Hydroxychloroquine for the Management of CVD in CKD

心血管疾病（CVD）是心血管疾病患者发病和死亡的最主要原因。 慢性肾病（CKD）和终末期肾病（ESKD）。不幸的是，在目前的时间，我们有 没有有效的治疗方法来降低这些人群的高CVD死亡率。加速 动脉粥样硬化、炎症和血管僵硬是导致CKD中CVD的主要因素。 能够有效应对这些因素的干预措施可能会为管理 CKD中的CVD。羟氯喹（HCQ）是一种廉价而安全的抗炎药， 临床使用超过40年，甚至在CKD和ESKD患者中。近年来，在体外，体内， 基于人类队列的数据表明，HCQ有益于CVD的多个参数，包括 炎症、内皮功能、代谢综合征、胰岛素敏感性和动脉粥样硬化。最近我们 通过动物实验证实HCQ确实具有显著的抗动脉粥样硬化和血管保护作用 在CKD环境中。我们进一步进行了一项小型的人类可行性研究，显示了HCQ在以下方面的潜力： CKD中CVD相关参数。 下一步需要评估HCQ在CKD中治疗CVD的作用。但由于没有 一个普遍认可的CVD替代品，需要一个概念验证的临床研究来验证抗- HCQ在CKD中的动脉粥样硬化和血管保护潜力。我们提出这样一项研究，将招募90名 在1：1分配（HCQ：安慰剂）的随机对照试验（RCT）中，白蛋白尿、3b期CKD受试者， 根据他们的糖尿病状态分层，并治疗18个月。我们将研究HCQ对 动脉粥样硬化和CVD的结构、功能和生化指标。 特异性目的（SA）1将评价HCQ与安慰剂相比减缓或逆转进展的能力 动脉粥样硬化我们将评估颈动脉粥样硬化的进展与非增强MRI进行 在基线和用HCQ或安慰剂治疗9个月和18个月后。主要结果指标将 总颈动脉斑块体积（TPV）的变化。次要结局指标将是 斑块总表面积、最大狭窄、斑块类型（纤维性、稳定性或不稳定性）和斑块稳定性。 具体目标2：将评价HCQ对炎症（SA 2a）和血管僵硬度的影响程度 （SA2b）。我们将检查HCQ和安慰剂在基线、6、9、12和18个月时的效果 高敏C反应蛋白（SA 2a）和主动脉脉搏波的次要结局指标 速度（SA 2b）。 虽然样本量和功效计算是针对主要结局（SA 1）设计的，但我们 将有足够的把握度评价HCQ对SA 2中次要结局的有意义影响。 具体目标3将检查HCQ和安慰剂对硬性心脏和肾脏结局趋势的影响 和药物安全。虽然没有把握度检测这些临床事件发生率的差异，但 结果，药物安全性和耐受性是强制性的，将有助于未来的规划， RCT。 如果本试验的结果是积极的，AE特征良好，则将提供关键的初步数据， 证明并计划一项明确的多中心随机对照试验，以检查HCQ对CKD患者CVD硬结局的影响。 此外，这项研究可能会提供选择炎症和血管因素的重要性， CVD对CKD患者和普通人群具有更广泛的未来影响。

Cardiovascular disease (CVD) is the most prominent cause of morbidity and mortality among patients with chronic kidney disease (CKD), and end stage kidney disease (ESKD). Unfortunately at the present time, we do not have an effective treatment to reduce the high CVD mortality in these populations. Accelerated atherosclerosis, inflammation, and vascular stiffness are prominent factors contributing to CVD in CKD. Interventions that can effectively counter these factors may provide significant benefits for the management of CVD in CKD. Hydroxychloroquine (HCQ) is an inexpensive and safe anti-inflammatory drug that has been in clinical use for over 4 decades even in patients with CKD and ESKD. In recent times, multiple in vitro, in vivo, and human cohort based data have shown that HCQ benefits multiple parameters of CVD, including inflammation, endothelial function, metabolic syndrome, insulin sensitivity and atherosclerosis. Recently we through our animal validated that HCQ indeed has significant anti-atherosclerosis and vasculoprotective effects in CKD milieu. We further conducted a small, human, feasibility study that shows a potential for HCQ on parameters relevant to CVD in CKD. The next step requires evaluation of HCQ's role for the treatment of CVD in CKD. However, in the absence of a universally agreed-on surrogate for CVD, a proof-of-concept clinical study needed to validate the anti- atherosclerosis and vasculoprotective potential of HCQ in CKD. We propose such a study that will enroll 90 albuminuric, stage 3b CKD subjects in a randomized controlled trial (RCT) with 1:1 allocation (HCQ : placebo), stratified by their diabetes status, and treat for a duration of 18 months. We will examine the effects of HCQ on structural, functional, and biochemical measures of atherosclerosis and CVD. Specific Aim (SA) 1 will evaluate the ability of HCQ, compared to placebo, to slow the progression, or reverse atherosclerosis. We will evaluate the progression of carotid atherosclerosis with a non-contrast MRI performed at baseline and after 9 and 18 months of treatment with HCQ or placebo. The primary outcome measure will be change in total carotid plaque volume (TPV). Secondary outcome measures will be changes over time in total plaque surface area, maximal stenosis, and the type (fibrous, stable, or unstable), and stability of plaques. Specific Aim 2: will evaluate the extent to which HCQ can affect inflammation (SA2a), and vascular stiffness (SA2b) in CKD. We will examine the effects of HCQ and placebo at baseline, and at 6, 9, 12, and 18 months on the secondary outcome measures of high-sensitivity C-reactive protein (SA2a) and aortic pulse wave velocity (SA2b). Though the sample size and power calculations have been designed for the primary outcome (SA1), we will have adequate power to evaluate meaningful impacts of HCQ on the secondary outcomes in SA2. Specific Aim 3 will examine the effect of HCQ and placebo on the trends of hard cardiac and renal outcomes and drug safety. While not powered to detect the differences in the rates of these clinical events, trends in outcomes, drug safety, and tolerability are mandatory and will assist in the planning of the future, definitive RCT. If the results of this trial are positive with a favorable AE profile, it will provide critical preliminary data to justify and plan a definitive, multicenter RCT to examine the effects of HCQ on hard outcomes of CVD in CKD. Additionally, this study may provide insights into the importance of select inflammatory and vascular factors in CVD with wider future implications for those with CKD and perhaps the general population.