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

补充烟酰胺核苷可治疗中度至重度 CKD 患者的动脉僵硬度和收缩压升高。

• 批准号: 10400032
• 负责人: Michel Benjamin Chonchol
• 金额: $ 44.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-23 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400032
• 关键词: Adherence; Adult; Aftercare; Arteries; Biological; Biological Availability; Blood Pressure; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials; Collagen; Complication; Conduct Clinical Trials; Dementia; Deposition; Development; Double-Blind Method; Effectiveness; Elderly; Event; Functional disorder; Future; Goals; Gold; Health; Hour; Human; Hypertension; Impaired cognition; Inflammation; Measures; Mediating; Mus; Muscle Tonus; Nephrology; Obesity; Oral; Organ; Overweight; Oxidative Stress; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmacology; Phase; Physiologic pulse; Physiological; Placebo Control; Placebos; Population; Prevention strategy; Process; Randomized; Randomized Clinical Trials; Regimen; Renal function; Research; Research Priority; Risk; Risk Factors; Safety; Site; Skeletal Muscle; Smooth Muscle; Stroke; Supplementation; Testing; Translating; Vascular Smooth Muscle; Vasoconstrictor Agents; Ventricular Remodeling; Woman; arterial stiffness; bone mass; capsule; cardiovascular disorder risk; cardiovascular risk factor; circulating biomarkers; clinically relevant; comorbidity; dieting; effectiveness evaluation; evidence base; femoral artery; improved; insight; men; middle age; mimetics; muscle form; nicotinamide riboside supplementation; nicotinamide-beta-riboside; novel; nutrition; oral supplementation; pressure; primary outcome; reduced muscle mass; response; secondary outcome; standard measure; vasoconstriction

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.

项目摘要 患有慢性肾脏疾病（CKD）的患者心血管疾病（CVD）的风险显着升高。 但是，这种增加的风险仅由传统的简历风险因素部分解释。动脉功能障碍是 重要的非传统简历危险因素在肾脏科领域获得了增加的识别。而很多 变化可能导致CKD患者动脉功能障碍的发展， 最大的关注是大型弹性动脉僵硬的发展。这个过程是最好的代表， 从身体和病理生理上，通过增加动脉僵硬的黄金标准测量， 颈动脉脉冲波速度（CFPWV），特别反映主动脉的增加 刚性。用CKD的主动脉僵硬由结构和功能介导（血管平滑增加 肌肉张力）通过氧化应激和慢性低度刺激的动脉壁变化 热量限制（CR）是预防与CKD相关的动脉的承诺策略 功能障碍和CVD。在这种情况下，我们已经表明，CR会减少老鼠和在 超重/肥胖的中年和老年人。但是，长期遵守慢性CR方案 最佳营养很难实现，并且在不久的将来不太可能在临床上变得相关 减少肌肉和骨骼。结果，我们已经证明了将NAD+生物利用度提升到 刺激SIRT-1，一种“ cr模仿”方法，减少了旧小鼠的CFPW和氧化应激，我们最近 在对正常肾脏的中年和老年人的研究中迈出了第一步 功能和收缩压升高（SBP）。我们发现补充烟酰胺 核苷是NAD+和新型Cr模拟物的天然，可商购的前体，耐受性良好，并且 NAD+生物利用度增加，CFPWV和SBP降低。在这里，我们提出了一个随机的安慰剂 - 受控的双盲，单位点IIA期临床试验，以评估口服的安全性和效率 烟酰胺核苷（500 mg胶囊2倍/天；Niagen®; Chromadex Inc.）3个月与安慰剂 （n = 59/组），以III和IV期降低男性和女性（35 - 80年）的主动脉僵硬和SBP（35 - 80年） CKD。我们假设治疗将是安全且耐受性良好的，并且会减少CFPWV和SBP，因为 与全身性NAD+生物利用度的增加以及氧化应激，注射和减少 血管收缩因素。 目标1：在烟酰胺核糖剂与安慰剂治疗之前/之后测量CFPWV（主要结果）； 目标2：在治疗前后，测量休闲和24h ambulatory SBP（次要结果）； 目标3：确定烟酰胺核苷与安慰剂的治疗的安全性和耐受性； 目标4：测量系统性NAD+和NAD+相关的代谢物浓度以及循环 治疗前后的氧化应激，感染和血管收缩因子的标记。