Effect of mycophenolate mofetil on rat kidney grafts with prolonged cold preservation.
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.
Fuller
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TF
Department of Urology, Charité Universitaetsmedizin Berlin Campus Mitte, Berlin, Germany. Florian.Fuller@charite.de
Hoff
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Rose
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Linde
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Freise
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Dragun
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Feng
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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
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1; D003404:Creatinine; D009173:Mycophenolic Acid