Longitudinal Study of Predictors and Consequences of Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）在美国影响约1900万成年人，并与心血管疾病（CVD）和死亡率的风险升高相关。临床实践指南根据蛋白尿和肾功能下降来定义CKD，最常见的评估方法是使用血清肌酐（SCr）估算肾小球滤过率（eGFR）。国家组织已经提出将CKD纳入CVD风险分层算法，但迄今为止还没有大型前瞻性研究将蛋白尿和估计GFR数据结合起来检查CVD发生率。最近对老年人的研究表明，胱抑素C （Cystatin C, CysC）可以提供对肾功能的估计，比基于SCr的估计更能预测随后的GVD事件，SCr容易因肌肉损失而产生偏差。尽管对CKD的前瞻性研究有限，但CKD与CVD有一些共同的危险因素和致病机制。社区动脉粥样硬化风险（ARIC）研究自1987年以来跟踪了15,792名非裔美国人和白人，并提供了CKD风险因素和后果的重要数据。我们建议收集新的数据并进行系统分析，以达到以下目的：1)调查1996-1998年11,336名成年人中流行的CKD作为心血管疾病和死亡的独立危险因素的最新评估。普遍的CKD定义为肾功能下降（现有SCr和建议的CysC测量）和肾脏损害（蛋白尿）的组合。2)在巢式病例队列设计中测试6年内肾功能下降的新预测因子，其中包括-800例基于CysC估计GFR<60 ml/min/1.73m2的病例。我们将重点关注炎症和晚期糖基化终产物（AGEs）的标志物，以及3)识别预测CKD事件的染色体区域和遗传变异。通过扩展正在进行的基因分型，我们将进行：(A)通过非裔美国人的混合连锁不平衡（MALD）扫描进行全基因组定位；(B) - 2000个基因的候选基因研究。阳性结果将在其他确定的队列（杰克逊心脏研究、弗雷明汉心脏研究和心血管心脏研究）中进行重复性测试。该建议直接解决了与当前政策问题相关的几个问题，包括如何最好地量化CKD并将其纳入心血管疾病风险预测算法。此外，它将提供急需的数据，与更大的科学界分享CKD的血清学和遗传风险因素，这是美国日益增长的公共卫生问题。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects an estimated 19 million adults in the US, and is associated with an elevated risk of cardiovascular disease (CVD) and mortality. Clinical practice guidelines define CKD on the basis of both albuminuria and decreased kidney function, most frequently assessed by estimating the glomerular filtration rate (eGFR) using serum creatinine (SCr). National organizations have proposed including CKD in CVD risk stratification algorithms, but no large prospective studies to date have combined data on albuminuria and estimated GFR to examine CVD incidence. Recent studies in the elderly suggest Cystatin C (CysC) can provide estimates of kidney function that are more predictive of subsequent GVD events than estimates based on SCr, which are susceptible to biases due to muscle loss. CKD shares several risk factors and pathogenic mechanisms with CVD though the prospective studies of CKD have been limited. The Atherosclerosis Risk in Communities (ARIC) Study has followed 15,792 African Americans and Whites since 1987, and provided important data on CKD risk factors and consequences. We propose to collect new data and conduct systematic analyses to achieve the following aims: 1) Investigate a state of the art assessment of prevalent CKD as an independent risk factor for cardiovascular disease and mortality among 11,336 adults examined in 1996-1998. Prevalent CKD is defined by a combination of decreased kidney function (existing SCr and proposed CysC measures) and kidney damage (albuminuria). 2) Test novel predictors of declining kidney function over 6 years in a nested case-cohort design including -800 cases with estimated GFR<60 ml/min/1.73m2 based on CysC. We will focusing on markers of inflammation and advanced glycation end-products (AGEs), and 3) Identify chromosomal regions and genetic variants predictive of incident CKD. By extending ongoing genotyping we will conduct: (A) genome wide Mapping by Admixture Linkage Disequilibrium (MALD) scan in African-Americans and (B) Candidate gene study of -2,000 genes. Positive results will be tested for replication in additional identified cohorts (Jackson Heart Study, Framingham Heart Study and the Cardiovascular Heart Study). This proposal directly addresses several questions relevant to current policy issues, including how best to quantify CKD and incorporate it into CVD risk prediction algorithms. In addition, it will provide much-needed data to be shared with the larger scientific community on serologic and genetic risk factors for CKD, a growing public health concern in the US.