Complement therapy in atypical haemolytic uraemic syndrome (aHUS)

Abstract

Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.

Keywords: Complement; Eculizumab; Haemolytic Uraemic Syndrome; Treatment.

Fig. 1

Complement activation and the mechanism of action of Eculizumab. The AP constantly undergoes ‘tick-over’ but can also be primed by the CP and LP pathways. The C3b that is formed interacts with factor B (B), which is then cleaved by factor D to form the AP C3 convertase (C3bBb). This enzyme complex is attached to the target covalently via C3b while Bb is the catalytic serine protease subunit. Because C3 is the substrate for this convertase, a powerful feedback loop is created. Unchecked, this will lead to activation of the terminal complement pathway with generation of the effector molecules; the anaphylatoxin C5a and the membrane attack complex (MAC). Eculizumab binds C5 and prevents its entry into the C5 convertase (C3bBbC3b), thus precluding cleavage into the effector molecules, C5a and C5b and ultimately the MAC.