Mechanisms for Adverse Renal Effects from Lead Exposure

铅暴露对肾脏造成不良影响的机制

• 批准号: 7090483
• 负责人: VIRGINIA M WEAVER
• 金额: $ 39.94万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090483
• 关键词: Mechanisms; Adverse; Renal; Effects; Lead

DESCRIPTION (provided by applicant): Prevention strategies for end stage renal disease are essential, however, environmental nephrotoxicants are seldom considered. We are investigating a broad set of causes of renal function decline, including lead and cadmium dose, blood pressure, diabetes, and age, in a longitudinal study of current and former Korean lead workers and controls. This cohort had three annual evaluations from 1997-2001 and is currently undergoing the fourth evaluation (first of three in the current competing continuation grant (NIEHS 2 R01 ES07198)). We are enrolling 610 participants from the original grant and 200 new current or former lead workers over age 40 years to enrich our population with workers at greater risk for renal function decline. Study subjects have a wide range of lead dose measures and renal outcome data. Analysis to date has identified two potential mechanisms for the adverse renal effects of lead: 1) associations between higher lead levels and worse renal function in older lead workers may be mediated by uric acid; and 2) inverse associations (higher lead dose with higher creatinine clearances) suggest hyperfiltration may be a factor in younger lead workers and those with the ALAD variant allele. Recent research indicates that the adverse impact of lead on renal function may be reduced with chelation, even at lead body burdens previously considered normal. Information on mechanisms for lead-related nephrotoxicity would be extremely useful in targeting therapy. Thus, the specific aims of this supplement are to determine if: 1) lead dose is associated with uric acid measures longitudinally in all participants; 2) uric acid, measures are associated with renal function longitudinally, and, if so, whether associations between lead dose and renal function are altered by adjustment for uric acid, and; 3) lead dose is associated with 6 hemodynamic biomarkers (urinary prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, thromboxane B2, and total nitrites/nitrates and plasma renin level), and whether these biomarkers are associated with adverse renal outcomes, at cross-section, in a subset of 200 participants. The proposed work will inform research on specific treatments for high-risk populations, such as those with chronic renal insufficiency who also have increased lead body burdens.

描述(由申请人提供)：终末期肾病的预防策略是必不可少的，但很少考虑环境中的肾病毒物。我们正在对现任和前任韩国铅工人和对照组进行纵向研究，调查导致肾功能下降的一系列广泛原因，包括铅和镉剂量、血压、糖尿病和年龄。这一群体在1997-2001年期间进行了三次年度评估，目前正在进行第四次评估(目前竞争的延续赠款(NIEHS 2 R01 ES07198)中的三次评估中的第一次)。我们从最初的赠款中招募了610名参与者，并招募了200名年龄在40岁以上的现任或前任领队工人，以使我们的人口中有更多有肾功能下降风险的工人。研究对象有广泛的铅剂量测量和肾脏结果数据。到目前为止，分析已经确定了铅对肾脏的不利影响的两个潜在机制：1)在老年铅工人中，较高的铅水平与较差的肾功能之间的关联可能是由尿酸介导的；以及2)相反的关联(较高的铅剂量与较高的肌酐清除率)表明，高滤过可能是较年轻的铅工人和携带ALAD变异等位基因的人的一个因素。最近的研究表明，即使在以前被认为是正常的铅负荷下，通过螯合也可以减轻铅对肾功能的不利影响。有关铅相关肾毒性机制的信息将在靶向治疗中非常有用。因此，本附录的具体目的是确定：1)铅剂量与所有参与者的尿酸水平纵向相关；2)尿酸水平与肾功能纵向相关，如果是，在200名参与者中，铅剂量与肾功能之间的关系是否会通过尿酸调整而改变；3)铅剂量与6个血流动力学生物标志物(尿前列腺素E2、前列腺素F2α、6-酮-前列腺素F1α、血栓素B2、总亚硝酸盐/硝酸盐和血浆肾素水平)有关，以及这些生物标志物是否与横断面的肾功能不良结局有关。这项拟议的工作将为针对高危人群的特定治疗研究提供信息，例如那些患有慢性肾功能不全的人，他们也增加了铅体负担。