Therapeutic regulation of complement in patients with renal disease - where is the promise?

Abstract

Numerous renal diseases are characterized by complement activation within the kidney, and several lines of evidence implicate complement activation as an important part of the pathogenesis of these diseases. Investigators have long anticipated that complement inhibitors would be important and effective therapies for renal diseases. Eculizumab is a monoclonal antibody to the complement protein C5 that has now been administered to patients with several types of renal disease. The apparent efficacy of this agent may herald a new era in the treatment of renal disease, but many questions about the optimal use of therapeutic complement inhibitors remain. Herein we review the rationale for using complement inhibitors in patients with renal disease and discuss several drugs and approaches that are currently under development.

Figure 1.. Simplified overview of the complement cascade. The complement cascade is comprised of more than 30 proteins. The cascade can be activated through three distinct pathways. C3 and C4 are routinely measured in patients suspected of having glomerular disease. C3 is the central component of the cascade, and activation of all three pathways can lead to C3 cleavage. Activation of the classical and mannose binding lectin pathway causes cleavage of C4. Activation through all three pathways generates the same downstream pro-inflammatory fragments: C3a, C5a, C3b, and C5b-9.