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 long 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 immunosuppressants 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.
Herrero-Fresneda
Immaculada
I
Laboratory of Experimental Nephrology, Department of Medicine, Universitat de Barcelona, Hospital Universitari de Bellvitge, Barcelona, Spain.
Torras
Joan
J
Vidal
August
A
Lloberas
Nuria
N
Cruzado
Josep M
JM
Grinyó
Josep M
JM
D000818:Animals; D002455:Cell Division; D006085:Graft Survival / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D007166:Immunosuppressive Agents; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1