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.

项目摘要/摘要 在过去的二十年中，越来越多的农业社区面临着一个显然是新的， 无法解释的和致命的肾脏疾病，被称为慢性病因肾病（CKDU）。第一的 在萨尔瓦多的甘蔗工人和斯里兰卡的水稻农民中指出，有类似肾脏疾病的报道 出现的出现来自尼加拉瓜，哥斯达黎加，印度危地马拉，（最近）美国，尽管 这种肾脏疾病流行的尺度和严重程度，需要的流行病学和机械研究 解决它非常有限。因为患有疾病的人是健康的农业 工人，许多专家和受影响的人口可疑的农业化学暴露是负责的。在两个键中 来自斯里兰卡的初步研究，我们发现农业工人正在从浅水井中喝酒 在EPA饮用水上方被有机磷酸盐和有机氯农化学污染 法规，井的消耗增加了活检证实的CKDU的可能性，并且更快地进展 已建立的肾脏疾病。在我们的初步工作确定的600名高风险参与者中 如果遇到水，我们将获得基线环境样品，包括水样和肾脏活检 经过验证的CKDU临床定义，我们提出了以下假设。 污染井水引起CKDU。我们将：1）运行不靶向和目标质谱法 井水的分析，2）确定各个农产品及其混合物与入射的混合物的关联 CKDU病例状态，考虑工作强度和热应力，3）测量肾毒性的生物负担 病例与对照组中的农业化学物质，以及4）对早期肾脏活检进行分子分析 用大量和单细胞RNA测序在细胞水平上指定损伤反应模式。在对齐中 通过Niddk-Niehs-Fogarty推荐的CKDU调查方法，该提案将 牙科医生，病理学家，分子生物学家和环境的纪律跨国团队 地球化学家。根据我们的初步数据，我们专注于通过井水的农业化学暴露 在此提案中，环境风险因素感兴趣，但是现场工作将与广泛 生物库促进多个候选假设的测试。互补分子分析 将精确地表征CKDU的损伤，在其他原发性肾小管间隙肾脏疾病中， 并创建一个严格的脚手架，用于测试可能触发CKDU特定响应的潜在代理 肾。就像先前的区域性肾脏疾病流行病（例如巴尔干肾病）一样 在我们的概述目标中确定原因的努力有可能查明其他脆弱人群和 区域，更重要的是，通过消除暴露来消除肾脏疾病。