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.

项目概要/摘要 在过去的二十年里，越来越多的农业社区面临着一个明显的新问题， 原因不明的致命性肾脏疾病，称为病因不明的慢性肾脏病（CKDu）。第一的 萨尔瓦多的甘蔗工人和斯里兰卡的稻农都发现了类似的肾脏疾病的报道 来自尼加拉瓜、哥斯达黎加、危地马拉、印度和（最近）美国的 这种肾脏疾病流行的规模和严重程度，需要进行流行病学和机制调查 解决这个问题的能力极其有限。因为患有这种疾病的人在其他方面都是健康的农业 工人、许多专家和受影响人群怀疑农用化学品接触是造成这种情况的原因。在两键 斯里兰卡的初步研究发现，农业工人从浅水井饮用 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的 CKDu 和更快进展的可能性 已确定的肾脏疾病。在我们的初步工作中确定的 600 名高危参与者中， 如果符合标准，我们将获得基线环境样本，包括水样和肾活检 验证了 CKDu 的临床定义，我们建议检验特定农用化学品的假设 污染井水会导致 CKDu。我们将：1) 运行非目标和目标质谱分析 井水分析，2) 确定单个农用化学品及其混合物与事故的关联 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 病例与对照中的农用化学品，4) 对早期肾活检进行分子分析，以 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。对齐 根据 NIDDK-NIEHS-Fogarty 推荐的 CKDu 调查方法，该提案整合了多种 由肾脏病学家、病理学家、分子生物学家和环境学家组成的多学科学科团队 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用化学品暴露，因为 本提案中关注的是环境风险因素，但是现场工作将与广泛的研究相结合 生物样本库努力促进多种候选假设的测试。互补的分子分析 将在其他原发性肾小管间质性肾病的背景下精确表征 CKDu 的损伤， 并创建一个严格的支架来测试可以触发 CKDu 特异性反应的潜在药物 肾。与巴尔干肾病等先前区域性肾脏疾病流行的情况一样， 在我们概述的目标中找出原因的努力有可能查明其他弱势群体和 地区，更重要的是，通过消除暴露来消除肾脏疾病。