title: Effect of mycophenolate mofetil on rat kidney grafts with prolonged cold preservation.
abstract: The impact of mycophenolate mofetil (MMF) on initial renal transplant function is not well characterized. We tested how MMF may modulate graft function and survival in a syngeneic rat kidney transplantation model after prolonged cold preservation. Donor kidneys were preserved in University of Wisconsin for either 24 or 39 h prior to transplantation into nephrectomized rats. Recipients received MMF (20 mg/kg/day) or vehicle. Mycophenolic acid (MPA) blood concentrations were measured by high-performance liquid chromatography. The inflammatory response, tubular epithelial proliferation, and histologic damage 3 days post-transplantation were assessed microscopically. In the 24 h cold storage (c.s.) group serum-creatinine was measured. In the 39 h c.s. group 1-week recipient survival was determined. After 24 h of c.s., recipient survival was 100%. The number of T-cell infiltrates was low and not influenced by MMF, whereas renal ED1+ cell infiltration was significantly suppressed by MMF. Tubular cell proliferation was enhanced by MMF. Serum-creatinine levels and renal histology were comparable between MMF and vehicle-treated animals. In the 39 h c.s. group, recipient survival was 20% in MMF-treated vs 90% in vehicle-treated animals (P=0.001). MMF effectively suppressed inflammatory cell infiltration and inhibited tubular cell proliferation. MMF-induced structural damage was most striking in the renal papilla. In rat kidney grafts with moderate preservation injury (24 h c.s.), MMF, given at an immunosuppressive dose, showed predominantly antiinflammatory effects without compromising graft function. In grafts with severe preservation injury (39 h c.s.), MMF caused irreversible structural damage and inhibited tubular cell regeneration resulting in renal failure.
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin Campus Mitte, Berlin, Germany. Florian.Fuller@charite.de
authors.forename: T F
authors.initials: TF
authors.lastname: Fuller
authors.forename: U
authors.initials: U
authors.lastname: Hoff
authors.forename: F
authors.initials: F
authors.lastname: Rose
authors.forename: Y
authors.initials: Y
authors.lastname: Linde
authors.forename: C E
authors.initials: CE
authors.lastname: Freise
authors.forename: D
authors.initials: D
authors.lastname: Dragun
authors.forename: S
authors.initials: S
authors.lastname: Feng
mesh_terms: D000818:Animals; D002455:Cell Division; D018932:Chemokine CCL2 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D015925:Cryopreservation; D006084:Graft Rejection / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology*; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D009393:Nephritis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1; D003404:Creatinine; D009173:Mycophenolic Acid