COMPLEMENT ABNORMALITIES IN PRIMARY MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Primary membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic renal disease that occurs principally in children and young adults. No specific treatment is available. Children with MPGN have an unfavorable prognosis and develop end stage renal disease during childhood or late adolescence. The disease recurs in almost all patients who received a kidney transplant and recurrence greatly worsens graft function and survival. Familial forms have been reported, indicating that MPGN has genetic causes. Data on incidence and prevalence of MPGN are scanty. A first aim of this project is to collect clinical data and biological samples from well characterized patients with primary MPGN. This will ameliorate diagnosis and clinical management and will provide the basis for future clinical trials. A MPGN website will be created including clinical practice guidelines that will be public and aimed at promoting the harmonization of MPGN management. The pathogenesis of primary MPGN is ill defined. The available data indicate that excessive activation of complement due to autoimmune and genetic abnormalities plays a role in inducing damage to the kidney and other organs. The complement is a complex system that mediates the immune response against bacteria and viruses. In normal conditions human cells are protected from complement attack by several inhibitors that restrict complement activation to the surface of pathogens. Such regulatory system is defective in MPGN. A major goal of this project will be the identification of the genetic and acquired defects underlying complement activation in MPGN and to establish whether specific complement abnormalities are associated with disease progression, response to therapy and recurrence on a transplanted kidney. In further studies we will search specific treatments by evaluating the efficacy of complement inhibitors to cure the disease and to prevent recurrence in the kidney graft, in a mouse model of MPGN and in a pilot clinical study in patients with MPGN who do not respond to available therapies.