title: Mycophenolate mofetil is associated with altered expression of chronic renal transplant histology.
abstract: Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.
authors.affiliation: Department of Renal Medicine, University of Sydney, Westmead Hospital, Westmead 2145, Sydney, NSW, Australia. Brian_Nankivell@wsahs.nsw.gov.au
authors.forename: B J
authors.initials: BJ
authors.lastname: Nankivell
authors.forename: M D
authors.initials: MD
authors.lastname: Wavamunno
authors.forename: R J
authors.initials: RJ
authors.lastname: Borrows
authors.forename: M
authors.initials: M
authors.lastname: Vitalone
authors.forename: C L-S
authors.initials: CL
authors.lastname: Fung
authors.forename: R D M
authors.initials: RD
authors.lastname: Allen
authors.forename: J R
authors.initials: JR
authors.lastname: Chapman
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D000328:Adult; D015331:Cohort Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid