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: 10425232
• 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/10425232
• 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 control; blood pressure intervention; 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.

慢性肾脏疾病（CKD）是一个主要的公共卫生问题，已达到流行病的比例， 仅在美国就影响了约2000万人（约占人口的13.1%）。心血管 CKD患者的心血管疾病风险显著升高;然而， 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 血管钙化是一种常见的和公认的危险因素， 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）而衍生的二级胆汁酸。在CKD中，胆汁 酸水平升高并且DCA的比例与其主要胆汁酸前体相比增加， 胆酸。有资料表明，DCA与血管功能障碍有关，对血管有直接毒性作用， 平滑肌细胞通过内质网应激诱导血管钙化。如何循环DCA 和其他丰富的胆汁酸（胆酸，鹅去氧胆酸，石胆酸）水平的变化， 功能下降需要进一步表征。此外，无论循环DCA和其他胆汁酸（胆酸） 胆酸、鹅去氧胆酸、石胆酸）水平与有意义的临床结果相关， 心血管疾病事件和全因死亡率未知。这项流行病学提案的目的 是评估血浆DCA和其他胆汁酸（胆酸、鹅去氧胆酸、石胆酸）水平， 肾功能的全谱，并评估循环DCA和其他胆汁酸（胆酸）的相关性 胆酸、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的参与者中收集的基线数据， 血压控制（SPRINT）和参与者的同型半胱氨酸降低对死亡率的影响 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来自正常估计肾小球的全谱肾功能。 终末期肾病的滤过率以及裁定的心血管疾病事件和全因 mortality.第一个目的是测量血浆DCA和其他胆汁酸（胆酸、鹅去氧胆酸、胆汁酸）的水平。 酸，石胆酸），该研究招募了肾功能正常的患者， 轻度-中度CKD（平均估计肾小球滤过率47 mL/min/1.73 m2），以及HOST中的受试者， 该研究招募了重度CKD患者（平均估计肾小球滤过率18 mL/min/1.73 m2）， 终末期肾病第二个目的是评估血浆DCA和其他胆汁酸的相关性 （胆酸、鹅去氧胆酸、石胆酸）水平与裁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， 心血管疾病事件和全因死亡率的风险更高。先前的观察表明， 循环DCA水平可以通过饮食、锻炼和胆汁酸螯合剂来改变。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干预靶点 CKD的预后和过早死亡率。