Air pollution has become one of the most significant global environmental hazards on human health [1]. Southeast Asia, the most polluted region in the world, recorded a total of 2.6 and 3.3 million deaths related to outdoor and indoor air pollution respectively in 2012 [1, 14]. Taiwan, an island country in East Asia, is geographically close to the most polluted area. The most important sources of air pollution are particulate pollution, gaseous pollution, and heavy metals [14]. In the current study, we selected three representative groups of gaseous pollution, including SO2 (non-volatile gas), THC (volatile gas), and CH4 (greenhouse gas), and investigated the impact of their exposure on the risk of INS in children. Our cohort study revealed that Taiwanese children exposed to higher concentrations of SO2, THC, and CH4 were at increased risk of developing INS, regardless if potential confounding factors such as age, sex, monthly income, and urbanization level were adjusted. Our results demonstrate that a clear dose–response relationship exists between concentration of air pollution and risk of INS.

When we looked at the differences in NS incidences and associated HRs in participants exposed to various daily average concentrations of air pollutants stratified by 3 period of time in 2000–2012, we noticed the HR for the onset of INS was not as significantly associated with the concentration of air pollution when the cohort following for 9–12 years (Year 2009–2012) as following for 1–4 years and 5–8 years (Year 2000–2004 and Year 2005–2008). The explanation was because age at initial presentation has an important impact on analysis of disease distribution frequency of epidemiological studies. MCD is a major cause (approximately 90%) of INS [7]. MCD mostly appears in children younger than 10 years, with the peak incidence of 2 to 6 years of age (approximately 70%) [7].

SO2 is generated from industrial sulfur-based products. SO2 is a well-known environmental pollutant that can be easily obtained from drinking water and inhalation. Several animal and epidemiological studies have demonstrated that SO2 causes not only respiratory system disease but also multiple organ damage in the brain, heart, kidney, liver, spleen, and testis [15,16,17]. SO2 may result in an imbalance of pro- and antioxidant systems, subsequently exerting its toxic effects through oxidative stress and inflammatory responses [18, 19]. Previous studies in mice showed that SO2 exposure induced serious ultrastructural lesions in renal proximal tubular lining cells, while glomeruli and distal tubular lining cells were damaged in a dose-dependent manner [15]. Moreover, SO2 can be immediately converted into HSO3-, SO32-, and H + in the interstitial fluid after entering the body, inducing cytosine deamination into uracil, further leading to deoxyribonucleic acid damage [20, 21].

THCs, which are often referred to as volatile organic compounds are a large group that have a significant impact on environmental and human health due to their toxic, mutagenic, and carcinogenic properties [22, 23]. Due to rapid industrialization and urbanization, total hydrocarbons (THCs) are recently responsible for the great majority of the global energy consumption (approximately 85%). Based on previous studies, hydrocarbons may have toxic effect on the glomerular basement membrane. It might give the explanation for that the cumulative incidence of THC increases more rapidly in the last 6 years. In addition, we also found that participants exposed to higher concentrations of THC had higher accumulative incidence of INS than those exposed to lower concentrations in our study. Based on the two case reports published in the late twentieth century, heavy occupational exposure to hydrocarbons was highly associated with NS [24, 25]. The mechanisms of hydrocarbon-induced glomerulonephritis are considered to be threefold, including antibody formation in alveolar cells and glomerular basement membrane due to chemical damage, glomerular deposition of immune complexes, and direct toxic effect of hydrocarbons on the glomerular basement membrane [26, 27].

CH4 is the second largest contributor to global warming and its concentration in the atmosphere has been increasing rapidly in the last decade [28]. CH4 emissions can be grouped into anthropogenic and natural sources. Anthropogenic activities, such as fossil fuel production, agriculture, wastewater production, and biomass burning, produce the majority of CH4 emissions, accounting for 50%–65% of the total CH4 [29]. Human activities in urban areas are recognized as a globally important source of CH4 to the atmosphere [29]. Although CH4 is generally considered nontoxic, little is known about the adverse health effects of direct CH4 exposure [30]. In our study, we first identified that CH4 exposure might lead to an increased risk of NS development. The following reasons might explain this finding. Firstly, infections are recognized most frequent triggers of NS relapse, particular viral upper respiratory tract infection. CH4 accelerates global warming and subsequent changes in climate, that may alter the incidence and severity of respiratory infections by affecting vectors and host immune responses [30, 31]. Children appear to be particularly vulnerable to rapid fluctuations in ambient temperature. For example, CH4 from rapid industrialization and urbanization gives rise to the epidemiology of infectious diseases, such as EBV, CMV and HHV7 infection [31, 32]. The higher potential for pathogen transmission probably would be a trigger for the onset or relapse of NS [7]. Secondly, NS can be precipitated by allergic reactions and children with NS also may show increased serum immunoglobulin E levels [7, 11]. Allergic disorders are common in children with NS, especially within the first year after diagnosis [11].The prevalence of asthma and allergies has increased during the past decades, particularly in developed countries. Global warming is linked to the emission of hydrocarbon combustion products, since both carbon dioxide and heat increase pollen emission into the atmosphere, and all these particles make up PM10 [28,29,30]. A rise in the concentrations of pollens and pollutants in the air parallels the increase in the number of people presenting with allergic symptoms, which results in increased risks of NS.

From the literature, only few studies have analyzed the effect of air pollution on the glomerulopathy in adults [8, 9]. Little is known about air pollution and its impact on childhood INS, with the etiologies, management, and outcomes of INS significantly different between children and adults [7,8,9,10]. Xu et al. found that long-term exposure to high levels of PM2.5 was associated with an increased risk of membranous nephropathy (MN), whereas the proportions of other major glomerulopathies remained stable regardless of the PM2.5 level [8]. From their adult series, MN was the leading cause of NS in adults aged > 40 years, while MCD was the most common histologic diagnosis among adults aged ≤ 39 years [8]. Exposure to the M-type phospholipase A2 receptor (PLA2R1) is critical for triggering the pathogenesis of PLA2R1-associated MN. Inflammation induced by air pollution, such as PM2.5, has been proposed to alter the microenvironment of PLA2R1-expressing cells [33]. PM2.5 also causes early kidney damage through oxidative stress or inflammation in the kidney microenvironment [34]. Lin et al. reported that higher concentrations of PM2.5, NO, NO2, and SO2 are associated with an increased risk of NS in adults [9]. However, in their study, the pathologic type of NS was not associated with air pollution [9]. In our study, we found that children exposed to higher concentrations of SO2, THC, and CH4 were associated with the risks of INS, mostly MCD. Although the exact biological mechanisms of air pollution and its effects on NS remain unclear, it is generally accepted that air pollutants entering the respiratory tract can be absorbed into the bloodstream through alveolar capillaries, resulting in systemic inflammation and oxidative stress [35,36,37]. An increase of reactive oxygen species (ROS) and the imbalance of ROS and ROS-inhibitory system were found in the blood of MCD patients [38, 39]. The systemic inflammation and oxidative stress disrupt the glomerular basement membrane and reduce de novo proteoglycan production, leading to the increase of glomerular basement membrane permeability and therefore cause proteinuria [40].

Overall, the importance and distinctiveness of our study were based on several aspects. First, our study appears to be the first population-based study assessing the association between air pollutants and INS in children. Children, one of the most susceptible subgroups of the population due to their immature respiratory, immune, reproductive, central nervous, and digestive systems, have a higher inhalation and resting metabolic rate of oxygen consumption per unit body weight than adults [41]. Second, except for nitrogen oxide, ozone, and particulate matter, which have been studies previously, our current study demonstrated the association of three types of gaseous pollutants, SO2, THC, and CH4, and INS. Third, in this study, we assessed the real-world data from the NHI program as our datasets; hence, the potential for selection bias could be minimized. Furthermore, we also tried to adjust for the confounding factors including sex, age, monthly income, and urbanization level to alleviate possible bias as well.

Our study had several limitations. First of all, the migration of our study population during the study period may be neglected. However, the bias could be minimized based on the 12-year compulsory education in Taiwan. The majority of children would stay studying in the fixed school district till the compulsory education ended. And the fact, change the place of residence is not quite common in children in Taiwan. Second, we were unable to acquire the individual results of kidney biopsy, which is often recommended in patients with NS to establish the pathologic subtype of the disease, to assess disease activity, or to confirm the diagnosis of diseases. Since kidney biopsy is usually not indicated for first presentation of childhood INS and empirical steroid treatment can be considered prior to kidney biopsy. Nevertheless, according to a previous study, even though most of children with INS had been coded as unspecified pathological lesion in kidney, their pathology should be MCD [11]. Third, several potential risk factors for NS, such as familial predisposition, genetic mutations, lifestyle, diet preference, previous over-the-counter medication, family history, exposure to other toxic substances, such as water pollution, heavy metals and smoking/tobacco exposure, and known viral and other infections like CMV, syphilis, malaria etc., could not be estimated in this study due to the insufficient information available in the NHIRD.

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