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)患者患心血管疾病(CVD)的风险显著增加； 然而，这种增加的风险只能用传统的简历风险因素部分解释。动脉功能障碍是一种 重要的非传统心血管危险因素在肾脏病领域得到越来越多的重视。虽然很多人 这些变化可能有助于CKD患者动脉功能障碍的发展，其中 最令人担忧的是大的弹性动脉硬化的发展。这一过程得到了最好的代表， 在生理和病理生理学上，通过动脉硬化黄金标准的增加， 颈动脉到股动脉的脉搏波速度(CFPWV)，它特别反映了主动脉中的增加 僵硬。CKD患者的主动脉硬化是由结构和功能(增加的血管平滑度)介导的 肌肉张力)氧化应激和慢性低度损伤刺激的动脉壁改变 发炎。热量限制(CR)是预防CKD相关动脉疾病的一种有前景的策略 功能障碍和心血管疾病。在这种情况下，我们已经证明CR可以降低老年小鼠的CFPWV和SBP。 超重/肥胖的中老年人。然而，长期坚持慢性CR方案与 最佳营养是很难实现的，而且在不久的将来不太可能成为临床相关的，尽管它可能 减少肌肉和骨量。因此，我们已经证明，提高NAD的生物利用度 刺激SIRT-1，一种类似CR的方法，可以减少老年小鼠的CFPW和氧化应激，我们最近 在一项肾脏正常的中老年人的研究中，第一步将这些发现转化为 收缩压(SBP)升高。我们发现补充烟酰胺 核糖苷是一种NAD的天然商业前体和新型CR模拟物，耐受性良好， 提高NAD的生物利用度，降低CFPWV和SBP。在这里，我们提出一种随机的安慰剂- 评价口服的安全性和有效性的对照、双盲、单部位IIa期临床试验 烟酰胺核苷(500毫克胶囊，每天2次；NIAGEN®；ChromaDex Inc.)3个月与安慰剂对照 (n=59/组)用于降低III和IV期男性和女性(35-80岁)的主动脉僵硬和SBP CKD。我们假设治疗将是安全和耐受性良好的，并将降低CFPWV和SBP，如 与增加全身NAD的生物利用度和减少氧化应激、炎症和 血管收缩因子。 目的1：比较烟酰胺核苷与安慰剂治疗前后的CFPWV(主要结果)； 目的2：测定治疗前后随机和24小时动态SBP(次要结局)； 目的3：比较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和与NAD相关的代谢物浓度以及循环 治疗前后氧化应激、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.