# Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $715,659

## Abstract

~37 million (or 15% of US adults) have chronic kidney disease (CKD) and are at profoundly increased
risk of cardiovascular mortality by virtue of having reduced renal function. CKD patients have exaggerated
increases in blood pressure (BP) during physical activity that contributes to increased cardiovascular risk and
poor physical capacity. Our prior work has demonstrated that this augmented pressor response in CKD is due
to exaggerated increases in reflex activation of the sympathetic nervous system (SNS) during exercise that is
mediated by muscle afferent nerve activation, referred to as the exercise pressor reflex. Importantly, such
heightened SNS and pressor responses contribute to increased risk of adverse cardiovascular events,
including sudden death, during physical activity, as well as exercise intolerance that has a profound negative
impact on quality of life. While we now know that exaggerated muscle afferent nerve activation underlies the
exaggerated exercise pressor reflex in CKD, the mechanisms that mediate heightened muscle afferent nerve
activation to induce heightened BP reactivity remain unknown. Elucidating mechanisms of augmented exercise
pressor reflex is critical for revealing new treatment targets to improve cardiovascular risk and physical
functioning in this highly prevalent, high-risk patient population. We have compelling preliminary evidence that
muscle interstitial acidosis plays a major role in activating muscle afferent nerves, leading to an exaggerated
exercise pressor reflex in CKD. During exercise, ischemic metabolites including H+ accumulate in the muscle
interstitium and activate receptors on muscle afferent nerve endings to induce reflex increases in SNS
activation. Bicarbonate (HCO3-) is the major buffer preventing excessive reductions in muscle interstitial pH
during exercise; however, CKD patients have decreased HCO3- bioavailability starting at CKD Stage IIIB due to
an impaired ability of the diseased kidneys to excrete the daily acid load, resulting in decreased buffering
capacity. Our central hypothesis is that muscle interstitial acidosis resulting from decreased muscle buffering
capacity augments the exercise pressor reflex in CKD. We will test this hypothesis using direct
microneurographic recording of SNS activity, hemodynamics, biomarkers and innovative imaging techniques at
rest and during exercise in CKD patients. We will also determine if acute restoration of HCO3- bioavailability
ameliorates exercise-induced hypertension in CKD, and whether oral bicarbonate supplementation enhances
the beneficial effects of exercise training in CKD. Current treatment guidelines recommend bicarbonate therapy
only in CKD patients with overt acidosis ([HCO3-] ≤21 mmol/L); however, bicarbonate may be a simple, safe
and innovative method to target muscle afferent nerve activation and improve exercise hemodynamics and
function in CKD patients even without overt resting acidosis. Thus, these studies have high potential ...

## Key facts

- **NIH application ID:** 10522648
- **Project number:** 2R01HL135183-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jeanie Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $715,659
- **Award type:** 2
- **Project period:** 2017-01-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522648

## Citation

> US National Institutes of Health, RePORTER application 10522648, Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease (2R01HL135183-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10522648. Licensed CC0.

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