What clinical trials have tested sodium bicarbonate supplementation on human endothelial function or flow-mediated dilation?

1. The early signal: Kendrick 2018 pilot crossover that suggested benefit

A prospective, randomized, open‑label 14‑week crossover pilot enrolled 20 patients with CKD stages 3b–4 and low serum bicarbonate (16–21 mEq/L) and compared 6 weeks of oral sodium bicarbonate treatment versus control, finding that bicarbonate treatment increased serum bicarbonate and was associated with improved brachial artery FMD during the treatment period in this small cohort ^{[1] [4]}. The study design was short and open‑label with small N, and the authors reported some nonsignificant differences in pre‑post comparisons, underscoring that the result was preliminary and intended to motivate larger trials ^[1].

2. A larger, rigorous test: the 12‑month randomized double‑blind trial that tempered enthusiasm

A multicenter randomized, double‑blind, placebo‑controlled trial randomized 109 participants with CKD stage 3b–4 and normal serum bicarbonate (22–27 mEq/L) to sodium bicarbonate or placebo (0.5 mEq/kg lean body weight/day) for 12 months, with coprimary endpoints of brachial artery FMD and aortic pulse wave velocity (aPWV); sodium bicarbonate increased plasma bicarbonate but did not improve aPWV and only produced a statistically significant increase in FMD at 1 month that was not sustained at 6 or 12 months, leading investigators to conclude there was no long‑term vascular benefit in that population ^{[2] [3]}.

3. Where other trials and reviews place these findings in context

Systematic reviews and narrative reviews of bicarbonate therapy in CKD note the small pilot trial’s positive FMD signal and have concluded that alkali therapy may potentially improve endothelial function in CKD, but they emphasize heterogeneity across studies and limited trial sizes and durations; a 2021 meta‑analysis stated treatment "may" improve vascular endothelial function while calling for larger trials ^{[5] [6]}. The BASE pilot and other dose‑finding trials have explored safety, tolerability, and pharmacodynamics of bicarbonate but have not established durable cardiovascular outcomes or long‑term FMD effects ^[7].

4. Mechanistic hypotheses, counterevidence, and unresolved questions

Proposed mechanisms for a beneficial effect include correction of acidosis reducing endothelin and angiotensin II activity and local complement activation in CKD interstitium, plausibly improving endothelial biology; animal data, observational associations, and some small trials support this pathway ^{[8] [6]}. Yet there is counterevidence: animal models show alkali correction can increase vascular calcification, and observational studies link higher bicarbonate above ~26 mEq/L with heart failure risk, illustrating potential harm and complicating a simple “bicarbonate is good” narrative ^[7]. Importantly, the 12‑month randomized trial tested patients with normal baseline bicarbonate and found no sustained FMD benefit, highlighting that baseline acid status and trial duration critically shape outcomes ^{[2] [3]}.

5. Bottom line, limitations, and next steps the literature demands

The clinical trial record contains a small pilot crossover (N=20) showing short‑term FMD improvement ^[1] and a larger, well‑powered 12‑month randomized placebo‑controlled trial (N=109) that documented only a transient FMD increase at 1 month with no sustained benefit at 6–12 months ^{[2] [3]}; systematic reviews acknowledge possible vascular benefit but stress heterogeneity and call for larger, longer, and mechanistically stratified trials ^{[5] [6]}. Reporting limitations include small sample sizes, varying baseline bicarbonate/CKD status, different doses and durations, and few data outside CKD populations; these gaps mean robust conclusions about sodium bicarbonate’s effect on human endothelial function beyond select CKD subgroups remain unresolved ^{[1] [2] [7]}.