Nicotinamide riboside supplementation for treating arterial stiffness and elevated systolic blood pressure in patients with moderate to severe CKD.

项目摘要 慢性肾脏疾病（CKD）患者的心血管疾病（CVD）风险显著升高; 然而，这种增加的风险仅部分由传统CV风险因素解释。动脉功能障碍是一种 重要的非传统CV风险因素在肾脏学领域获得越来越多的认可。虽然许多 这些变化可能导致CKD患者发生动脉功能障碍，其中 最大的问题是大弹性动脉硬化的发展。这一过程是最好的代表， 在生理学和病理生理学上，通过动脉硬化的金标准测量的增加， 颈动脉-股动脉脉搏波速度（CFPWV），特别是反映主动脉血流速度的增加。 刚度CKD患者的主动脉硬化是由结构和功能（血管平滑性增加）介导的 氧化应激刺激的动脉壁的肌张力）变化和慢性低级别 炎症热量限制（CR）是预防CKD相关动脉粥样硬化的一种有前途的策略。 功能障碍和CVD。在这种情况下，我们已经表明，CR降低老年小鼠和老年小鼠的CFPWV和SBP。 超重/肥胖的中年和老年人。然而，长期坚持慢性CR方案， 最佳营养是很难实现的，在不久的将来不太可能成为临床相关的， 减少肌肉和骨质。因此，我们已经证明，提高NAD+的生物利用度， 刺激SIRT-1，一种“CR模拟”方法，减少老年小鼠的CFPW和氧化应激，我们最近 在一项针对肾脏正常的中老年人的研究中， 收缩压（SBP）升高。我们发现补充烟酰胺 核苷是一种天然的、市售的NAD+前体和新型CR模拟物，耐受性良好， NAD+生物利用度增加，CFPWV和SBP降低。我们提出一个随机的安慰剂- 对照、双盲、单中心IIa期临床试验，评估口服 烟酰胺核苷（500 mg胶囊2x/天; NIAGEN®; ChromaDex Inc.）3个月vs.安慰剂 （n=59/组）用于降低III期和IV期男性和女性（35-80岁）的主动脉僵硬度和SBP CKD。我们假设治疗是安全的，耐受性良好，并将降低CFPWV和SBP， 与全身NAD+生物利用度的增加和氧化应激、炎症和 血管收缩因子 目的1：测量烟酰胺核苷与安慰剂治疗前后的CFPWV（主要结局）; 目的2：测量治疗前后的偶然和24小时动态SBP（次要结局）; 目的3：确定烟酰胺核苷与安慰剂治疗的安全性和耐受性; 目的4：测量全身NAD+和NAD+相关代谢物浓度，以及循环 治疗前后的氧化应激、炎症和血管收缩因子的标志物。

Project Summary Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD); however, this increased risk is only partially explained by traditional CV risk factors. Arterial dysfunction is an important nontraditional CV risk factor gaining increased recognition in the field of nephrology. While many changes likely contribute to the development of arterial dysfunction in patients with CKD, among those of greatest concern is the development of stiffening of the large elastic arteries. This process is best represented, both physiologically and pathophysiologically, by increases in the gold standard measure of arterial stiffening, carotid to femoral artery pulse wave velocity (CFPWV), which reflects, in particular, increases in aortic stiffness. Aortic stiffening with CKD is mediated by structural and functional (increased vascular smooth muscle tone) changes in the arterial wall stimulated by oxidative stress and chronic low-grade inflammation. Caloric restriction (CR) is a promising strategy for prevention of CKD-associated arterial dysfunction and CVD. In this context, we have shown that CR reduces CFPWV and SBP in older mice and in overweight/obese middle-age and older adults. However, long-term adherence to chronic CR regimens with optimal nutrition is very difficult to achieve and unlikely to become clinically relevant in the near future as it may reduce muscle and bone mass. As a result, we have since shown that boosting NAD+ bioavailability to stimulate SIRT-1, a “CR mimetic” approach, reduces CFPW and oxidative stress in old mice, and we recently took the first step in translating these findings in a study of middle-age and older adults with normal kidney function and elevated systolic blood pressure (SBP). We found that supplementation with nicotinamide riboside, a natural, commercially available precursor of NAD+ and novel CR mimetic, was well tolerated and increased NAD+ bioavailability and reduced CFPWV and SBP. Here we propose a randomized, placebo- controlled, double-blind, single-site phase IIa clinical trial to assess the safety and efficacy of oral nicotinamide riboside (500 mg capsules 2x/day; NIAGEN®; ChromaDex Inc.) for 3 months vs. placebo (n=59/group) for decreasing aortic stiffness and SBP in men and women (35-80 years) with stage III and IV CKD. We hypothesize that treatment will be safe and well-tolerated, and will reduce CFPWV and SBP, as related to increases in systemic NAD+ bioavailability and reductions in oxidative stress, inflammation and vasoconstrictor factors. Aim 1: To measure CFPWV (primary outcome) before/after nicotinamide riboside vs. placebo treatment; Aim 2: To measure casual and 24h-ambulatory SBP (secondary outcome) before and after treatment; Aim 3: To determine the safety and tolerability of treatment with nicotinamide riboside vs. placebo; Aim 4: To measure systemic NAD+ and NAD+–related metabolite concentrations, as well as circulating markers of oxidative stress, inflammation, and vasoconstriction factors before and after treatment.