Cardiovascular effects of oral bicarbonate in CKD

口服碳酸氢盐对 CKD 的心血管作用

• 批准号: 10464574
• 负责人: Michal L Melamed
• 金额: $ 55.19万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464574
• 关键词: Acidosis; Acids; Adverse effects; Affect; Aldosterone; Alkalies; American; Angiotensin II; Animal Model; Antihypertensive Agents; Atrial Natriuretic Factor; Bicarbonates; Biological Markers; Blood; Blood Plasma Volume; Blood Pressure; Body Weight; Brain natriuretic peptide; Cardiovascular Diseases; Cardiovascular system; Catabolism; Characteristics; Chronic Kidney Failure; Clinical; Clinical Trials; Data; Development; Diuresis; Diuretics; Double-Blind Method; End stage renal failure; Equation; Excretory function; Fluid Balance; Funding; Goals; Hormones; Human; Hypertension; Impairment; Individual; Kidney; Knowledge; Lead; Learning; Liquid substance; Measurement; Mediating; Meta-Analysis; Metabolic acidosis; Modeling; Morbidity - disease rate; Muscle; N-terminal; Natriuresis; Natriuretic Peptides; Oral; Participant; Patients; Persons; Physiological; Placebo Control; Placebos; Population; Public Health; Randomized; Rattus; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Research Personnel; Safety; Sampling; Serum; Sodium; Sodium Bicarbonate; Specimen; Testing; Time; Tumor necrosis factor receptor 11b; Vascular calcification; alpha-Fetoproteins; alternative treatment; base; blood pressure elevation; bone; bone morphogenic protein; calcification; cardiovascular effects; cardiovascular risk factor; demineralization; fibroblast growth factor 23; global health; high risk; improved; indexing; inhibitor; innovation; kidney preservation; mortality; novel; particle; phase III trial; pilot trial; prevent; primary outcome; promoter; translational impact; treatment group; treatment response

Chronic kidney disease (CKD) is a major global health problem associated with high risk of morbidity and mortality. Due to impaired kidney acid excretion, up to 35% of patients with CKD develop metabolic acidosis. Such individuals are often treated with sodium bicarbonate to prevent acidosis-induced bone demineralization and muscle catabolism and preserve kidney function. However, sodium bicarbonate may also cause cardiovascular harm in two main ways. One is by causing sodium and fluid retention leading to increased blood pressure. While individual trials have not shown a substantial increase in body weight or blood pressure, a meta-analysis found that sodium bicarbonate treatment was associated with higher risks of escalating antihypertensive or diuretic therapy. High blood pressure and elevated markers of volume overload, including N-terminal pro-brain natriuretic peptide (NT-proBNP), are associated with an increased risk of cardiovascular mortality. Yet, it is unclear what effect, if any, sodium bicarbonate has on hormones that regulate sodium levels and plasma volume. A major goal of this project is to determine the effect of sodium bicarbonate treatment on levels of natriuretic peptides (NT-proBNP and atrial natriuretic peptide) and components of the renin- angiotensin-aldosterone system (renin, angiotensin II, and aldosterone) in individuals with CKD. Another major cardiovascular concern is that sodium bicarbonate may promote vascular calcification. This has been observed in animal models but has been incompletely investigated in humans. A second major goal of this project is to determine the effect of sodium bicarbonate on blood levels of inhibitors, promoters and other indices of vascular calcification (fetuin A, fibroblast growth factor-23, osteoprotegerin, bone morphogenic protein-2, calciprotein particle 2 size, and the propensity of serum to calcify [T50]) in individuals with CKD. These goals will be achieved by combining data and performing measurements using stored samples obtained from 395 participants in three randomized, double-blind, placebo-controlled, sodium bicarbonate studies conducted in the US. Measurements will be performed at baseline, 3- and 6-months. Change from baseline between the placebo and sodium bicarbonate treatment groups will be determined and mediating effects of these changes in response to treatment will be investigated using longtitudinal structural equation modeling. Although sodium bicarbonate may slow the progression of CKD, there is concern about the long-term cardiovascular safety of sodium bicarbonate. This proposal will investigate mechanisms involved with two main cardiovascular concerns, fluid retention and vascular calcification, and potentially identify individuals who may be prone to these adverse effects. These issues are large and clinically important knowledge gaps in the field. The results will have a high impact on the field and will inform clinicians and investigators about the potential for cardiovascular harm with sodium bicarbonate treatment.

慢性肾脏疾病（CKD）是与高发病风险和高风险有关的主要全球健康问题 死亡。由于肾酸排泄受损，多达35％的CKD患者会出现代谢性酸中毒。 这些个体通常用碳酸氢钠处理以防止酸中毒引起的骨骼脱矿。 和肌肉分解代谢并保留肾脏功能。但是，碳酸氢钠也可能导致 心血管造成两种主要方式。一种是导致钠和液体保留，导致血液增加 压力。虽然单个试验尚未显示体重或血压的大幅增加，但 荟萃分析发现，碳酸氢钠处理与升级的风险更高有关 降压或利尿治疗。高血压和体积超负荷标记的升高，包括 N末端的脑力尿尿素肽（NT-Probnp）与心血管风险增加有关 死亡。但是，尚不清楚碳酸氢钠对调节钠水平的激素有什么影响（如果有） 和等离子体体积。该项目的主要目标是确定碳酸氢钠处理对 亚钠肽的水平（NT-促肽和心房脂肪肽）和肾素的成分 CKD个体中的血管紧张素 - 醛固酮系统（肾素，血管紧张素II和醛固酮）。另一个专业 心血管问题是碳酸氢钠可能促进血管钙化。已经观察到 在动物模型中，但在人类中未完全研究。该项目的第二个主要目标是 确定碳酸氢钠对抑制剂，启动子和其他指数的血液水平的影响 血管钙化（Fetuin A，成纤维细胞生长因子23，骨蛋白蛋白蛋白蛋白，骨形态发生蛋白2， 钙蛋白颗粒2大小，以及CKD个体中血清钙化[T50]的倾向。这些目标 将通过使用从395获得的存储样本组合数据和进行测量来实现 参与三个随机，双盲，安慰剂对照的碳酸氢钠研究的参与者 美国。测量将在基线，3个月和6个月进行。从基线变化 将确定安慰剂和碳酸氢钠治疗组，并介导这些变化的效果 应对治疗的响应，将使用长传动结构方程建模进行研究。虽然钠 碳酸氢盐可能会减慢CKD的进展，担心长期心血管安全 碳酸氢钠。该建议将调查与两个主要心血管有关的机制 关注，流体保留和血管钙化，并有可能识别可能容易容易出现的个体 这些不利影响。这些问题是该领域的较大且在临床上重要的知识差距。结果 将对该领域产生很大的影响，并将告知临床医生和调查人员 碳酸氢钠治疗的心血管伤害。