烟酰胺核糖苷与辅酶Q10对慢性肾脏病代谢健康和线粒体生物能量学影响的随机交叉临床试验
Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD.
作者信息
Ahmadi Armin, Valencia Ana P, Begue Gwénaëlle, Norman Jennifer E, Fan Sili, Durbin-Johnson Blythe P, Jenner Bradley N, Campbell Matthew D, Reyes Gustavo, Kapahi Pankaj, Himmelfarb Jonathan, de Boer Ian H, Marcinek David J, Kestenbaum Bryan R, Gamboa Jorge L, Roshanravan Baback
机构信息
Department of Medicine, Division of Nephrology, University of California, Davis, CA, USA.
Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA.
出版信息
medRxiv. 2024 Aug 23:2024.08.23.24312501. doi: 10.1101/2024.08.23.24312501.
BACKGROUND
Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD.
METHODS
We conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m). We assessed changes in the blood transcriptome using 3'-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer.
RESULTS
The (mean±SD) age, eGFR, and BMI of the participants were 61±11 years, 37±9 mL/min/1.73m, and 28±5 kg/m respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, -0.12, 95% CI of -0.24 to -0.01 pg/mL) and CRP (estimated difference, -0.11, 95% CI of -0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, -0.16 and -0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes.
CONCLUSION
Six weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.
背景
线粒体驱动的氧化/氧化还原应激和炎症在慢性肾脏病（CKD）的病理生理过程中起主要作用。靶向线粒体代谢的化合物可能改善线粒体功能、炎症和氧化还原应激；然而，其在CKD中的疗效证据有限。
方法
我们进行了一项随机、双盲、安慰剂对照的交叉试验，比较了25例中重度CKD（估算肾小球滤过率[eGFR]<60mL/（min/1.73m²））患者每日补充1200mg辅酶Q10（CoQ10）或1000mg烟酰胺核糖（NR）与安慰剂的效果。我们使用3'-标签测序基因表达谱评估血液转录组的变化，以及炎症和氧化应激生物标志物预先设定的次要结局的变化。对于部分参与者的子样本（n = 14），我们使用细胞外通量分析仪评估淋巴细胞和单核细胞的生物能量学。
结果
参与者的（均值±标准差）年龄、eGFR和体重指数（BMI）分别为61±11岁、37±9mL/（min/1.73m²）和28±5kg/m²。参与者中，16%患有糖尿病，40%为女性。与安慰剂相比，NR介导的转录组变化在与碳水化合物/脂质代谢和免疫信号相关的基因本体（GO）术语中富集，而CoQ10的变化在免疫/应激反应和脂质代谢GO术语中富集。与安慰剂相比，NR使血浆白细胞介素-2（IL-2）升高（估计差异为0.32，95%置信区间为0.14至0.49pg/mL），CoQ10使IL-13（估计差异为-0.12，95%置信区间为-0.24至-0.01pg/mL）和C反应蛋白（CRP）（估计差异为-0.11，95%置信区间为-0.22至0.00mg/dL）均降低。NR和CoQ10均降低了5系列F2-异前列腺素（估计差异分别为-0.16和-0.11pg/mL；两者P<0.05）。NR而非CoQ10增加了单核细胞的生物能量健康指数（BHI）（估计差异为0.29，95%置信区间为0.06至0.53）和备用呼吸能力（估计差异为3.52，95%置信区间为0.04至7pmol/（min/10000个细胞））。
结论
6周的NR和CoQ10改善了中重度CKD患者的氧化应激、炎症和细胞生物能量学。
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