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

项目摘要 痛风的管理是次优的，并发症的高患病率，包括慢性 肾脏疾病（CKD）;美国71%的痛风患者患有CKD 2期或更高。的一个关键原因 次优痛风护理是缺乏知识和接受的效用，降低血清尿酸盐（sUA）水平， < 6 mg/dl（基于6.8 mg/dl的溶解度阈值），称为达标治疗（TTT）。虽然sua < 6 mg/dl的阈值对于管理痛风是有价值的，但尚未检查其对于肾功能保护的作用。 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 采用sUA TTT方法的“Stop Gout”（VA CSP 594）研究，将评估 别嘌呤醇与非布司他。我们提出的研究，用降尿酸药物保护肾功能（PROUD）， 这项创新性试验的机制辅助研究将利用试验数据评估是否达到目标 sUA首次对肾功能保护有价值，具有以下两个特定目的。 具体目标1是评价降低sUA和别嘌呤醇和非布司他剂量在 保护痛风患者的肾功能我们假设以下因素中的每一个都将是 通过基于血清的eGFR变化评估，与肾功能保留呈正相关 72周时的肌酐（主要结局）和48周时的血清胱抑素C（次要结局）： 24周时sUA降低且目标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周时的最终上调别嘌呤醇剂量（假设 1d），以及18周时最终上调的非布司他剂量（假设1 e）。具体目标2将评估 痛风患者肾功能保护的机制我们假设在24周时， 以下因素与72周时的肾功能保留相关：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-PGF 2a引起的脂质过氧化; 通过羰基形成、3-硝基酪氨酸形成和还原巯基状态的蛋白质氧化;假设2c）。 PROUD将对公共卫生产生重大影响，并将通过解决未回答的问题来推动该领域的发展 与痛风患者使用XOI保护肾功能及其潜在机制有关。亚拉巴马大学 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制问题的理想场所。 我们的协作专业知识，辅以拟议的NIAMS的杠杆资源，支持P50 UAB翻译研究中心（CORT）将用于执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.