Complement-Mediated Kidney Diseases: Role of Alternative Pathway in Glomerular Inflammation

Complement-mediated kidney diseases (CMKDs) comprise a diverse group of rare disorders characterized by the activation of the complement system, leading to glomerular inflammation, kidney injury, and in some cases, kidney failure. Although the contribution of complement activation to disease pathogenesis varies across CMKDs, the alternative complement pathway appears to play a pivotal role in driving inflammation and tissue damage in the kidney by amplifying complement activation, regardless of the initiating complement pathway. A growing body of evidence links the alternative pathway with glomerular inflammation in CMKDs, including key mechanistic insights from preclinical in vivo models, the association of alternative pathway components with histologic kidney injury and disease severity, and the efficacy of alternative pathway inhibition in patients with these disorders. With an improved understanding of the mechanisms of alternative pathway overactivation in CMKDs, many novel complement inhibitors targeting the alternative pathway are in clinical development for the management of CMKDs, potentially offering a more precise, better-tolerated, and effective approach than conventional immunosuppressive agents or therapeutics that provide broader inhibition of the common terminal complement pathway. This review summarizes the role of the alternative pathway in the pathogenesis of CMKDs and provides evidence supporting its involvement in glomerular inflammation. In addition, we provide a future perspective on the principles guiding the treatment of glomerular inflammation with therapies that target the alternative pathway.