Cardiovascular effects of oral bicarbonate in CKD

Chronic kidney disease (CKD) is a major global health problem associated with high risk of morbidity and mortality. Due to impaired kidney acid excretion, up to 35% of patients with CKD develop metabolic acidosis. Such individuals are often treated with sodium bicarbonate to prevent acidosis-induced bone demineralization and muscle catabolism and preserve kidney function. However, sodium bicarbonate may also cause cardiovascular harm in two main ways. One is by causing sodium and fluid retention leading to increased blood pressure. While individual trials have not shown a substantial increase in body weight or blood pressure, a meta-analysis found that sodium bicarbonate treatment was associated with higher risks of escalating antihypertensive or diuretic therapy. High blood pressure and elevated markers of volume overload, including N-terminal pro-brain natriuretic peptide (NT-proBNP), are associated with an increased risk of cardiovascular mortality. Yet, it is unclear what effect, if any, sodium bicarbonate has on hormones that regulate sodium levels and plasma volume. A major goal of this project is to determine the effect of sodium bicarbonate treatment on levels of natriuretic peptides (NT-proBNP and atrial natriuretic peptide) and components of the renin- angiotensin-aldosterone system (renin, angiotensin II, and aldosterone) in individuals with CKD. Another major cardiovascular concern is that sodium bicarbonate may promote vascular calcification. This has been observed in animal models but has been incompletely investigated in humans. A second major goal of this project is to determine the effect of sodium bicarbonate on blood levels of inhibitors, promoters and other indices of vascular calcification (fetuin A, fibroblast growth factor-23, osteoprotegerin, bone morphogenic protein-2, calciprotein particle 2 size, and the propensity of serum to calcify [T50]) in individuals with CKD. These goals will be achieved by combining data and performing measurements using stored samples obtained from 395 participants in three randomized, double-blind, placebo-controlled, sodium bicarbonate studies conducted in the US. Measurements will be performed at baseline, 3- and 6-months. Change from baseline between the placebo and sodium bicarbonate treatment groups will be determined and mediating effects of these changes in response to treatment will be investigated using longtitudinal structural equation modeling. Although sodium bicarbonate may slow the progression of CKD, there is concern about the long-term cardiovascular safety of sodium bicarbonate. This proposal will investigate mechanisms involved with two main cardiovascular concerns, fluid retention and vascular calcification, and potentially identify individuals who may be prone to these adverse effects. These issues are large and clinically important knowledge gaps in the field. The results will have a high impact on the field and will inform clinicians and investigators about the potential for cardiovascular harm with sodium bicarbonate treatment.