Molecular mechanisms of renal allograft fibrosis.
BACKGROUND
Chronic graft nephropathy (CGN) remains the leading cause of renal allograft loss after the first year following transplantation. Histologically it is characterized by glomerulosclerosis, intimal hyperplasia and interstitial 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 no impact on CGN.


METHODS
A review of the current literature on renal transplantation, novel immunosuppression regimens and advances in the molecular pathogenesis of renal allograft fibrosis was performed.


CONCLUSIONS
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 extracellular matrix. Repeated insults trigger upregulation of the tissue inhibitors of matrix metalloproteinases, favouring accumulation of extracellular matrix. To date, no drug has proved effective in inhibiting or reducing allograft fibrosis. The deleterious consequences of chronic immunosuppression on the development of such fibrosis are now recognized; newer immunosuppressive drugs, including rapamycin and mycophenolate mofetil, reduce profibrotic gene expression in both experimental and clinical settings, and offer potential strategies for prolonging allograft survival.
Waller
J R
JR
Division of Transplant Surgery, University of Leicester, Leicester, UK. julian@waller79.fsnet.co.uk
Nicholson
M L
ML
D000804:Angiotensin II / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000473:pathology* / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D014184:Transplantation, Homologous
D016207:Cytokines; D007166:Immunosuppressive Agents; D000804:Angiotensin II; D020782:Matrix Metalloproteinases