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

• 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
• 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

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.

项目摘要 沿着太平洋沿岸出现了病因不明的慢性肾脏病（CKDu）流行病 中美洲（中美洲肾病），斯里兰卡北方（斯里兰卡肾病），安得拉邦 Pradesh和印度其他地区（Uddanam Nephropathy），以及墨西哥韦拉克鲁斯州。在所有情况下， 组织学表现为慢性间质性肾炎伴不同程度的肾小球硬化。去约会各种各样的 原因已被考虑，包括重金属，农用化学品，传染病，和经常性的热 压力和脱水在这里，我们评估新的假设，无定形二氧化硅，释放到空气中， 甘蔗和稻米的燃烧可能是主要原因。支持这一假设的证据包括 以下情况：1.无定形二氧化硅存在于甘蔗和大米中，当甘蔗燃烧时释放出来 或稻壳被烧掉。2.燃烧甘蔗和水稻的颗粒物组分（PM2.5） 含有80- 90%的无定形纳米颗粒大小的二氧化硅。3. PM2.5和暴露于二氧化硅都与 有记录显示，中美洲的甘蔗燃烧量和中美洲的大米燃烧量都有可能导致CKD。 斯里兰卡与这些国家的流行病类似。4.给予无定形纳米颗粒大小的二氧化硅的大鼠 发生CKD伴轻微呼吸体征，活检显示慢性间质性肾炎伴二氧化硅颗粒 在小管中。5.患有中美洲肾病、斯里兰卡肾病和 Uddanam肾病显示肾小管中显著存在无定形纳米级二氧化硅颗粒， 通过暗视野光谱显微镜观察并通过肾组织的ICP-质谱法确认。 鉴于这些发现，我们建议1）确定纳米二氧化硅可以 在大鼠模型中引起肾损伤，评价口服和鼻内方法;改变纳米颗粒大小， 并进行时间和剂量反应;评估热的潜在协同效应;确定 机制涉及溶酶体摄取和炎性小体活化;评估其他器官（如 肺），并测试麦考酚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 增强暗场超光谱成像。3)确定二氧化硅肾病在两种流行病中的影响 CKDu和其他肾脏疾病，通过更好地表征已知肾脏活检中的二氧化硅肾病 流行地区，预测和测试其他地区的二氧化硅肾病，其中甘蔗燃烧（或 4）评估先前在丹佛和斯德哥尔摩以及世界其他地区收集的肾活检标本。 以确定与其他肾脏疾病相比，CKDu中的二氧化硅是否增加。这些研究将 表征二氧化硅肾病，可能是与空气污染相关的第一种主要肾脏疾病， 这对肾病学、公共卫生、环境安全以及人类和动物健康具有重大意义。