Bicarbonate Administration in CKD

CKD 中碳酸氢盐的管理

基本信息

批准号：
9324442
负责人：
Jessica B Kendrick
金额：
$ 44.85万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324442
关键词：
Acidosis Acids Alkalies Alkaline Phosphatase Arteries Bicarbonates Blood Vessels Bone Diseases C-terminal Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Chronic Kidney Failure Clinical Trials Collagen Type I Complication Data Development Diet Disease Progression Double-Blind Method Endothelin-1 Endothelium Equilibrium Functional disorder Gadolinium General Population Goals Health Heart Heart failure Human Hypertension Inflammation Intervention Trial Kidney Kidney Diseases Laboratories Left Ventricular Hypertrophy Left Ventricular Mass Left ventricular structure Link Magnetic Resonance Imaging Measures Mediating Metabolic acidosis N-terminal Observational Study Oral Outcome Patients Physicians Physiologic pulse Placebo Control Placebos Population Procedures Randomized Recommendation Reporting Research Risk Risk Factors Serum Sodium Bicarbonate Staging Surrogate Markers Testing Time Vascular calcification Vasoconstrictor Agents arterial stiffness base bone bone loss bone metabolism bone turnover brachial artery calcification calcium phosphate clinical practice endothelial dysfunction gadolinium oxide improved indexing mortality novel novel marker novel therapeutics patient population prospective randomized trial trial comparing week trial

项目摘要

PROJECT SUMMARY/ABSTRACT Metabolic acidosis, reflected by a lower serum bicarbonate level, is a common complication of chronic kidney disease (CKD) as the diseased kidney is unable to excrete the daily dietary acid load. Lower serum bicarbonate levels, even within the normal laboratory range, are strongly linked to risks of hypertension, cardiovascular disease (CVD), CKD progression and death. Arterial dysfunction begins early in the course of kidney disease and is a key factor responsible for the development of left ventricular hypertrophy (LVH) in this population. LVH is the strongest predictor of cardiovascular mortality in CKD. Acidosis increases inflammation, induces endothelin-1 (a potent vasoconstrictor) and increases calcium and phosphate efflux from bone, all of which are risk factors for arterial dysfunction and LVH. Small interventional trials have shown that treatment with alkali therapy slows progression of kidney disease, even in patients with normal serum bicarbonate levels. Because risk factors for CVD and CKD progression often overlap, it is biologically plausible that alkali therapy in CKD patients may also result in improved cardiovascular outcomes. In our preliminary data, alkali therapy improved vascular endothelial function in 16 patients with CKD stage 3-4. Hence, treatment with alkali therapy may represent an inexpensive and novel therapeutic paradigm in CKD. We are proposing a randomized, double-blinded, placebo-controlled, 52 week trial of 108 patients with CKD stage 3-4 to examine the effect of sodium bicarbonate therapy on surrogate measures of CVD. Our overall hypothesis is that treatment with bicarbonate will improve indicators of vascular function and LVH in patients with CKD stage 3-4. Our primary goal is to determine the efficacy of alkali therapy for improving vascular endothelial function and reducing large elastic artery stiffness in patients with CKD stage 3-4 using noninvasive procedures. In Aim 1, we will compare changes over time in brachial artery flow-mediated dilation and aortic pulse wave velocity after 52 weeks of sodium bicarbonate therapy or placebo. In Aim 2, we will compare changes over time in LVMI, measured by gadolinium free cardiac magnetic resonance imaging, after 52 weeks of sodium bicarbonate therapy or placebo. In Aim 3, we will compare changes over time in a novel test of calcification that provides a measure of the overall calcification propensity of serum (T50) and in markers of bone metabolism (bone specific alkaline phosphatase, beta C-terminal telopeptide, and N-terminal propeptide of type 1 collagen) after 52 weeks of sodium bicarbonate therapy or placebo. The results of this novel study have the potential to inform clinical practice by providing the necessary evidence to establish sodium bicarbonate therapy as an inexpensive and easy to administer option for the treatment of arterial dysfunction in patients with CKD stage 3-4.

项目概要/摘要代谢性酸中毒是慢性肾脏病的常见并发症，表现为血清碳酸氢盐水平较低慢性肾病（CKD），因为患病的肾脏无法排泄每日膳食酸负荷。降低血清碳酸氢盐水平，即使在正常的实验室范围内，也与高血压的风险密切相关，心血管疾病 (CVD)、CKD 进展和死亡。动脉功能障碍在病程早期就开始肾脏疾病，是导致左心室肥厚 (LVH) 发展的关键因素人口。 LVH 是 CKD 心血管死亡率的最强预测因子。酸中毒会加剧炎症，诱导内皮素-1（一种有效的血管收缩剂）并增加钙和磷酸盐从骨中的流出，所有这些这是动脉功能障碍和 LVH 的危险因素。小型介入试验表明，治疗即使对于血清碳酸氢盐水平正常的患者，碱疗法也可以减缓肾脏疾病的进展。由于 CVD 和 CKD 进展的危险因素经常重叠，因此碱疗法在生物学上是合理的 CKD 患者的心血管结局也可能得到改善。根据我们的初步数据，碱疗法改善了 16 名 CKD 3-4 期患者的血管内皮功能。因此，采用碱疗法治疗可能代表一种廉价且新颖的 CKD 治疗范例。我们提出一个随机的、对 108 名 CKD 3-4 期患者进行的双盲、安慰剂对照、为期 52 周的试验，以检验以下药物的效果碳酸氢钠疗法作为 CVD 的替代指标。我们的总体假设是，治疗碳酸氢盐将改善 CKD 3-4 期患者的血管功能和 LVH 指标。我们的小学目标是确定碱疗法对于改善血管内皮功能和减少大量血管内皮细胞的疗效。使用无创手术治疗 CKD 3-4 期患者的弹性动脉僵硬度。在目标 1 中，我们将比较 52周后肱动脉血流介导的扩张和主动脉脉搏波速度随时间的变化碳酸氢钠疗法或安慰剂。在目标 2 中，我们将比较 LVMI 随时间的变化，测量方法为无钆心脏磁共振成像，碳酸氢钠治疗 52 周后或安慰剂。在目标 3 中，我们将在一种新颖的钙化测试中比较随时间的变化，该测试提供了血清的总体钙化倾向（T50）和骨代谢标志物（骨特异性碱性 52 周后，磷酸酶、β C 端肽和 1 型胶原蛋白 N 端前肽）碳酸氢钠疗法或安慰剂。这项新颖的研究结果有可能为临床提供信息通过提供必要的证据来证明碳酸氢钠疗法是一种廉价且有效的疗法易于管理的选择，用于治疗 CKD 3-4 期患者的动脉功能障碍。