Project 4: Protecting Renal functiOn with Urate-lowering Drugs (PROUD)

项目4：用降尿酸药物保护肾功能（PROUD）

• 批准号: 10263207
• 负责人: Jasvinder A Singh
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263207
• 关键词: 3-nitrotyrosine; Address; Alabama; Aldosterone; Allopurinol; Ancillary Study; Animal Model; Arterial Disorder; C-reactive protein; CCL2 gene; Caring; Chronic Kidney Failure; Clinical; Clinical Trials; Collaborations; Communities; Complement; Creatinine; Data; Dose; Double-Blind Method; Fibrosis; Flare; Funding; Future; Genetic Polymorphism; Gout; High Prevalence; Human; Hypertension; Hyperuricemia; Immunology; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-1 beta; Interleukin-6; Investigation; Kidney; Knowledge; Link; Lipid Peroxidation; Medical; Medical center; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nebraska; Nitric Oxide Synthase; Outcome; Oxidative Stress; Oxidative Stress Pathway; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Placebos; Plasma; Platelet-Derived Growth Factor; Positioning Attribute; Prevalence; Proteins; Public Health; Randomized; Rattus; Renal function; Renin; Renin-Angiotensin System; Research; Resources; Rest; Rodent; Rodent Model; Role; Serum; Site; Smooth Muscle Myocytes; Solubility; Specialist; Sulfhydryl Compounds; TNF gene; Time; Titrations; Translating; Translational Research; United States Department of Veterans Affairs; Universities; Urate; Urate Oxidase; Uric Acid; Vascular Smooth Muscle; base; care providers; comorbidity; comparative effectiveness; cost effective; cytokine; double-blind placebo controlled trial; efficacy evaluation; febuxostat; innovation; interstitial; macrophage; multidisciplinary; novel; open label; oxidation; post gamma-globulins; preservation; prevent; primary outcome; secondary outcome; systemic inflammatory response; translational study; xanthine oxidase inhibitor

PROJECT SUMMARY The management of gout is suboptimal and complicated by high prevalence of comorbidities, including chronic kidney disease (CKD); 71% of gout patients in U.S. have CKD stage 2 or higher. A key reason for suboptimal gout care is lack of knowledge and acceptance for the utility of lowering serum urate (sUA) levels to < 6 mg/dl (based on the solubility threshold of 6.8 mg/dl), known as treat-to-target (TTT). While a sUA threshold of < 6 mg/dl is valuable for managing gout, it has not been examined for renal function preservation. Recently, the Department of Veterans Affairs (VA) funded a 4-year randomized, double-blinded, non-inferiority “Stop Gout” (VA CSP594) study with a sUA TTT approach, which will assess the comparative effectiveness of allopurinol vs. febuxostat. Our proposed study, Protecting Renal functiOn with Urate-lowering Drugs (PROUD), a mechanistic ancillary study to this innovative trial, will leverage trial data to assess whether achieving target sUA is valuable for renal function preservation for the first time, with the following two specific aims. Specific Aim 1 is to evaluate the efficacy of sUA lowering and allopurinol and febuxostat dose in preserving renal function in gout patients. We hypothesize that each of the following factors will be positively associated with renal function preservation as assessed by change in eGFR based on serum creatinine at 72-weeks (primary outcome) and serum Cystatin C at 48-weeks (secondary outcome): Achieving a sUA reduction and a target sUA level < 6 mg/dl at 24-weeks (Hypotheses 1a and 1b), baseline CKD Stage 3 (compared to CKD stage 1 or 2; Hypothesis 1c), the final up-titrated allopurinol dose at 21-weeks (Hypothesis 1d), and the final up-titrated febuxostat dose at 18-weeks (Hypothesis 1e). Specific Aim 2 will assess the mechanisms of renal function preservation in gout. We hypothesize that reduction at 24-weeks in each of the following will be associated with renal function preservation at 72-weeks: Renin-angiotensin system activation (plasma renin and aldosterone; Hypothesis 2a), systemic inflammation (IL-1β, IL-6, TNF-α, MCP-1, PDGF, C-reactive protein; Hypothesis 2b), and oxidative stress level (lipid peroxidation by 8-epi-PGF2a; protein oxidation by carbonyl formation, 3-nitrotyrosine formation and reduced thiol status; Hypothesis 2c). PROUD will have high public health impact and will advance the field by addressing unanswered questions related to renal function preservation with XOI in gout and underlying mechanisms. The University of Alabama at Birmingham (UAB) and the University of Nebraska Medical Center (UNMC), two large academic gout and immunology research centers, are ideally positioned to address the clinical and mechanistic questions posed. Our collaborative expertise, complemented by the leveraged resources of the proposed NIAMS supported P50 UAB Center of Research Translation (CORT) will be used to execute this novel translational study.

项目摘要 痛风的管理是次优的，并因合并症的高流行而变得复杂，包括慢性 肾脏疾病（CKD）；美国痛风患者中有71％的患者患有CKD阶段2或更高。关键原因 痛风的痛风护理缺乏降低血清尿酸含量（SUA）水平的知识和接受 <6 mg/dL（基于6.8 mg/dl的溶解度阈值），称为靶标（TTT）。而sua <6 mg/dl的阈值对于管理痛风是有价值的，尚未对其进行肾功能准备。 最近，退伍军人事务部（VA）资助了为期4年的随机，双盲，非效率 采用SUA TTT方法的“停止痛风”（VA CSP594）研究，该研究将评估比较有效性 别嘌醇与Febosostat。我们提出的研究，通过降低尿酸盐的药物保护肾功能（骄傲）， 这项创新试验的机械辅助研究将利用试验数据来评估是否实现目标 SUA首次对肾功能保存非常有价值，并具有以下两个特定目标。 特定目的1是评估SUA降低和别嘌呤醇和FeBosostat剂量的效率 保留患者的肾功能。我们假设以下每个因素是 通过基于序列的EGFR的变化评估，与肾功能保存正相关 肌酐在72周（主要结果）和48周的血清囊蛋白C（次要结果）：实现 在24周（假设1A和1B），基线CKD阶段3的SUA降低和目标SUA水平<6 mg/dl（假设1A和1B） （与CKD阶段1或2;假设1C相比），最终的上吐丁素剂量在21周（假设） 1d），以及在18周（假设1E）的最终上吐剂剂量。具体目标2将评估 痛风中肾功能制备的机制。我们假设在每个24周的减少 以下将与72周的肾功能制备有关：肾素 - 血管紧张素系统 激活（血浆肾素和醛固酮；假设2a），全身注射（IL-1β，IL-6，TNF-α，MCP-1， PDGF，C反应蛋白；假设2b）和氧化应激水平（8-EPI-PGF2A的脂质过氧化； 通过羰基形成，3-硝基酪氨酸形成和硫醇状况降低的蛋白质氧化；假设2C）。 骄傲将对公共卫生产生巨大影响，并通过解决未解决的问题来推进该领域 在痛风和潜在机制中使用XOI的肾功能保存相关。阿拉巴马大学 在伯明翰（UAB）和内布拉斯加州大学医学中心（UNMC），两个大型学术痛风和 免疫学研究中心，理想的位置可以解决提出的临床和机械问题。 我们的合作专业知识，由拟议的Niams支持P50的杠杆资源完成 UAB研究翻译中心（CORT）将用于执行这项新颖的翻译研究。