PURPOSE: Extensive ischemia-reperfusion injury significantly increases the immunogenicity of renal allograft which may be associated with increased risk of acute rejection (AR). This study investigated the AR of renal allograft donated after cardiac death (DCD) and whether the enhanced immunosuppression could improve the function of DCD renal allograft function in a large animal model. METHODS: Landrace pig recipients of renal allografts that had 0.5hr warm ischemia time (WIT) and 3.5hr cold ischemia time (CIT) were treated with either low- or high-dose immunosuppression (LI or HI, oral Tacrolimus 0.065 or 0.130 mg/kg/day, n=6/group, respectively), while the recipients with 4hr CIT and LI served as controls (n=3). All the recipients were euthanized at day 5 after transplantation. RESULTS: The blood urea nitrogen (BUN) and creatinine (CR) levels were remarkably increased in the DCD recipients compared with the non-DCD recipients. In contrast, HI significantly decreased the BUN and CR levels in the DCD recipients compared with those receiving LI. Histology studies indicated that the HI significantly reduced the AR and CD3⁺ lymphocyte infiltration as well as significantly decreased the mRNA expression of ifn-g, il-6, tgf-b, and il-4 in the allograft, and decreased serum cytokines levels of IFN-g and IL-17 at day 4 and 5 after transplant. Western blots showed that the HI therapy decreased phosphorylation of STAT3 and NFkB-p65 but increased the phosphorylation of ERK, and decreased the expression of BAX, and Caspase-3 in the renal allografts. CONCLUSION: These results demonstrate that the intensified immunosuppressive therapies improved the early DCD renal graft function after transplantation in a large animal model.

CITATION INFORMATION: Xu M., Wang X., Garcia-Aroz S., Banan B., Rabe B., Zhang Z., Jia J., Upadhya G., Manning P., Gaut J., Lin Y., Chapman W. Intensified Immunosuppression Improves Early Renal Allograft Function after Transplantation in a Porcine Model with Extended Asystolic Warm Ischemic Time Am J Transplant. 2017;17 (suppl 3).

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