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: 10682599
• 负责人: Jared Michael Brown
• 金额: $ 62.97万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682599
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Agrochemicals; Air; Air Pollution; Allopurinol; Animals; Area; Biopsy; Burn injury; Cell Culture Techniques; Cells; Central America; Characteristics; Chronic; Chronic Kidney Failure; Clinical; Communicable Diseases; Country; Darkness; 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; Intranasal Administration; Kidney; Kidney Diseases; Lung; Masks; Mass Spectrum Analysis; Mediating; Mesoamerican; Methods; Mexico; Microscopy; Modeling; Mycophenolate; Nature; Nephrology; Occupations; Oral; Oral Ingestion; Organ; Particulate Matter; Pathologic; Pathologist; Public Health; Raman Spectrum Analysis; Rattus; Records; Recurrence; Reporting; Research; Rice; Risk; Role; Route; Saccharum; Safety; Sampling; Seasons; Silicic Acid; Silicon Dioxide; Site; Testing; Thailand; Time; Tissues; Toxicology; Tubular formation; Tubulointerstitial Nephritis; Urine; agricultural region; amorphous silicate; climate change; comparison control; drinking; effective therapy; exposure route; fine particles; glomerulosclerosis; human disease; kidney biopsy; male; mycophenolate mofetil; nanoparticle; nanosized; novel; particle; 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.

项目总结

项目成果

Mini Review: Reappraisal of Uric Acid in Chronic Kidney Disease.

• DOI: 10.1159/000519491
• 发表时间: 2021
• 期刊: American journal of nephrology
• 影响因子: 4.2
• 作者: Goldberg A;Garcia-Arroyo F;Sasai F;Rodriguez-Iturbe B;Sanchez-Lozada LG;Lanaspa MA;Johnson RJ
• 通讯作者: Johnson RJ

A Quantitative Method for Determining Uptake of Silica Nanoparticles in Macrophages by Single Particle Inductively Coupled Plasma-Mass Spectrometry.

• DOI: 10.1002/cpz1.396
• 发表时间: 2022-03
• 期刊: Current protocols
• 作者: Rogers KL;Cruz-Hernandez A;Brown JM
• 通讯作者: Brown JM

A Single-Step Digestion for the Quantification and Characterization of Trace Particulate Silica Content in Biological Matrices Using Single Particle Inductively Coupled Plasma-Mass Spectrometry.

使用单颗粒电感耦合等离子体质谱法对生物基质中痕量二氧化硅颗粒含量进行单步消解定量和表征。

• DOI: 10.1007/s12011-022-03163-0
• 发表时间: 2023
• 期刊: Biological trace element research
• 影响因子: 3.9
• 作者: Rogers,KeeganL;Brown,JaredM
• 通讯作者: Brown,JaredM

Inhaled silica nanoparticles cause chronic kidney disease in rats.

吸入二氧化硅纳米粒子会导致大鼠慢性肾病。

• DOI: 10.1152/ajprenal.00021.2022
• 发表时间: 2022
• 期刊: American journal of physiology. Renal physiology
• 作者: Sasai,Fumihiko;Rogers,KeeganL;Orlicky,DavidJ;Stem,Arthur;Schaeffer,Joshua;Garcia,Gabriela;Fox,Jacob;Ray,MatthewS;Butler-Dawson,Jaime;Gonzalez-Quiroz,Marvin;Leiva,Ricardo;Taduri,Gangadhar;Anutrakululchai,Sirirat;Venugopal,Vidh
• 通讯作者: Venugopal,Vidh