The complement system in IgAN: mechanistic context for therapeutic opportunities

ABSTRACT The complement system plays a crucial role in innate immunity, providing essential defense against pathogens. However, uncontrolled or prolonged activation of the complement cascade can significantly contribute to kidney damage, especially in cases of glomerulonephritis. Immunoglobulin A nephropathy (IgAN), the most prevalent form of primary glomerulonephritis, has growing evidence supporting the involvement of complement alternative and lectin pathways. In fact, patients with IgAN experience complement activation within their kidney tissue, which may be involved in the development of glomerular damage and the progression of IgAN. Complement activation has emerged as a significant area of interest in IgAN, with numerous complement-targeting agents currently being explored within this field. Nevertheless, the exact mechanisms of complement activation and their role in IgAN progression require comprehensive elucidation. This review seeks to contextualize the proposed mechanisms of complement activation within the various stages (“hits”) of IgAN pathogenesis, while also addressing the clinical implications and anticipated outcomes of complement inhibition in IgAN.