Deoxycholic Acid and Outcomes across Stages of Chronic Kidney Disease

慢性肾脏疾病(CKD)是一个主要的公共卫生问题，已经达到流行的程度， 仅在美国就有约2000万人(约占总人口的13.1%)受到影响。患心血管疾病的风险 慢性肾脏病患者的疾病显著增加；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，而血管钙化是常见的和公认的危险因素和预测因子 慢性肾脏病患者的心血管疾病事件和全因死亡率。脱氧胆酸(DCA)是 一种次级胆汁酸，通过肠道细菌对初级胆汁酸胆酸的转化而产生。在慢性肾脏病中，胆汁 与其初级胆汁酸前体相比，酸水平升高，DCA的比例增加， 胆酸。数据显示，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。如何循环DCA 而其他丰富的胆汁酸(胆酸、鹅去氧胆酸、石胆酸)水平随着肾脏的变化而变化 功能衰退需要进一步的表征。此外，循环中的DCA和其他胆汁酸(胆酸 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原因死亡尚不清楚。这项流行病学提案的目标是 是评估血浆DCA和其他胆汁酸(胆酸、鹅去氧胆酸、石胆酸)的水平 全谱肾功能和评估循环DCA与其他胆汁酸(胆酸)的相关性 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之间的关系。 我们将使用从强化与标准随机试验参与者那里收集的基线数据 血压控制(Sprint)和同型半胱氨酸降低对死亡率影响的参与者 晚期慢性肾脏病和终末期肾病中的血管疾病(宿主)。同舟共济 这两个独特的队列包括正常估计的肾小球的全谱肾功能。 对终末期肾脏疾病的滤过率以及判定的心血管疾病事件和所有原因 死亡率。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 酸，石胆酸)在Sprint的参与者中，该研究招募了肾功能正常和 轻-中度CKD(平均估计肾小球滤过率47毫升/分钟/1.73平方米)，以及宿主参与者， 入选重度CKD患者(平均估计肾小球滤过率18毫升/分钟/1.73平方米)和 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)水平与判定的心血管疾病事件和 全因死亡。我们假设血浆中DCA和其他胆汁酸(胆酸、 鹅去氧胆酸、胆石酸)在慢性肾脏病患者中很常见，并将与 心血管疾病事件和全因死亡的风险更大。之前的观察表明， 循环中的DCA水平可以通过饮食、运动和胆汁酸阻滞剂来改变。因此，DCA可能是一种 减少血管功能障碍和钙化并改善心血管疾病的干预目标 慢性肾脏病的预后和过早死亡率。

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.