Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

• Published in: American journal of transplantation Vol. 7; no. 2; pp. 366 - 376
• Main Authors: Nankivell, B. J., Wavamunno, M. D., Borrows, R. J., Vitalone, M., Fung, C. L‐S, Allen, R. D. M., Chapman, J. R., O'Connell, P. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2007; Blackwell
• Subjects: Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Azathioprine; Biological and medical sciences; chronic allograft nephropathy; Cohort Studies; Cyclosporine - adverse effects; Cyclosporine - therapeutic use; cyclosporine nephrotoxicity; Enzyme Inhibitors - therapeutic use; Female; Fibrosis - pathology; Graft Rejection - pathology; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Kidney Glomerulus - pathology; kidney transplantation; Kidney Transplantation - immunology; Kidney Transplantation - pathology; Kidney Tubules - pathology; Male; Medical sciences; mycophenolate mofetil; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - therapeutic use; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pharmacology. Drug treatments; Renal failure; Retrospective Studies; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Time Factors; Mofetil; Mycophenolic acid; chronic allograft nephropathy; Toxicity; Homograft; Homotransplantation; Association; Surgery; Graft; Antiviral; Ciclosporin; Kidney disease; Urinary system disease; cyclosporine nephrotoxicity; Histology; Gene expression; Immunomodulator; Rejection; Antibiotic; Chronic; Nephropathy; Treatment; Renal failure; Immunosuppressive agent; Mycophenolate mofetil; Azathioprine; Kidney transplantation
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01633.x

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. Comparison of protocol kidney biopsies in two patients treated with cyclosporine plus either mycophenolate or azathioprine revealed decreased fibrosis and glomerulopathy, and a reduction in features associated with cyclosporine nephrotoxicity, suggesting that MMF limits immune‐mediated injury and may directly reduce fibrosis.