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.

慢性肾病（CKD）是一个主要的全球健康问题，与高发病风险和 死亡。由于肾脏酸排泄受损，高达 35% 的 CKD 患者会出现代谢性酸中毒。 这些人经常接受碳酸氢钠治疗，以防止酸中毒引起的骨脱矿 和肌肉分解代谢并保护肾功能。然而，碳酸氢钠也可能导致 心血管危害主要有两个方面。一种是通过引起钠和液体潴留导致血液增加 压力。虽然个别试验并未显示体重或血压显着增加，但 荟萃分析发现，碳酸氢钠治疗与病情升级的较高风险相关。 抗高血压或利尿治疗。高血压和容量超负荷标志物升高，包括 N 末端脑钠肽前体 (NT-proBNP) 与心血管疾病风险增加相关 死亡。然而，尚不清楚碳酸氢钠对调节钠水平的激素有何影响（如果有的话） 和血浆量。该项目的一个主要目标是确定碳酸氢钠处理对 钠尿肽（NT-proBNP 和心房钠尿肽）和肾素成分的水平 CKD 患者的血管紧张素-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。这已被观察到 在动物模型中存在，但在人类中的研究尚未完全。该项目的第二个主要目标是 确定碳酸氢钠对抑制剂、促进剂和其他指标的血液水平的影响 血管钙化（胎球蛋白 A、成纤维细胞生长因子-23、骨保护素、骨形态发生蛋白-2、 CKD 患者的钙蛋白颗粒 2 大小以及血清钙化倾向 [T50]）。这些目标 第395章 被人欺负了 参加三项随机、双盲、安慰剂对照、碳酸氢钠研究的参与者 美国。测量将在基线、3 个月和 6 个月时进行。与基线之间的变化 将确定安慰剂和碳酸氢钠治疗组以及这些变化的中介作用 将使用纵向结构方程模型研究对治疗的反应。虽然钠 碳酸氢盐可能会减缓 CKD 的进展，但人们担心其长期心血管安全性 碳酸氢钠。该提案将研究涉及两种主要心血管疾病的机制 问题、液体潴留和血管钙化，并可能识别出可能容易出现这种情况的个体 这些不良影响。这些问题是该领域巨大且具有临床意义的知识缺口。结果 将对该领域产生重大影响，并将告知临床医生和研究人员有关潜在的 碳酸氢钠治疗对心血管的危害。