Clinical trial NCT04600323
Conditions: Metabolic Acidosis Chronic Kidney Disease Cognitive Dysfunction
Sponsor: University of Colorado, Denver
Start date: 2021-02-01; Completion date: 2023-08-30
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a pilot, randomized, double-blinded, placebo-controlled, 12-month trial of 50 patients with CKD stage 3b-4 with metabolic acidosis to examine the effect of sodium bicarbonate therapy on cognitive and cerebrovascular function.

Detailed description:

Arms: arm 1: Placebo medication will be used at a dose of 0.5 mEq/kg-lean body weight/day arm 2: Sodium bicarbonate will be used at a dose of 0.5 mEq/kg-lean body weight/day.
Interventions: intervention 1: Sodium Bicarbonate Tablets intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be given sodium bicarbonate at 0.5 mEq/kg-LBW/day for 12 months intervention 2: Participants will be given placebo at 0.5 mEq/kg-LBW/day for 12 months

Protocol documents:
Prot_SAP_000.pdf: 
Title: Bicarbonate Administration and Cognitive Function in Midlife and Older Adults with 
CKD 
 
NCT number: NCT04600323 
 
Document Date: 5/3/2023 
 
Document included: Study Protocol 


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w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 20-1672 
Project Title: 
Bicarbonate administration and cognitive function in midlife and older adults with 
CKD 
 
 
 
Principal Investigator:  Jessica Kendrick MD 
Version Date: 5/3/23  
 
 
  
 
I. Hypotheses and Specific Aims:   
Specific Aims 
Chronic kidney disease (CKD) is largely an age-related clinical disorder with accelerated 
cognitive and cardiovascular aging. Cognitive impairment is a well-documented 
occurrence in midlife and older adults with CKD and affects multiple domains. Cognitive 
function worsens as kidney function declines. Twenty to 50% of adults aged 50 or older 
with moderate CKD have cognitive impairment or dementia. Cognitive impairment in CKD 
results in increased mortality, functional decline, depression, frailty and reduced quality of 
life. Additionally, it disqualifies patients from kidney transplantation. Thus, there is a need 
to identify novel treatments for cognitive impairment in CKD.  
 
Acid base homeostasis is very important for neurologic function. Metabolic acidosis may 
be a contributing factor to the development of dementia through overexcitation and 
imbalance of cortical pyramidal neurons and GABAergic neurons. Additionally, metabolic 
acidosis results in increased inflammation, activation of the renin-angiotensin-aldosterone 
system (RAAS) and oxidative stress, all of which are significant contributors to vascular 
dysfunction of the peripheral circulation causing blood flow to be delivered to the brain in a 
higher pulsatile pressure manner. These abnormalities will cause damage of small 
cerebral vessels creating a vascular pathway to cognitive impairment and dementia in 
midlife and older adults with kidney disease. 
 
In CKD, the ability of the kidney to excrete the daily dietary acid load progressively 
declines and patients develop a positive acid balance. The prevalence of metabolic 
acidosis increases as kidney function declines and is a common complication in patients 
with moderate CKD. Metabolic acidosis is associated with many complications in CKD 
including all-cause and cardiovascular mortality, kidney disease progression and vascular 
dysfunction. Metabolic acidosis results in inflammation and oxidative stress, both of which 
are associated with vascular endothelial dysfunction, arterial stiffness and decline in 
cognitive function. Central artery stiffening reduces cerebral blood flow impairing 
cerebrovascular function. Patients with cognitive impairment have lower mean cerebral 
blood flow compared to patients with normal cognition.  
 
In our preliminary data, we show that treatment of metabolic acidosis with alkali 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. Alkali therapy replacement may represent an inexpensive and novel 
therapeutic option for cognitive impairment in CKD. However, no interventional trials 
have been performed examining the effect of alkali therapy on cognitive function in 
older CKD patients. 
 


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Our primary goal of the present proposal is to perform a pilot study to determine the effect 
of alkali therapy on cognitive function in older adults (age 50-80 years) with CKD stage 
3b-4 and metabolic acidosis (defined as serum bicarbonate level 16-22 mEq/L). 
Secondary goals are to determine the effect of alkali therapy on cerebrovascular 
dysfunction and established mediators of urinary acidification. We will conduct a pilot, 
prospective, randomized, double-blind clinical trial comparing the effect of oral sodium 
bicarbonate therapy vs. placebo in 50 CKD stage 3b-4 patients with metabolic acidosis to 
test the following aims: 
 
Hypothesis 1: Treatment with sodium bicarbonate therapy vs. placebo will improve 
cognitive function in midlife and older adults with CKD stage 3b-4. 
Specific Aim 1: To determine domains of 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. 
 
Hypothesis 2: Treatment with sodium bicarbonate therapy vs. placebo will improve 
cerebrovascular function in midlife and older adults with CKD stage 3b-4. 
Specific Aim 2: To determine changes 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. 
 
Hypothesis 3: Treatment with sodium bicarbonate therapy vs placebo will decrease 
markers of oxidative stress and inflammation. 
Specific Aim 3: To measure circulating markers of oxidative stress (plasma oxidized LDL, 
total antioxidant status) and inflammation (IL1-b, IL-6, C-reactive protein and TNF-a) 
before and after 12 months of sodium bicarbonate therapy or placebo. 
 
This novel study will be conducted by an experienced PI and investigative team with 
expertise in vascular and cognitive function and studies in CKD. The results from this pilot 
study will inform the design of a larger randomized controlled trial examining the effect of 
alkali therapy on cognitive and cerebrovascular function in midlife and older CKD patients. 
 
II. Background and Significance:  
A. SIGNIFICANCE 
1. Cognitive impairment in midlife and older adults with chronic kidney disease (CKD). 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 3-4.1-3 Midlife and older adults with CKD have an accelerated risk of cognitive aging 
equivalent to 3.6 to 7 years compared to the general population.1-3 Cognitive impairment negatively 
affects quality of life and other health-related outcomes and contributes significantly to the high cost 
of CKD.4-8 Prevention and treatment of CKD-related cognitive impairment is limited, as very few 
studies have been performed. It is therefore imperative to identify novel strategies targeting 
CKD-specific mechanisms to improve cognitive outcomes in midlife and older adults with 
CKD. 
 
2. Cognitive impairment in midlife and older adults with CKD is related to vascular disease.  
CKD is a state of increased vascular dysfunction characterized by increased pulse wave velocity 
resulting in damage to cerebral vessels.9-11 Patients with CKD are at an increased risk for vascular 
disease-related cognitive impairment rather than Alzheimer’s disease. In a study of over 7800 
patients over the age of 65 years, faster estimated glomerular filtration rate (eGFR) decline was 
associated with global cognitive decline and incident dementia with a vascular component.12 Older 
CKD patients have an increased prevalence of subclinical cerebrovascular disease evidenced by 
more white matter lesions (WML) and silent brain infarcts (SBI) detected on brain imaging.13 Both 


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WML and SBI are associated with increased risk for cognitive decline, dementia and stroke in CKD 
patients.14,15 Moreover, the pattern of cognitive disorders in older adults with CKD (e.g. impairment 
in processing and executive function) suggest cerebrovascular disease as the main cause.16  
 
3. Arterial stiffness and endothelial dysfunction of peripheral and cerebral arteries create a 
pathway to cognitive decline in midlife and older adults with CKD. In CKD, studies have found 
that medial calcification results in higher aortic pulse wave velocity (PWV).10 Arterial stiffness 
reduces the capacity of blood vessels to buffer pulsatile flow, resulting in vascular alterations and 
hemodynamic stress leading to vascular damage in high-volume blood flow organs like the brain.11 
Numerous studies have found an association between arterial stiffness and cognitive decline.17-19 
Higher PWV (a measurement of arterial stiffness) predicts poor cognitive performance and faster 
cognitive decline.  In 4,461 patients from the Atherosclerosis Risk in Communities Study, PWV ≥ 
75th percentile was associated with mild cognitive impairment and dementia after adjustment for 
demographics, education, prevalent cardiovascular disease and cardiovascular risk factors.18 
Individuals with worse brachial artery flow mediated dilation (FMD), a measurement of vascular 
endothelial function, demonstrate greater WML20 and worse working memory activation.21 Adults 
>60 years old with mild cognitive impairment also demonstrate impaired FMD compared to age-
matched controls.22 Animal studies have shown significant deficits in working memory in mice after 
carotid calcification.23 Significant reductions in cerebral blood flow and compromise in the blood-
brain barrier (marker of endothelial dysfunction) were present before the cognitive deficits;23 
suggesting that arterial stiffness as a single risk factor, impairs cerebrovascular function and 
cognition. Patients with cognitive impairment also have lower mean cerebral blood flow in middle 
cerebral arteries compared to patients with normal cognition.24 Arterial stiffness is associated with 
these hemodynamic changes in the middle cerebral artery.25 Taken together, these studies suggest 
that peripheral and cerebral endothelial dysfunction and arterial stiffness may be important in the 
development and progression of cognitive decline. In our preliminary data, we show that 
bicarbonate therapy improves vascular dysfunction in CKD and that low bicarbonate is 
associated with cognitive dysfunction. Sodium bicarbonate therapy may improve cognitive 
and cerebrovascular function in CKD, which constitute the main aims of the current 
proposal.  
 
4. Metabolic acidosis is common in patients with CKD. As kidney function declines, the kidneys 
progressively lose the ability to synthesize ammonia and excrete hydrogen ions.26 In general, 
ammonium excretion decreases in CKD stage 3b-4. Metabolic acidosis is more common in patients 
with decreasing kidney function and approximately 19%-37% of patients with CKD stage 3b-4 have 
a serum bicarbonate level <22 mEq/L.27-30 Recent studies suggest that positive acid balance is 
present in CKD even with low normal serum bicarbonate levels.29-31 Metabolic acidosis results in 
unfavorable effects that can lead to adverse outcomes.  
 
5. Metabolic acidosis results in increased production of angiotensin II (AII), aldosterone and 
endothelin-1 (ET-1). There are a number of humoral regulatory mechanisms that play a role in 
increasing urinary acidification in CKD including increased levels of AII, aldosterone and ET-1.31-35 
Experimental and human studies have shown that metabolic acidosis results in increased levels of 
these factors and increased expression of AII-type 1 receptors which are 
found in numerous tissues including the blood vessels, kidney and brain.31-
36 Angiotensin II stimulates ammoniagenesis and increases distal nephron 
acidification.32,37 It also stimulates ET-1 and aldosterone.38,39 ET-1 
increases both proximal and distal tubule acidification and indirectly 
increases acidification by stimulating aldosterone.34 In CKD stage 3 
patients, treatment with alkali therapy for 3 years resulted in reduced 
urinary angiotensinogen (an index of AII), reduced blood pressure (BP) and preserved kidney 
function.40 Although all subjects were on angiotensin converting enzyme inhibition (ACEi), urinary 
angiotensinogen only decreased in those patients on alkali therapy, supporting an important role 
for dietary acid reduction in the decrease of AII. Alkali therapy has also been shown to reduce ET-1 
and aldosterone levels in CKD.31 
 


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6. Persistent activation of AII, aldosterone and ET-1 by metabolic acidosis in CKD may 
result in cognitive dysfunction by inducing endothelial dysfunction41-43 and arterial 
stiffness.41,44,45 RAAS activated mice models show declined cognitive function due to decreased 
cerebral surface blood flow and increased oxidative stress.46 In humans, RAAS blockade is 
associated with reduced risks of cognitive decline and dementia.47,48 We have previously shown 
that sodium bicarbonate administration improves peripheral vascular dysfunction in CKD.49 
To date, no studies have examined whether treatment of metabolic acidosis improves cognitive 
function or cerebrovascular hemodynamics in CKD. The proposed mechanism of action of the 
cerebrovascular protective effects of alkali is presented in Figure 1.  
 
7. Oxidative stress has been identified as a key driver of aging and development of disease. 
Oxidative stress and inflammation are associated with cardiovascular pathophysiology and 
neurodegeneration.76-78 Several studies have found that oxidative stress and inflammation are 
associated with a decline in cognitive function.79-81 Markers of oxidative stress and inflammation are 
increased in patients with CKD.82-83 Both oxidative stress and inflammation are associated with 
cardiovascular disease in CKD patients. Metabolic acidosis results in inflammation and oxidative 
stress.84 Plasma oxidized LDL, IL1-b, IL-6, C-reactive protein and TNF-a have been shown to be 
higher in patients with CKD.85-86 Our laboratory has experience with these measurements.87-89 
 
8. Dietary intake is associated with dietary acid reduction through consumption of fruit, 
vegetables, and other non-alkaline foods. 
Several studies have demonstrated an association of dietary intake among serum bicarbonate, 
metabolic acidosis, blood pressure, and kidney function.93-95 Specifically, provision of alkaline fruits 
and vegetables had effects comparable to sodium bicarbonate on levels of plasma TCO2 in 
patients with stage 3 CKD with TCO2 levels ranging from 22-24 mmol/l.93 Patients with CKD 
provided with alkaline fruits and vegetables had a reduced dietary acid load which resulted in 
reduced kidney injury events and attenuations in eGFR reduction.94 These data support the 
important of evaluating diet in the context of metabolic acidosis in CKD.93-95 
 
9. Rigor of the prior research: Compelling data from observational studies position bicarbonate 
administration as a promising therapy for patients with CKD. Metabolic acidosis is associated with 
vascular dysfunction and cognitive impairment in CKD. We have shown that treatment of metabolic 
acidosis improves vascular endothelial function in CKD stage 3b-4. However, key questions 
regarding the efficacy of bicarbonate administration on cognitive and cerebrovascular function need 
to be addressed. To date, no randomized controlled studies have been performed examining the 
effect of sodium bicarbonate treatment on cognitive or cerebrovascular function.   
 
B. INNOVATION. The proposed study will fill critical scientific gaps through 4 innovations: 
1. This is the first randomized-controlled study examining the effect of bicarbonate 
administration on cognitive function and cerebrovascular function in CKD stage 3b-4. 
2. This proposal represents the critical first step to establish the efficacy of bicarbonate 
administration for improving cerebrovascular function and cognitive function. 
3. We are combining measures of domains of cognitive function with the NIH Toolbox 
with cerebrovascular reactivity and pulsatility of the middle cerebral artery using 
noninvasive measures.  
4. We will obtain mechanistic insight into the potential effects of bicarbonate 
administration on cognitive and cerebrovascular function through measurement of 
humoral mediators of urinary acidification. 
Overall, this work has the potential to inform clinical practice guidelines by establishing a 
novel, inexpensive, easy to deliver therapy for improving cerebrovascular dysfunction in 
CKD patients. 
 
 
 


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III. Preliminary Studies/Progress Report:   
a) Lower serum bicarbonate levels are associated with worse cognitive function. Dr. 
Chonchol, a Collaborator of this proposal, examined with other 
investigators in the Systolic BP Intervention Trial (SPRINT) the 
association between serum bicarbonate level and cognitive function in 
2853 older hypertensive adults with and without CKD.50 Serum 
bicarbonate levels were measured at baseline. Serum bicarbonate 
were analyzed continuously and categorically in clinically relevant 
groups (≤ 24 mEq/L, 25-28 mEq/L (reference group) and >28 mEq/L). 
Five cognitive summary scores were measured at baseline. Multivariate linear regression models 
were used to evaluate the cross-sectional association between serum bicarbonate and cognition. 
Results: The mean age (SD) and mean (SD) eGFR were 68 (8.5) years and 71 ml/min/1.73m2, 
respectively. Global cognitive and executive functions were positively associated with serum 
bicarbonate (Table 1). These findings suggest that low bicarbonate levels may be detrimental 
to neuronal activity and support the need for an interventional trial examining whether 
correction of acidosis has a beneficial effect on cognitive function.  
 
b) Bicarbonate administration results in improved vascular endothelial function (FMD) in 
patients with CKD stage 3b-4.49 We performed a pilot, prospective, open label 14-week crossover 
study examining the effect of treatment of metabolic acidosis (defined by a low serum bicarbonate 
level of 16-22 mEq/L), with oral sodium bicarbonate therapy (dose 0.5 mEq/kg-lean body 
weight/day) in 20 patients with CKD stage 3b-4.  The primary endpoint was change in FMD 
between treatment and control conditions. Results: The mean (SD) age and eGFR was 58.5 (12.8) 
years and 25.3 (8.3) ml/min/1.73m2, respectively. The mean (SD) bicarbonate level increased after 
sodium bicarbonate therapy from 19.6 (2.9) mEq/L to 22.4 (3.0) mEq/L. BP control was similar 
between the two conditions. FMD significantly improved after 6 weeks of sodium bicarbonate 
therapy compared to control conditions (mean difference in %FMD 1.1% in the treatment arm vs. -
0.70% in the control arm, p=0.027), Figure 2. Bicarbonate therapy was well tolerated and there 
were no significant adverse events.  
 
c) Feasibility of Aim 2 is demonstrated by our groups experience with cerebrovascular 
hemodynamics. In a small interventional trial of 8 adults over the age of 50 with baseline blood 
pressure >120 mmHg, 6 weeks of inspiratory muscle strength training (IMST) improved 
cerebrovascular reactivity compared to control. 
 
DCVR (DMCAvelocity/Dend tidal CO2) from baseline 
Mean (SE) 
IMST (Treatment Group) n=4 
0.99 (0.31) 
Control Group n=4 
-0.14 (0.60) 
 
IV. Research Methods 
Subjects. After obtaining their written informed consent, 50 patients with CKD stage 3b-4 (defined 
as estimated GFR (eGFR) 15-44 ml/min/1.73m2) with metabolic acidosis (defined as a serum 
bicarbonate level of 16-22 mEq/L, on 2 separate measurements at least 1 day apart), will serve as 
subjects. Relevant biological variables: Men and women 50-80 years old of all races/ethnicities 
will be included. Major inclusion/exclusion criteria are presented in the table below (Table 1). Only 
participants aged 50-80 years are included given the high prevalence of cognitive impairment in 
this age group. We chose a bicarbonate level of 16-22 mEq/L as this defines metabolic acidosis in 
CKD and safely allows us to have a placebo group since patients with severe metabolic acidosis 
(<16 mEq/L) are excluded. For additional rationale for inclusion/exclusion criteria, please see the 
Recruitment and Retention Plan. Patients will undergo screening for eGFR and serum bicarbonate 
at the Kidney Disease Research Center (KDRC) at the University of Colorado Anschutz Campus. 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) prediction equation will be 
used to calculate eGFR.51 A race modifier will not be used to correct the eGFR equation (all 
subjects will be categorized as “other”.52 Patients will be recruited from nephrology clinics at the 
University of Colorado where the PI has access to over 4,000 CKD patients. We will also recruit 


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from our CKD database, which contains over 300 CKD patients willing to participate in trials. The 
Health Data Compass services will also be used to generate a list of potential participants. 
 
Rigorous Experimental Design. A 12-month pilot, randomized, placebo-controlled, double-
blinded study with sodium bicarbonate will be conducted. The study will include 5 phases: 
screening, run-in, baseline, randomization and follow-up. 
• 
Screening: Subjects will undergo screening for inclusion/exclusion criteria during a 1-2 
week period. The Montreal Cognitive Assessment (MOCA) will be performed, which 
takes 10 minutes to administer. Participants who score <24, indicating severe 
cognitive impairment, will be excluded. Due to COVID-19 we are performing 
telephone/telemedicine consenting and screening to limit the number of patients 
coming into the research center. We will utilize the MOCA telemed protocol if the 
patient is able to do a video visit. This protocol has been validated in several studies 
and is scored the same as the original in-person MOCA. Should a patient not have 
telehealth video capabilities, we will utilize the phone MOCA (Blind MOCA) protocol, 
which has been validated in patients with vision issues as the visual abilities have 
been removed and thus it can be administered over the phone. The scoring is out of a 
possible score of 22 and adjusting the score to full MOCA, participants with a score 
<18 (equivalent to <24 on full MOCA) will be excluded. A urine pregnancy test will be 
performed if indicated. 
When logistically feasible, an ultrasound probe will be 
placed in the temporal bone acoustic window to locate the middle cerebral artery to 
ensure we can perform the cerebrovascular functions testing 
• 
Run-in: A 1-month run-in period will occur if patients do not meet the blood pressure 
(BP) goal of <140/90 mmHg. The rationale for this run-in phase is to achieve a stable 
antihypertensive regimen and BP <140/90 mmHg, such that changes in 
antihypertensive agents throughout the course of the study are minimal. During the 
run-in phase, an up-titration of patient’s current antihypertensive medication(s) will 
occur to reach a target BP of <140/90 mmHg. The duration of the run-in phase will be 
4 weeks with weekly visits to achieve the target BP. If the patient is not able to achieve 
a BP of <140/90 mmHg during this period, the participant will not be included in the 
study. This overall approach will allow for inclusion of the typical population of patients 
with CKD 3b-4 and increase the generalizability of our expected results.  
• 
Resting BP: Arterial BP will be measured in triplicate while seated at rest using an 
automated oscillometric machine (Omron) at all in person study visits. 
• 
Baseline: During the baseline phase cognitive function, cerebrovascular 
hemodynamics, grip strength test, pegboard dexterity test, 30 second chair sit stand 
test, 4 meter walk test, physical functioning scale of the Short Form 36 (SF-36)  serum 
basic chemistry panel, plasma oxidized LDL, total antioxidant status, IL1-b, IL-6, C-
reactive protein and TNF-a and venous blood gas will be performed and the GI 
symptom questionnaire will be assessed. Spot urine will be collected for albumin to 
creatinine ratio. Demographics, medical history and physical will be performed.  
• 
Randomization: Participants will be randomized with a 1:1 allocation ratio to treatment 
and placebo group using block randomization. Block randomization will be based on 
sex, age (within 5 years) and CKD stage (3b or 4). List of randomization will be 
generated by the study statistician and sent to the study pharmacist (A) Green 
Mountain Pharmaceutical, Denver, CO, and/or B) University of Colorado Research 
Pharmacy) blinded to the PI. Study investigators, healthcare providers, participants, 
data collectors, outcome adjudicators and data analysts will be blinded to treatment 
assignment.  


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• 
Follow-up: The follow-up schedule includes: 
o 1, 2, 4, 5, 7, 8, 10, and 11 months: safety check-in call via phone to complete 
adverse event assessment and GI symptom questionnaire 
o 3 and 9 months: safety visit (basic chemistry panel, adverse event 
assessment, GI symptoms questionnaire, BP, pill compliance).  
o 6 months: 1) Adverse event assessment, GI symptoms questionnaire, BP, pill 
compliance; 2) outcome measures: cognitive function, grip strength test, 
pegboard dexterity test, 30 second chair sit stand test, 4 meter walk test, 
physical functioning scale of the SF-36, serum basic chemistry panel, plasma 
oxidized LDL, total antioxidant status, IL1-b, IL-6, C-reactive protein and TNF-
a; 3) spot urine for albumin to creatinine ratio. 
o 
12 months: 1) Adverse event assessment, GI symptoms questionnaire, BP, pill 
compliance; 2) outcome measures: cognitive function, cerebrovascular 
hemodynamics, grip strength test, pegboard dexterity test, 30 second chair sit 
stand test, 4 meter walk test, physical functioning scale of the SF-36serum 
basic chemistry panel, plasma oxidized LDL, total antioxidant status, IL1-b, IL-
6, C-reactive protein and TNF-a and venous blood gas; 3) spot urine for 
albumin to creatinine ratio. 
 
Table 1 
Inclusion Criteria 
Exclusion Criteria 
• 
Age 50-80 years old 
• 
Serum bicarbonate 16-22 mEq/L on 2 separate 
measurements (at least 1 day apart)  
• 
CKD stage 3b or 4 at time of screening (eGFR 15-
44 ml/min/1.73m2)  
• 
Blood 
pressure 
<140/90 
mm 
Hg 
prior 
to 
randomization 
• 
Stable anti-hypertensive regimen for at least one 
month prior to randomization 
• 
Montreal Cognitive Assessment Score > or = 24 
• 
No history of stroke 
• 
No history of dementia 
• 
No history of neurologic disease 
• 
Able to provide consent 
 
      
• 
Significant comorbid conditions that lead the 
investigator to conclude that life expectancy is 
less than 1 year 
• 
Use of chronic daily oral alkali within the last 3 
months (including sodium bicarbonate, calcium 
carbonate or baking soda) 
• 
Uncontrolled hypertension 
• 
Serum potassium < 3.3 or ≥ 5.5 mEq/L at 
screening 
• 
New York Heart Association Class 3 or 4 heart 
failure symptoms, known EF ≤30%, or hospital 
admission for heart failure within the past 3 
months 
• 
Factors 
judged 
to 
limit 
adherence 
to 
interventions 
• 
Anticipated initiation of dialysis or kidney 
transplantation within 12 months 
• 
Current participation in another research study 
• 
Pregnancy or planning to become pregnant or 
currently breastfeeding 
• 
Chronic use of supplemental oxygen 
4. Study Drug Dosing. The study drugs (bicarbonate and the matched placebo) will be 
prepared by A) Green Mountain Pharmaceutical and B) University of Colorado Research 
Pharmacy and will be identical in size, color, shape and taste. Each sodium bicarbonate 
capsule contains 7.7 mEq of bicarbonate and 178 mg of sodium. The matching placebo 
capsule will contain cornstarch. Green Mountain Pharmaceutical and/or University of 
Colorado Research Pharmacy will bottle the capsules and label the bottles with code 
numbers to maintain the study’s double blind and Green Mountain Pharmaceutical will 
ship the bottles directly to the investigative site. Study drug supplied by the on-campus 
pharmacy will be managed and picked up directly from University of Colorado Research 
Pharmacy for each study participant. 
  


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a) Sodium bicarbonate: Subjects randomly assigned to sodium bicarbonate therapy will 
receive 0.5 mEq/kg-lean body weight (LBW)/day for the entire 12 months. Participants will 
take ½ the daily dose in the morning and the other ½ in the evening. The number of 
capsules will be rounded to the nearest whole capsule. To reduce pill burden and increase 
compliance the maximum number of pills per day will be six.  
 
Rationale for sodium bicarbonate dose: A dose of 0.5 mEq/kg-LBW/day has been 
shown to be safe and effective for treatment of metabolic acidosis in patients with 
CKD.49,53-54 Previous studies using this dose of sodium bicarbonate have not reported 
significant changes in edema, body weight or BP.49,53-55 In our preliminary data, sodium 
bicarbonate administration was not associated with an increase in BP or fluid gain in 
patients with CKD stage 3b-4.49 Additionally, we will dose sodium bicarbonate based on 
LBW, not actual body weight. The volume of distribution of bicarbonate is approximately 
that of total body water. Total body water is dependent on lean body mass. Standard 
equations will be used to determine LBW.56 
 
b) Placebo: Subjects randomly assigned to placebo will take the same number of capsules 
as if they were assigned to receive 0.5 mEq/kg-LBW/day of sodium bicarbonate. 
Participants will take ½ the daily dose in the morning and the other ½ in the evening. The 
number of capsules will be rounded to the nearest whole capsule. To reduce pill burden 
and increase compliance the maximum number of pills per day will be six. 
 
Rationale for placebo: A placebo group is necessary to successfully complete our aims. 
If a placebo group were not included both the investigators and participants would know 
that they are receiving sodium bicarbonate, which could influence medical management 
and perception of side effects in the study.  
 
Dose Titration of Study Drug: If at month 3 the serum bicarbonate level not ³ 23 mEq/L, 
we will increase the dose of sodium bicarbonate to 0.8 mEq/kg/LBW. This dose was 
recently used in a randomized trial comparing the safety and efficacy of doses of sodium 
bicarbonate therapy and was found to be well tolerated without any significant differences 
in adverse events or hospitalization compared with placebo.57  
 
5. Rationale for study duration. Changes in cognitive function, cerebrovascular 
reactivity and pulsatility can be seen within 4-6 weeks in adults 50 years and older but 
may require longer periods of time and published data use a period of 3 months to 1 
year.57-61 Hence, we are proposing a 12-month intervention. 
 
5. Safety monitoring: Sodium bicarbonate therapy may cause bloating, flatulence and 
abdominal discomfort. Although previous studies using similar doses of sodium 
bicarbonate have not reported significant changes in edema, body weight or BP,49,53-55 
sodium bicarbonate may cause edema to develop or worsen thereby increasing BP. 
Sodium bicarbonate also has the potential for causing metabolic alkalosis and 
hypokalemia if it is retained rather than excreted in the urine. These expected adverse 
events will be monitored during the study. Serum bicarbonate may fall due to natural 
progression of CKD, particularly in the placebo group. Rescue therapy with open-label 
sodium bicarbonate will be initiated if serum bicarbonate is <16 mEq/L on 2 
consecutive measurements until the serum bicarbonate is ³ 16 mEq/L. Participants 
will not discontinue study medications if open-label sodium bicarbonate is prescribed. 
Please see the protection of human subjects section for full safety monitoring details. 
 


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Medical Supervision and Subject Surveillance. The Kidney Disease Research Center 
nursing staff will have the responsibility of performing blood draws from participants. The 
vascular technician will have the responsibility of performing the cerebrovascular function 
measurements under the supervision of Dr. Kristen Nowak Director of the Vascular 
Biology Lab at the University of Colorado Anschutz Medical Campus. The research study 
coordinator will be responsible for performing the cognitive function tests and for collecting 
information about treatment adverse events. Dr. Kendrick, the PI, will be responsible for 
supervision of the entire study. Dr. Kendrick will make final decisions regarding subject 
screening/enrollment and monitor/oversee clinical status and subject safety.  
 
a) Data Safety Monitoring Plan. To ensure the safety of subjects, they will need to meet 
rigorous inclusion/exclusion criteria, including comprehensive health screening 
procedures. The participants’ personal physicians will also be informed of their patients’ 
participation in the study. 
 
Data Safety Monitoring Board (DSMB). A DSMB including clinicians and a statistician 
(independent of the study investigators but part of the faculty at the University of Colorado 
School of Medicine) will be formed to assess potential adverse events. The data will be 
prepared by the DSMB statistician, ensuring the study statistician remains blinded until the 
final analysis. The DSMB will meet at least 1 time per year to review the protocol and will 
follow the guidelines established by the NIH National Center for Research Resources, 
which include: a) monitoring the progress of the protocol (e.g. reviewing subject 
recruitment, attrition and minority involvement) and the safety of research participants 
(e.g. reviewing unblinded data for safety); b) assuring compliance with requirements 
regarding the reporting of adverse events; c) assuring that any action that results in the 
temporary or permanent suspension of the protocol is reported to all of the appropriate 
monitoring bodies (IRB, NIH, etc.) and d) assuring data accuracy and protocol 
compliance. Any unexpected adverse events will be reported immediately to the Colorado 
Institutional Review Board, the funding I/C and the NIH Office of Biotechnology Activities. 
This study is not solidly considered as a confirmatory study and as such no interim 
analysis has been planned. The PI, Dr. Kendrick, will provide ongoing day-to-day 
monitoring of the study and the protocol will be reviewed by the IRB on an annual basis. 
 
b) Reporting of Side Effects. Subjects will be instructed to report serious or worrisome 
side effects to the investigators and their primary care physician (who will have been 
informed of their patient’s participation in and the nature of the study). A subject 
experiencing side effects during off hours will contact Dr. Kendrick, who is available 24 
hours a day. Any unexpected adverse events will be reported immediately to the Colorado 
Institutional Review Board, the funding I/C and the NIH Office of Biotechnology Activities. 
 
• 
Expected adverse events: Sodium bicarbonate therapy may cause bloating, 
flatulence and abdominal discomfort. Although previous studies using similar 
doses of sodium bicarbonate have not reported significant changes in edema, 
body weight or BP,49,53-55 sodium bicarbonate may cause edema to develop or 
worsen thereby increasing BP. As shown in our preliminary data, sodium 
bicarbonate did not result in increased BP.49 Sodium bicarbonate also has the 
potential for causing metabolic alkalosis and hypokalemia if it is retained rather 
than excreted in the urine. These expected adverse events will be monitored 
during the course of the study and in general, can be medically managed by 


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adjusting 
antihypertensive 
and/or 
diuretic 
agents, 
providing 
potassium 
replacement and by dietary changes. Of note, none of these adverse events were 
observed in our previous short-term pilot study. Patients will have safety visits and 
check-in calls to assess side effects and check laboratory values. 
 
• 
Dose reduction and discontinuation: 
• 
Serum bicarbonate >28 mEq/L: The intervention dose (study drug) will be reduced 
by 50% and diuretics will be adjusted as appropriate. The participant will return for 
a visit one week later to have serum chemistries rechecked. If the bicarbonate 
remains >28 mEq/L the intervention will be stopped and the participant will have 
serum bicarbonate measured weekly until it is <28 mEq/L. PI will monitor for 
symptoms of hypocalcemia as an increase in pH can decrease the ionized calcium 
concentration.117,118 Management of low calcium will be at the discretion of the PI 
based on symptoms reported by the patient. 
• 
Systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 90 mmHg: 
Potential reasons for uncontrolled BP, such as poor compliance or running out of 
medications will be evaluated and managed appropriately. If an identifiable cause 
is not found, the PI will increase anti-hypertensive medications and/or diuretics. 
The participant will return 1 week later for follow-up. If BP remains >160/90 mmHg 
at the second visit, medications will again be increased and the intervention dose 
will be reduced by 50%. The participant will return 1 week later. If BP remains 
unchanged at the third visit, the intervention will be stopped and medications will 
again be escalated. Participants will continue to have PRN visits weekly until BP is 
<160/90 mmHg.  
• 
Serum potassium < 3.0 mEq/L: The intervention dose will be reduced by 50%, 
diuretics will be adjusted as appropriate and potassium replacement will be 
prescribed. The participant will return 1 week later for repeat labs. If serum 
potassium remains < 3.0 mEq/L, the intervention will be discontinued. The 
participant will return weekly until serum potassium is > 3.0 mEq/L. 
• 
Severe edema: If in the opinion of the PI severe edema (4+) is present and 
another etiology cannot be identified the dose of the intervention will be reduced 
by 50% and diuretics will be adjusted. If fluid retention remains severe at follow-up 
visits, the intervention will be discontinued.  
• 
Rescue therapy with oral sodium bicarbonate: Rescue therapy with open-label 
sodium bicarbonate will be initiated if serum bicarbonate is <16 mEq/L on 2 
consecutive measurements at least 1 week apart since a level <16 mEq/L may be 
associated with adverse outcomes. In this instance, open-labeled sodium 
bicarbonate will be given to target serum bicarbonate of ³ 16 mEq/L.  Participants 
will not discontinue study medications if open-labeled sodium bicarbonate is 
prescribed.  
 
 
c) Exit Criteria. The primary exit criteria will include: 
• 
Completion of the study 
• 
Failure to comply with the requirements of the study 
• 
The development of side effects described above as determined by the PI, Dr. 
Kendrick 
• 
Subjects will have the option of withdrawing from the study at any time for personal 


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reasons.  
 
The number of subjects exiting the study and the reason for the exit will be carefully 
documented. 
 
 
 
7. Outcome Measures  
a) Primary Outcome 
• 
Cognitive Function:  Cognitive function will be assessed using the NIH Toolbox-
Cognition Battery computerized tests62 at baseline, 6 months, and 12 months. The NIH 
Toolbox-Cognition Battery entails seven computerized tests that assess five major 
cognitive subdomains including: 1) attention, 2) episodic memory, 3) working memory, 
4) language, 5) executive function, and 6) processing speed. Administering the NIH 
Toolbox cognitive battery will yield the following summary scores, in addition to 
individual measure scores: Cognitive Function Composite Score (‘g’ factor, or general 
cognitive ability based on performance of each subdomain), Fluid Cognition 
Composite Score (includes tests of attention, executive function, working memory, and 
processing speed) and Crystallized Cognition Composite Score (includes Picture 
Vocabulary and Reading Recognition measures). These instruments have been 
validated in 476 participants ranging in age from 3 to 85 years, with representation 
from both sexes, 3 racial/ethnic categories and 3 levels of education.62  In addition, the 
Trail Making Test (TMT) parts A and B will be administered to determine processing 
speed and executive function, respectively.63  The investigative team has experience 
administering these assessments.64 
• 
Justification for primary outcome: Our preliminary data suggests that correction of 
acidosis may improve cerebrovascular function. The use of the NIH Toolbox and the 
TMT parts A and B allow for assessing cognitive function in approximately 30-45 
minutes and has been validated in numerous patient populations. Our research group 
has experience with these cognitive function measurements.64  
 
b) Secondary Outcomes 
• 
Cerebrovascular hemodynamics: 1) Cerebrovascular reactivity will be measured 
using Transcranial Doppler US by assessing the change in mean blood flow velocity of 
the middle cerebral artery (MFVMCA) in response to a vasodilatory hypercapnic 
challenge (i.e. via CO2 breathing) at baseline and 12 months.65 An ultrasound probe 
will be positioned at the temporal window and held in place by an adjustable 
headband. This location offers an ideal exposure for Doppler ultrasonography of the 
middle cerebral artery since the temporal window is the thinnest part of the temporal 
bone. After baseline recordings at room air, subjects will breathe room air 
supplemented with 5% CO2 to induce mild hypercapnia. Each condition is recorded for 
at least 5 minutes to achieve a steady state velocity. MFVMCA will be determined for 
each condition by calculating the average velocity over each cardiac cycle for the last 
minute of each condition. ΔMFVMCA will be calculated as: hypercapnic MFVMCA – 
normocapnic MFVMCA and used to compare cerebrovascular reactivity between 
sodium bicarbonate and placebo. Breath-by-breath end-tidal partial pressures of CO2 
(ETCO2) will be continuously monitored and will be used to normalize the MFVMCA 
response to changes in this arterial blood gas.65 The assessment of ETCO2 is 
noninvasive and correlates strongly with (invasive) serial blood measures of arterial 


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blood gases.65 The hypercapnia protocol used in this study has been used in the 
research setting for many years without any adverse events.65-67 Brachial arterial BP 
will also be measured during these assessments for correction due to any changes 
during hypercapnia.  2) Cerebrovascular Pulsatility Index and Resistance: Pulsatile 
cerebrovascular velocity will be determined using the Gosling Pulsatility index = 
(MCAV(systolic)- MCAV(diastolic)/MFVMCA) and baseline and 12 months.68 The mean, systolic 
and diastolic velocity of the MCA will be measured.   
• 
9-Hole Pegboard Dexterity Test (NIH Toolbox): This test records the time required for 
the participant to accurately place and remove 9 plastic pegs into a plastic pegboard. 
The protocol includes 1 practice and 1 test trial with each hand. Raw scores are 
recorded as time in seconds that it takes the participant to complete the task with each 
hand (a separate score for each). 
• 
Grip Strength Test (NIH Toolbox): Participants are seated in a chair with their feet 
touching the ground. Participants are instructed to squeeze the Jamar Plus Digital 
Dynamometer as hard as they can for a count of three. A practice trial at less than full 
force and 1 test trial are completed with each hand.  
• 
30-second chair sit stand test: The patient will be seated in the middle of a chair with 
their hands on the opposite shoulder crossed at the wrists. Feet will be flat on the 
floor. On “Go”, the patient will rise to a full standing position, then sit back down again. 
This will be repeated for 30 seconds and the number of times the patient stands in 30 
seconds will be recorded. IF the patient must use his/her arms to stand, the test will be 
stopped and a 0 will be recorded for the number and score. 
• 
4-meter walk test: 4-meter walk test will be performed using protocol from NIH 
Toolbox. Patient will be asked to walk 4 meters at their usual pace. The patient will 
complete one practice and then two timed trials. The time in seconds to walk 4 meters 
on each of the two trials will be recorded. The test take approximately 3 minutes to 
administer.   
• 
Physical Functioning Scale from the SF-36: Participants will complete the short 
questionnaire on their physical functioning. This is a validated scale that has been 
used in several CKD studies. The scale takes approximately 3-5 minutes to complete.  
 
• 
Oxidative stress and inflammation: Oxidized LDL will be measured with Mercodia 
ELISA kit at the University of Colorado CTRC. Total antioxidant status will be 
measured at the CTRC with Randox Laboratories assay. C-reactive protein will be 
measured by immunoturbideimetric (Beckman Coulter) at the CTRC.  
 
• 
Food frequency questionnaire (FFQ): This FFQ was developed for use in 
CKD/ESKD (end-stage kidney disease) to investigate highly/ultra-processed food 
consumption patterns that are typically high in sodium, potassium, and phosphorus. It 
was modified to include categories of alkaline fruits/vegetables and other acid/alkaline 
ash foods in the diet.  
 
Justification for secondary outcomes: Transcranial Doppler Ultrasound is a 
noninvasive and safe way to examine cerebrovascular hemodynamics. Cerebrovascular 
reactivity (the vasodilation of cerebral arterioles in response to hypercapnia) is a surrogate 
marker of endothelial function in cerebral arteries and the pulsatility index is positively 
associated with arterial stiffness,69 correlates with white matter hyperintensities,70 and 
predicts cognitive impairment in patients.70 Our research group has experience with these 
measurements (Dr. Seals and Nowak) and Dr. Nowak has established a cerebrovascular 


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laboratory in the KDRC. Oxidative stress has been identified as a key driver of aging and 
development of disease. Oxidative stress and inflammation are associated with 
cardiovascular pathophysiology and neurodegeneration.78-80 Several studies have found 
that oxidative stress and inflammation are associated with a decline in cognitive 
function.81-83 Markers of oxidative stress and inflammation are increased in patients with 
CKD.84-85 Both oxidative stress and inflammation are associated with cardiovascular 
disease in CKD patients. Metabolic acidosis results in inflammation and oxidative stress.86 
Plasma oxidized LDL, IL1-b, IL-6, C-reactive protein and TNF-a have been shown to be 
higher in patients with CKD.87-88 Our laboratory has experience with these 
measurements.89-91 The FFQ will inform if there were any changes in self-reported food 
consumption throughout the study. The FFQ will also inform if changes in study outcomes 
/ measures were associated with changes in self-reported food consumption throughout 
the study (association, correlation, differences, confounding between study measures and 
outcomes). Additionally, it will be for participant stratification and for exploratory 
categorization of participants by self-reported foods consumed. This data will elude at 
categories of diets: alkaline, acidic, processed, high-sodium/potassium/phosphorus, and 
high–protein. 
 
8. Power and Statistical Analysis: Briefly, in this pilot study a total of 50 patients will be 
enrolled and equally randomized to the two groups. The two-sample t-test is applicable to 
compare the change between the two groups for each cognitive function subdomain and 
is the basis for power analysis. This sample size was determined based on feasibility and 
availability, not a specified statistical power. With a two-sided type I error rate of 0.05, the 
study will have a power of 79% to detect an effect of 0.80 if 25 patients per group can be 
included in the final analysis. This power calculation applies to the secondary and other 
outcome variables.  For Aim 1, we will assess the treatment effect on each of the six 
subdomains of cognitive function by a linear regression model with the measure at end of 
study regressed on treatment along with the baseline measure of the subdomain, sex, 
age, and baseline eGFR. Conclusion will be subdomain specific. For Aims 2 and 3, the 
linear regression model will be used to examine the treatment effect on the secondary and 
other outcomes. Particularly, the measure of an outcome variable at end of study will be 
regressed on intervention indicator and baseline measure of the outcome variable plus 
sex, age and baseline eGFR for adjustment purpose.   
 
9. Potential Problems and Alternative Strategies 
• 
Although subject recruitment and retention are always challenging, we should be able 
to complete the study in the proposed timeline given our groups excellent track record 
in recruiting participants in clinical trials.  
• 
We should have few difficulties with the proposed experimental procedures and 
protocols as they are already established in the vascular laboratories at the KDRC by 
Dr. Nowak. 
• 
We recognize that alternative approaches exist for examining the effects of alkali 
therapy on cognitive function in patients with CKD. For example, one alternative would 
be to undertake a larger study to examine structural changes with brain MRIs rather 
than the investigation proposed in the current application. However, our proposed 
study is the most cost-effective approach to obtain confirmation of the study 
hypotheses. 


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• 
We recognize that different dosages of sodium bicarbonate therapy can be used. 
However, the proposed dose in the current study has been shown to be safe and 
effective in treating metabolic acidosis in CKD 3-4. 
• 
Systolic BP is an important determinant of vacular function and cognitive impairment 
and could be a theoretical confounder. However, we do not expect this to be an issue 
as all participants must have their BP controlled prior to entering the study and all 
patients must be on an ACEi or ARB or spironolactone. We will adjust for BP if 
differences in BP control is observed between the groups. 
• 
We acknowledge that there may be other potential mechanisms by which acid 
retention results in cerebral vessel dysfunction. Acidosis induces inflammation and 
oxidative stress and net calcium and phosphate efflux from bone. We will collect 
plasma and serum to store for future analyses of these other mechanisms. 
 
 
G.  Summarize Knowledge to be Gained:   
The new knowledge generated from this proposal will facilitate planning of future clinical 
trials in CKD patients that will aim to reduce the burden of cognitive dysfunction. 
 
 
 H. References: 
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