What human clinical trials have tested oral sodium bicarbonate for endothelial function or blood flow?
Executive summary
Three types of human studies have tested oral sodium bicarbonate with endpoints tied to endothelial function or blood flow: small randomized trials (including a 2018 pilot crossover trial), short single‑center intervention studies reporting arterial stiffness or endothelial markers, and a handful of observational analyses and meta‑analyses that synthesize these small trials; collectively they hint at possible vascular benefit in chronic kidney disease (CKD) but are underpowered, heterogeneous and inconclusive [1] [2] [3].
1. What trials directly measured “endothelial function” after oral sodium bicarbonate?
The most frequently cited controlled human experiment is a pilot randomized, crossover study described as “Effect of treatment of metabolic acidosis on vascular endothelial function in patients with CKD,” which tested bicarbonate replacement against control and used endothelial endpoints — this trial is singled out in multiple reviews and trial lists (Clin J Am Soc Nephrol, 2018) [1] [4]. Systematic reviews of oral bicarbonate trials list this study among the small randomized trials that reported improvements in vascular endothelial function or surrogate measures in CKD cohorts [2] [5].
2. Trials measuring blood‑flow or cerebrovascular reactivity
A separate pilot randomized, double‑blind trial tested oral bicarbonate’s effects on cognitive and cerebrovascular function in midlife/older adults with CKD, explicitly linking correction of metabolic acidosis with cerebrovascular reactivity and downstream blood‑flow implications; that pilot enrolled 34 patients and used cerebrovascular function as an outcome [6]. Other intervention studies have assessed arterial stiffness, systolic blood pressure and related hemodynamic surrogates after 3 months of oral sodium bicarbonate in non‑dialysed CKD patients, reporting mixed effects on arterial stiffness and modest reductions in systolic blood pressure in pooled analyses [7] [2].
3. What do systematic reviews and meta‑analyses say about endothelial/blood‑flow outcomes?
Two recent systematic reviews/meta‑analyses conclude that oral sodium bicarbonate may “potentially significantly improve vascular endothelial function” in CKD patients, and report a modest reduction in systolic blood pressure in pooled trials; those reviews caution that most included studies were small, single‑center, often open‑label, heterogeneous in dose and duration, and lacked long‑term, patient‑centered cardiovascular endpoints [5] [2] [8].
4. Large randomized trials and negative/null findings
The BiCARB pragmatic randomized, double‑blind, placebo‑controlled trial in older patients with advanced CKD addressed clinical and cost‑effectiveness of bicarbonate therapy and raised questions about net clinical benefit and safety in this population; while not focused solely on endothelial function, it is a major RCT that tempered enthusiasm for broad use because of concerns about sodium load and uncertain cardiovascular outcomes [9] [3]. Reviews point out that some RCTs did not find consistent benefit on renal or cardiovascular endpoints and that heterogeneity precludes a firm consensus [2] [3].
5. Observational and mechanistic evidence that informed trials
Retrospective multi‑institutional observational analyses have reported associations between sodium bicarbonate use and lower risk of major adverse cardiovascular events in advanced CKD, but observational designs cannot establish causality and may reflect confounding by indication [3]. Mechanistic rationales cited in the literature link acidosis to endothelial inflammation via endothelin/aldosterone pathways and proton‑sensing receptors, providing biological plausibility for trialing alkali therapy on vascular function [3] [9].
6. Bottom line, caveats and research gaps
Human clinical trials testing oral sodium bicarbonate with explicit endothelial or blood‑flow outcomes exist but are predominantly small, often single‑center and heterogeneous in design (pilot RCTs, short intervention trials); meta‑analyses report possible improvements in surrogate endothelial measures and modest blood‑pressure effects but emphasize limited follow‑up, inconsistent masking, variable doses and safety concerns related to sodium load, so definitive evidence that oral bicarbonate improves clinically meaningful vascular outcomes in humans is lacking [2] [1] [9]. No large, multicenter RCT powered for hard cardiovascular endpoints specifically testing endothelial function as a primary outcome has emerged from the provided reporting [2] [3].