Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease

Authors: AHMADI, ARMIN - University Of California, Davis; BEGUE, GWENAELLE - California State University; VALENCIA, ANA - University Of Washington; NORMAN, JENNIFER - University Of California, Davis; LIDGARD, BENJAMIN - University Of Washington; Bennett, Brian; VAN DOREN, MATTHEW - Fred Hutchinson Cancer Research Center; MARCINEK, DAVID - University Of Washington; FAN, SILI - University Of Washington; PRINCE, DAVID - University Of Washington; GAMBOA, JORGE - Vanderbilt University; HIMMELFARB, JONNATHAN - University Of Washington; DE BOER, IAN - University Of Washington; KESTENBAUM, BRYAN - University Of Washington; ROSHANRAVAN, BABACK - University Of California, Davis

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2023
Publication Date: 5/9/2023
Citation: Ahmadi, A., Begue, G., Valencia, A.P., Norman, J.E., Lidgard, B., Bennett, B.J., Van Doren, M.P., Marcinek, D.J., Fan, S., Prince, D.K., Gamboa, J., Himmelfarb, J., De Boer, I.H., Kestenbaum, B.R., Roshanravan, B. 2023. Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease. Journal of Clinical Investigation. 8(11). Article e167274. https://doi.org/10.1172/jci.insight.167274.
DOI: https://doi.org/10.1172/jci.insight.167274

Interpretive Summary: Patients with chronic kidney disease (CKD) suffer from a loss of functional independence and frailty. Co-morbid illnesses associated with CKD undoubtedly play a role in impaired muscle function and physical endurance. In addition, several lines of evidence suggest that kidney dysfunction itself contributes directly to a reduction in skeletal muscle function and mass. Among the mechanisms under investigation, disruption of mitochondrial oxidative capacity is considered to be a central candidate linking kidney disease with skeletal muscle impairment. Interventions that target mitochondrial function in CKD have not been evaluated in human studies. Given the central role of mitochondrial dysfunction in the pathogenesis of kidney related skeletal muscle dysfunction, we hypothesized that therapies targeting muscle mitochondrial metabolism would improve physical endurance and systemic markers of mitochondrial metabolism in CKD. We conducted a randomized placebo-controlled crossover trial to test the impact of CoQ10 and NR on physical endurance and metabolic profile in CKD patients.

Technical Abstract: Background: Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in CKD patients. Methods: We conducted a randomized placebo-controlled, double blind, cross-over trial with 3 treatment periods to compare CoQ10, NR, and placebo in 25 patients with eGFR of <60ml/min/1.73m2. Subjects received NR (1000 mg/day), CoQ10 (1200 mg/day), or placebo for 6 weeks each with 1-week washout periods between interventions. Exercise endurance outcomes were assessed using graded cycle ergometry testing. Plasma samples underwent semi-targeted metabolomics and lipidomics profiling using gas and liquid chromatography. Results: Participants’ mean age was 61.0±11.6 with a mean eGFR of 36.9±9.2 ml/min/1.73m2. Compared to placebo, we found no differences in VO2 peak (P=0.71, 0.70), total work (P=0.86, 0.94), and respiratory exchange ratio (RER) at 60W (P=0.63, 0.83) post NR or CoQ10 supplementation. CoQ10 had no impact on plasma metabolites but significantly increased free fatty acids and decreased complex medium/long chain triglycerides. NR supplementation significantly altered three TCA cycle intermediates and glutamate that exclusively use NAD+ and NADP+ as cofactors. NR significantly decreased a broad range of lipid groups including triglycerides and ceramides. Conclusions: During a treatment period of 6 weeks, NR and CoQ10 each improved markers of systemic mitochondrial metabolism and lipid profiles but did not significantly affect exercise tolerance in patients with CKD. Trial registration: ClinicalTrials.gov (NCT03579693) Funding: This study was supported by National Institutes of Diabetes and Digestive and Kidney Diseases R01 DK101509 (to BK), R03 DK114502 (to BR), R01 DK125794 (to BR), R01 DK101509 (to JG), Dialysis Clinics Incorporated C-4112 (to BR).