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.

项目摘要/摘要慢性肾脏疾病（CKD）在很大程度上是一种与年龄相关的临床疾病，具有加速的认知和心血管老化。在CKD中，认知障碍高度普遍，影响20-50％的50岁患者或与CKD阶段3-4更老。随着肾功能下降，认知功能会恶化。认知障碍 CKD导致死亡率增加，功能下降，抑郁和生活质量降低。代谢酸中毒是CKD的常见并发症，因为患病的肾脏无法排泄每日饮食酸加载。代谢性酸中毒与心血管疾病，CKD进展，认知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。这三个这三个体液因素都是显着的外周循环的血管功能障碍的贡献者，导致血流传递到大脑以较高的脉动方式。这些异常会导致小脑血管损害产生血管中年和老年人患有肾脏疾病的认知障碍和痴呆症的途径。在我们的初步数据，我们表明，用碳酸氢盐治疗的代谢性酸中毒可以改善外周血管功能障碍，我们证明了代谢性酸中毒与认知障碍有关 2853年有或没有CKD的老年高血压参与者。碱疗法是否改善认知功能或脑血管功能是未知的，是当前研究的目的。我们正在提议飞行员，随机，双盲，安慰剂对照，12个月的试验，50名患者，50-75岁的CKD 与代谢性酸中毒的3B-4期，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盐的代谢性酸中毒将改善CKD阶段3b-4患者的认知和脑血管功能。在AIM 1中，我们将比较使用NIH工具箱认知电池测试和步道制作测试随着时间的推移而变化。在12个月的碳酸氢钠治疗或安慰剂之前和之后。在AIM 2中，我们将比较更改使用经颅多普勒，脑动脉的脑血管反应性和脉动指数的时间超声检查前后12个月的碳酸氢钠治疗或安慰剂。在AIM 3中，我们将比较随着时间的流逝，尿酸排泄的体液介质会促进血管内皮功能障碍和刚度（血管紧张素II，内皮素-1和醛固酮）在碳酸氢钠12个月之前和之后治疗或安慰剂。这项新型试点研究的结果将为较大的随机控制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和CKD的老年人。该提议代表了建立功效的关键第一步碳酸氢盐给药是一种便宜且易于管理的认知治疗选择中年和CKD阶段3B-4患者的损伤和脑血管功能障碍。