Bicarbonate Administration in CKD

CKD 中碳酸氢盐的管理

• 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
• 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

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.

项目摘要/摘要 由较低的血清碳酸氢盐水平反射的代谢性酸中毒是慢性肾脏的常见并发症 疾病（CKD）由于患病的肾脏无法排泄每日饮食酸负荷。低血清 甚至在正常实验室范围内，碳酸氢盐水平也与高血压风险密切相关， 心血管疾病（CVD），CKD进展和死亡。动脉功能障碍在早期开始 肾脏疾病是负责左心室肥大（LVH）发展的关键因素 人口。 LVH是CKD中心血管死亡率的最强预测指标。酸中毒会增加炎症， 诱导内皮素-1（一种有效的血管收缩剂），并增加骨骼的钙和磷酸外排出 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 随着碱性疗法的发展，即使在血清碳酸氢盐正常的患者中，肾脏疾病的进展也会减慢。 因为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 在CKD中，患者也可能导致心血管结局改善。在我们的初步数据中，碱疗法 16例CKD阶段3-4患者的血管内皮功能改善了。因此，使用碱疗法治疗 可能代表CKD中廉价且新颖的治疗范式。我们正在提出一个随机的， 108例CKD阶段3-4患者的双盲，安慰剂对照，52周试验，以检查 碳酸氢钠治疗CVD的替代措施。我们的总体假设是与 碳酸氢盐将改善CKD阶段3-4患者血管功能和LVH的指标。我们的主要 目标是确定碱疗法改善血管内皮功能的功效并降低大量 使用非侵入性手术，CKD 3-4阶段患者的弹性动脉刚度。在AIM 1中，我们将比较 在52周后，臂动脉流介导的扩张和主动脉脉冲波速度随着时间的变化 碳酸氢钠治疗或安慰剂。在AIM 2中，我们将比较LVMI随时间的变化，以 52周碳酸氢钠治疗或 安慰剂。在AIM 3中，我们将在新的钙化测试中比较随着时间的推移的变化，该测试提供了一定的量度 血清（T50）和骨代谢标记的总钙化倾向（骨特异性碱性 52周后 碳酸氢钠治疗或安慰剂。这项新研究的结果有可能告知临床 通过提供必要的证据来建立碳酸氢钠疗法作为便宜的和 CKD阶段3-4患者的动脉功能障碍的治疗方案易于治疗。