Caspase inhibition during cold storage improves graft function and histology in a murine kidney transplant model

Background Prolonged cold ischemia is a risk factor for delayed graft function of kidney transplants, and is associated with caspase-3 mediated apoptotic tubular cell death. We hypothesized that treatment of tubular cells and donor kidneys during cold storage with a caspase inhibitor before transplant would reduce tubular cell apoptosis and improve kidney function after transplant. Methods Mouse tubular cells were incubated with either DMSO or Q-VD-OPh during cold storage in saline followed by rewarming in normal media. For in vivo studies, donor kidneys from C57BL/6 mice were perfused with cold saline, DMSO (vehicle), or QVD-OPh. Donor kidneys were then recovered, stored at 4°C for 60 minutes, and transplanted into syngeneic C57BL/6 recipients Results Tubular cells treated with a caspase inhibitor had significantly reduced capsase-3 protein expression, caspase-3 activity, and apoptotic cell death compared to saline or DMSO (vehicle) in a dose-dependent manner. Treatment of donor kidneys with a caspase inhibitor significantly reduced serum creatinine, and resulted in significantly less tubular cell apoptosis, brush border injury, tubular injury, cast formation, and tubule lumen dilation compared to DMSO and saline-treated kidneys. Conclusion: Caspase inhibition resulted in decreased tubular cell apoptosis and improved renal function after transplantation. Caspase inhibition may be a useful strategy to prevent cold ischemic injury of donor renal grafts. Trevor L. Nydam, MD, Robert Plenter, Swati Jain, Authors contributed equally to this work. Address for Correspondence: Alkesh Jani, University of Colorado Denver Division of Renal Diseases and Hypertension, 12700 East 19th Avenue, C281, Aurora, Colorado 80045: Email address: Alkesh.jani@ucdenver.edu Authorship TN participated in performance of the research, research design, writing the paper and data analysis; RP participated in performance of the research, writing the paper and data analysis; SJ participated in performance of the research, writing the paper and data analysis; SL participated in data analysis and AJ participated in performance of the research, research design, writing the paper and data analysis. Disclosures The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding This work was supported by a T32 award 5T32DK007, in addition to a 135 VA Merit Award 1I01BX001737 to AJ and the 2014 American Society of Transplant Surgeons –Astellas Faculty Development Award to TN. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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