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

患有 CKD 的中年和老年人的碳酸氢盐给药和认知功能

基本信息

批准号：
10038711
负责人：
Jessica B Kendrick
金额：
$ 44.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038711
关键词：
Acids Adult Affect Age Age-Years Aging Aldosterone Alkalies Angiotensin II Bicarbonates Blood Circulation Blood Vessels Blood flow Brain Cardiovascular system Central Artery Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Cessation of life Chronic Kidney Failure Clinical Clinical Trials Cognition Cognitive Complication Data Dementia Development Diet Disease Disease Progression Double-Blind Method Elderly Endothelin-1 Equilibrium Excretory function Goals Health Homeostasis Impaired cognition Impairment Inflammation Intervention Trial Kidney Kidney Diseases Kidney Transplantation Link Measures Mediator of activation protein Mental Depression Metabolic acidosis Nervous System Physiology Neurons Oral Oxidative Stress Participant Pathway interactions Patients Peripheral Physicians Pilot Projects Placebos Plasma Prevalence Production Quality of life Randomized Randomized Controlled Trials Recommendation Renal function Renin-Angiotensin-Aldosterone System Replacement Therapy Research Risk Serum Sodium Bicarbonate Structure Testing Time Trail Making Test Transcranial Doppler Ultrasonography United States National Institutes of Health Vascular Diseases age related aged arterial stiffness base cardiovascular disorder risk cerebral artery cerebrovascular cognitive function design experience frailty functional decline hippocampal pyramidal neuron improved indexing middle age middle cerebral artery mortality novel novel therapeutics older patient pressure prospective trial comparing urinary vascular endothelial dysfunction

项目摘要

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.

项目概要/摘要慢性肾病（CKD）主要是一种与年龄相关的临床疾病，其认知能力和认知能力都会加快。心血管老化。认知障碍在 CKD 中非常普遍，影响 20-50% 的 50 岁或年龄较大，患有 CKD 3-4 期。随着肾功能下降，认知功能也会恶化。认知障碍 CKD 会导致死亡率增加、功能衰退、抑郁和生活质量下降。代谢酸中毒是 CKD 的常见并发症，因为患病的肾脏无法排出日常饮食中的酸加载。代谢性酸中毒与心血管疾病、CKD 进展、认知障碍的风险密切相关功能障碍和死亡。代谢性酸中毒导致血管紧张素 II、内皮素-1 和醛固酮以增强尿酸排泄。所有这三个体液因素都很重要导致外周循环血管功能障碍的因素，导致血流输送到大脑以更高的脉动方式。这些异常会导致小脑血管损伤，从而形成血管患有肾病的中年和老年人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障碍有关 2853 名患有或不患有 CKD 的老年高血压参与者。碱疗法能否改善认知功能或脑血管功能未知，是当前研究的目的。我们正在提议一个试点，对 50 名 50-75 岁 CKD 患者进行的为期 12 个月的随机、双盲、安慰剂对照试验伴有代谢性酸中毒的 3b-4 阶段，检查碳酸氢钠治疗对认知和认知功能的影响脑血管功能。我们的总体假设是，用碳酸氢盐治疗代谢性酸中毒将改善 CKD 3b-4 期患者的认知和脑血管功能。在目标 1 中，我们将比较使用 NIH Toolbox 认知电池测试和轨迹测试测试认知功能随时间的变化碳酸氢钠治疗或安慰剂治疗前后 12 个月。在目标 2 中，我们将比较以下方面的变化使用经颅多普勒测量脑血管反应时间和大脑中动脉搏动指数碳酸氢钠治疗或安慰剂治疗前后 12 个月进行超声检查。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使用碳酸氢钠 12 个月之前和之后的硬度（血管紧张素 II、内皮素-1 和醛固酮）疗法或安慰剂。这项新颖的试点研究的结果将为更大的随机对照研究的设计提供信息试验检查碱疗法对中年认知和脑血管功能和结构的影响以及患有 CKD 的老年人。该提案代表了确定有效性的关键的第一步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 CKD 3b-4 期中年和老年患者的损伤和脑血管功能障碍。