**Sofia Andrighetto 1,2, Jeremy Leventhal 1, Gianluigi Zaza <sup>2</sup> and Paolo Cravedi 1,\***


Received: 14 November 2019; Accepted: 10 December 2019; Published: 16 December 2019

**Abstract:** The complement cascade is part of the innate immune system whose actions protect hosts from pathogens. Recent research shows complement involvement in a wide spectrum of renal disease pathogenesis including antibody-related glomerulopathies and non-antibody-mediated kidney diseases, such as C3 glomerular disease, atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. A pivotal role in renal pathogenesis makes targeting complement activation an attractive therapeutic strategy. Over the last decade, a growing number of anti-complement agents have been developed; some are approved for clinical use and many others are in the pipeline. Herein, we review the pathways of complement activation and regulation, illustrate its role instigating or amplifying glomerular injury, and discuss the most promising novel complement-targeting therapies.

**Keywords:** complement; alternative complement pathway; complement-targeting therapies; C3 glomerulopathy; hemolytic uremic syndrome; focal segmental glomerulosclerosis

## **1. Complement Cascade**

The complement system consists of soluble or membrane-bound molecules, mostly zymogens, activated through a tightly regulated proteolytic cascade [1,2]. Current understanding of complement immune mechanisms include (1) functioning as opsonins; (2) producing chemoattractants to recruit immune cells thereby enhancing site specific angiogenesis, vasodilation and coagulation cascade regulator; and (3) functioning as an enhancing bridge to adaptive T and B lymphocyte responses [3]. Current research suggests that abnormal complement activation plays a role in autoimmune inflammatory diseases and particularly in those targeting the kidney.
