Acid retention is a common complication of chronic kidney disease (CKD) as the diseased kidney is unable to excrete the daily dietary acid load. Lower serum bicarbonate levels, even within the normal laboratory range, are strongly linked to risks of hypertension, cardiovascular disease (CVD), CKD progression and death. Arterial dysfunction begins early in the course of kidney disease and is a key factor responsible for the development of left ventricular hypertrophy (LVH) in this population. LVH is the strongest predictor of cardiovascular mortality in CKD. Acid retention results in increased production of angiotensin II, endothelin-1 and aldosterone in order to enhance urinary acid excretion. All three of these humoral factors both directly and indirectly induce endothelial dysfunction, vascular stiffness, LVH and vascular calcification. Small interventional trials have shown that treatment with alkali therapy slows progression of kidney disease, even in patients with normal serum bicarbonate levels. Because risk factors for CVD and CKD progression often overlap, it is biologically plausible that alkali therapy in CKD patients may also result in improved cardiovascular outcomes. In our preliminary data, alkali therapy improved vascular endothelial function in 16 patients with CKD stage 3-4. Hence, treatment with alkali therapy may represent an inexpensive and novel therapeutic paradigm in CKD. We are proposing a randomized, double-blinded, placebo-controlled, 12-month trial of 108 patients with CKD stage 3-4 to examine the effect of sodium bicarbonate therapy on surrogate measures of CVD. Our overall hypothesis is that treatment with bicarbonate will improve indicators of vascular function and LVH in patients with CKD stage 3-4. Our primary goal is to determine the efficacy of alkali therapy for improving vascular endothelial function and reducing large elastic artery stiffness in patients with CKD stage 3-4 using noninvasive procedures.
In Aim 1, we will compare changes over time in brachial artery flow-mediated dilation and aortic pulse wave velocity after 12 months of sodium bicarbonate therapy or placebo.
In Aim 2, we will compare changes over time in LVMI, measured by gadolinium free cardiac magnetic resonance imaging, after 12 months of sodium bicarbonate therapy or placebo.
In Aim 3, we will compare changes over time in humoral mediators of urinary acid excretion that promote vascular calcification (angiotensin II, endothelin-1 and aldosterone) and a novel test of calcification that provides a measure of the overall calcification propensity of serum (T50) after 12 months of sodium bicarbonate therapy or placebo. The results of this novel study have the potential to inform clinical practice by providing the necessary evidence to establish sodium bicarbonate therapy as an inexpensive and easy to administer option for the treatment of arterial dysfunction in patients with CKD stage 3-4.

Public Health Relevance

Low serum bicarbonate levels, even within the normal laboratory range, are strongly associated with increased risks of hypertension, endothelial dysfunction, cardiovascular disease and death. The current proposal will investigate whether bicarbonate administration in patients with chronic kidney disease (CKD) will improve the health and function of arteries and reduce the size of the left ventricle of the heart. Overall, the proposed research will provide important new scientific evidence upon which physicians can base recommendations to patients with CKD to decrease the risk of developing cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132868-02
Application #
9395946
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2017-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kendrick, Jessica; Linas, Stuart (2017) Approaches to and Clinical Benefits of Reducing Dietary K in CKD. Clin J Am Soc Nephrol 12:1559-1560