中等度から重度のCKD患者における動脈硬化および収縮期血圧上昇を治療するためのニコチンアミドリボシド補給

Background: Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD). Arterial dysfunction is an important nontraditional CV risk factor gaining increased recognition in the field of nephrology. While many changes likely contribute to the development of arterial dysfunction in patients with CKD, among those of greatest concern is the development of stiffening of the large elastic arteries. Caloric restriction (CR) is a promising strategy for prevention of CKD-associated arterial dysfunction and CVD; however, adherence to CR is poor and may be detrimental in CKD patients due to reduced skeletal muscle and bone mass. Therefore, identification of more practical interventions that mimic the beneficial effects of CR, with stronger adherence and less risk of adverse consequences, is of significant biomedical importance.

Nicotinamide riboside is a naturally occurring precursor of nicotinamide adenine dinucleotide (NAD+), a critical mediator of the beneficial effects of CR, and therefore, a novel CR mimetic compound. We recently completed a study of nicotinamide riboside supplementation in healthy middle-age and older adults and demonstrated that 6 weeks of supplementation with nicotinamide riboside lowered carotid-femoral pulse wave velocity (CFPWV), the gold-standard clinical measure of aortic stiffness and a strong independent predictor of CVD and related morbidity and mortality in patients with and without kidney disease. In addition, treatment with nicotinamide riboside decreased systolic blood pressure (SBP) by 8 mmHg compared with placebo.

As a next translational step, we propose to conduct a randomized, placebo-controlled, double-blind, single site phase IIa clinical trial to further assess the safety and efficacy of oral nicotinamide riboside (3 months vs. placebo) for decreasing aortic stiffness and SBP in patients with stage III and IV CKD. We hypothesize that nicotinamide riboside will lower aortic stiffness and SBP and that these improvements will be related to increases in systemic NAD+ bioavailability, selective influences on vascular smooth muscle tone, and reductions in markers of systemic oxidative stress and/or inflammation.

Primary Outcome Measure (Aim 1): Aortic stiffness will be evaluated as CFPWV, the gold-standard measurement technique and clinically relevant marker of vascular function. CFPWV will be measured before and after 3 months of treatment with nicotinamide riboside or placebo.

Secondary Outcome Measures (Aim 2): Casual and ambulatory SBP will be the main secondary outcomes measures: (a) Casual (resting) SBP will be measured according to American Heart Association/American College of Cardiology guidelines, with an automated oscillometric sphygmomanometer. Casual SBP will be measured before and after 3 months of treatment with nicotinamide riboside or placebo; (b) Ambulatory SBP is an independent risk factor for CVD and a predictor of target organ damage. Ambulatory SBP (24-hour, daytime, nighttime mean pressures) will be measured before and after 3 months of treatment with nicotinamide riboside or placebo.

Other Outcome Measures (Aims 3 and 4): To evaluate the safety of nicotinamide riboside, we will monitor treatment-emergent adverse events at each visit (once every 2 weeks). The most common adverse events associated with nicotinamide riboside include mild-to-moderate headache, feelings of warmth, hot flushing sensations, gastrointestinal discomfort, and fatigue. We will also evaluate safety before and after 3 months of treatment with nicotinamide riboside or placebo by measuring the following clinical markers: standard blood hematology, standard clinical chemistry profiles, and standard urinalysis.

Tolerability will be assessed as subject dropout due to treatment-emergent adverse events.

Adherence to the intervention will be assessed by pill count performed once every 2 weeks.

Concentrations of NAD+ and associated metabolites will be evaluated to determine whether oral supplementation with nicotinamide riboside increases systemic NAD+ bioavailability. Peripheral blood mononuclear cells will be isolated and quantitative targeted metabolomics will be employed to evaluate concentrations of associated metabolites.

CKD and aortic stiffness and increased blood pressure are associated with increased systemic oxidative stress, inflammation, and pro-vasoconstriction factors. Nicotinamide riboside may reduce vascular stiffness by acting on one or more of these pathways. Circulating biomarkers of potential mechanisms of action (norepinephrine, endothelin-1, C-reactive protein, oxidized low density lipoprotein, total antioxidant status, tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta and interleukin-10) will be evaluated to provide mechanistic insight. All of the discussed other outcome measures will be evaluated before and after 3 months of supplementation with nicotinamide riboside or placebo.