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: 10212382
• 负责人: Jared Michael Brown
• 金额: $ 63.22万
• 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/10212382
• 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 未知病因（CKDU）的慢性肾脏疾病的流行病已经沿太平洋海岸出现 位于北斯里兰卡（Sri Lankan肾病）的中美洲（中美洲肾病），安得拉 印度和其他地区（Uddanam Nephropathy）和墨西哥Veracruz。在所有情况下，主要 组织学发现是慢性间质性肾炎，具有变化程度的肾小球硬化。迄今为止有各种各样的 已经考虑了原因，包括重金属，农产品，传染病和复发性热 压力和脱水。在这里，我们评估了新的假设，即无定形二氧化硅在 甘蔗和大米的燃烧可能是主要原因。支持该假设的证据是 以下内容：1。无定形二氧化硅存在于甘蔗和大米中，并在摄入甘蔗时释放 或每个季节都会燃烧稻壳。 2。燃烧的甘蔗和大米的特定物质分数（PM2.5） 包含80-90％的无定形，纳米粒子大小的二氧化硅。 3。PM2.5和暴露于二氧化硅 有CKD风险，并且记录显示，中美洲甘蔗量的燃烧量和米饭 斯里兰卡与这些国家的流行相似。 4。大鼠给施用无定形纳米粒子尺寸二氧化硅 开发具有最小呼吸迹象的CKD，活检显示慢性间质性肾炎和二氧化硅颗粒 在小管中。 5。患有中美洲肾病的受试者的人类活检，斯里兰卡肾病和 uddanam肾病表现出小管中无定形纳米大小的二氧化硅颗粒的显着存在 通过Darkfield光谱显微镜对照，并通过肾脏组织的ICP质量光谱法证实。 鉴于这些发现，我们建议1）确定纳米颗粒二氧化硅可以的途径和机制 在大鼠模型中引起肾脏损伤，评估口服和鼻内方法；改变纳米颗粒的大小， 并做时间和剂量反应；评估热量的潜在协同作用；确定是否 机制涉及溶酶体摄取和炎症体激活；评估其他器官是否（例如 肺参与，并测试霉酚酸盐和别嘌醇的治疗潜力。 2）表征 使用ICP-MS，拉曼光谱，电子显微镜和肾脏活检组织和尿液中的二氧化硅 增强的Darkfield高光谱成像。 3）确定二氧化硅肾病对两种流行病的影响 通过更好地表征已知的肾脏活检中的硅肾病，CKDU和其他肾脏疾病。 流行病区，预测和测试在摄入甘蔗的其他地区二氧化硅肾病（或 不是）; 4）评估丹佛和斯德哥尔摩的先前收集的肾脏活检，以及 与其他肾脏疾病相比，CKDU中二氧化硅是否增加的世界。这些研究会 硅肾病的特征是，可能是与空气污染相关的首次主要肾脏疾病之一， 对肾脏病，公共卫生，环境安全以及人类和动物健康具有重大影响。