Short-term immunosuppressive treatment of the donor ameliorates consequences of ischemia/ reperfusion injury and long-term graft function in renal allografts from older donors.
BACKGROUND
Grafts from so-called "marginal donors" are increasingly used for organ transplantation. The combination of reduced organ quality and additional inflammatory damages may be particularly detrimental in these grafts. In a previous study, we showed the beneficial effects on long-term graft outcome of "suboptimal" grafts by the induction of heme oxygenase-1. Here we tested the impact of short-term donor treatment with established immunosuppressants.


METHODS
Twelve-month-old Fischer 344 donor rats either were treated with prednisolone, mycophenolate mofetil, RAD, or FK506 24 hr and 1 hr before organ harvesting or remained untreated. Renal allografts were perfused with University of Wisconsin solution and kept at 4 degrees C for an ischemic period of 2 hr. Morphologic, immunohistologic, and real time reverse transcriptase-polymerase chain reaction analyses for relevant markers were performed at serial intervals and at the end of the observation period (6 months).


RESULTS
All animals survived the observation period, although the ischemic time resulted in accelerated chronic graft dysfunction. Grafts from donors treated with prednisolone or FK506 demonstrated significantly improved graft function and structure by 6 months. Mononuclear infiltrates were significantly reduced by the end of the observation period, whereas intragraft mRNA levels of tumor necrosis factor-alpha and interleukin-10 were significantly altered during the early period after transplantation. Minor improvements in graft function and histologic alterations of suboptimal grafts were observed after pretreatment with mycophenolate mofetil and RAD.


CONCLUSIONS
Donor treatment with approved immunosuppressants, in particular prednisolone or FK506, represents a novel therapeutic strategy of clinical relevance, most importantly when using grafts from marginal donors.
Reutzel-Selke
Anja
A
Department of General and Transplantation Surgery, Charite-Campus Virchow Clinic, Berlin, Germany.
Zschockelt
Thomas
T
Denecke
Christian
C
Bachmann
Ulrike
U
Jurisch
Anke
A
Pratschke
Johann
J
Schmidbauer
Georg
G
Volk
Hans-Dieter
HD
Neuhaus
Peter
P
Tullius
Stefan G
SG
D000367:Age Factors; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000188:drug therapy*; D016559:Tacrolimus / Q000494:pharmacology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000954:Antigens, Surface; D016207:Cytokines; D007166:Immunosuppressive Agents; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D011239:Prednisolone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D009173:Mycophenolic Acid; D016559:Tacrolimus