Molecular mechanisms of renal allograft fibrosis

Background: Chronic graft nephropathy (CGN) remains the leading cause of re nal allograft loss after the first year following transplantation. Histolog ically it is characterized by glomerulosclerosis, intimal hyperplasia and i nterstitial fibrosis. The pathogenesis is unclear, but is likely to involve both immunological and non-immunological factors. Despite improvements in short-term graft survival rates, new immunosuppressive regimens have made n o impact on CGN. Methods: A review of the current literature on renal transplantation, novel immunosuppression regimens and advances in the molecular pathogenesis of r enal allograft fibrosis was performed. Results and conclusion: Recent advances in understanding of the underlying molecular mechanisms involved suggest autocrine secretion of cytokines and growth factors, especially transforming growth factor beta, are associated with a change in fibroblast phenotype leading to the deposition of extracel lular matrix. Repeated insults trigger upregulation of the tissue inhibitor s of matrix metalloproteinases, favouring accumulation of extracellular mat rix. To date, no drug has proved effective in inhibiting or reducing allogr aft fibrosis. The deleterious consequences of chronic immunosuppression on the development of such fibrosis are now recognized; newer immunosuppressiv e drugs, including rapamycin and mycophenolate mofetil, reduce profibrotic gene expression in both experimental and clinical settings, and offer poten tial strategies for prolonging allograft survival.