研究背景: 慢性腎臟病為當今重要的公共衛生議題，近年雖有研究探討空氣汙染對腎功能的影響，但其結果不很一致，且多數未考量各空氣污染物間的相關性，而鮮少有文獻研究慢性腎臟病快速進展與空氣污染的關聯。
研究目的: 本研究旨在探討粗懸浮微粒、細懸浮微粒、一氧化碳、二氧化氮、二氧化硫、及臭氧此六種空氣污染物和慢性腎臟病發生及其快速進展的相關性。
研究方法: 本研究為回溯性世代研究。研究對象選取自2002至2017年參與美兆健康檢查計畫的族群。慢性腎臟病定義為腎絲球過濾率小於60 ml/min/1.73m2，或尿液潛血、尿蛋白檢驗呈陽性。本研究以克利金/土地利用迴歸混合模型估算參與者的空氣污染物暴露濃度，並以參與者第一次接受健檢當月及前23個月之空氣污染物之平均濃度為暴露指標，最後以Cox迴歸分析評估各空氣污染物和慢性腎臟病發生及其快速進展之關聯，亦檢定各污染物間的關聯性；若兩兩空氣污染物有關，則納入雙空氣污染物模型分析。
結果: 本研究結果顯示空氣中之一氧化碳每增加1 ppm，慢性腎臟病之發生及其快速進展風險分別顯著增加7%及32%；二氧化氮每增加1 ppb，慢性腎臟病之發生及其快速進展風險皆顯著增加1%。二氧化硫及臭氧濃度增加則與慢性腎臟病之發生及其快速進展風險下降有顯著關聯，粗懸浮微粒則和慢性腎臟病之發生無顯著相關。雙空氣污染物模型結果顯示，校正二氧化氮暴露後，一氧化碳暴露濃度仍與慢性腎臟病之快速進展風險有顯著關聯。
結論：一氧化碳及二氧化氮暴露濃度增加可能會對腎功能產生不良的影響，而二氧化硫及臭氧暴露可能為腎功能的保護因子。

Background: Chronic kidney disease (CKD) leads to heavy public health burden. Some studies have evaluated the association between air pollution and renal function, but the results were not consistent, and few of them have investigated the relationship between rapid progression of CKD and air pollution.
Objective: This study aimed to examine the association between air pollutants and the risks of CKD incidence and its rapid progression.
Methods: This study recruited participants of the MJ Medical Examination Program from 2002 to 2017. CKD was defined as eGFR less than 60 ml/min/1.73m2, or a positive test for urine occult blood or proteinuria. We used hybrid kriging/land-use regression models to estimate the participants’ air pollutant exposure levels, including those of particulate matters (PM), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3). Cox regressions were conducted to exam the associations between air pollutants and the incidence of CKD and its rapid progression. We also evaluated the correlation between the pollutants, and if any two of them were highly correlated, two–pollutant Cox regression models were used for further analyses.
Results: Each increment of 1 ppm in CO exposure was associated with a 1.07–fold risk of CKD incidence and with a 1.32–fold risk of rapid progression of CKD. Each increment of 1 ppb in NO2 was associated with a 1% increase in both the risks of CKD and its rapid progression. There was no significant association between PM10 and the risk of CKD. In two–pollutant Cox regressions, after adjusting for NO2 exposure, we found CO was still significantly associated with the rapid progression of CKD.
Conclusion: CO and NO2 might have adverse effects on renal function, and SO2 and O3 had inverse correlations with the risks of CKD and its rapid progression.

Blum, M.F., Surapaneni, A., Stewart, J.D., Liao, D., Yanosky, J.D., Whitsel, E.A., Power, M.C., Grams, M.E., 2020. Particulate matter and albuminuria, glomerular filtration rate, and incident CKD. Clin. J. Am. Soc. Nephrol. 15, 311–319. https://doi.org/10.2215/cjn.08350719.
Bowe, B., Xie, Y., Li, T., Yan, Y., Xian, H., Al–Aly, Z., 2017. Associations of ambient coarse particulate matter, nitrogen dioxide, and carbon monoxide with the risk of kidney disease: A cohort study. Lancet Planet. Health. 1, e267–e276. https://doi.org/10.1016/s2542–5196(17)30117–1.
Bragg–Gresham, J., Morgenstern, H., McClellan, W., Saydah, S., Pavkov, M., Williams, D., Powe, N., Tuot, D., Hsu, R., Saran, R., 2018. County–level air quality and the prevalence of diagnosed chronic kidney disease in the US medicare population. PLoS One. 13, e0200612. https://doi.org/10.1371/journal.pone.0200612.
Cachofeiro, V., Goicochea, M., de Vinuesa, S.G., Oubina, P., Lahera, V., Luno, J., 2008. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease. Kidney Int. Suppl. S4–9. https://doi.org/10.1038/ki.2008.516.
Chan, T.–C., Zhang, Z., Lin, B.–C., Lin, C., Deng, H.B., Chuang, Y.–C., Chan, J.W.M., Jiang, W.–K., Tam, T., Chang, L.–Y., Hoek, G., Lau, A.K.H., Lao, X.Q., 2018. Long–term exposure to ambient fine particulate matter and chronic kidney disease: A cohort study. Environ. Health Perspect. 126, 107002. https://doi.org/10.1289/ehp3304.
Chen, S.–Y., Chu, D.–C., Lee, J.–H., Yang, Y.–R., Chan, C.–C., 2018. Traffic–related air pollution associated with chronic kidney disease among elderly residents in Taipei city. Environ. Pollut. 234, 838–845. https://doi.org/10.1016/j.envpol.2017.11.084.
Chen, T.–H., Hsu, Y.–C., Zeng, Y.–T., Candice Lung, S.–C., Su, H.–J., Chao, H.–J., Wu, C.–D., 2020. A hybrid kriging/land-use regression model with Asian culture–specific sources to assess NO2 spatial–temporal variations. Environ. Pollut. 259, 113875. https://doi.org/10.1016/j.envpol.2019.113875.
Cheng, Y.–Y., Huang, N.–C., Chang, Y.–T., Sung, J.–M., Shen, K.–H., Tsai, C.–C., Guo, H.–R., 2017. Associations between arsenic in drinking water and the progression of chronic kidney disease: A nationwide study in Taiwan. J. Hazard Mater. 321, 432–439. https://doi.org/10.1016/j.jhazmat.2016.09.032.
Chin, M.T., 2015. Basic mechanisms for adverse cardiovascular events associated with air pollution. Heart. 101, 253–256. https://doi.org/10.1136/heartjnl–2014–306379.
Cockwell, P., Fisher, L.A., 2020. The global burden of chronic kidney disease. Lancet. 395, 662–664. https://doi.org/10.1016/s0140–6736(19)32977–0.
Güçlü, A., Erken, H.A., Erken, G., Dodurga, Y., Yay, A., Özçoban, Ö., Şimşek, H., Akçılar, A., Koçak, F.E., 2016. The effects of ozone therapy on caspase pathways, TNF–α, and HIF–1α in diabetic nephropathy. Int. Urol. Nephrol. 48, 441–450. https://doi.org/10.1007/s11255–015–1169–8.
Gao, Y., Liang, C., Zhang, J., Ma, J., Wang, J., Niu, R., Tikka, C., Wang, Y., Wang, J., 2018. Combination of fluoride and SO2 induce DNA damage and morphological alterations in male rat kidney. Cell Physiol. Biochem. 50, 734–744. https://doi.org/10.1159/000494239.
Gekle, M., 2017. Kidney and aging – a narrative review. Exp. Gerontol. 87, 153–155. https://doi.org/10.1016/j.exger.2016.03.013.
Guarnieri, G., Zanetti, M., Vinci, P., Cattin, M.R., Pirulli, A., Barazzoni, R., 2010. Metabolic syndrome and chronic kidney disease. J. Ren. Nutr. 20, S19–23. https://doi.org/10.1053/j.jrn.2010.05.006.
Guarnieri, M., Balmes, J.R., 2014. Outdoor air pollution and asthma. Lancet. 383, 1581–1592. https://doi.org/10.1016/s0140–6736(14)60617–6.
Gupta, J., Mitra, N., Kanetsky, P.A., Devaney, J., Wing, M.R., Reilly, M., Shah, V.O., Balakrishnan, V.S., Guzman, N.J., Girndt, M., Periera, B.G., Feldman, H.I., Kusek, J.W., Joffe, M.M., Raj, D.S., 2012. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin. J. Am. Soc. Nephrol. 7, 1938–1946. https://doi.org/10.2215/CJN.03500412.
Haroun, M.K., Jaar, B.G., Hoffman, S.C., Comstock, G.W., Klag, M.J., Coresh, J., 2003. Risk factors for chronic kidney disease: A prospective study of 23,534 men and women in Washington County, Maryland. J. Am. Soc. Nephrol. 14, 2934–2941. https://doi.org/10.1097/01.asn.0000095249.99803.85.
Hommos, M.S., Glassock, R.J., Rule, A.D., 2017. Structural and functional changes in human kidneys with healthy aging. J. Am. Soc. Nephrol. 28, 2838–2844. https://doi.org/10.1681/asn.2017040421.
Hsu, C.–C., Hwang, S.–J., Wen, C.–P., Chang, H.–Y., Chen, T., Shiu, R.–S., Horng, S.–S., Chang, Y.–K., Yang, W.–C., 2006. High prevalence and low awareness of CKD in Taiwan: A study on the relationship between serum creatinine and awareness from a nationally representative survey. Am. J. Kidney Dis. 48, 727–738. https://doi.org/10.1053/j.ajkd.2006.07.018.
Hwang, S.–J., Tsai, J.–C., Chen, H.–C., 2010. Epidemiology, impact and preventive care of chronic kidney disease in Taiwan. Nephrology (Carlton). 15 Suppl 2, 3–9. https://doi.org/10.1111/j.1440–1797.2010.01304.x.
Jeong, S.M., Park, J.H., Kim, H.J., Kwon, H., Hwang, S.E., 2020. Effects of abdominal obesity on the association between air pollution and kidney function. Int. J. Obes (Lond). https://doi.org/10.1038/s41366–020–0540–8.
Jiang, B., Su, Y., Chen, Q., Dong, L., Zhou, W., Li, H., Wang, Y., 2020. Protective effects of ozone oxidative postconditioning on long–term injury after renal ischemia/reperfusion in rat. Transplant. Proc. 52, 365–372. https://doi.org/10.1016/j.transproceed.2019.10.004.
Jung, C.–C., Lin, W.–Y., Hsu, N.–Y., Wu, C.–D., Chang, H.–T., Su, H.–J., 2020. Development of hourly indoor PM2.5 concentration prediction model: The role of outdoor air, ventilation, building characteristic, and human activity. Int. J. Environ. Res. Publ. Health. 17, 5906. https://doi.org/10.3390/ijerph17165906.
Karagulian, F., Belis, C.A., Dora, C.F.C., Prüss–Ustün, A.M., Bonjour, S., Adair–Rohani, H., Amann, M., 2015. Contributions to cities' ambient particulate matter (PM): A systematic review of local source contributions at global level. Atmospheric Environ. 120, 475–483. https://doi.org/https://doi.org/10.1016/j.atmosenv.2015.08.087.
Kidney Disease Improving Global Outcomes (KDIGO) Work Group. 2013. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 1–163.
Kim, H.J., Min, J.Y., Seo, Y.S., Min, K.B., 2018a. Association between exposure to ambient air pollution and renal function in Korean adults. Ann. Occup. Environ. Med. 30, 14. https://doi.org/10.1186/s40557–018–0226–z.
Kim, W.Y., Kim, Y.J., Sohn, C.H., Seo, D.W., Oh, B.J., Lim, K.S., Chang, J.W., 2018b. Analysis of the development and progression of carbon monoxide poisoning–related acute kidney injury according to the kidney disease improving global outcomes (KDIGO) criteria. Clin. Toxicol (Phila). 56, 759–764. https://doi.org/10.1080/15563650.2018.1424890.
Koike, E., Kobayashi, T., Utsunomiya, R., 2001. Effect of exposure to nitrogen dioxide on alveolar macrophage–mediated immunosuppressive activity in rats. Toxicol. Lett. 121, 135–143. https://doi.org/10.1016/s0378–4274(01)00331–9.
Kuo, H.–W., Tsai, S.–S., Tiao, M.–M., Yang, C.–Y., 2007. Epidemiological features of CKD in Taiwan. Am. J. Kidney Dis. 49, 46–55. https://doi.org/https://doi.org/10.1053/j.ajkd.2006.10.007.
Lai, Y.–J., Chen, Y.–Y., Lin, Y.–K., Chen, C.–C., Yen, Y.–F., Deng, C.–Y., 2019. Alcohol consumption and risk of chronic kidney disease: A nationwide observational cohort study. Nutrients. 11, https://doi.org/10.3390/nu11092121.
Langer, S., Bekö, G., 2013. Indoor air quality in the Swedish housing stock and its dependence on building characteristics. Build. Environ. 69, 44–54. https://doi.org/https://doi.org/10.1016/j.buildenv.2013.07.013.
Lee, Y.–H., Huang, W.–C., Tsai, J.–Y., Lu, C.–M., Chen, W.–C., Lee, M.–H., Hsu, H.–S., Huang, J.–K., Chang, L.–S., 2002. Epidemiological studies on the prevalence of upper urinary calculi in Taiwan. Urol. Int. 68, 172–177. https://doi.org/10.1159/000048445.
Levey, A.S., Coresh, J., Balk, E., Kausz, A.T., Levin, A., Steffes, M.W., Hogg, R.J., Perrone, R.D., Lau, J., Eknoyan, G., 2003. National kidney foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann. Intern. Med. 139, 137–147. https://doi.org/10.7326/0003–4819–139–2–200307150–00013.
Levey, A.S., Coresh, J., Greene, T., Marsh, J., Stevens, L.A., Kusek, J.W., Van Lente, F., 2007. Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin. Chem. 53, 766–772. https://doi.org/10.1373/clinchem.2006.077180.
Lew, Q.J., Jafar, T.H., Talaei, M., Jin, A., Chow, K.Y., Yuan, J.M., Koh, W.P., 2017. Increased body mass index is a risk factor for end–stage renal disease in the Chinese Singapore population. Kidney Int. 92, 979–987. https://doi.org/10.1016/j.kint.2017.03.019.
Lim, J.M., Jeong, J.H., Lee, J.H., Moon, J.H., Chung, Y.S., Kim, K.H., 2011. The analysis of PM2.5 and associated elements and their indoor/outdoor pollution status in an urban area. Indoor Air. 21, 145–155. https://doi.org/10.1111/j.1600–0668.2010.00691.x.
Lin, S.–Y., Ju, S.–W., Lin, C.–L., Hsu, W.–H., Lin, C.–C., Ting, I.–W., Kao, C.–H., 2020. Air pollutants and subsequent risk of chronic kidney disease and end–stage renal disease: A population–based cohort study. Environ. Pollut. 261, 114154. https://doi.org/10.1016/j.envpol.2020.114154.
Lin, Y.–C., Hsu, C.–Y., Kao, C.–C., Chen, T.–W., Chen, H.–H., Hsu, C.–C., Wu, M.–S., 2014. Incidence and prevalence of ESRD in Taiwan renal registry data system (TWRDS): 2005–2012. Acta. Nephrologica. 28, 65–68. https://doi.org/10.6221/an.2014011.
Liu, C.–Y., Hung, Y.–T., Chuang, Y.–L., Chen, Y.–J., Weng, W.–S., Liu, J.–S., Liang, K.–L., 2006. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J. Healthc. Manag. 4, 1–22. https://doi.org/10.29805/JHM.200606.0001.
Low, S.K., Sum, C.F., Yeoh, L.Y., Tavintharan, S., Ng, X.W., Lee, S.B., Tang, W.E., Lim, S.C., 2015. Prevalence of chronic kidney disease in adults with type 2 diabetes mellitus. Ann. Acad. Med. Singapore. 44, 164–171.
Lung, S.–C.C., Mao, I.–F., Liu, L.–J.S., 2007. Residents' particle exposures in six different communities in Taiwan. Sci. Total Environ. 377, 81–92. https://doi.org/https://doi.org/10.1016/j.scitotenv.2007.01.092.
Meng, Z., Qin, G., Zhang, B., Bai, J., 2004. DNA damaging effects of sulfur dioxide derivatives in cells from various organs of mice. Mutagenesis. 19, 465–468. https://doi.org/10.1093/mutage/geh058.
Metzger, K.B., Tolbert, P.E., Klein, M., Peel, J.L., Flanders, W.D., Todd, K., Mulholland, J.A., Ryan, P.B., Frumkin, H., 2004. Ambient air pollution and cardiovascular emergency department visits. Epidemiology. 15, 46–56. https://doi.org/10.1097/01.Ede.0000101748.28283.97.
Ministry of Economic Affairs (MOEA), 2020. Energy transition whitepaper. https://energywhitepaper.tw/ (accessed 21 Jane 2020).
Ministry of Health and Welfare (MOHW), 2019. National health insurance annual statistical report. https://www.nhi.gov.tw/english/Content_List.aspx?n=D8ECF7F6C9D80FC1&topn=BCB2B0D2433F6491 (accessed 20 April 2020).
Ministry of Health and Welfare (MOHW), 2019. Cause of death statistics. https://www.mohw.gov.tw/np–128–2.html (accessed 20 April 2020).
[dataset] MJ Health Research Foundation, 2014. MJ health survey database, MJ biodata. http://www.mjhrf.org.
National Health Research Institutes (NHRI), Taiwan Society of Nephrology, 2021. 2020 Annual report on kidney disease in Taiwan, Taipei.
Nehus, E., 2018. Obesity and chronic kidney disease. Curr. Opin. Pediatr. 30, 241–246. https://doi.org/10.1097/mop.0000000000000586.
Ritz, E., Benck, U., Franek, E., Keller, C., Seyfarth, M., Clorius, J., 1998. Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease. J. Am. Soc. Nephrol. 9, 1798–1804.
Rovira, J., Domingo, J.L., Schuhmacher, M., 2020. Air quality, health impacts and burden of disease due to air pollution (PM10, PM2.5, NO2 and O3): Application of AirQ+ model to the Camp de Tarragona County (Catalonia, Spain). Sci. Total Environ. 703, 135538. https://doi.org/10.1016/j.scitotenv.2019.135538.
Shen, G., Ainiwaer, S., Zhu, Y., Zheng, S., Hou, W., Shen, H., Chen, Y., Wang, X., Cheng, H., Tao, S., 2020. Quantifying source contributions for indoor CO2 and gas pollutants based on the highly resolved sensor data. Environ. Pollut. 267, 115493. https://doi.org/10.1016/j.envpol.2020.115493.
Tsai, M.–H., Hsu, C.–Y., Lin, M.–Y., Yen, M.–F., Chen, H.–H., Chiu, Y.–H., Hwang, S.–J., 2018. Incidence, prevalence, and duration of chronic kidney disease in Taiwan: Results from a community–based screening program of 106,094 individuals. Nephron. 140, 175–184. https://doi.org/10.1159/000491708.
Tsuboi, N., Okabayashi, Y., Shimizu, A., Yokoo, T., 2017. The renal pathology of obesity. Kidney Int. Rep. 2, 251–260. https://doi.org/10.1016/j.ekir.2017.01.007.
United States Renal Data System, 2020. USRDS annual data report: Epidemiology of kidney disease in the United States. https://adr.usrds.org/2020/end–stage–renal–disease (accessed 31 July 2021).
Vallianou, N.G., Mitesh, S., Gkogkou, A., Geladari, E., 2019. Chronic kidney disease and cardiovascular disease: Is there any relationship? Curr. Cardiol. Rev. 15, 55–63. https://doi.org/10.2174/1573403x14666180711124825.
Van Laecke, S., Van Biesen, W., 2017. Smoking and chronic kidney disease: Seeing the signs through the smoke? Nephrol. Dial. Transplant. 32, 403–405. https://doi.org/10.1093/ndt/gfw448.
Wang, L., Chen, Z., Liu, Y., Du, Y., Liu, X., 2018. Ozone oxidative postconditioning inhibits oxidative stress and apoptosis in renal ischemia and reperfusion injury through inhibition of mapk signaling pathway. Drug Des. Devel. Ther. 12, 1293–1301. https://doi.org/10.2147/dddt.S164927.
Wang, M., Sampson, P.D., Sheppard, L.E., Stein, J.H., Vedal, S., Kaufman, J.D., 2019. Long–term exposure to ambient ozone and progression of subclinical arterial disease: The multi–ethnic study of atherosclerosis and air pollution. Environ. Health Perspect. 127, 57001. https://doi.org/10.1289/ehp3325.
Weaver, A.M., Wang, Y., Wellenius, G.A., Young, B., Boyle, L.D., Hickson, D.A., Diamantidis, C.J., 2019. Long–term exposure to ambient air pollution and renal function in African Americans: The Jackson Heart Study. J. Expo. Sci. Environ. Epidemiol. 29, 548–556. https://doi.org/10.1038/s41370–018–0092–3.
Weaver, L.K., 2009. Clinical practice. Carbon monoxide poisoning. N. Engl. J. Med. 360, 1217–1225. https://doi.org/10.1056/NEJMcp0808891.
Wen, C.–P., Cheng, T.–Y.D., Tsai, M.–K., Chang, Y.–C., Chan, H.–T., Tsai, S.–P., Chiang, P.–H., Hsu, C.–C., Sung, P.–K., Hsu, Y.–H., Wen, S.–F., 2008. All–cause mortality attributable to chronic kidney disease: A prospective cohort study based on 462,293 adults in Taiwan. Lancet. 371, 2173–2182. https://doi.org/https://doi.org/10.1016/S0140–6736(08)60952–6.
Wu, C.–D., Zeng, Y.–T., Lung, S.–C., 2018. A hybrid kriging/land-use regression model to assess PM2.5 spatial–temporal variability. Sci. Total Environ. 645, 1456–1464. https://doi.org/10.1016/j.scitotenv.2018.07.073.
Wu, Y.–S., Tsai, C.–Y., Chang, K.–H., Chiang, C.–F., 2021. Impact of air pollutants emitted by Taichung power plant on atmospheric PM2.5 in central Taiwan. Aerosol Air Qual. Res. 21, 200358. https://doi.org/10.4209/aaqr.2020.06.0358.
Xia, J., Wang, L., Ma, Z., Zhong, L., Wang, Y., Gao, Y., He, L., Su, X., 2017. Cigarette smoking and chronic kidney disease in the general population: A systematic review and meta–analysis of prospective cohort studies. Nephrol. Dial. Transplant. 32, 475–487. https://doi.org/10.1093/ndt/gfw452.
Yamagata, K., Ishida, K., Sairenchi, T., Takahashi, H., Ohba, S., Shiigai, T., Narita, M., Koyama, A., 2007. Risk factors for chronic kidney disease in a community–based population: A 10–year follow–up study. Kidney Int. 71, 159–166. https://doi.org/10.1038/sj.ki.5002017.
Yang, Y.–R., Chen, Y.–M., Chen, S.–Y., Chan, C.–C., 2017. Associations between long–term particulate matter exposure and adult renal function in the Taipei metropolis. Environ. Health Perspect. 125, 602–607. https://doi.org/10.1289/ehp302.
Yu, G., Bai, Z., Chen, Z., Chen, H., Wang, G., Wang, G., Liu, Z., 2017. The NLRP3 inflammasome is a potential target of ozone therapy aiming to ease chronic renal inflammation in chronic kidney disease. Int. Immunopharmacol. 43, 203–209. https://doi.org/10.1016/j.intimp.2016.12.022.
Zhang, X., Lerman, L.O., 2017. The metabolic syndrome and chronic kidney disease. Transl. Res. 183, 14–25. https://doi.org/10.1016/j.trsl.2016.12.004.