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

项目总结 痛风的治疗是次优的，并且由于包括慢性痛风在内的高发病率的并存而变得复杂。 肾脏疾病(CKD)；在美国，71%的痛风患者具有CKD 2级或更高级别。一个关键原因是 次优的痛风护理是缺乏对将血清尿酸(SuA)水平降低到 &lt；6 mg/dl(基于6.8 mg/dl的溶解度阈值)，称为治疗靶点(TTT)。而阿苏阿 阈值为6 mg/dl对痛风的治疗有价值，尚未对其进行肾功能保护检查。 最近，退伍军人事务部(VA)资助了为期4年的随机、双盲、非自卑 使用Sua TTT方法进行的“阻止痛风”(VA CSP594)研究，该方法将评估 别嘌醇与非布索斯特。我们建议的研究，用降尿酸药物保护肾功能(PROW)， 这项创新试验的机械性辅助研究将利用试验数据来评估是否达到目标 SUA首次对肾功能保护有价值，有以下两个具体目的。 具体目的1是评价降低尿酸、别嘌醇和非布司坦剂量的疗效。 保护痛风患者的肾功能。我们假设以下每个因素都将是 根据血清中EGFR的变化评估与肾功能保护呈正相关 72周时肌酐(主要结果)和48周时血清胱抑素C(次要结果)：达到 24周(假设1a和1b)的尿酸减少和目标尿酸水平&6 mg/dl，基线CKD阶段3 (与CKD阶段1或2相比；假设1c)，21周时最终上调的别嘌醇剂量(假设 1d)，以及18周时的最终向上滴定剂量(假设1e)。《特定目标2》将评估 痛风患者肾功能保护机制的研究。我们假设每一次减少24周 以下与72周时肾功能保存有关：肾素-血管紧张素系统 激活(血浆肾素和醛固酮；假设2a)，全身炎症(IL-1β，IL-6，肿瘤坏死因子-α，单核细胞趋化蛋白-1， PDGF，C-反应蛋白；假设2b)，以及氧化应激水平(8-epi-PGF2a； 蛋白质通过羰基形成、3-硝基酪氨酸形成和还原的硫醇状态氧化；假说2c)。 骄傲将对公共卫生产生很大影响，并将通过解决未回答的问题来推动该领域的发展 XOI在痛风患者肾功能保护中的作用及其机制。阿拉巴马大学 在伯明翰(UAB)和内布拉斯加大学医学中心(UNMC)，两个大型学术痛风和 免疫学研究中心是解决临床和机械问题的理想选择。 我们的协作专业知识，加上拟议的NIAMS的杠杆资源，支持P50 UAB翻译研究中心(CORT)将被用来进行这项新的翻译研究。

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.