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.
Mouse tubular cells were incubated with either dimethyl sulfoxide (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.
Tubular cells treated with a caspase inhibitor had significantly reduced capsase-3 protein expression, caspase-3 activity, and apoptotic cell death compared with 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, BBI, tubular injury, cast formation, and tubule lumen dilation compared with DMSO and saline-treated kidneys.
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.
The authors investigate the efficacy of caspase inhibitor on improvement of graft function and attenuation of tubular cell apoptosis in a mouse kidney transplantation model (in vivo) as well as mouse tubular cells (in vitro).
1 Division of Renal diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO.
2 Denver Veterans Affairs Medical Center Denver, CO.
Received 28 August 2017. Revision received 24 January 2018.
Accepted 30 January 2018.
T.L.N., R.P., and S.J. contributed equally to this work.
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.
The authors declare no conflicts of interest.
T.N. participated in the performance of the research, research design, writing the article, and data analysis. R.P. participated in performance of the research, writing the article, and data analysis. S.J. participated in performance of the research, writing the article, and data analysis. S.L. participated in data analysis. A.J. participated in performance of the research, research design, writing the article, and data analysis.
Correspondence: Alkesh Jani, MD, Division of Renal Diseases and Hypertension, University of Colorado Denver, 12700 East 19th Ave, C281, Aurora, CO 80045. (Alkesh.firstname.lastname@example.org).
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