Abstract

Background: The systemic inflammatory cascade triggered in donors after brain death enhances the ischemia-reperfusion injury after organ transplantation. Intravenous steroids are routinely used in the intensive care units for the donor preconditioning. Immunosuppressive medications could be potentially used for this purpose as well. Data regarding donor preconditioning with calcineurin inhibitors or inhibitors of mammalian target for Rapamycin is limited. The aim of this project is to investigate the effects of (oral) donor preconditioning with a calcineurin inhibitor (Cyclosporine) vs. an inhibitor of mammalian target for Rapamycin (Everolimus) compared to the conventional administration of steroid in the setting of donation after brain death in porcine renal transplantation.Methods: Six hours 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 with a repeated dose just before organ procurement. Control donors received intravenous Methylprednisolone (n = 8). Kidneys were procured, cold-stored in Histidine-Tryptophane-Ketoglutarate solution at 4°C and transplanted in nephrectomized recipients after a mean cold ischemia time of 18 h. No post-transplant immunosuppression was given to avoid confounding bias. Blood samples were obtained at 4 h post reperfusion and daily until postoperative day 5 for complete blood count, blood urea nitrogen, creatinine, and electrolytes. Graft protocol biopsies were performed 4 h after reperfusion to assess early histological and immunohistochemical changes.Results: There was no difference in the hemodynamic parameters, hemoglobin/hematocrit and electrolytes between the groups. Serum blood urea nitrogen and creatinine peaked on postoperative day 1 in all groups and went back to the preoperative levels at the conclusion of the study on postoperative day 5. Histological assessment of the kidney grafts revealed no significant differences between the groups. TNF-α expression was significantly lower in the study groups compared with Methylprednisolone group (p = 0.01) Immunohistochemistry staining for cytochrome c showed no difference between the groups.Conclusion: Oral preconditioning with Cyclosporine or Everolimus is feasible in donation after brain death pig kidney transplantation and reduces the expression of TNF-α. Future studies are needed to further delineate the role of oral donor preconditioning against ischemia-reperfusion injury.

Highlights

  • During the process of organ transplantation, the ischemia reperfusion injury (IRI) together with the systemic inflammatory response to brain death causes infrastructural organ injury which could lead to initial poor function and primary non-function [1]

  • The duration of brain death and the ischemia did not vary between the groups, either (Table 2)

  • blood urea nitrogen (BUN) and Cr increased posttransplant in all groups and returned to normal through postoperative day (POD) 4 to 5 (Figures 2, 3) and were not significantly different between the groups except for higher BUN after preconditioning with Everolimus compared to other groups on POD 2 (30 Cyclosporine vs. 43 in Everolimus vs. 24.5 in Methylprednisolone groups, p = 0.01) (Figure 2), and higher Cr after preconditioning with Cyclosporine on POD 1 (2.39 in Cyclosporine vs. 1.98 in Everolimus vs. 1.58 in Methylprednisolone, p = 0.02) (Figure 3)

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Summary

Introduction

During the process of organ transplantation, the ischemia reperfusion injury (IRI) together with the systemic inflammatory response to brain death causes infrastructural organ injury which could lead to initial poor function and primary non-function [1]. Preconditioning with calcineurin inhibitors (CNIs) has been shown to have protective effects in a model of renal transplantation in rats compared to vehicle-treated animals [4]. This renoprotective effect was seen with only one dose of CNI and was not different between cyclosporine and tacrolimus regarding measured outcomes. Data regarding donor preconditioning with calcineurin inhibitors or inhibitors of mammalian target for Rapamycin is limited The aim of this project is to investigate the effects of (oral) donor preconditioning with a calcineurin inhibitor (Cyclosporine) vs an inhibitor of mammalian target for Rapamycin (Everolimus) compared to the conventional administration of steroid in the setting of donation after brain death in porcine renal transplantation

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