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

项目摘要/摘要 在过去的二十年里，越来越多的农业社区面临着一种明显新的、 不明原因的、致命的肾脏疾病，称为不明原因慢性肾脏病(CKDu)。第一 萨尔瓦多的甘蔗工人和斯里兰卡的稻农注意到，有类似肾脏疾病的报告 来自尼加拉瓜、哥斯达黎加、危地马拉、印度和(最近)美国，尽管 这一肾脏疾病流行的规模和严重性，需要进行流行病学和机械性调查 解决这一问题的能力极其有限。因为患有这种疾病的人在其他方面是健康的农业 工人、许多专家和受影响的人群怀疑是农用化学品暴露造成的。用两个键 在斯里兰卡的初步研究中，我们发现农业工人喝的是浅水井 被美国环保局饮用水中的有机磷和有机氯农药污染 法规和井水消耗增加了活检证实的CKDU的可能性和更快的进展 已确诊的肾脏疾病。在我们初步工作确定的600名有风险的参与者中， 我们将获得基线环境样本，包括水样本和肾脏活检，如果它们符合 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 污染井水是造成CKDu的原因。我们将：1)运行非靶向和靶向质谱学 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病例情况，考虑工作强度和热应激，3)测定肾毒性的生物负荷 病例与对照中的农用化学物质，以及4)对早期肾脏活检进行分子分析，以 通过批量和单细胞RNA测序，在细胞水平上指定伤害反应模式。在路线上 通过NIDDK-NIEHS-Fogarty推荐的CKDu调查方法，该提案整合了多个 由肾病学家、病理学家、分子生物学家和环境学家组成的多国学科团队 地球化学家。根据我们的初步数据，我们将重点放在通过井水进行的农业化学品暴露上 环境风险因素对这一提议感兴趣，但实地工作将伴随着广泛的 促进多个候选假说测试的生物库工作。互补的分子分析 将准确地描述CKDU在其他原发肾小管间质疾病背景下的损伤特征， 并创建一个严格的脚手架来测试潜在的代理，这些代理可以在 肾脏。就像以前的地区性肾病流行一样，如巴尔干肾病，重症 在我们概述的目标中找出原因的努力有可能准确地定位其他脆弱人群和 更重要的是，通过消除接触来根除肾脏疾病。

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.