A Pilot Trial of Nicotinamide Riboside and Coenzyme Q10 on Inflammation and Oxidative Stress in CKD

Abstract

Key Points:

1. Nicotinamide riboside and coenzyme Q10 supplementation showed distinct beneficial effects on whole-blood transcriptome, inflammatory cytokines, and oxidative stress.

2. Nicotinamide riboside treatment altered the expression of genes associated with metabolism and immune response coinciding with a decrease in markers of oxidative stress.

3. Coenzyme Q10 supplementation altered genes associated with lipid metabolism coinciding with reductions in markers of oxidative stress and inflammatory cytokines.

Background: Mitochondria-driven oxidative/redox stress and inflammation play a major role in 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 pilot, randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/d of coenzyme Q10 (CoQ10) or 1000 mg/d of nicotinamide riboside (NR) supplementation with placebo in 25 patients with moderate-to-severe CKD (eGFR <60 ml/min per 1.73 m²). We assessed changes in blood transcriptome using 3′-Tag-Seq gene expression profiling and changes in prespecified 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 body mass index of the participants were 61±11 years, 37±9 ml/min per 1.73 m², and 28±5 kg/m², respectively. Of the participants, 16% had diabetes and 40% were female. Compared with placebo, NR-mediated transcriptomic changes were enriched in gene ontology terms associated with carbohydrate/lipid metabolism and immune signaling, whereas CoQ10 changes were enriched in immune/stress response and lipid metabolism gene ontology terms. NR increased plasma IL-2 (estimated difference, 0.32; 95% confidence interval [CI], 0.14 to 0.49 pg/ml), and CoQ10 decreased both IL-13 (estimated difference, −0.12; 95% CI, −0.24 to −0.01 pg/ml) and C-reactive protein (estimated difference, −0.11; 95% CI, −0.22 to 0.00 mg/dl) compared with placebo. Both NR and CoQ10 reduced five-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 (estimated difference, 0.29; 95% CI, 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52; 95% CI, 0.04 to 7 pmol/min per 10,000 cells) in monocytes.

Conclusions: Six weeks of NR and CoQ10 improved markers of oxidative stress, inflammation, and cell bioenergetics in patients with moderate-to-severe CKD.

Clinical Trial registry name and registration number:: NCT03579693.

Graphical abstract

Figure 1

Effect of 6 weeks of NR and CoQ10 supplementation on whole-blood transcriptomics profile in CKD. Volcano plot of differentially expressed genes comparing (A) NR versus placebo and (C) CoQ10 versus placebo illustrated by plotting the fold change of gene expression (Log2, x axis) against P value for DGE (−Log10, y axis). Red dots represent genes that are significantly altered (P value < 0.05) after NR or CoQ10 supplementation. The top ten genes by P value are indicated with their gene symbol. Two of the top ten genes in (A) are unnamed novel genes. GO analysis representing altered BP upon (B) NR and (D) CoQ10 supplementation. GO analysis was performed using gene set enrichment analysis. Bars represent the P value (−Log10). Top 20 altered BP terms are shown. n=25. BP, biological process; CoQ10, coenzyme Q10; DGE, differential gene expression; GO, gene ontology; JAK-STAT, Janus kinase signal transducer and activator of transcription; miRNA, MicroRNA; NR, nicotinamide riboside; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase.

Figure 2

Effect of short-term NR and CoQ10 supplementation on circulating inflammatory biomarkers in CKD (n=25). (A) C-reactive protein, (B) IL-6, (C) IL-12, (D) IL-13, (E) IL-2, (F) IL-4, (G) IL-10, (H) IL-8, (I) TNF-α, and (J) IFN-γ. The data are presented as log (concentration). The box plots represent median and IQR, and the whiskers represent minimum and maximum values. Significance was determined using mixed-effects modeling with a P < 0.05. Unadjusted P values are shown. *P < 0.05, **P < 0.001. IQR, interquartile range; sCRP, serum C-reactive protein.

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 five-series F2-isoprostanes and (C) 5-F2t-isoprostane, (D) 5-F2c-isoprostane, and (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-effects modeling with a P < 0.05. *P < 0.05, **P < 0.001.

Figure 4

Effects of NR and CoQ10 on monocyte (CD14⁺) bioenergetics (n=14). Bioenergetic parameters include (A) basal respiration, (B) proton leak, (C) maximal respiratory capacity, (D) spare respiratory capacity, (E) ATP-linked respiration, (F) BHI, calculated by the log ([ATP-linked respiration×spare respiratory capacity]/[proton leak×nonmitochondrial respiration]). The box plots represent median and IQR, and the whiskers represent minimum and maximum values. *P < 0.05 compared with placebo. BHI, bioenergetic health index; OCR, oxygen consumption rate.