Environmental & Genetic Risk Factors for Renal Function

环境的

• 批准号: 6617068
• 负责人: VIRGINIA M WEAVER
• 金额: $ 46.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617068
• 关键词: Asians; bone imaging /visualization /scanning; cadmium; chronic renal failure; clinical research; environmental exposure; environmental toxicology; epidemiology; gene environment interaction; genetic polymorphism; human subject; hypertension; lead; lead poisoning; longitudinal human study; metal poisoning; occupational health /safety; renal toxin; urinalysis

DESCRIPTION (provided by applicant): End stage renal disease (ESRD) is associated with substantial morbidity and mortality. Strategies to prevent the renal function decline that can ultimately result in ESRD are essential. The impact of environmental exposures has received relatively little attention in this regard, despite the fact that exposures such as cadmium and lead are known renal toxicants that are stored long-term in the body and ubiquitous in humans. In fact, the lead and cadmium dose-effect curves for renal function remain uncertain for the low to moderate range of doses. The proposed study will investigate a broad set of causes of renal function decline, including lead, cadmium, blood pressure, diabetes, nephrotoxic medication use, genetic polymorphisms, and age. This application is a competing renewal application of the study "Exposure, dose, body burden, and health effects of lead" (Schwartz BS, PI) conducted from 1997-2001. It will build on data, from the large cohort of current and former lead workers and participants without occupational lead exposure in the originally funded grant. Study subjects have a wide range of lead exposure and dose measures and renal outcome data from three visits each over an average of 2.2 years. Analysis of existing data has already provided very important results, including longitudinal decline in renal function associated with lead dose measures; interaction between age and lead dose on renal function and renal function decline; interaction between ALAD genotype and lead dose on renal function; and associations of environmental level cadmium dose with elevated NAG in a subset of lead workers. However, in order to better understand the causes of renal function decline, cadmium dose must be characterized in all subjects, additional genotypes must be measured, and additional follow-up time is needed because of the slow rate of renal function decline. We propose to include 675 participants from the first study and enroll 225 new current or former lead workers over age 45 years, those at greater risk for renal function decline. We will obtain blood and tibia lead, genotyping, urinary cadmium, BUN, serum creatinine, measured and calculated creatinine clearances, NAG and RBP during 3 evaluations at yearly intervals. The specific aims are to determine: 1) if lead and cadmium dose are or continue to be associated with renal function at cross-section and longitudinally; 2) if there is effect modification by lead or cadmium dose, respectively, on associations between cadmium or lead dose and renal function decline; 3) if hypertension modifies the relations of lead or cadmium dose with renal function decline; and 4) whether polymorphisms in the genes for ALAD, VDR, ACE, and eNOS modify or continue to modify relations of lead and/or cadmium dose with renal outcomes. We believe the proposed work will allow a more complete understanding of the causes of renal function decline and lead to the development of public health interventions to prevent this considerable public health problem.

描述(由申请人提供)：终末期肾病(ESRD)与相当大的发病率和死亡率有关。预防最终导致终末期肾病的肾功能下降的策略是至关重要的。在这方面，环境暴露的影响相对较少受到关注，尽管镉和铅等暴露是已知的肾脏毒物，它们长期储存在人体内，在人类中无处不在。事实上，铅和镉对肾功能的剂量-效应曲线在低到中等剂量范围内仍然不确定。这项拟议的研究将调查导致肾功能下降的一系列广泛原因，包括铅、镉、血压、糖尿病、肾毒性药物使用、基因多态和年龄。这项申请是1997年至2001年进行的研究“铅的暴露、剂量、身体负担和健康影响”(施瓦茨BS，PI)的竞争性续展申请。它将建立在最初资助的赠款中没有职业性铅暴露的现任和前任铅工人和参与者的大量队列数据的基础上。研究对象有广泛的铅暴露和剂量测量以及平均2.2年的三次就诊的肾脏结果数据。对现有数据的分析已经提供了非常重要的结果，包括与铅剂量测量相关的肾功能纵向下降；年龄和铅剂量对肾功能和肾功能下降的交互作用；ALAD基因和铅剂量对肾功能的交互作用；以及环境水平镉剂量与部分铅作业工人NAG升高的关联。 然而，为了更好地了解肾功能下降的原因，必须确定所有受试者的镉剂量，必须测量额外的基因型别，而且由于肾功能下降的速度较慢，还需要额外的随访时间。我们建议纳入第一项研究中的675名参与者，并招募225名45岁以上的现任或前任首席工作人员，这些人肾功能下降的风险更大。每隔一年进行3次评估，分别测定血铅、胫骨铅、基因分型、尿镉、尿素氮、血肌酐、肌酐清除量、NAG和RBP。其具体目的是确定：1)铅和镉剂量是否在横断面和纵向上与肾功能有关；2)铅或镉剂量是否分别对镉或铅剂量与肾功能下降之间的关系产生影响；3)高血压是否改变了铅或镉剂量与肾功能下降的关系；以及4)ALAD、VDR、ACE和eNOS基因的多态性是否改变或继续改变铅和/或镉剂量与肾脏预后的关系。我们相信，拟议的工作将使人们能够更全面地了解肾功能下降的原因，并导致制定公共卫生干预措施，以预防这一相当大的公共卫生问题。