Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD

Abstract

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 m²). 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/1.73m², and 28±5 kg/m² 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.

Keywords: Nephrology; clinical trial; metabolism.

Figure 1.. The impact of six weeks of NR and CoQ10 supplementation on whole blood transcriptomics profile in CKD.

Volcano plot of differentially expressed genes comparing A) NR vs placebo and C) CoQ10 vs placebo illustrated by plotting the fold change of gene expression (Log2, x axis) against P-value for differential gene expression (−Log10, y axis). Red dots represent genes that are significantly altered (P-value <0.05) post NR or CoQ10 supplementation. The top 10 genes by p-value are indicated with their gene symbol. Gene ontology analysis representing altered biological processes upon B) NR and D) CoQ10 supplementation. Gene Ontology analysis was performed using GSEA. Bars represent the P-value (−Log10). Top 20 altered terms are shown. N=25

Figure 2.. The impact of short-term NR and CoQ10 supplementation on circulating inflammatory biomarkers in CKD (n=25).

A) sCRP, B) IL-6, C) IL-12, D) IL-13, E) IL-2, F) IL-4, G) IL-10, H) IL-8, I) TNF-α, J) IFNγ The data is presented as log (concentration). The box plots represent median and IQR and the whiskers represent minimum and maximum values. Significance was determined using mixed effect modeling with a P < 0.05. Unadjusted P-values are shown. *P < 0.05, **P < 0.001.

Figure 3.. Changes in plasma markers of oxidative stress in response to NR and CoQ10 in CKD (n=25). A) F2 Isoprostanes, B) sum of 5 series F2-isoprostanes C) 5-F2t-Isoprostane, D) 5-F2c_Isoprostane, E) 15-F2t-Isoprostane.

The box plots represent median and IQR and the whiskers represent minimum and maximum values. Unadjusted P-values are shown. Significance was determined using mixed effect modeling with a P < 0.05. *P < 0.05, **P < 0.001.

Figure 4.. The effects of NR and CoQ10 on monocyte (CD14⁺) bioenergetics (n=14).

Bioenergetic parameters include A) basal respiration, B) proton leak respiration, C) maximal respiratory capacity E) spare respiratory capacity, E) ATP-linked respiration, F) bioenergetic health index, calculated by the log [(ATP-linked respiration × spare respiratory capacity)/(proton leak × non-mitochondrial respiration]. The box plots represent median and IQR and the whiskers represent minimum and maximum values., *P<0.05 compared to placebo.