Particulate matter (PM) is a mixture of suspended liquid and solid particles in air. The PM has a number of components, including nitrates, sulfates, ammonium, other inorganic ions, and metals (1). Air pollutants involving particles with diameter <10 μm (PM₁₀) and 2.5 μm (PM_2.5), nitrogen dioxide (NO₂), ozone, carbon monoxide (CO), and sulfur dioxide are common health-related concerns. Exposures to high levels of air pollutants are associated with increased risk of hypertension, cardiovascular disease, chronic kidney disease (CKD), stroke, lung cancer, and death (2–11).

The high global burden of kidney disease may be attributed to air pollution (12). In vitro and in vivo studies have shown that traffic-related diesel PM exposure can induce nephrotoxicity by promoting oxidative stress, inflammation, and DNA damage (13, 14). Residential proximity to major roadways and increased levels of PM_2.5 in a cohort of patients with acute ischemic stroke were associated with reduced estimated glomerular filtration rate (eGFR) (15). In the Veterans Administrative Normative Aging Study cohort, long-term environmental exposure to higher concentrations of ambient fine PM in elderly patients with mean eGFR of 76.5 ml/min/1.73 m² was associated with increased risk of eGFR decline (8). Two United States Veterans cohort studies demonstrated significant associations between exposure to PM, NO₂, and CO and risk of CKD, eGFR decline, and end-stage renal disease (ESRD) (5, 6). A non-CKD Taiwanese cohort study indicated that long-term exposure to ambient PM_2.5 was associated with increased risk of CKD development (16).

However, participants in the above studies were not representative of the population of patients with advanced CKD and eGFR <45 ml/min/1.73 m². Limited studies have examined the association between PM_2.5 and CKD progression in patients with advanced CKD. Whether PM_2.5 has an impact on the deterioration of kidney disease in this sensitive population is a topic worthy of further study. In the present study, we aimed to evaluate the relationships of air pollutants and eGFR deterioration in patients with pre-ESRD and stage 3b to stage 5 CKD.

It has been suggested that the resolution of location-based air pollution data is frequently lower than for location-based health data. Hence, when integrating these two types of data to characterize the relationship between exposure and health, variation in the spatial correspondence between the two can be an issue. The model used to predict the exposure concentrations of PM_2.5 and NO₂ in this study was a kriging/LUR model. The output cell size was 50 ×50 m. The simulation model was validated using a 10-fold cross-validation approach: 90% Taiwan EPA monitoring data for model development and 10% data for validation. The R² value for the kriging/LUR model was 0.85 compared with 0.66 for the conventional LUR model (21). This demonstrated that the model showed good performance in predicting the concentrations of air pollution and enhancing the quality of characterization of exposure. It improved the accuracy of generation of reliable exposure data for health risk assessment (20, 23, 24). Limited studies have explored the effect of air pollutants on CKD progression, especially for patients with pre-ESRD. Consequently, in the present work, we used a kriging/LUR model to simulate the exposure concentrations. We found linear and nonlinear relationships of PM_2.5 and NO₂ with eGFR deterioration after adjusting for smoking status, baseline eGFR stage, and other traditional clinical factors.

We focused on patients with pre-ESRD because patients with CKD stage 3b had a high risk of mortality and kidney outcomes compared to those with stage 3a (25). The percentage of patients with stage 3b was also lower than that of patients with stage 3a (25). In this regard, studies on patients with pre-ESRD including stages 3b, 4, and 5 are important but scarce. Previous studies showed that eGFR deterioration was consistently associated with increased risks of death (26) and ESRD (27). In the present study, we found that air pollution was a significant risk factor for eGFR deterioration in patients with pre-ESRD. This finding implies that air pollution would probably contribute to death and ESRD in these patients in the future.

Several hypotheses can explain the relationship between PM_2.5 and eGFR deterioration. First, inhaled particles may provoke pulmonary inflammation, leading to systemic inflammation, including elevated levels of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), plasminogen activator inhibitor-1, and oxidative stress (28, 29). Second, inhaled pollutants may induce disturbances in the autonomic nervous system, as evident in increased atherosclerotic plaque area and decreased flow-mediated dilatation (30, 31). Finally, studies also suggest that exposure to ambient air pollutants can lead to metabolic disturbances, including insulin resistance and high blood lipid concentrations, which are known risk factors for kidney diseases (32).

In Taiwan, ambient air pollution has been a severe environmental problem and has attracted considerable attention from researchers and the general public (20, 33, 34). A widespread monitoring network was implemented beginning in 1998. Air pollution data were retrieved from all 76 fixed-site air-quality monitoring stations supervised by the Taiwan Air Quality Monitoring Network. The major sources of air pollution are local traffic as well as stationary pollution, such as industrial areas, incinerators, and cremations. Approximately 80% of the study participants lived in Taichung city, within an area of about 2,200 km², which included 20 industrial areas, three incinerators, two cremation sites, one large steelmaking plant, and the largest coal-fired power plant in Taiwan. Thus, extreme pollution episodes are not unusual in Taichung, especially in autumn (35). We also considered the above important land-use variables of the surrounding environment in our hybrid kriging/LUR models to estimate the levels of PM_2.5 and NO₂ for the residential address of each study patient (20). To reduce the potential interaction of air pollutants, we included the two pollutants in the same model. We found linear and nonlinear relationships of PM_2.5 and NO₂ with eGFR deterioration, especially for those exposed to the highest levels of PM_2.5 ≥ 31.44 μg/m³ and NO₂ ≥ 15.00 ppb.

One factor that cannot be ignored is that the aforementioned air pollution sources in Taichung, including thermal power plants, steel plants, and municipal waste incinerators, all utilize combustion processes and can generate incomplete combustion products. Studies have indicated that particle-bound metals play a very important role in the impact on human health (36, 37). For example, iron, manganese, lead (Pb), zinc are dominant species emitted from basic oxygen steelmaking and iron ore sinter plants (38). It is suggested that arsenic (As), selenium, mercury (Hg) are the major metals emitted with coal combustion (39, 40), and cadmium (Cd), Pb, and Hg are indicators of emissions from municipal solid waste incineration (41). Therefore, exposure to one or more of these metals is unavoidable in our study area. Moreover, metals such as As, Cd, Hg, and Pb are nephrotoxicants (42). Chronic exposure to one or more of these metals can lead to additional reductions in renal function.

Although many studies have explored the associations between air pollution and CKD incidence, this is the first study to explore eGFR deterioration of patients with pre-ESRD. Mehta et al. (8) studied long-term exposure to PM_2.5 and decline in renal function in older adults living in the Boston area of the US. They found that for every 2.1 μg/m³ increase in 1-year average PM_2.5 exposure, eGFR decreased by 1.87 ml/min/1.73 m² (95% CI: −2.99 to −0.76). Another study conducted in the US also found that a 10 μg/m³ increase in PM_2.5 concentration was associated with increased risk of eGFR decline of ≥ 30% in analyses considering baseline exposure (HR = 1.28; 95% CI: 1.26–1.39) (6). One study conducted in Taiwan showed that for every 8.7 μg/m³ increase in PM_2.5 exposure, progression to kidney failure with replacement therapy increased by 19% (HR = 1.19; 95% CI: 1.08–1.31) (43). Our study specifically focused on pre-ESRD patients and found that a unit increase in PM_2.5 exposure was associated with a significantly increased risk of eGFR deterioration (HR = 1.12; 95% CI: 1.10–1.13). Our results demonstrated that exposure to PM_2.5 is a risk factor for eGFR deterioration for patients with pre-ESRD.

The strength of this study is the retrospective cohort design with at least two repeated measurements of eGFR and regular follow-up in an integrated CKD care program. However, our study has some limitations that should be carefully considered. First, the estimates of individual PM_2.5 levels obtained using the hybrid kriging/LUR model may not reflect the actual exposure to air pollution because people may stay indoors more than 90% of the time. Second, exposure levels to air pollution were calculated as means from the period from recruitment to the date of eGFR deterioration, with an average time of about 1.5 years. A decline in renal function in such a short period of time seems unusual. We further used the various duration times from the earliest available air pollution data time to the date of eGFR deterioration (about 5.5 years) and obtained similar results (data not shown). Selecting another study design and analytical method, such as lag effect of short-term PM_2.5 and NO₂ exposure on eGFR deterioration, may be needed to clarify the observed relationships in future studies. Our study results indicate that exposure to high levels of PM_2.5 and NO₂ could be predictive risk factors for renal function decline in patients with advanced CKD. This work also supports an anti-air-pollution approach to prevent progression of advanced CKD. Additional evidence should be obtained from a variety of regions and populations to clarify the effects of PM_2.5 and NO₂ on renal health. Linear or nonlinear associations between the levels of PM_2.5 and NO₂ and the incidence risk of eGFR deterioration were observed.

This cohort study on patients with advanced CKD demonstrated that exposure to high levels of PM_2.5 and NO₂ could promote eGFR deterioration. This finding supports the global strategy to reduce air pollution and prevent the development of ESRD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and this study was approved by the Research Ethics Committee of Taichung Veterans General Hospital (CG20301A). All methods were performed in accordance with the relevant guidelines and regulations of Taichung Veterans General Hospital. The Ethics Committee waived the requirement of written informed consent for participation.

H-TH: had full access to all data in the study and takes responsibility for data integrity and accuracy of the data analysis, and administrative, technical, or material support. Y-HW, M-CC, C-DW, C-HC, C-JC, and H-TH: concept and design. M-CC, H-TH, L-YW, and C-JC: acquisition, analysis, or interpretation of data. M-CC, C-JC, and H-TH: manuscript drafting. M-CC and H-TH: critical revision of the manuscript for important intellectual content. L-YW: statistical analysis. All authors contributed to the article and approved the submitted version.

This study was supported by the Ministry of Science and Technology of Taiwan under Grant No. MOST 109-2221-E-039-011-MY2 given to H-TH.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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