Advance-CTR

Advance-CTR Mentored Research Awards (2017)

"An In Vivo Study of Treprostinil, a Prostacyclin Analog, in the Prevention of Ischemia-Reperfusion Injury to the Kidney"

Approximately 2 million people worldwide and more than 650,000 Americans are affected by end-stage kidney diseases (ESRD). Kidney transplantation (KTx) is the only cure for ESRD, however, donor shortage is a major factor limiting the organs available for transplantation. This shortage has forced medical centers to accept extended criteria donors (ECD), whose organs are most susceptible to ischemia-reperfusion (I/R) injury and a 30-70% risk of delayed graft function (DGF). I/R injury is the main cause of initial poor function and primary graft non-function, carrying a high mortality if patients are not re-transplanted immediately, further depleting the limited donor pool. Currently, no treatment for I/R injury is available and therapeutic strategies are urgently needed to address these unmet needs of KTx. Prostaglandins, including prostacyclin (PGI2) analogs, have been shown to reduce the extent of I/R injury in clinical and animal studies of liver transplantation (LTx), as well as improve renal function. Treprostinil (Remodulin®), a PGI2 analog, is FDA-approved to treat pulmonary arterial hypertension and, among PGI2 analogs commercially available, it has the most potent systemic vasodilatory and platelet anti-aggregatory effects in vitro and in vivo. Notably, treprostinil ameliorated I/R injury during rat orthotopic LTx (Ghonem et al. AJT, 2011) and it is currently in clinical trials for LTx. Preliminary data show that treprostinil reduced inflammatory cytokine secretion in human macrophages. The objectives of this study are to determine the safety and efficacy of treprostinil in reducing acute kidney injury in a rat kidney I/R injury model. Male Sprague Dawley rats will be randomized to 3 groups: sham, I/R-placebo, or I/R-treprostinil. Animals will undergo bilateral ischemia for a predetermined period of time and will be sacrificed at 1 hr - 7 days post-reperfusion to determine kidney injury. Blood will be collected to measure serum creatinine, a marker of kidney function and a measure of I/R injury, and kidney tissue for histologic evaluations. Additional in vitro studies may examine the regulatory role of treprostinil in renal I/R injury. Proof of concept findings in animals may be translated to clinical studies to investigate the ability of treprostinil to reduce I/R-mediated dysfunction of the kidney graft during adult KTx. Long-term goals of this research are to identify a novel pharmacological therapy to reduce I/R injury, improve graft function and outcomes in kidney and potentially other organs of transplantation.