Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease

慢性肾病患者运动期间的神经血管调节

基本信息

批准号：
10522648
负责人：
Jeanie Park
金额：
$ 71.57万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522648
关键词：
ASIC channel Acidosis Acids Activities of Daily Living Acute Adult Aerobic Exercise Affect Bicarbonates Biological Availability Biological Markers Blood Pressure Buffers Cardiovascular system Chronic Kidney Failure Clinical Combined Modality Therapy Disease Event Exercise Funding Gene Expression Generations Goals H-Reflex Human Hypertension Imaging Techniques Impairment Individual Inflammation Interleukin-6 Intravenous infusion procedures Isometric Exercise Isotonic Exercise Kidney Kidney Diseases Knee Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mediating Metabolic acidosis Methods Muscle Near-Infrared Spectroscopy Nerve Nerve Endings Oral Outcome Patients Periodicity Physical Capacity Physical Function Physical activity Physiological Placebos Play Population Quality of life Randomized Reflex action Regulation Renal function Research Rest Risk Role Serum Spinal Ganglia Sudden Death Supplementation Sympathetic Nervous System Testing Translating Translational Research Work afferent nerve blood pressure elevation cardiovascular risk factor clinical practice exercise capacity exercise intolerance exercise training hemodynamics high risk improved innovation insight interstitial lean body mass mortality neurovascular novel therapeutic intervention patient population prevent primary outcome programs protein expression receptor rehabilitation strategy relating to nervous system response restoration secondary outcome systemic inflammatory response therapeutic target treatment guidelines

项目摘要

~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.

〜3700万（或美国成年人的15％）患有慢性肾脏病（CKD），并且已大大增加由于肾功能降低而出现心血管死亡的风险。 CKD患者夸张体育活动期间血压（BP）的升高导致心血管风险增加和身体能力不佳。我们先前的工作表明，CKD中的这种增强的施加响应应到期在运动过程中夸大了交感神经系统（SN）反射激活的增加由肌肉传入的神经激活介导，称为运动式压力反射。重要的是，这样的社交媒体和施加反应的增强导致心血管不良事件的风险增加，包括猝死，体育锻炼期间以及具有深刻负面的运动肠对生活质量的影响。虽然我们现在知道夸张的肌肉传入神经激活是 CKD中夸大的运动式训练反射，介导增强肌肉传入神经的机制诱导BP反应性升高的激活仍然未知。阐明增强运动的机制压力反射对于揭示新的治疗目标至关重要，以改善心血管风险和身体在这个高度普遍的高风险患者人群中发挥作用。我们有令人信服的初步证据表明肌肉间质性酸中毒在激活肌肉传入神经中起着重要作用，导致夸张 CKD中的运动式压力反射。在运动过程中，包括H+在内的缺血代谢产物积聚在肌肉中肌肉传入神经端的间质和激活受体在社交媒体中引起反射增加激活。碳酸氢盐（HCO3-）是预防肌肉间质pH值过多的主要缓冲液在锻炼期间；但是，CKD患者从CKD阶段IIIB开始提高了HCO3-生物利用度患病肾脏极端每日酸负荷的能力受损，导致缓冲下降容量。我们的中心假设是，肌肉缓冲减少引起的肌肉间质酸中毒容量增加了CKD中的运动式训练反射。我们将使用直接检验该假设社交媒体活动，血液动力学，生物标志物和创新成像技术的微图记录休息和在CKD患者运动中。我们还将确定HCO3-生物利用度的急性恢复是否减轻CKD中运动诱导的高血压，以及是否补充口服碳酸氢盐 CKD运动训练的有益影响。当前的治疗指南建议碳酸氢盐治疗仅在CKD患有明显的酸中毒患者中（[HCO3-]≤21mmol/L）；但是，碳酸氢盐可能是一个简单，安全的和创新方法来靶向肌肉传入神经激活并改善运动血液动力学和 CKD患者的功能，即使没有明显的静止酸中毒。那就是这些研究具有很高的影响有关血清[HCO3-]目标的临床实践，碳酸氢盐治疗的适应症和肾脏康复改善CKD长期心血管风险的策略。