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

描述（由申请人提供）：本提案的目的是促进候选人Jalal博士的科学发展和实验室技能，使其成为能够进行临床翻译研究的独立研究者。肾脏部门与科罗拉多丹佛大学临床和转化研究中心合作，能够为Jalal博士提供最佳环境，以检查降低血清尿酸水平对中度慢性肾脏病（CKD）患者内皮功能的影响，包括临床、生化和细胞水平。Jalal博士目前是丹佛健康科学中心科罗拉多大学的助理教授。通过她的主要导师约翰逊博士和经验丰富的科学和临床研究人员的广泛网络，Jalal博士将获得独立学术生涯发展的基础。内皮功能障碍、炎症和氧化应激在CKD患者中普遍存在，并在动脉粥样硬化和CKD进展中发挥核心作用。由于多种因素，CKD患者会出现高尿酸血症。尿酸与内皮功能障碍的病因有关。实验证据表明，它通过炎症和氧化应激介导其对血管系统的下游作用。我们假设尿酸诱导氧化应激和炎症，并导致高尿酸血症的III期CKD患者的内皮功能障碍。在她的资助中，Jalal博士提出了一项随机对照临床试验，其中80名患有III期CKD且血清尿酸水平> 7 mg/dL的患者将随机接受安慰剂或别嘌呤醇治疗3个月。该提案的具体目标包括：1.通过测量肱动脉血流介导的舒张功能，确定降低血清尿酸改善内皮依赖性舒张功能，2.确定降低血清尿酸水平将减轻全身炎症和氧化应激，以及3.通过免疫荧光法确定降低血清尿酸水平将抑制炎症和氧化途径的内皮细胞活化。对于这些特定目标中的每一个，将在基线和研究期结束时获得测量值，并将在随机分配至别嘌呤醇组和随机分配至安慰剂组之间对比相对于基线的变化。这项研究的结果将回答一个重要的临床问题，并将导致可靠的工作。此外，本试验的结果可能为更大规模的临床试验奠定基础，以评估轻度-中度CKD患者中降尿酸治疗对心血管事件和CKD进展的影响。 公共卫生相关性：我们提出了一项临床试验，以测试这一假设，即降低血清尿酸水平与黄嘌呤氧化酶抑制剂（别嘌呤醇）将改善内皮功能，炎症和氧化应激在临床，生化和细胞水平，在III期CKD患者谁也高尿酸血症。本申请为临床研究培训提供了理想的工具，因为科罗拉多丹佛大学的肾脏部门处于有利地位，能够使候选人完成拟议的研究。该奖项将允许正式的课程工作，以获得临床研究，出版物和参加国家会议的博士学位，并建立合作关系。此外，它将教育候选人在内皮细胞恢复和蛋白质表达，一种技术，可以在未来的其他研究中使用。这项拟议的研究将得出可靠的结果，并可能导致更大规模的临床试验，旨在评估降尿酸药物对CKD患者结局的影响。

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.