PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) is largely an age-related clinical disorder with accelerated cognitive and cardiovascular aging. Cognitive impairment is highly prevalent in CKD affecting 20-50% of patients aged 50 or older with CKD stage 3-4. Cognitive function worsens as kidney function declines. Cognitive impairment in CKD results in increased mortality, functional decline, depression and reduced quality of life. Metabolic acidosis is a common complication of CKD as the diseased kidney is unable to excrete the daily dietary acid load. Metabolic acidosis is strongly linked to risks of cardiovascular disease, CKD progression, cognitive dysfunction and death. Metabolic acidosis results in increased production of angiotensin II, endothelin-1 and aldosterone in order to enhance urinary acid excretion. All three of these humoral factors are significant contributors to vascular dysfunction of the peripheral circulation causing blood flow to be delivered to the brain in a higher pulsatile manner. These abnormalities cause damage of small cerebral vessels creating a vascular pathway to cognitive impairment and dementia in midlife and older adults with kidney disease. In our preliminary data, we show that treatment of metabolic acidosis with bicarbonate therapy improves peripheral vascular dysfunction and we demonstrate that metabolic acidosis is associated with cognitive impairment in 2853 older hypertensive participants with and without CKD. Whether alkali therapy improves cognitive function or cerebrovascular function is unknown and are the aims of the current study. We are proposing a pilot, randomized, double-blinded, placebo-controlled, 12-month trial of 50 patients, 50-75 years of age with CKD stage 3b-4 with metabolic acidosis to examine the effect of sodium bicarbonate therapy on cognitive and cerebrovascular function. Our overall hypothesis is that treatment of metabolic acidosis with bicarbonate will improve cognitive and cerebrovascular function in patients with CKD stage 3b-4. In Aim 1, we will compare changes over time in cognitive function using the NIH Toolbox Cognitive Battery Test and the Trail Making Test before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 2, we will compare changes over time in cerebrovascular reactivity and pulsatility index of the middle cerebral artery using Transcranial Doppler Ultrasound before and 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 endothelial dysfunction and stiffness (angiotensin II, endothelin-1 and aldosterone) before and after 12 months of sodium bicarbonate therapy or placebo. The results of this novel pilot study will inform the design of a larger randomized controlled trial examining the effect of alkali therapy on cognitive and cerebrovascular function and structure in midlife and older adults with CKD. This proposal represents the critical first step to establish the efficacy of bicarbonate administration as an inexpensive and easy to administer option for the treatment of cognitive impairment and cerebrovascular dysfunction in midlife and older patients with CKD stage 3b-4.

R21AG068657

2020-09-15

2022-08-31