Final Report Summary - OSAI (Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI))
Membranous nephropathy is a rare disease that affects the kidney glomerulus and is responsible for massive urinary loss of proteins and renal failure in 30% of patients. It results in the formation of immune deposits on the outer aspect of the glomerular basement membrane and formation of the membrane attack complex of complement (MAC) which is the major effector of proteinuria. Since the recent identification of podocyte target antigens, it is considered a model of organ-specific auto-immune disease. Therefore any progress in the understanding of its pathophysiology may enhance diagnosis, monitoring and treatment of many other diseases. We have made significant advances in all aspects of the pathophysiology of membranous nephropathy, identifying new antigens (exostosin1/2, arylsulfatase), dissecting the genetics of the disease, unraveling key aspects of antibody effects and complement activation, and providing the first all-atom model of MAC. These results have been translated into substantial progress in the diagnosis and care of patients with primary and secondary (lupus) membranous nephropathy, including kidney biopsy staining of the new antigens (exostosin 1/2), quantitative assay for THSD7A antibody, determination of a genetic risk score for recurrence of the disease after transplantation. We have laid the ground for the design of specific inhibitors of complement and for targeted delivery of drugs to the glomerulus. We believe that the significant advances that we have made will open new perspectives in the understanding of the pathophysiology of other organ-specific auto-immune diseases and new approaches to patients care.