Complement activation and effector pathways in membranous nephropathy

Complement activation has long been recognized as a central feature of membranous nephropathy. Evidence for its role has been derived from the detection of complement products in biopsy tissue and urine from membranous nephropathy patients and from mechanistic studies primarily based on the passive Heymann nephritis model. Only recently, more detailed insights into the exact mechanisms of complement activation and effector pathways have been gained from patient data, animal models and in vitro models based on specific target antigens relevant to the human disease. These data are of clinical relevance, as they parallel the recent development of numerous specific complement therapeutics for clinical use. Despite efficient B cell depletion, many patients with membranous nephropathy achieve only partial remission of proteinuria, which may be explained by the persistence of subepithelial immune complexes and ongoing complement-mediated podocyte injury. Targeting complement therefore represents an attractive adjunct treatment for membranous nephropathy, but it will need to be tailored to the specific complement pathways relevant to membranous nephropathy. This review summarizes the different lines of evidence for a central role of complement in membranous nephropathy and for the relevance of distinct complement activation and effector pathways, with a focus on recent developments.