Research Project
7995024
DESCRIPTION (provided by applicant): Renal transplantation has been a clinical reality for nearly 40 years. Transplantation is the only effective solution for organ end-stage renal failure. Long term renal function following transplantation has been shown to be better when kidneys are not subjected to cold preservation storage. However, despite the fact that cold preservation elicits significant kidney injury, cold preservation is essential for successful transplants today because it permits optimal patient selection and transport of kidneys derived from deceased donors. Cold preservation impacts both the quality of transplanted organs and the number of organs available for transplant. Therefore, therapeutic interventions that target the mechanisms by which kidneys are damaged by cold preservation could have a significant impact on the quality and availability of kidneys for transplant. We hypothesize that cold preservation induces mitochondrial damage, which leads to generation of superoxide and renal damage, and that inclusion of a novel mitochondrial antioxidant, MitoQ, preserves mitochondrial and renal function during cold preservation. Preliminary data in support of this hypothesis employing a rodent model are presented. The purpose of this proposal is to test the feasibility of decreasing oxidant production, mitochondrial and renal damage in two specific aims using a large animal porcine kidney model. In Specific Aim 1 oxidant production and renal damage will be compared in the presence of several doses of MitoQ, an inactive control compound, and a no treatment control group over a 48 hour cold preservation period. In Specific Aim 2 mitochondrial function 1 MitoQ will be investigated to determine whether or not there is a mitochondrial protective effect of MitoQ during renal cold preservation. It remains unknown whether cold renal preservation first induces mitochondrial damage which leads to oxidant damage or if oxidant damage causes mitochondrial damage. Feasibility for progression from this Phase I to a Phase II SBIR proposal will be determined by demonstration that the presence of MitoQ decreases oxidant production, renal damage and mitochondrial injury by 50% over untreated controls for at least 24 hours. Phase II would consist of translational studies to test the effectiveness of MitoQ therapy on post-transplantation renal function using the porcine autotransplantation model, as well as evaluation of the effect of adding MitoQ to human research kidneys ex vivo. PUBLIC HEALTH RELEVANCE: There is a significant kidney demand/supply imbalance, for example there were 16,520 kidney transplants in 2008 and there were 82,455 patients on the waiting list for kidneys on November 9th, 2009. Improving the quality and supply of kidneys would reduce the Medicare costs of patients otherwise on dialysis and improve patient quality of life. The costs of taking this technology to market are low because MitoQ is being developed for other, larger clinical applications and it is anticipated that the organ preservation application of MitoQ will be regulated as a device not a drug. This is because it is employed outside the body and the patient will not be exposed to it. MitoQ may also benefit other organ types used for transplantation, which are viable for much shorter times during cold preservation.
