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: 10657387
• 负责人: Alkesh Harihar Jani
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657387
• 关键词: Affect; Aorta; 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; Diet; Disease Outcome; End stage renal failure; Endothelial Cells; Enrollment; Epidemic; Epidemiology; Event; Exercise; Glomerular Filtration Rate; Homocysteine; Individual; Intervention; Intervention Trial; Kidney Diseases; Link; Lithocholic Acid; Measures; Observational Study; Outcome; Participant; Patients; Physiologic pulse; Plasma; Population; Premature Mortality; Prevalence; Public Health; Renal function; Risk Factors; Risk Marker; Sampling; Serum; Smooth Muscle Myocytes; Toxic effect; United States; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; Veterans; adjudication; arterial stiffness; blood pressure control; blood pressure intervention; cardiovascular disorder risk; cardiovascular risk factor; cohort; cooperative study; coronary artery calcification; endoplasmic reticulum stress; endothelial dysfunction; gut bacteria; improved; mortality; novel; participant enrollment; 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，已经达到了流行病， 仅在美国，就会影响约2000万个人（约占人口的13.1％）。心血管风险 CKD患者的疾病显着升高；但是，这种增加的心血管风险只是 部分用传统的风险因素解释。血管功能障碍，包括动脉僵硬，内皮 功能障碍和血管钙化是一个常见且建立良好的危险因素，也是预测因素 CKD患者的心血管疾病事件和全因死亡率。脱氧胆酸（DCA）是 通过肠道细菌转化的胆汁酸，胆汁酸的次生胆汁酸。在CKD，胆汁 与其主要的胆汁酸前体相比，酸水平升高，DCA的比例增加了 胆酸。数据表明，DCA与血管功能障碍有关，并且对血管直接有毒 平滑肌细胞通过内质网应激诱导血管钙化。如何流通DCA 随着肾脏 功能下降需要进一步的表征。此外，循环DCA和其他胆汁酸是否 酸，氯氧基胆酸，岩性酸）水平与有意义的临床结局有关 心血管疾病事件和全因死亡率尚不清楚。这个流行病学建议的目的 是评估血浆DCA和其他胆汁酸（胆酸，氯氧基胆酸，岩性酸）水平 全频谱肾功能并评估循环DCA和其他胆汁酸的关联（chololic 具有心血管疾病事件和全因死亡率的酸，氯氧化胆酸，岩性酸水平）。 我们将使用从参与者中收集的基线数据，以进行密集与标准的随机试验 血压控制（SPRINT）和参与者对同半胱氨酸降低对死亡率的影响 晚期慢性肾脏疾病和终末期肾病（宿主）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部肾功能 终末期肾脏疾病的过滤率以及裁决的心血管疾病事件和全因事件 死亡。第一个目的是测量血浆DCA和其他胆汁酸的水平（胆酸，chenexycholic Sprint参与者中的酸性，岩性酸） 轻度中度CKD（平均估计的肾小球过滤率47 mL/min/1.73 m2），宿主的参与者， 招募严重CKD的患者（平均估计的肾小球过滤率18 mL/min/1.73 m2）和 末期肾脏疾病。第二个目的是评估血浆DCA和其他胆汁酸的关联 （胆酸，氯氧化胆酸，岩性酸）水平，具有裁决的心血管疾病事件和 全因死亡率。我们假设血浆DCA和其他胆汁酸的血浆水平升高（胆酸， Chendoxyoxycholic，岩性酸）在CKD的个体中很常见，将与 心血管疾病事件和全因死亡率的更大风险。以前的观察表明 循环DCA水平可以通过饮食，运动和胆汁酸螯合剂来改变。因此，DCA可能是 干预措施以减少血管功能障碍和钙化并改善心血管疾病的目标 CKD的结果和过早死亡率。