Reduction of postischemic immune inflammatory response:: An effective strategy for attenuating chronic allograft nephropathy

Background. Ischemia added to the allogeneic background accelerates the cellular mechanisms involved in alloresponsiveness, supporting the influence of early nonspecific inflammatory injury on chronic allograft nephropathy(CAN). The authors hypothesize that reinforcing initial immunosuppressive regimens may prevent immunogenicity derived from postischemic inflammatory responses, attenuating CAN. Methods. Lewis rats engrafted with Fischer kidneys received for 15 days overimmunosuppressive doses of rapamycin, a standard cyclosporine regimen, or both, and were followed functionally for 24 weeks. Animals were grouped according to the initial immunosuppressant or cold-ischemia period. Grafts were evaluated for acute inflammatory response at 1 week and for chronic histologic damage at 24 weeks. Results. Rats under cyclosporine alone displayed the highest mortality, which was decreased in the lope term by reducing cold ischemia or by strengthening immunosuppression. At 24 weeks, all rapamycin-treated groups displayed much less severe tubulointerstitial and vascular damage. The combination of both immunosuppresants offered better functional outcome and a global reduction in chronic histologic damage. After 1 week, ATN and profibrotic features appeared in all 5-hr ischemic animals, indicating that cyclosporine and rapamycin co-treatment did not induce further nephrotoxicity. Treatment with rapamycin, alone or combined with cyclosporine, greatly reduced the severe immune-inflammatory damage, including vessels, shown in cyclosporine-treated ischemic grafts. Conclusions. Strengthening initial immunosuppression attenuates the intensity, and extent of the early postischemic immune-inflammatory response as well as later function and structure of renal allografts. Severe CAN may be prevented by reducing cold ischemia or strengthening immunosuppression. Because the former approach is not always possible, reinforcement of early immunosuppression constitutes an excellent alternative.