Deoxycholic Acid and Outcomes across Stages of Chronic Kidney Disease

脱氧胆酸和慢性肾病各阶段的结果

• 批准号: 9892282
• 负责人: Anna Jovanovich
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892282
• 关键词: Affect; Bile Acids; Blood Vessels; Cardiovascular Diseases; Cessation of life; Chenodeoxycholic Acid; Cholic Acids; Chronic Kidney Failure; Clinical; Clinical Trials; Cross-Sectional Studies; Data; Deoxycholic Acid; Dialysis procedure; Disease Outcome; End stage renal failure; Endothelial Cells; Enrollment; Epidemic; Epidemiology; Event; Glomerular Filtration Rate; Homocysteine; Individual; Intervention; Intervention Trial; Link; Lithocholic Acid; Measures; Observational Study; Outcome; Participant; Patients; Physiologic pulse; Plasma; Population; Premature Mortality; Prevalence; Public Health; Renal function; Risk Factors; Sampling; Serum; Smooth Muscle Myocytes; Toxic effect; United States; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; Veterans; adjudicate; arterial stiffness; blood pressure intervention; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; cohort; cooperative study; coronary artery calcification; diet and exercise; endoplasmic reticulum stress; endothelial dysfunction; gut bacteria; improved; mortality; novel; randomized trial

Chronic kidney disease (CKD) is a major public health concern that has reached epidemic proportions, affecting ~20 million individuals (~13.1% of the population) in the United States alone. Risk of cardiovascular disease is significantly elevated among patients with CKD; however, this increased cardiovascular risk is only partially explained by traditional risk factors. Vascular dysfunction including arterial stiffening, endothelial dysfunction, and vascular calcification is a common and well-established risk factor and predictor of cardiovascular disease events and all-cause mortality among individuals with CKD. Deoxycholic acid (DCA) is a secondary bile acid derived via gut bacteria transformation of the primary bile acid, cholic acid. In CKD, bile acid levels are elevated and the proportion of DCA is increased compared to its primary bile acid precursor, cholic acid. Data show that DCA is associated with vascular dysfunction, and it is directly toxic to vascular smooth muscle cells inducing vascular calcification through endoplasmic reticulum stress. How circulating DCA and other abundant bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels change as kidney function declines needs further characterization. Moreover, whether circulating DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels are associated with meaningful clinical outcomes such as cardiovascular disease events and all-cause mortality is unknown. The objective of this epidemiologic proposal is to assess plasma DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels across a full spectrum of kidney function and evaluate the association of circulating DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels with cardiovascular disease events and all-cause mortality. We will use baseline data collected from participants in the Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT) and from participants in the Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease (HOST). Together these two unique cohorts include the full spectrum of kidney function from normal estimated glomerular filtration rate to end-stage renal disease as well as adjudicated cardiovascular disease events and all-cause mortality. The first aim is to measure levels of plasma DCA and other bile acids (cholic acid, chenodeoxycholic acid, lithocholic acid) among participants in SPRINT, which enrolled patients with normal kidney function and mild-moderate CKD (mean estimated glomerular filtration rate 47 mL/min/1.73 m2), and participants in HOST, which enrolled patients with severe CKD (mean estimated glomerular filtration rate 18 mL/min/1.73 m2) and end-stage renal disease. The second aim is to evaluate the association of plasma DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels with adjudicated cardiovascular disease events and all-cause mortality. We hypothesize that elevated plasma levels of DCA and other bile acids (cholic acid, chenodeoxycholic acid, lithocholic acid) are common among individuals with CKD and will be associated with greater risk of cardiovascular disease events and all-cause mortality. Previous observations suggest that circulating DCA levels may be modified by diet, exercise, and bile acid sequestrants. Therefore, DCA may be a target for intervention to reduce vascular dysfunction and calcification and improve cardiovascular disease outcomes and premature mortality in CKD.

慢性肾脏病（CKD）是一个重大的公共卫生问题，已达到流行病的程度， 仅在美国就影响了约 2000 万人（约占人口的 13.1%）。心血管风险 CKD 患者的患病率显着升高；然而，这种增加的心血管风险只是 部分原因是传统的风险因素。血管功能障碍，包括动脉硬化、内皮细胞功能障碍 功能障碍，血管钙化是常见且公认的危险因素和预测因子 CKD 患者的心血管疾病事件和全因死亡率。脱氧胆酸 (DCA) 是 通过肠道细菌转化初级胆汁酸胆酸而衍生的次级胆汁酸。在 CKD 中，胆汁 与其主要胆汁酸前体相比，酸水平升高并且 DCA 的比例增加， 胆酸。数据表明，DCA与血管功能障碍有关，对血管有直接毒性。 平滑肌细胞通过内质网应激诱导血管钙化。 DCA如何循环 和其他丰富的胆汁酸（胆酸、鹅去氧胆酸、石胆酸）水平随着肾脏的变化而变化 功能下降需要进一步表征。此外，循环中的 DCA 和其他胆汁酸（胆酸）是否 酸、鹅去氧胆酸、石胆酸）水平与有意义的临床结果相关，例如 心血管疾病事件和全因死亡率尚不清楚。本流行病学提案的目的 旨在评估血浆 DCA 和其他胆汁酸（胆酸、鹅去氧胆酸、石胆酸）水平 全方位的肾功能并评估循环 DCA 和其他胆汁酸（胆酸）的关联 酸、鹅去氧胆酸、石胆酸）水平与心血管疾病事件和全因死亡率的关系。 我们将使用从强化与标准随机试验参与者收集的基线数据 血压控制 (SPRINT) 和来自同型半胱氨酸降低对死亡率影响的参与者 以及晚期慢性肾病和终末期肾病 (HOST) 中的血管疾病。一起 这两个独特的队列包括正常估计肾小球的全谱肾功能 终末期肾病的滤过率以及判定的心血管疾病事件和全因 死亡。第一个目标是测量血浆 DCA 和其他胆汁酸（胆酸、鹅去氧胆酸）的水平 SPRINT 的参与者中加入了酸、石胆酸），该项目招募了肾功能正常的患者， 轻度至中度 CKD（平均估计肾小球滤过率 47 mL/min/1.73 m2），以及 HOST 参与者， 其中纳入了严重 CKD 患者（平均估计肾小球滤过率 18 mL/min/1.73 m2）和 终末期肾病。第二个目的是评估血浆 DCA 和其他胆汁酸的关联 （胆酸、鹅去氧胆酸、石胆酸）水平与判定的心血管疾病事件和 全因死亡率。我们假设 DCA 和其他胆汁酸（胆酸、 鹅去氧胆酸、石胆酸）在 CKD 患者中很常见，并且与 心血管疾病事件和全因死亡率的风险更大。先前的观察表明 饮食、运动和胆汁酸螯合剂可以改变循环 DCA 水平。因此，DCA 可能是 减少血管功能障碍和钙化并改善心血管疾病的干预目标 CKD 的结局和过早死亡率。