the MAC. MAC binds and permeabilizes bacterial walls (e.g. Neisseria), thereby killing the microorganism. b Eculizumab is a long-acting humanized monoclonal antibody targeted against complement C5. It inhibits the cleavage of C5 into C5a and C5b and hence inhibits deployment of the terminal complement system including the formation of MAC