Cardiovascular effects of oral bicarbonate in CKD

慢性肾脏疾病（CKD）是一个主要的全球健康问题，与高发病风险相关， mortality.由于肾脏酸排泄受损，高达35%的CKD患者发生代谢性酸中毒。 这类个体通常用碳酸氢钠治疗以防止酸中毒引起的骨脱矿 和肌肉痉挛并保护肾功能。然而，碳酸氢钠也可能导致 心血管疾病的危害主要有两种。一种是通过引起钠和液体潴留导致血液增加 压力虽然个别试验没有显示体重或血压的实质性增加， 荟萃分析发现，碳酸氢钠治疗与升高的风险相关， 抗高血压或利尿剂治疗。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。 mortality.然而，目前还不清楚碳酸氢钠对调节钠水平的激素有什么影响，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 利钠肽（NT-proBNP和心房利钠肽）和肾素-血管紧张素Ⅱ（RAS）组分的水平。 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）。另一个主要 心血管问题是碳酸氢钠可能会促进血管钙化。这个表情也会 在动物模型中，但在人类中尚未完全研究。该项目的第二个主要目标是 测定碳酸氢钠对血液中抑制剂、促进剂和其他指标的影响， 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， 钙蛋白颗粒2大小和血清钙化倾向[T50]）。这些目标 将通过组合数据并使用从395个样本中获得的存储样本进行测量来实现 参与了三项随机、双盲、安慰剂对照、碳酸氢钠研究， 美方将在基线、3个月和6个月时进行测量。与基线相比 将确定安慰剂和碳酸氢钠治疗组以及这些变化的介导效应 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，但人们担心碳酸氢盐的长期心血管安全性。 碳酸氢钠这项建议将调查机制涉及两个主要的心血管疾病 关注，液体潴留和血管钙化，并可能识别可能倾向于 这些不利影响。这些问题是该领域中巨大且临床上重要的知识差距。结果 将对该领域产生很大影响，并将告知临床医生和研究人员关于 碳酸氢钠治疗的心血管危害。

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.