233.2: Oral preconditioning of donors after brain death with calcineurin inhibitors vs. inhibitors of mammalian target for rapamycin in pig kidney transplantation.

Abstract

Background: The systemic inflammatory cascade triggered in donors after brain death (DBD) enhances the ischemia-reperfusion injury (IRI) after organ transplantation. Data regarding donor preconditioning with calcineurin inhibitors (CNIs) and/or inhibitors of mammalian target for Rapamycin (mTORIs) is limited. The aim of this project is to investigate the effects of (oral) donor preconditioning with a CNI (Cyclosporine A) versus an mTORi (Everolimus) compared to the conventional administration of steroid in the setting of DBD in porcine renal Transplantation. Methods: After the induction of brain death, German landrace donor pigs (33.2±3.9 kg) were randomly preconditioned with either Cyclosporine (n=9) or Everolimus (n=9) administered via nasogastric tube. Control donors received intravenous (i.v.) Methylprednisolone (n=8). Kidneys were procured, cold-stored in HTK solution at 4 °C and transplanted in nephrectomized recipients after a mean cold ischemia time of 19.32±2.92 (SD) hrs (range: 15.33-25.83). No immunosuppression was performed to avoid confounding bias. Blood samples were obtained at 4 hrs postreperfusion and daily until postoperative day (POD) 5 for complete blood count, blood urea nitrogen (BUN), creatinine (Cr), and electrolytes. Graft protocol biopsies were performed 4 hrs after reperfusion. Results: There was no difference in the hemodynamic parameters, hemoglobin / hematocrit and electrolytes between the groups. Serum BUN peaked on POD1 in all groups but trended to remain higher after donor preconditioning with Everolimus. Serum Cr also peaked on POD1 but was significantly higher after donor preconditioning with Cyclosporine on POD 1 (p=0.017) and at the conclusion of the study on POD 5 (p=0.009). There was no difference between serum Cr after donor preconditioning with Everolimus compared to steroids. Histological assessment of acute tubular necrosis revealed no significant differences between the Groups. Conclusions: Donor oral preconditioning with Everolimus (but not Cyclosporine) resulted in similar posttransplant serum Cr values compared to the conventional donor preconditioning with i.v. steroids after porcine kidney transplantation. The histological Tissue damages were the same in the 3 groups, showing no advantage in the conventional preconditioning group.