Uric Acid as a Mediator of Endothelial Dysfunction in Patients with CKD

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DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and laboratory skills of the candidate, Dr. Jalal, so that she may become an independent investigator, who can perform clinical translation research. The Renal Division in collaboration with the Clinical and Translation Research Center at the University of Colorado Denver are in a position to provide Dr. Jalal with the optimal environment to examine the impact of lowering serum uric acid levels on endothelial function, at the clinical, biochemical, and cellular level, in patients with moderate chronic kidney disease (CKD). Dr. Jalal is currently as assistant professor at the University of Colorado at Denver Health Sciences Center. Through her primary mentor, Dr. Johnson, and an extensive network of experienced scientific and clinical researchers, Dr. Jalal will obtain the foundation for the development of an independent academic career. Endothelial dysfunction, inflammation, and oxidative stress are prevalent in patients with CKD, and play a central role in atherosclerosis and in CKD progression. Due to a variety of factors, patients with CKD are hyperuricemic. Uric acid has been implicated in the etiology of endothelial dysfunction. Experimental evidence suggests it mediates its downstream effects on the vasculature via inflammation and oxidative stress. We hypothesize that uric acid induces oxidative stress and inflammation, and contributes to endothelial dysfunction in patients with stage III CKD who are also hyperuricemic. In her grant, Dr. Jalal proposes a randomized controlled clinical trial, where 80 patients with stage III CKD and serum uric acid levels acid > 7mg/dL will be randomized to either placebo or allopurinol for 3 months. The specific aims of the proposal include: 1. determine of lowering serum uric acid improves endothelial dependant dilation by measuring brachial artery flow mediated dilation, 2. determine that lowering serum uric acid levels will mitigate systemic inflammation and oxidative stress, and 3. determine that lowering serum uric acid levels will curb endothelial cellular activation of inflammatory and oxidative pathways by immunofluorescence. For each of these specific aims, measurements will be obtained at baseline and the end of the study period, and changes from baseline will be contrasted between the group randomized to allopurinol and the group randomized to placebo. The results of this study will answer an important clinical question, and will result in publishable work. In addition, the findings of this trial will likely set the stage for larger clinical trials to evaluate the impact of uric acid lowering therapies on cardiovascular events and CKD progression in patients with mild- moderate CKD. PUBLIC HEALTH RELEVANCE: We are proposing a clinical trial to test that hypothesis that lowering serum uric acid levels with a xanthine oxidase inhibitor (allopurinol) will improve endothelial function, inflammation, and oxidative stress at the clinical, biochemical, and cellular level, in patients with stage III CKD who are also hyperuricemic. This application presents an ideal vehicle for training in clinical research, as the Renal Division at the University of Colorado Denver is in a strong position to enable the candidate to complete the proposed study. This award will allow for formal course work to obtain a doctorate degree in clinical research, publications and participation in national conferences, and the establishment of collaborative relationships. In addition, it will educate the candidate in endothelial cell recovery and protein expression, a technique that can be utilized in other studies in the future. The proposed study will result in publishable findings, and may lead to larger clinical trials aimed to evaluate the impact of uric acid lowering agents on outcomes in patients with CKD.