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: 9762288
• 负责人: Michel Benjamin Chonchol
• 金额: $ 46.66万
• 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/9762288
• 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; Comorbidity; Complication; Conduct Clinical Trials; Dementia; Deposition; Development; Diet; 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; Pharmacology; Phase; Physiologic pulse; Physiological; 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; Structure; 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; evidence base; femoral artery; improved; insight; men; middle age; mimetics; muscle form; 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.

项目概要 慢性肾脏病（CKD）患者患心血管疾病（CVD）的风险显着升高； 然而，传统的心血管危险因素只能部分解释这种风险增加。 重要的非传统心血管危险因素在肾脏病学领域获得越来越多的认可。 这些变化可能会导致 CKD 患者（其中包括以下患者）出现动脉功能障碍： 最令人担忧的是大弹性动脉的硬化，这一过程得到了最好的体现。 在生理和病理生理学上，通过增加动脉硬化的金标准测量， 颈动脉到股动脉的脉搏波速度（CFPWV），这尤其反映了主动脉的增加 CKD 导致的主动脉僵硬是由结构和功能（血管平滑度增加）介导的。 肌张力）氧化应激和慢性低度刺激引起的动脉壁变化 热量限制（CR）是预防 CKD 相关动脉炎症的一种有前景的策略。 在这方面，我们已经证明了老年小鼠和老年小鼠的 CR CFPWV 和 SBP。 然而，超重/肥胖的中老年人需要长期坚持慢性 CR 治疗方案。 最佳营养很难实现，并且在不久的将来不太可能变得具有临床意义，因为它可能 因此，我们已经证明，提高 NAD+ 的生物利用度可以减少肌肉和骨量。 刺激 SIRT-1（一种“CR 模拟”方法）可减少老年小鼠的 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，迈出了将这些发现转化为研究成果的第一步 我们发现补充烟酰胺会影响功能和收缩压（SBP）升高。 核苷是一种天然的、市售的 NAD+ 前体和新型 CR 模拟物，具有良好的耐受性和 增加 NAD+ 生物利用度并降低 CFPWV 和 SBP 在这里，我们提出了一种随机安慰剂。 对照、双盲、单中心 IIa 期临床试验，评估口服药物的安全性和有效性 烟酰胺核苷（500 毫克胶囊，2 次/天；NIAGEN®；ChromaDex Inc.）3 个月与安慰剂相比 （n=59/组）用于降低 III 期和 IV 期男性和女性（35-80 岁）的主动脉僵硬度和收缩压 我们追求治疗安全且耐受性良好，并将降低 CFPWV 和 SBP，因为 与全身 NAD+ 生物利用度的增加以及氧化应激、炎症和炎症的减少有关 血管收缩因素。 目标 1：测量烟酰胺核苷与安慰剂治疗之前/之后的 CFPWV（主要结果）； 目标 2：测量治疗前后的随意和 24 小时动态 SBP（次要结果）； 目标 3：确定烟酰胺核苷与安慰剂治疗的安全性和耐受性； 目标 4：测量全身 NAD+ 和 NAD+ 相关代谢物浓度以及循环 治疗前后氧化应激、炎症和血管收缩因素的标志物。