Bicarbonate Administration and Cognitive Function in Midlife and Older Adults with CKD

项目摘要/摘要 慢性肾脏疾病(CKD)主要是一种与年龄相关的临床疾病，其认知和 心血管老化。认知障碍在CKD中非常普遍，影响20-50%的50岁或50岁以上的患者 年龄较大的慢性肾脏病3-4期。随着肾功能的下降，认知功能也会恶化。认知功能障碍 慢性肾脏病导致死亡率增加、功能衰退、抑郁和生活质量下降。新陈代谢 酸中毒是慢性肾脏病的常见并发症，因为患病的肾脏不能排泄日常饮食中的酸。 装填。代谢性酸中毒与心血管疾病、慢性肾脏病进展、认知 功能障碍和死亡。代谢性酸中毒导致血管紧张素II、内皮素-1和 以增加尿酸排泄。这三个幽默因素都很重要。 导致血液流向大脑的外周循环血管功能障碍的因素 以一种更高的脉动方式。这些异常导致小脑血管受损，形成血管 患有肾脏疾病的中老年患者认知障碍和痴呆的途径。在我们的 初步数据显示，用碳酸氢盐疗法治疗代谢性酸中毒可改善外周血。 血管功能障碍，我们证明代谢性酸中毒与认知功能障碍有关。 2853例合并和不合并慢性肾功能不全的老年高血压患者。碱疗法是否改善认知功能 或脑血管功能未知，是目前研究的目标。我们提出了一项试点计划， 50名50-75岁慢性肾脏病患者的随机、双盲、安慰剂对照、为期12个月的试验 阶段3b-4代谢性酸中毒以检查碳酸氢钠治疗对认知和 脑血管功能。我们的总体假设是，用碳酸氢钠治疗代谢性酸中毒将 改善慢性肾脏病3b-4期患者的认知功能和脑血管功能。在目标1中，我们将比较 使用NIH工具箱认知电池测试和连线测试的认知功能随时间的变化 在碳酸氢钠治疗或安慰剂治疗12个月前后。在目标2中，我们将比较以下变化 经颅多普勒测定脑血管反应性时间及大脑中动脉搏动指数 在碳酸氢钠治疗或安慰剂治疗12个月前后进行超声检查。在目标3中，我们将比较 促进血管内皮功能障碍的尿酸排泄体液介质随时间的变化 和僵硬(血管紧张素II、内皮素-1和醛固酮)在碳酸氢钠服药12个月前后 治疗或安慰剂。这项新的先导性研究的结果将为设计一个更大的随机对照 碱疗法对中年人群认知和脑血管功能结构的影响 以及患有慢性肾脏病的老年人。这项建议是确立 碳酸氢盐给药是治疗认知障碍的一种廉价且易于给药的选择 慢性肾脏病3b-4期中老年患者的损害和脑血管功能障碍。

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (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. Cognitive function worsens as kidney function declines. Cognitive impairment in CKD results in increased mortality, functional decline, depression and reduced quality of life. Metabolic acidosis is a common complication of CKD as the diseased kidney is unable to excrete the daily dietary acid load. Metabolic acidosis is strongly linked to risks of cardiovascular disease, CKD progression, cognitive dysfunction and death. Metabolic acidosis results in increased production of angiotensin II, endothelin-1 and aldosterone in order to enhance urinary acid excretion. All three of these humoral factors are significant contributors to vascular dysfunction of the peripheral circulation causing blood flow to be delivered to the brain in a higher pulsatile manner. These abnormalities cause damage of small cerebral vessels creating a vascular pathway to cognitive impairment and dementia in midlife and older adults with kidney disease. In our preliminary data, we show that treatment of metabolic acidosis with bicarbonate 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. Whether alkali therapy improves cognitive function or cerebrovascular function is unknown and are the aims of the current study. We are proposing a pilot, randomized, double-blinded, placebo-controlled, 12-month trial of 50 patients, 50-75 years of age with CKD stage 3b-4 with metabolic acidosis to examine the effect of sodium bicarbonate therapy on cognitive and cerebrovascular function. Our overall hypothesis is that treatment of metabolic acidosis with bicarbonate will improve cognitive and cerebrovascular function in patients with CKD stage 3b-4. In Aim 1, we will compare changes over time in 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. In Aim 2, we will compare changes over time 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. In Aim 3, we will compare changes over time in humoral mediators of urinary acid excretion that promote vascular endothelial dysfunction and stiffness (angiotensin II, endothelin-1 and aldosterone) before and after 12 months of sodium bicarbonate therapy or placebo. The results of this novel pilot study will inform the design of a larger randomized controlled trial examining the effect of alkali therapy on cognitive and cerebrovascular function and structure in midlife and older adults with CKD. This proposal represents the critical first step to establish the efficacy of bicarbonate administration as an inexpensive and easy to administer option for the treatment of cognitive impairment and cerebrovascular dysfunction in midlife and older patients with CKD stage 3b-4.