Chronic kidney disease of unknown etiology: applying a multidisciplinary approach to investigate the world's most common tubulointerstitial kidney disease

病因不明的慢性肾病：应用多学科方法研究世界上最常见的肾小管间质性肾病

• 批准号: 10561691
• 负责人: Shuchi Anand
• 金额: $ 54.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-28 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561691
• 关键词: Accounting; Address; Adult; Affect; Agricultural Workers; Agriculture; Agrochemicals; Archives; Area; Autoimmune Diseases; Balkan Nephropathy; Biological; Biopsy; Blood; California; Canes; Categories; Cessation of life; Chlorinated Hydrocarbons; Chronic Kidney Failure; Cicatrix; Classification; Climate; Clinical; Communicable Diseases; Consumption; Costa Rica; Coupled; Data; Diazinon; Dichlorodiphenyl Dichloroethylene; Disease; El Salvador; End stage renal failure; Endosulfan; Environmental Risk Factor; Epidemic; Epidemiology; Etiology; Experimental Models; Family member; Farm; Fresh Water; Future; Gene Expression; Gene Expression Profile; Guatemala; Guidelines; Heat Stress Disorders; Histology; Household; Hypersensitivity; India; Individual; Industry; Injury; International; Investigation; Kidney; Kidney Diseases; Link; Mass Spectrum Analysis; Measures; Molecular; Molecular Analysis; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Environmental Health Sciences; Nephrons; Nicaragua; Organophosphates; Participant; Pathologist; Pathway interactions; Patients; Pattern; Persons; Population; Prospective cohort; Protocols documentation; Reaction; Recommendation; Recording of previous events; Regulation; Relative Risks; Renal function; Reporting; Rice; Risk; Running; Sampling; Severities; Site; Specific qualifier value; Specimen; Sri Lanka; Testing; Texas; Toxic Environmental Substances; Transplantation; Tubular formation; Urine; Vulnerable Populations; Water Supply; Water consumption; Work; acute infection; agricultural community; biobank; cohort; drinking; drinking water; epidemiology study; farmer; field study; improved; interdisciplinary approach; interest; kidney biopsy; meetings; multidisciplinary; nephrotoxicity; premature; prevent; prospective; recruit; response; response to injury; risk prediction; scaffold; single-cell RNA sequencing; sugar; tool; transcriptome sequencing; transcriptomic profiling; water sampling; well water

PROJECT SUMMARY/ABSTRACT Over the last twenty years, an increasing number of agricultural communities have faced an apparently new, unexplained, and fatal kidney disease, known as chronic kidney disease of unknown etiology (CKDu). First noted in sugar cane workers in El Salvador and rice farmers in Sri Lanka, reports of a similar kidney disease have emerged come from Nicaragua, Costa Rica, Guatemala, India, and (most recently) the U.S. Despite the scale and severity of this kidney disease epidemic, the epidemiological and mechanistic investigations needed to address it have been extremely limited. Because persons with the disease are otherwise healthy agricultural workers, many experts and the affected population suspect agrochemical exposure is responsible. In two key preliminary studies from Sri Lanka, we find that agricultural workers are drinking from shallow water wells that are contaminated by organophosphate and organochlorine agrochemicals above EPA drinking water regulations, and well water consumption raises likelihood of biopsy-proven CKDu and faster progression of established kidney disease. In a cohort of 600 at-risk participants identified by our preliminary work in whom we will obtain baseline environmental samples including water samples and kidney biopsies if they meet a validated clinical definition of CKDu, we propose to examine the hypothesis that specific agrochemicals contaminating well water are causing CKDu. We will: 1) run untargeted and targeted mass spectrometry analysis of well water, 2) determine the association of individual agrochemicals and their mixtures with incident CKDu case status, accounting for work intensity and heat stress, 3) measure the bioburden of nephrotoxic agrochemicals in cases versus controls, and 4) perform molecular analyses of early-stage kidney biopsies to specify the injury response pattern at a cellular level with bulk and single-cell RNA sequencing. In alignment with NIDDK-NIEHS-Fogarty recommended approach to CKDu investigations, this proposal integrates a multi- disciplinary, multi-national team of nephrologists, pathologists, molecular biologists and environmental geochemists. Based on our preliminary data we focus on agrochemical exposure via well water as the environmental risk factor of interest in this proposal, however field work will be coupled with an extensive biobanking effort to facilitate testing of multiple candidate hypotheses. The complementary molecular analyses will precisely characterize the injury in CKDu in the context of other primary tubulointerstitial kidney diseases, and create a rigorous scaffold for testing potential agents that can trigger CKDu-specific responses in the kidney. As in the case of prior regional kidney disease epidemics such as Balkan nephropathy, the intensive effort to identify cause in our outlined aims has the potential to pinpoint other vulnerable populations and regions, and more importantly, to abrogate the kidney disease by eliminating the exposure.

项目总结/摘要 在过去的二十年里，越来越多的农业社区面临着一个显然是新的， 原因不明的致命性肾病，称为病因不明的慢性肾病（CKDu）。第一 据报道，萨尔瓦多的甘蔗工人和斯里兰卡的稻农也出现了类似的肾脏疾病 来自尼加拉瓜、哥斯达黎加、危地马拉、印度和（最近的）美国。 这种肾病流行病的规模和严重程度，需要进行流行病学和机制研究 解决这个问题的能力非常有限。因为患有这种疾病的人在其他方面都是健康的 工人、许多专家和受影响的人口怀疑是接触农用化学品造成的。在两个关键 在斯里兰卡的初步研究中，我们发现农业工人从浅水威尔斯井中饮水， 被EPA饮用水上方的有机磷和有机氯农用化学品污染 法规和井水消耗增加了活检证实CKDu的可能性， 确诊的肾病在我们初步工作确定的600名高危参与者中， 我们会收集基线环境样本，包括水样本和肾脏活组织检查，如果它们符合 确认CKDu的临床定义，我们建议检查特定农用化学品 污染的井水导致了CKDU我们将：1）运行非靶向和靶向质谱 分析井水，2）确定单个农用化学品及其混合物与事件的关联 CKDu病例状态，考虑工作强度和热应激，3）测量肾毒性的生物负荷 农业化学品在病例与对照中的作用，以及4）对早期肾活检进行分子分析， 通过批量和单细胞RNA测序在细胞水平上指定损伤反应模式。对准 与NIDDK-NIEHS-Fogarty推荐的CKDu调查方法，该建议集成了多个 由肾脏病学家、病理学家、分子生物学家和环境学家组成的跨学科多国团队 地球化学家根据我们的初步数据，我们重点关注通过井水的农业化学品暴露， 环境风险因素的利益，但实地工作将结合广泛的 生物库的努力，以促进测试多个候选假设。互补分子分析 将精确描述CKDu在其他原发性肾小管间质性肾病背景下的损伤， 并创建一个严格的支架来测试潜在的代理，可以触发CKDu特异性反应， 肾与先前的区域性肾病流行病如巴尔干半岛的肾病一样， 在我们概述的目标中查明原因的努力有可能查明其他弱势群体， 更重要的是，通过消除暴露来消除肾脏疾病。