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: 10017010
• 负责人: Jasvinder A Singh
• 金额: $ 19.9万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017010
• 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; Universities; Urate; Urate Oxidase; Uric Acid; Vascular Smooth Muscle; Veterans; base; care providers; comorbidity; comparative effectiveness; cost effective; cytokine; double-blind placebo controlled trial; febuxostat; innovation; interstitial; macrophage; multidisciplinary; novel; open label; oxidation; post gamma-globulins; preservation; prevent; primary outcome; secondary outcome; 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.

项目概要 痛风的治疗并不理想，而且由于合并症（包括慢性病）的高患病率而变得复杂。 肾脏疾病 (CKD)；美国 71% 的痛风患者患有 CKD 2 期或更高阶段。 痛风护理欠佳是因为人们对降低血清尿酸 (sUA) 水平的效用缺乏了解和接受 < 6 mg/dl（基于 6.8 mg/dl 的溶解度阈值），称为目标治疗 (TTT)。 < 6 mg/dl 的阈值对于控制痛风很有价值，但尚未对其肾功能保存进行检查。 最近，退伍军人事务部 (VA) 资助了一项为期 4 年的随机、双盲、非劣效性研究 采用 sUA TTT 方法的“停止痛风”（VA CSP594）研究，该研究将评估以下方法的比较有效性 别嘌呤醇与非布索坦的比较我们提出的研究，用降尿酸药物保护肾功能（PROUD）， 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首次对肾功能保存有价值，具有以下两个具体目标。 具体目标 1 是评估降低 sUA 以及别嘌呤醇和非布索坦剂量的功效 我们认为以下因素将是保护痛风患者的肾功能。 通过基于血清的 eGFR 变化评估，与肾功能保存呈正相关 72 周时的肌酐（主要结果）和 48 周时的血清胱抑素 C（次要结果）： 实现 24 周时 sUA 减少且目标 sUA 水平 < 6 mg/dl（假设 1a 和 1b），基线 CKD 3 期 （与 CKD 1 期或 2 期相比；假设 1c），21 周时最终滴定的别嘌呤醇剂量（假设 1d)，以及 18 周时最终滴定的非布索坦剂量（假设 1e）将评估 我们勇敢地在 24 周时进行了痛风肾功能保护的机制。 以下因素与 72 周时的肾功能保存相关： 肾素-血管紧张素系统 激活（血浆肾素和醛固酮；假设 2a）、全身炎症（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 造成的脂质过氧化； 通过羰基形成、3-硝基酪氨酸形成和还原硫醇状态的蛋白质氧化；假设2c)。 PROUD 将对公共卫生产生重大影响，并将通过解决悬而未决的问题来推动该领域的发展 XOI 在痛风中与肾功能保护的关系及其潜在机制。 伯明翰 (UAB) 和内布拉斯加大学医学中心 (UNMC) 两个大型学术中心和 免疫学研究中心非常适合解决所提出的临床和机制问题。 我们的协作专业知识，辅之以拟议的 NIAMS 支持的 P50 的杠杆资源 阿拉巴马大学研究翻译中心 (CORT) 将用于执行这项新颖的翻译研究。