Prolongation of canine allograft survival with donor pretreatment

Donor pretreatment of 100 mg/kg each of cyclophosphamide (CY) and methylprednisolone (P) infused 5 hours before nephrectomy invariably prolongs the survival of DLA mismatched, MLC incompatible nonlittermate Beagle renal allografts as well as the survival of mongrel renal allografts. The effect of donor pretreatment appears to be mediated by cyclophosphamide and its metabolites because methylprednisolone pretreatment does not significantly prolong survival. Methylprednisolone is needed, however, because it abolishes cyclophosphamide pretreatment mediated early but transient postoperative renal (allograft) insufficiency. The effect of donor pretreatment appears to be mediated by drugs residing in the graft; mannitol infusions given 1 hour prior to donor nephrectomy or peroperatively into the recipient decrease the renal cortical content of carbon 14 cyclophosphamide and its metabolites and abolishes the prolonged survival. Because donor pretreated kidneys contain less than 0.5% of the infused dose of carbon 14 cyclophosphamide, the drugs appear to exert their effect locally in the transplanted kidney. Donor pretreatment mediating prolonged canine renal allograft survival appears to be an example of influencing a biological process by a localized drug delivery by virtue of unique properties of the drug and because early postoperatively host sensitization occurs mainly at the site of the graft.