Discussion
CKD, adverse metabolic complications, kidney disease, nondialysis CKD, dyslipidemia, albuminuria
KIDNEY DISEASE, DYSLIPIDEMIA
In a randomized crossover trial testing 6 weeks of NR and CoQ10 treatments in patients with CKD, neither therapy improved the primary study outcomes of physical endurance measured by maximal aerobic capacity (VOOur findings are consistent with previous studies that also show no physical performance-enhancing effect from short-term CoQ10 or NR supplementation across a wide range of ages and physical fitness levels. A prior study of NR supplementation involving older males showed improved skeletal muscle NADContrary to previous studies, we detected changes in VOCoQ10 supplementation in our study was associated with metabolic changes suggesting improved mitochondrial β oxidation known to be disrupted in CKD. CKD is associated with adverse metabolic complications, including dyslipidemia (We found evidence that NR supplementation changed plasma levels of our targeted TCA cycle intermediates, suggesting improved systemic mitochondrial metabolism. Sufficient NADNR treatment led to changes in the lipidomic profile, decreasing a broad range of plasma lipid species including triglycerides. CKD is known to be associated with disordered lipid metabolism with lower kidney function and greater albuminuria associated with impairments in β oxidation and higher levels of ceramides, triglycerides, and phosphatidylcholines (In addition to reductions in triglycerides, NR treatment led to reductions in biologically relevant ceramides (a sphingolipid), LPEs, LPCs, and PEs (glycerophospholipids). The presence and severity of kidney disease is associated with increased ceramide levels known to adversely impact metabolic health (This study had notable strengths and limitations. First, we used an efficient and rigorous double dummy, placebo-controlled, randomized crossover trial design and physiologically relevant measures of endurance exercise capacity and substrate utilization during graded cycle ergometry testing. Second, we applied semitargeted metabolomics and lipidomics profiling and accounted for fasting status changes to identify changes in mitochondrial and lipid metabolism after NR and CoQ10 supplementation. However, this study had several limitations. First, the sample size was small and treatment duration was short, limiting evaluation to early potential treatment effects. This may have limited our ability to detect differences in muscle and exercise tolerance requiring longer-term treatment. Second, our study partially coincided with the start of the COVID-19 pandemic, leading to inevitable lifestyle changes among participants during the study period. We were unable to reliably track the impact this may have had on habitual physical activity. Third, a number of study participants were, on average, more active than the general CKD population who are, on average, much more sedentary (In contrast to the benefits of exercise in patients with CKD, our findings demonstrate NR or CoQ10 supplementation alone does not lead to improved maximal physical performance. Clinical trials of exercise training in persons with nondialysis CKD have shown significant improvements in maximal aerobic capacity, physical performance, and physical functioning (In conclusion, short term CoQ10 and NR supplementation in patients with moderate to severe CKD resulted in biologically plausible changes in mitochondrial metabolism and the plasma lipid profile. Metabolic changes were more pronounced for the plasma lipidome than the metabolome. CoQ10 treatment led to improved β oxidation resulting in a systemic increase in plasma FFAs and a decrease in complex triglycerides while NR supplementation altered levels of TCA cycle intermediates and resulted in a broad decrease of plasma lipid species, including lipotoxic subclasses of sphingolipids. These findings add to the body of preclinical evidence supporting the efficacy of NR and CoQ10 for improving markers of mitochondrial metabolism and the lipid profile in persons with CKD not treated with dialysis. Given the distinct beneficial impacts of NR and CoQ10 on plasma metabolome and lipid profile, future studies of longer duration are needed to investigate the potential synergistic effects of a combination therapy of NR and CoQ10 in sedentary patients with CKD.