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

烟酰胺腺嘌呤二核苷酸（NAD）依赖的去乙酰化酶sirtuin家族作为代谢能量传感器，介导热量限制对寿命的一些有益影响，并且是衰老过程的重要调节因子。通过给予NAD前体如烟酰胺单核苷酸（NMN）来增加NAD，可以预防或逆转许多与衰老相关的疾病，包括糖尿病和糖尿病肾病，并改善有氧运动表现。肾脏中NAD水平的降低与小鼠和人类糖尿病肾病（DKD）的致病机制密切相关，在DKD小鼠模型中，补充NMN可以阻止DKD的发展并降低死亡率。这些数据支持NMN增加NAD会降低尿白蛋白/肌酐比（UACR）的假设，UACR是DKD的一个标志，可预测肾脏和心血管预后。尽管有许多有效的DKD治疗方法，但发展为终末期肾脏疾病的大量残余风险仍然存在；因此，有必要采取新的办法，通过针对不同的机制进一步减少风险。sirtin - nad激活剂之所以具有吸引力，是因为：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，具有改善身体功能和其他与年龄相关的疾病的潜力。我们建议开展一项2a期、随机、安慰剂对照、双盲、平行组试验，研究对象为60岁或以上、患有2型糖尿病、UACR > 100 mg/g肌酐、肾小球滤过率(eGFR) > 30 mL/min/ /1.73m2的老年人。参与者将随机接受1.0 g NMN或安慰剂，每日两次，持续6个月，按性别和年龄（60-75岁，50 -75岁）分层。主要结果是6个月期间UACR的变化。次要结局包括6个月内与基线相比的以下变化：UACR下降30%或以上的参与者比例；血清肌酐和eGFR的变化；血糖控制（血红蛋白A1c、空腹血糖）；血压;衰老与肾损伤的生物标志物；自我报告（晚年功能和残疾指数-计算机自适应技术版本）和基于表现的身体功能测量（以vo2峰值测量有氧能力；6分钟步行距离）；NMN及其代谢物的循环水平和NAD水平。我们还将确定pbmc中NAD水平的升高和UACR的改善在治疗完成后3个月是否持续（遗留效应）。该试验的严谨性和创新性通过使用高质量的NMN晶体配方而得到强调；一种由仔细进行的药代动力学研究提供信息的剂量方案；严格的样品采集程序，确保分析前的稳定性；强有力的科学前提，建立在令人信服的临床前和人体研究NAD消耗在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.