Mitochondrial dysfunction, oxidative stress, and surgical acute kidney injury

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DESCRIPTION (provided by applicant): The candidate is an assistant professor of anesthesiology conducting translational research that tests mechanisms of acute kidney injury (AKI) following cardiac surgery. His immediate career goals are to 1) Test the hypothesis that mitochondrial dysfunction contributes to oxidative and AKI following cardiac surgery (see Specific Aims) and 2) Gain the skills and experiences required to become an independent investigator conducting clinical trials that test therapy for and mechanisms of surgery-induced AKI. His long-term career goals are to 1) Improve his capacity to develop and rigorously test hypotheses that decipher mechanisms of peri-operative organ dysfunction based on markers of pathophysiologic processes and 2) Establish, lead, and maintain funding for a multidisciplinary team that can test and develop new strategies to reduce acute organ dysfunction in patients undergoing surgery. The candidate, his mentor, and his mentorship committee have developed a comprehensive career development plan to meet these goals. The key elements of this plan are structured training in the pathophysiology of acute oxidant injury, mitochondrial dysfunction, and AKI, training in techniques relevant to hypothesis-testing clinical trial design and performance, structured mentorship from diverse physician-scientists with focus on scientific acumen development, and scheduled manuscript writing, presentation building, and grant preparation. He has published two papers on experimental models of AKI and three papers on the inflammatory/pro-oxidant response to surgery and therapy for AKI in humans. During the grant award period, the candidate will test the hypotheses that 1) Mitochondrial dysfunction is associated with oxidative stress during cardiac surgery and predicts AKI following cardiac surgery (Aim 1) and that 2) Treatment with a mitochondrial-targeted antioxidant, ubiquinone- 10, reduces mitochondrial dysfunction and oxidative stress in patients undergoing cardiac surgery (Aim 2). The candidate has recently shown that intraoperative concentrations of plasma and urine markers of oxidant injury (F2-isoprostanes and isofurans) predict the development of postoperative AKI. The pattern of F2- isoprostane and isofuran expression observed may be explained by mitochondrial dysfunction. In other preliminary studies, leukocyte mitochondrial DNA (mtDNA) coy number was significantly lower in cardiac surgery patients that developed AKI, intraoperative arterial lactate:pyruvate ratios correlated with postoperative urine concentrations of isofurans, and ubiquinone-10 reduced isofuran concentrations in chronic kidney disease patients. To accomplish Aim 1, the candidate will measure and compare preoperative, intraoperative, and postoperative plasma and urine concentrations of F2-isoprostanes and isofurans, markers of mitochondrial function (mitochondria redox potential, peroxisome proliferator-activated receptor ¿ coactivator 1-¿ (PGC-1¿) RNA expression, and mtDNA copy number from isolated leukocytes and arterial lactate:pyruvate ratios), and clinical AKI (defined using AKIN staging consensus criteria for AKI diagnosis) in 150 subjects who complete the Statin AKI Cardiac Surgery Randomized Clinical Trial, a trial testing the hypothesis that short-term high- dose perioperative atorvastatin treatment reduces the incidence of postoperative AKI in which 270 subjects have already been studied (PI: Billings). In Aim 1 we will test the hypothesis that mitochondrial dysfunction predicts systemic and renal markers of oxidative stress, and we will determine whether markers of mitochondrial function are lower in subjects who developed AKI compared to in subjects who did not. To accomplish Aim 2, we will perform a prospective, randomized, double-blind, placebo-controlled, dose- ranging, clinical study in which we will randomize 90 subjects undergoing cardiac surgery to placebo, 1200 mg, or 2400 mg of ubiquinone-10 five days prior to surgery and daily during hospitalization and test the effect of ubiquinone-10 dose on mitochondrial function and oxidative stress. These studies will provide new tools to examine the contribution of mitochondrial dysfunction to oxidant injury during surgery and AKI and may lead to new treatment strategies for patients undergoing surgery that will be tested in a future trial. Studies will be performed in Vanderbilt University Medical Center operating rooms, intensive care units, and clinics, and in Division of Clinical Pharmacology laboratories. As Associate Dean for Clinical and Translational Scientist Development from 2006-2010, the candidate's mentor built the institutional infrastructure to promote the success of junior physician-scientists and has received numerous awards for successfully mentoring physicians to scientific independence. Her laboratory conducts hypothesis-testing studies in humans and rodents that decipher mechanisms of cardiovascular and renal diseases. The Department of Anesthesiology provides unusual support including 80% protected non-clinical time and a research nurse dedicated exclusively to his research. Strong institutional investment in the candidate optimizes his likelihood of progressing to independence and impacting on adverse effects of surgery.