Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease

~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 to impact clinical practice regarding serum [HCO3-] goals, indications for bicarbonate therapy and renal rehabilitation strategies to improve long-term cardiovascular risk in CKD.