Hydroxychloroquine for the Management of CVD in CKD

心血管疾病(CVD)是糖尿病患者发病和死亡的最主要原因 慢性肾脏病(CKD)和终末期肾病(ESKD)。不幸的是，目前，我们需要 没有有效的治疗方法来降低这些人群的高心血管死亡率。加速 动脉粥样硬化、炎症和血管僵硬是导致CKD患者CVD的重要因素。 能够有效应对这些因素的干预措施可能会为管理人员提供显著的好处 CKD中的CVD。羟基氯喹(HCQ)是一种廉价、安全的抗炎药物，已在 临床应用超过40年，即使在慢性肾脏病和ESKD患者中也是如此。最近，在体外，在体内， 基于人类队列的数据表明，HCQ有益于心血管疾病的多个参数，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，氢氯喹酮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 CKD中与CVD相关的参数。 下一步需要评估HCQ在CKD的CVD治疗中的作用。然而，在缺席的情况下， 对于普遍同意的心血管疾病替代品，需要一项概念验证临床研究来验证抗- 慢性肾脏病动脉粥样硬化与氢氯喹酮的血管保护作用。我们提出了这样一项研究，将招收90人 蛋白尿，3b期CKD受试者，随机对照试验(RCT)，1：1分配(HCQ：安慰剂)， 根据他们的糖尿病状况进行分层，并治疗18个月。我们将研究HCQ对以下方面的影响 动脉粥样硬化和心血管疾病的结构、功能和生化测量。 特定目标(SA)1将评估与安慰剂相比，HCQ延缓或逆转进展的能力 动脉硬化。我们将通过非增强磁共振成像来评估颈动脉粥样硬化的进展。 在基线以及使用HCQ或安慰剂治疗9个月和18个月后。主要结果衡量标准将是 颈动脉总斑块体积(TPV)的变化。次要结果衡量标准将随着时间的推移而变化 斑块总面积、最大狭窄、斑块类型(纤维斑块、稳定斑块或不稳定斑块)、斑块稳定性。 具体目标2：将评估HCQ对炎症(SA2a)和血管僵硬的影响程度 (SA2B)在CKD中。我们将在基线、6个月、9个月、12个月和18个月时检查HCQ和安慰剂的效果 高敏C反应蛋白(SA2a)与主动脉脉搏波的次要结局研究 速度(SA2B)。 虽然样本量和能量计算是为主要结果(SA1)而设计的，但我们 将有足够的能力评估HCQ对SA2的次要结果的有意义的影响。 具体目标3将检查HCQ和安慰剂对硬心肾结局趋势的影响。 和药物安全。虽然无法检测这些临床事件发生率的差异，但在 结果、药物安全性和耐受性是强制性的，并将有助于未来的规划，最终 RCT。 如果这项试验的结果是积极的，具有良好的声发射曲线，它将提供关键的初步数据 证明并计划一个明确的、多中心的随机对照试验，以检查HCQ对CKD患者心血管疾病硬结局的影响。 此外，这项研究可能会提供对选择炎症和血管因子在 CVD对CKD患者以及可能对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.