Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology

项目摘要 原因不明的慢性肾脏病(CKDu)在太平洋沿岸流行 中美洲(中美洲肾病)、斯里兰卡北部(斯里兰卡肾病)、安得拉 印度的普拉德什和其他地区(Uddanam肾病)，以及墨西哥的Veracruz。在所有情况下，主要的 组织学表现为慢性间质性肾炎伴不同程度的肾小球硬化。与各种不同的 已经考虑了原因，包括重金属、农用化学品、传染病和反复发烧。 压力和脱水。在这里，我们评估了一种新的假设，即在空气中释放的无定形二氧化硅 烧毁甘蔗和大米，可能是主要原因。支持这一假设的证据包括 无定形二氧化硅存在于甘蔗和大米中，燃烧甘蔗时会释放出无定形二氧化硅 或者每个季节都会焚烧稻壳。2.焚烧甘蔗和大米中的特殊物质组分(PM2.5) 含有80%-90%的无定形纳米颗粒大小的二氧化硅。3.PM2.5和接触二氧化硅都有关联 有患慢性肾脏病的风险，记录显示，中美洲的甘蔗和#年的大米的焚烧量 斯里兰卡的疫情与这些国家的疫情相似。4.大鼠注射无定形纳米二氧化硅 发展为慢性肾脏病，有轻微的呼吸道症状，活检显示慢性间质性肾炎伴二氧化硅颗粒 在小管中。5.中美肾病、斯里兰卡肾病患者的人体活检 Uddanam肾病显示肾小管中有大量无定形纳米二氧化硅颗粒 用暗视野光谱分析和电感耦合等离子体质谱(ICPMS)对肾组织进行鉴定。 鉴于这些发现，我们建议1)确定纳米二氧化硅可能通过的途径(S)和机制 在大鼠模型上造成肾脏损伤，评估口服和鼻腔途径；改变纳米颗粒的大小， 并同时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激活；评估其他器官(如 肺)，并测试霉酚酸酯和别嘌醇的治疗潜力。2)描述 应用电感耦合等离子体质谱、拉曼光谱、电子显微镜和电子显微镜对肾活检组织和尿液中的二氧化硅进行了研究. 增强的暗场高光谱成像。3)确定二氧化硅肾病在这两种流行病中的影响 CKDu和其他肾脏疾病：更好地描述已知肾脏活检中的二氧化硅肾病 流行地区，预测和检测其他甘蔗烧毁地区的二氧化硅肾病(或 不)；以及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 以确定与其他肾脏疾病相比，慢性肾功能不全患者的二氧化硅是否增加。这些研究将 描述二氧化硅肾病的特征，这可能是与空气污染有关的第一大肾脏疾病之一，以及 对肾病学、公共卫生、环境安全以及人和动物健康具有重大影响。

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.