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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.

约 3700 万人（或 15% 的美国成年人）患有慢性肾病 (CKD)，并且这一数字正在急剧增加由于肾功能下降而导致心血管死亡的风险。 CKD患者夸大其词体力活动期间血压 (BP) 升高，导致心血管风险增加体能差。我们之前的工作已经证明 CKD 中这种增强的升压反应是由于运动期间交感神经系统 (SNS) 反射激活的过度增加由肌肉传入神经激活介导，称为运动升压反射。重要的是，这样的 SNS 和升压反应增强会增加不良心血管事件的风险，包括体力活动期间的猝死，以及具有深远负面影响的运动不耐受对生活质量的影响。虽然我们现在知道过度的肌肉传入神经激活是 CKD 中过度运动加压反射，介导肌肉传入神经增强的机制诱导 BP 反应性升高的激活仍然未知。阐明增强运动的机制升压反射对于揭示新的治疗目标以改善心血管风险和身体健康至关重要在这个高度流行、高风险的患者群体中发挥作用。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主要作用，导致过度酸中毒锻炼 CKD 的升压反射。运动期间，包括 H+ 在内的缺血代谢物在肌肉中积聚间质并激活肌肉传入神经末梢上的受体以诱导 SNS 反射增加激活。碳酸氢盐 (HCO3-) 是防止肌肉间质 pH 过度降低的主要缓冲剂运动时；然而，由于以下原因，CKD 患者从 CKD IIIB 期开始 HCO3- 生物利用度就降低了患病肾脏排泄每日酸负荷的能力受损，导致缓冲能力下降容量。我们的中心假设是肌肉缓冲减少导致肌肉间质性酸中毒能力增强 CKD 患者的运动升压反射。我们将使用直接测试这个假设 SNS 活动、血流动力学、生物标志物和创新成像技术的显微神经影像记录 CKD 患者的休息和运动期间。我们还将确定 HCO3- 生物利用度是否能迅速恢复改善 CKD 运动诱发的高血压，以及口服碳酸氢盐补充剂是否可以增强运动训练对 CKD 的有益作用。目前的治疗指南推荐碳酸氢盐治疗仅适用于有明显酸中毒（[HCO3-]≤21 mmol/L）的 CKD 患者；然而，碳酸氢盐可能是一种简单、安全的以及针对肌肉传入神经激活和改善运动血流动力学的创新方法即使没有明显的静息酸中毒，CKD 患者也能发挥功能。因此，这些研究具有很大的影响潜力关于血清 [HCO3-] 目标、碳酸氢盐治疗适应症和肾脏康复的临床实践改善 CKD 长期心血管风险的策略。