烟酰胺核糖与白藜芦醇（NRPT）增加急性肾损伤（AKI）患者的 NAD：一项随机、双盲、安慰剂对照、逐步递增剂量的 NRPT 在 AKI 患者中的安全性研究。
Nicotinamide riboside with pterostilbene (NRPT) increases NAD in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.
机构信息
Division of Nephrology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
出版信息
BMC Nephrol. 2020 Aug 13;21(1):342. doi: 10.1186/s12882-020-02006-1.
BACKGROUND
Preclinical studies have identified both NAD and sirtuin augmentation as potential strategies for the prevention and treatment of AKI. Nicotinamide riboside (NR) is a NAD precursor vitamin and pterostilbene (PT) is potent sirtuin activator found in blueberries. Here, we tested the effect of combined NR and PT (NRPT) on whole blood NAD levels and safety parameters in patients with AKI.
METHODS
We conducted a randomized, double-blind, placebo-controlled study of escalating doses of NRPT in 24 hospitalized patients with AKI. The study was comprised of four Steps during which NRPT (5 subjects) or placebo (1 subject) was given twice a day for 2 days. NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing.
RESULTS
AKI resulted in a 50% reduction in whole blood NAD levels at 48 h compared to 0 h in patients receiving placebo (p = 0.05). There was a trend for increase in NAD levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD response to treatment. Considering all Steps together, NRPT treatment increased NAD levels by 37% at 48 h compared to 0 h (p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects.
CONCLUSION
NRPT increases whole blood NAD levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted.
TRIAL REGISTRATION
NCT03176628 , date of registration June 5th, 2017.
背景
临床前研究已经确定 NAD 和沉默调节蛋白的增加是预防和治疗急性肾损伤（AKI）的潜在策略。烟酰胺核糖（NR）是 NAD 的前体维生素，而白藜芦醇（PT）是蓝莓中发现的有效的沉默调节蛋白激活剂。在这里，我们测试了联合 NR 和 PT（NRPT）对 AKI 患者全血 NAD 水平和安全性参数的影响。
方法
我们对 24 名 AKI 住院患者进行了 NRPT 递增剂量的随机、双盲、安慰剂对照研究。该研究由四个步骤组成，在每个步骤中，NRPT（5 名受试者）或安慰剂（1 名受试者）每天两次给药 2 天。NRPT 剂量在每个步骤中增加：步骤 1250/50mg、步骤 2500/100mg、步骤 3750/150mg 和步骤 41000/200mg。通过液相色谱-质谱法测量血液 NAD 水平，通过病史、体格检查和临床实验室检测评估安全性。
结果
与接受安慰剂的患者相比，AKI 导致全血 NAD 水平在 48 小时时降低了 50%（p=0.05）。与 0 小时相比，在所有 NRPT 步骤中，NAD 水平均呈升高趋势，但仅第 2 步的变化具有统计学意义（47%，p=0.04），并且 NAD 对治疗的反应存在相当大的个体间变异性。考虑到所有步骤，NRPT 治疗使 48 小时时的 NAD 水平增加了 37%（p=0.002）。NRPT 治疗并未改变所有安全性实验室测试，包括肌酐、估算肾小球滤过率（eGFR）、电解质、肝功能检查和血细胞计数。20 名接受 NRPT 治疗的患者中有 3 名报告有轻微的胃肠道副作用。
结论
NRPT 可增加 AKI 住院患者的全血 NAD 水平。此外，NRPT 每天两次、每次 1000mg/200mg 的剂量在这些患者中是安全且耐受良好的。需要进一步研究以评估 NRPT 在 AKI 中的潜在治疗益处。
试验注册
NCT03176628，注册日期 2017 年 6 月 5 日。
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