NAD Augmentation to Treat Diabetic Kidney Disease: A Randomized Controlled Trial

依赖于烟酰胺腺嘌呤二核苷酸(NAD)的sirtuin家族作为代谢能量感受器，介导了热量限制对寿命的一些有益影响，是衰老过程的重要调节因素。通过给予NAD前体，如烟酰胺单核苷酸(NMN)来增强NAD，可以预防或逆转一些与衰老有关的疾病，包括糖尿病和糖尿病肾病，并改善有氧运动能力。肾脏中NAD水平的降低与小鼠和人类糖尿病肾病(DKD)的发病机制密切相关，补充NMN可防止DKD的发展，并降低DKD小鼠模型的死亡率。这些数据支持这样的假设，即应用NMN增加NAD将降低尿白蛋白/肌酐比率(UACR)，这是DKD的一个标志，可以预测肾脏和心血管结果。尽管有许多有效的治疗DKD的方法可用，但仍然存在发生终末期肾病的相当大的残余风险；因此，需要新的方法，通过针对不同的机制来提供额外的风险降低。Sirtuin-NAD激活剂很有吸引力，因为：1)它们的作用机制与目前批准的药物不同；2)它们针对衰老机制，并有可能改善身体功能和其他与年龄有关的疾病。我们建议在60岁或60岁以上的老年人中进行一项2a期的随机、安慰剂对照、双盲、平行分组试验，对象为2型糖尿病患者，UACR&GT；100 mg/g肌酐，估计肾小球滤过率(EGFR)和GT；30毫升/分钟//1.73m2。参与者将被随机接受1.0克NMN或安慰剂，每天两次，持续6个月，按性别和年龄(60-75岁，75岁)分层。主要结果是UACR在6个月期间的变化。次要结果包括以下方面的变化：UACR下降30%或以上的参与者的比例；血清肌酐和EGFR的变化；血糖控制(血红蛋白A1c，空腹血糖)；血压；衰老和肾脏损伤的生物标志物；自我报告(晚年功能和残疾指数-计算机适应技术版本)和基于表现的身体功能指标(有氧能力以VO2峰值衡量；6分钟步行距离)；以及循环NMN及其代谢物水平和NAD水平。我们还将确定在治疗完成3个月后，外周血单核细胞中NAD水平的增加和UACR的改善是否持续(遗留效应)。这项试验的严谨和创新体现在：使用了高质量的NMN结晶配方；通过仔细进行的药代动力学研究了解到的剂量方案；严格的样本收集程序，以确保分析前的稳定性；以及建立在令人信服的临床前和人体研究基础上的强有力的科学前提，这些研究证明了NAD耗竭在DKD中的重要作用。

The sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases act as metabolic energy sensors, mediate some of the beneficial effects of caloric restriction on lifespan, and are important regulators of the aging process. NAD augmentation by administration of NAD precursors, such as nicotinamide mononucleotide (NMN), prevents or reverses a number of aging-related conditions, including diabetes and diabetic nephropathy, and improves aerobic performance. Reduced NAD levels in the kidney are closely linked to the pathogenic mechanisms of diabetic kidney disease (DKD) in mice as well as in humans, and NMN supplementation prevents the development of DKD and reduces mortality in a mouse model of DKD. These data support the hypothesis that NAD augmentation by NMN administration will reduce urinary albumin to creatinine ratio (UACR), a hallmark of DKD that is predictive of renal and cardiovascular outcomes. Despite the availability of a number of effective therapies for DKD, substantial residual risk to develop end-stage kidney disease still remains; thus, there is a need for new approaches that provide additional risk reduction by targeting different mechanisms. The sirtuin-NAD activators are attractive because: 1) they act by a mechanism distinct from that of currently approved drugs; and 2) they target aging mechanisms and have the potential to improve physical function and other age-related conditions. We propose to conduct a Phase 2a, randomized, placebo-controlled, double-blind, parallel group trial in older adults, 60 years or older, with type 2 diabetes mellitus, UACR > 100 mg/g creatinine, and estimated glomerular filtration rate (eGFR) > 30 mL/min/ /1.73m2. Participants will be randomized to receive either 1.0 g NMN or placebo twice daily for 6 months, stratified by sex and age (60-75, >75 years). The primary outcome is the change in UACR over the 6-month period. Secondary outcomes include change from baseline over 6-months in the following: the proportion of participants with 30% or greater reduction in UACR; change in serum creatinine and eGFR; glycemic control (hemoglobin A1c, fasting glucose); blood pressure; biomarkers of aging and kidney injury; self-reported (Late Life Function and Disability Index - Computer Adaptive Technology Version) and performance-based measures of physical function (aerobic capacity measured as VO2peak; 6-minute walking distance); and circulating levels of NMN and its metabolites, and NAD levels. We will also determine whether the increases in NAD levels in the PBMCs and improvements in UACR persist 3 months after treatment completion (legacy effect). The rigor and innovation in this trial is underscored by the use of a high-quality crystalline formulation of NMN; a dose-regimen informed by carefully performed pharmacokinetic studies; rigorous sample collection procedures to ensure preanalytical stability; and strong scientific premise founded on compelling preclinical and human studies of the important role of NAD depletion in DKD.