Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology

二氧化硅肾病和病因不明的慢性肾脏病

基本信息

批准号：
10029114
负责人：
Jared Michael Brown
金额：
$ 63.54万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029114
关键词：
Acute Renal Failure with Renal Papillary Necrosis Agrochemicals Air Air Pollution Allopurinol Animals Area Biopsy Burn injury Cell Culture Techniques Cell model Cells Central America Characteristics Chronic Chronic Kidney Failure Clinical Communicable Diseases Country Dehydration Deposition Disease Documentation Dose Electron Microscopy Epidemic Etiology Evaluation Exposure to Female HK2 gene Health Heat Stress Disorders Heavy Metals Histologic Human Hydration status Image India Individual Inductively Coupled Plasma Mass Spectrometry Inflammasome Inhalation Injury Injury to Kidney Intake Interstitial Nephritis Kidney Kidney Diseases Lung Masks Mass Spectrum Analysis Mediating Mesoamerican Methods Mexico Microscopy Modeling Mycophenolate Nature Nephrology Oral Oral Ingestion Organ Particulate Matter Pathologic Pathologist Public Health Raman Spectrum Analysis Rattus Reaction Time Records Recurrence Reporting Research Rice Risk Role Route Saccharum Safety Sampling Seasons Silicic Acid Silicon Dioxide Site Sri Lanka Testing Thailand Time Tissues Toxicology Tubular formation Tubulointerstitial Nephritis Urine agricultural region amorphous silicate base climate change drinking effective therapy exposure route glomerulosclerosis human disease kidney biopsy male mycophenolate mofetil nanoparticle nanosized novel particle predictive test respiratory response rural area therapeutic evaluation toxicant uptake xanthine oxidase inhibitor

项目摘要

Project Summary Epidemics of chronic kidney disease of unknown etiology (CKDu) have emerged along the Pacific Coast of Central America (Mesoamerican Nephropathy), in northern Sri Lanka (Sri Lankan nephropathy), in Andhra Pradesh and other regions of India (Uddanam Nephropathy), and in Veracruz, Mexico. In all cases, the primary histologic finding is chronic interstitial nephritis with variable degrees of glomerulosclerosis. To date a variety of causes have been considered, including heavy metals, agrochemicals, infectious diseases, and recurrent heat stress and dehydration. Here we evaluate the novel hypothesis that amorphous silica, released into the air during the burning of sugarcane and rice, may be a primary cause. The evidence supporting this hypothesis consists of the following: 1. Amorphous silica is present in sugarcane and rice and is released when sugarcane is burned or rice husks are burned each season. 2. The particular matter fraction (PM2.5) of burned sugarcane and rice contains 80-90 percent amorphous, nanoparticle sized silica. 3. Both PM2.5 and exposure to silica is associated with risk for CKD, and records show that the amount of burning of sugarcane in Central America and of rice in Sri Lanka parallel the epidemics in these countries. 4. Rats administered amorphous nanoparticle sized silica develop CKD with minimal respiratory signs and the biopsies show chronic interstitial nephritis with silica particles in tubules. 5. Human biopsies of subjects with Mesoamerican Nephropathy, Sri Lankan Nephropathy, and Uddanam nephropathy show dramatic presence of amorphous nano-sized silica particles in tubules compared to controls by darkfield spectral microscopy and confirmed by ICP-mass spectrometry of the kidney tissues. Given these findings, we propose to 1) Identify the Route(s) and Mechanisms by which nanoparticle silica may cause kidney injury in a rat model, evaluating both oral and intranasal approaches; varying the nanoparticle size, and doing both a time and dose response; evaluating the potentially synergistic effect of heat; determining if the mechanism involves lysosomal uptake and inflammasome activation; evaluating if other organs (such as the lung) are involved, and testing the therapeutic potential of mycophenolate and allopurinol. 2) To characterize the silica in the kidney biopsy tissue and urine using ICP-MS, Raman spectroscopy, electron microscopy and enhanced darkfield hyperspectral imaging. 3) To identify the Impact of Silica Nephropathy in both Epidemic CKDu and Other Renal Diseases by better characterizing silica nephropathy in kidney biopsies from known epidemic areas, predicting and testing for silica nephropathy in other regions where sugarcane is burned (or not); and 4) Evaluating previously collected kidney biopsies in Denver and Stockholm, and other areas of the world to determine if silica is increased in CKDu compared to other renal diseases. These studies will characterize silica nephropathy, possibly one of the first major kidney diseases associated with air pollution, and with major implications for nephrology, public health, environmental safety, and human and animal health.

项目概要太平洋沿岸出现了不明原因慢性肾病（CKDu）的流行中美洲（中美洲肾病），斯里兰卡北部（斯里兰卡肾病），安得拉邦印度邦和其他地区（Uddanam 肾病）以及墨西哥韦拉克鲁斯州。在所有情况下，主要组织学发现为慢性间质性肾炎，伴有不同程度的肾小球硬化。迄今为止各种已考虑了原因，包括重金属、农用化学品、传染病和反复高温压力和脱水。在这里，我们评估了一个新的假设，即无定形二氧化硅在甘蔗和大米的燃烧可能是主要原因。支持这一假设的证据包括 1. 无定形二氧化硅存在于甘蔗和大米中，并在甘蔗燃烧时释放出来或者每个季节都会焚烧稻壳。 2. 燃烧甘蔗和大米的颗粒物分数（PM2.5）含有 80-90% 无定形、纳米颗粒大小的二氧化硅。 3. PM2.5 和接触二氧化硅都相关存在慢性肾病风险，记录显示中美洲的甘蔗燃烧量和美国的大米燃烧量斯里兰卡的疫情与这些国家的情况相似。 4. 给大鼠施用无定形纳米颗粒大小的二氧化硅患有慢性肾病，呼吸系统症状极少，活检显示慢性间质性肾炎，伴有二氧化硅颗粒在小管中。 5. 患有中美洲肾病、斯里兰卡肾病和与 Uddanam 肾病相比，肾小管中显着存在无定形纳米尺寸二氧化硅颗粒通过暗场光谱显微镜进行对照，并通过肾组织的 ICP 质谱法进行确认。鉴于这些发现，我们建议 1) 确定纳米颗粒二氧化硅可能的途径和机制在大鼠模型中引起肾损伤，评估口服和鼻内方法；改变纳米颗粒的尺寸，并进行时间和剂量反应；评估热的潜在协同效应；确定是否机制涉及溶酶体摄取和炎症小体激活；评估其他器官（例如肺）参与其中，并测试霉酚酸酯和别嘌呤醇的治疗潜力。 2）表征使用 ICP-MS、拉曼光谱、电子显微镜和增强暗场高光谱成像。 3) 确定二氧化硅肾病对两种流行病的影响 CKDu 和其他肾脏疾病，通过更好地表征已知肾活检中的二氧化硅肾病流行地区，预测和检测其他烧甘蔗地区（或不是）; 4) 评估之前在丹佛和斯德哥尔摩以及美国其他地区收集的肾脏活检样本世界以确定 CKDu 与其他肾脏疾病相比二氧化硅是否增加。这些研究将二氧化硅肾病的特征，可能是与空气污染相关的最早的主要肾脏疾病之一，以及对肾脏病学、公共卫生、环境安全以及人类和动物健康具有重大影响。