Elevated exposure to air pollutants accelerates primary glomerular disease progression

Authors: Jonathan P Troost, Abhijit V Kshirsagar, Lawrence S Engel, Cassandra R O'Lenick, William E Smoyer, Jon Klein, Margaret Helmuth, Laura H Mariani, Matthias Kretzler, Abigail R Smith, Forrest Lacey, Howard Trachtman

Abstract

Air pollution is a global problem and a major contributor to adverse health outcomes in patients of all ages. Most research has focused on the adverse effects of air pollution on cardiopulmonary events such as myocardial infarction, stroke and lung disease, with less attention given to kidney outcomes. In recent years, there is emerging evidence that air pollution contributes to the onset and progression of chronic kidney disease and, specifically, glomerular disease. This has been confirmed in epidemiological studies performed around the world. In this review, we (i) the major sources and components of air pollution; (ii) published reports detailing the relationship between air pollution exposure and the incidence and the clinical course of chronic kidney disease; and (iii) the existing literature assessing the impact of air pollution on the progression of primary glomerular diseases. We highlight important gaps in knowledge and the need for future collaborative work involving environmental scientists, epidemiologists and nephrologists to better understand the contribution of air pollution to the increasing number of people worldwide with

chronic kidney disease. This work is important because air pollution exposure represents a potentially modifiable risk factor for chronic kidney disease progression that can be addressed by regulatory action, personal behaviors and implementation of interventions to prevent or limit exposure.

INTRODUCTION

Air pollution and effects on health

Air pollution is a global problem that affects individuals of all ages and has an adverse impact on virtually every body organ system [1]. In 2021, it ranked as the second most significant risk factor for mortality among persons across the lifespan regardless of gender, race or ethnicity [1]. More than 90% of the world's population resides in locations that exceed the World Health Organization (WHO) guideline for healthy air and nearly half are exposed to ambient conditions that do not satisfy the least strict criteria of satisfactory air quality [2, 3]. There is abundant epidemiological evidence linking exposure to air pollution and its specific components to organ-specific morbidity, including dementia [4] and schizophrenia [5], and low birth weight in newborn infants [6].

The effects of air pollution on cardiopulmonary disease are the most well-established adverse health consequence considering that the lungs are the primary locus of exposure and the integral linkage between lung and heart function [1, 2]. Thus, an estimated 50% of chronic obstructive pulmonary disease is attributable to air pollution exposure. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee has formulated recommendations to mitigate the risk [7]. Neighborhood environmental burden including levels of air pollution are associated with higher prevalence of cardiovascular risk factors, including hypertension, diabetes, and obesity and cardiovascular diseases, specifically coronary heart disease and stroke [8, 9]. Notably, the health consequences of air pollution tend to fall disproportionately on socially disadvantaged populations in the USA and those living in low-income countries, subgroups that are also more vulnerable to cardiovascular disease overall [10–12].

Despite widespread recognition of the close interaction between the cardiopulmonary system and the kidneys, until recently, there has been limited attention paid to the impact of air pollution on the occurrence and progression of kidney diseases in the general population and in patients receiving renal replacement therapy [13–15]. This is especially noteworthy in view of the dramatic rise in the prevalence of chronic kidney disease (CKD) globally, and the increase in disability and mortality attributable to this condition [3]. In this review, we summarize the existing data regarding the impact of air pollution on the course of CKD with a special emphasis on the subset of patients with primary glomerular disease. We offer suggestions to promote awareness of this problem and preliminary proposals to mitigate the burden of kidney disease attributable to this ubiquitous environmental exposure.

DESCRIPTION OF AIR POLLUTANTS

Air pollutants are gases and aerosols (particulates) that are created by the release of harmful solids, liquids and/or gases into the surrounding indoor or outdoor environment. Natural processes such as volcanic activity, wildfires, sea spray and dust storms release air pollutants; however, anthropogenic activity is responsible for most of the ambient air pollution impacting populated areas [16, 17]. Researchers and policy makers typically classify air pollutants generated by human activity based on whether their sources are mobile (e.g. transportation vehicles), stationary (e.g. power plants), or produced over a defined area (agricultural areas, cities). Another way to classify pollutants is based on whether pollutants are emitted directly (primary pollutants) or generated from chemical reactions in the atmosphere (secondary pollutants). The United States Environmental Protection Agency regulates six hazardous and abundant air pollutants, known as the Criteria Pollutants: carbon monoxide (CO), lead, nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2) and particulate matter. Other less common hazardous air pollutants include volatile organic compounds (VOCs) (e.g. benzene, formaldehyde, polycyclic aromatic hydrocarbons) which have both indoor and outdoor sources and are produced from various anthropogenic and natural processes. Although VOCs are necessary precursors to many pollutants including ozone and secondary organic aerosols which represent a significant fraction of total particulate matter concentrations, this class of molecules will not be covered in this review.

Particulate matter is further distinguished by the size of the particles and the chemical compounds (‘species’) that comprise the particles. Coarse particulate matter is defined as having an aerodynamic diameter <10 µm (PM10) and fine particulate matter as having an aerodynamic diameter <2.5 µm (PM2.5). Major sources of PM2.5 include wildland fire emissions, agricultural applications, windblown dust, sea spray, incomplete fuel combustion, traffic-related emissions (mobile sources) and industrial emissions (stationary sources). PM2.5 suspended in the atmosphere can be transported and deposited over long distances, far from its source [17]. In any given location, local meteorology and atmospheric conditions, as well as the interaction of diverse sources play a role in the formation of PM2.5, the dominant chemical constituents adhered to the particulate surface, and total PM2.5 mass [18–20]. Major PM2.5 constituents include metal oxides, sulfate, nitrate, ammonium, mineral dust, sea salt, organic matter, or organic carbon, and elemental or black carbon (BC) [21]. Particulates with a high fraction of BC are typically generated from incomplete combustion of traffic-related sources, with smaller contributions coming from residential and industrial sources. Organic carbon is a complex mixture often generated from biomass burning (e.g. wildfires) and reactions with VOCs from natural and anthropogenic sources, with additional sources from traffic, residential, industrial and secondary sources [22]. Major contributors to sulfate formation include volcanic activity, coal-fired power plants, and gasoline and diesel fuels containing sulfur. Ammonium and nitrate species are often generated by agricultural processes in rural locations, and by fossil fuel combustion in urban environments [22]. Figure 1 illustrates the common sources of air pollution and its specific components.

Fine particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) is especially concerning for human health as it can penetrate deep into the respiratory system and diffuse into the bloodstream through capillaries adjacent to the alveolar wall. This enables the particles and their adhered chemicals to translocate into the circulatory system and be transported to other organs. The kidney may be especially vulnerable because of the high renal blood flow, enabling delivery of the particulate matter to all the renal structural components, namely glomeruli and the tubulointerstitium [23]. Furthermore, the various chemical species adhered to the particulate surface are thought to have differential toxicity. Yet currently, complex source apportionment models, necessary to characterize the sources of PM2.5 species, may be challenging to undertake across multiple geolocations. Thus, few multi-city epidemiological studies have explored the health effects of source-specific PM2.5 species and our understanding of their contribution to adverse kidney health outcomes is in its infancy. PM2.5 chemical composition also varies geographically based on combustion sources, season/meteorology and atmospheric chemistry. Improvements in satellite- and land-based monitoring equipment will refine the quantitation of air pollution and its components and its impact on kidney health.

MECHANISM OF AIR POLLUTION-INDUCED INJURY

There has been extensive investigation into the injury pathways that are provoked by exposure to air pollution, mainly PM2.5, under both in vivo and in vitro conditions. Exposure to fine particulate matter triggers direct damage to endothelial cells, attributed in part to impaired function of endothelial stem/progenitor cells [24]. In addition, particulate matter disrupts epithelial barrier integrity in lung airways, leading to increased permeability and impaired cell proliferation and repair [25, 26]. Both of these cells would be prominent targets of injury in the kidney.

The two primary mechanisms of air pollution-induced injury include activation of inflammatory signaling and exacerbation of oxidative stress. Thus, exposure to PM2.5 is associated with increased circulating levels of a wide range of inflammatory mediators including platelet-derived growth factor, regulated on activation, normal T-cell-expressed and secreted (RANTES), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β and IL-8, and endothelin-1 [24, 27]. Exposure to both PM2.5 and ultrafine particles (<0.1 μM) is associated with increased pulmonary tissue levels of markers of reactive oxygen molecules such as superoxide, hydroxyl radical, nitric oxide and peroxynitrite [28]. Antioxidant interventions reduce the extent of lung injury secondary to air pollution exposure [29].

There is less literature focusing specifically on the effects of air pollution exposure on kidney cells or renal function. However, the existing evidence supports similar mechanisms of action in the lung and kidney. Thus, repeated exposure to fine particulate matter in experimental animals induces renal tubular injury evidenced by increased excretion of kidney injury molecule-1 in conjunction with upregulation of inflammatory cytokines, infiltration of inflammatory cells, and reduced activity of antioxidant enzymes [30]. PM2.5 exposure amplifies oxidant stress and exacerbates the degree of kidney dysfunction in the ischemia–reperfusion model of acute kidney injury [31]. Tubular injury and direct DNA damage exacerbates kidney dysfunction by activating the stimulator of interferon genes (STING) pathway and augmenting the inflammatory response [31]. PM2.5 exposure increased oxidative stress, autophagy and pyroptosis in mice, effects that were confirmed in cultured HK-2 cells (proximal tubule analog). Treatment with the free radical scavenger N-acetyl-l-cysteine attenuated the damage, both in vivo and in vitro [32, 33]. The schematic illustration summarizes the pathways that have been suggested to contribute to renal damage and potentially accelerate progression in patients with kidney disease (Fig. 2).

EPIDEMIOLOGIC STUDIES OF AIR POLLUTION AND KIDNEY DISEASE

Chronic kidney disease

Bowe et al. [34] were the first to demonstrate a relationship between air pollution and kidney events. They built an observational cohort of 2 482 737 US veterans using databases from the Environmental Protection Agency and the Department of Veterans Affairs. County-level exposure to PM2.5 was defined at baseline as the annual average PM2.5 concentrations in 2004 and then as time-varying with annual updates and as cohort participants moved. The median baseline exposure was 11.8 µg/m^3^. In a model that was adjusted for among other factors age, cardiovascular disease, chronic lung disease, diabetes mellitus, baseline estimated glomerular filtration rate (eGFR) and county % in poverty, a 10-µg/m^3^ increase in PM2.5 concentration was associated with increased risk of incident eGFR <60 mL/min/1.73 m^2^, {hazard ratio (HR) 1.21 [95% confidence interval (CI) 1.14–1.29]}, eGFR decline ≥30% [HR 1.28 (95% CI 1.18–1.39)] and end-stage kidney disease (ESKD) [HR 1.26 (95% CI 1.17–1.35)]. The time-varying analyses and exposures derived from an alternative source of PM2.5 exposure data, the National Aeronautics and Space Administration satellite data, yielded similar findings. Of note, in a separate analysis of data from 194 countries, these investigators confirmed a significant global health burden associated with exposure to particulate PM2.5 air pollution [35]. In the USA, county-level PM2.5 exposure in 1.1 million persons from the 2010 5% Medicare sample showed an adjusted prevalence ratio of 1.03 for diagnosed CKD for each 4 μg/m^3^ increase in PM2.5 level [36]. These findings have been confirmed in smaller regional studies. Among 10 997 participants from the Atherosclerosis Risk in Communities cohort who were followed from 1996–98 through 2016, each 1-μg/m^3^ higher annual average PM2.5 was associated with higher levels of albuminuria and a higher risk of incident CKD (HR 1.05) [37]. In 20 289 residents in the twin-cities area in Minnesota during the period 2012–19, PM2.5 exposure was associated with HR of 2.52, 2.18 and 1.72 of developing CKD (eGFR <45 mL/min/1.73 m^2^) among the fourth (PM2.5 >10.8), third (10.3 < PM2.5 ≤ 10.8) and second quartile (9.9 < PM2.5 ≤ 10.3) vs the first quartile (≤9.9 μg/m^3^), respectively [38].

Reports from Asia have replicated this association between air pollution and incident CKD, with the bulk of the studies having been conducted in China. Based on data from the China National Survey of CKD, which included a representative sample of 47 204 adults, an increase of 10 μg/m^3^ in PM2.5 was positively associated with CKD prevalence [odds ratio (OR) 1.28] and albuminuria (OR 1.39) [39]. In a larger sample of 80 225 adult participants in the China Multi-Ethnic Cohort, investigators estimated 3-year average concentrations of PM2.5 and SO2. They found that an increase of 1 μg/m^3^ in SO2 was positively associated with CKD [HR 1.07 (95% CI 1.00–1.14)]; per 10 μg/m^3^ increase in PM2.5, the HR for CKD was 1.17 (95% CI 0.99–1.38) [40]. A smaller study included 22 425 participants ≥18 years without CKD who lived in Hunan Province. Over a median follow-up of 3.8 years, a total of 2188 participants developed incident CKD. PM2.5 exposure was associated with incident CKD with an adjusted HR of 1.71 per 10-μg/m^3^ increase in long-term exposure [41]. In 8996 adults who did not have CKD at baseline, an interquartile range (IQR) increase in BC over a 3-year period was significantly associated with eGFR decline and the combined effect of the PM2.5 component mixture was found to be associated with lower eGFR [42]. Using data from nationwide representative cross-sectional surveys in China and validated composition datasets, significant associations between long-term exposures to specific PM2.5 components including PM2.5, BC and sulfate (SO4^2−^) were associated with significantly increased odds of CKD prevalence. Specifically, for a 10 μg/m^3^ increase in PM2.5 and an IQR increment in BC (3.3 μg/m^3^) and SO4^2−^ (9.7 μg/m^3^), the OR for CKD prevalence was 1.13, 1.28 and 1.23, respectively [43, 44]. In a smaller cohort study, based on 2082 residents living in Beijing from 2013 to 2018 and enrolled in the Beijing Health Management Cohort (BHMC), after adjusting for confounders, each 10 μg/m^3^ increase in PM2.5 and PM10 exposure was associated with an OR 1.84 and 1.37, respectively, of developing CKD [45]. Of note, the degree of urbanization may modify the relationship between PM2.5 exposure and the risk of developing CKD, with the most deleterious effect noted in middle-urbanized versus low or highly urbanized areas. This observation was unexplained and warrants further study [46].

Large scale studies have also been conducted in Taiwan to address the relationship between air pollution and CKD. In a cohort of 100 629 non-CKD adults at baseline between 2001 and 2014, during follow-up, 4046 incident CKD cases were identified. Every 10 μg/m^3^ increment in the PM2.5 concentration was associated with an HR 1.06 for development of CKD [47]. The Taiwan Air Quality Monitoring Database was linked to the Longitudinal Health Insurance Database in an observational cohort of 161 970 adults who did not have CKD at baseline. Compared with the lowest quartile of SO2, the highest quartile of exposure was associated with an increased HR 1.4 of developing CKD and increased HR 1.32 of ESKD. Similarly, the highest quartile of PM2.5 exposure had an HR 1.74 of developing CKD and HR 1.69 for ESKD [48]. Using data from the seventh Korean National Health and Nutrition Examination Survey 2016 through 2018, a total of 15 983 adults were included in the analysis. Long-term exposure to PM2.5 was associated with decreases in eGFR levels –4.67 mL/min/1.73 m^2^ from baseline and an OR 1.97 for incident CKD [49].

It is worth noting that two studies failed to detect an association between air pollution and incident CKD. The first, a study of 24 407 Korean adults, found no association for exposure to PM10, NO2, SO2 and CO with CKD in a fully adjusted analysis [50]. The second involved a survey of 164 093 adults ≥40 years old between 2002 and 2005 from the Korean National Health Insurance Service National Sample Cohort and it also did not show an association between exposures to PM10, NO2, SO2, CO and O3 and incident CKD after adjustments for age, sex, household income, area of residence and the Charlson comorbidity index [51].

The adverse impact of air pollution on CKD has also been documented in European populations. In a large multicenter population-based European cohort (n = 289 564), the HR for CKD-related mortality was 1.31 per 5 μg/m^3^ increase in PM2.5 and 1.26 per 0.5 × 10^−^  ^5^/m^3^ increase in BC [52]. Regional studies conducted in Norway involved 30 396 individuals followed for up to 25 years. Significantly elevated HRs for incident CKD were found for BC, 1.12 per interquartile range increase in exposure in the previous 1–5 years. For total PM2.5, there was a trend but the HR of 1.12 was not significant [53]. Two studies, leveraging the UK Biobank, reinforce the observed link between air pollution and CKD. Among 458 968 participants, during a median follow-up of 11.7 years, there was a positive association between air pollutant exposure and CKD risk, with an HR 1.09–1.12 for PM2.5 that was evident even at relatively low levels of exposure and small interquartile increments. There was minimal interaction with genetic background [54, 55].

The association between air pollution exposure and kidney function has been extended to the pediatric population in a single study from Taiwan. Among 10 942 children and adolescents (mean age 19 years) from Taiwan and Hong Kong between 2000 and 2017, each 10 μg/m^3^ increase in PM2.5 was associated with a 0.45 μL/min/1.73 m^2^ reduction in the yearly increase in eGFR and 1.53 HR of incident CKD [56].

Although most studies examined the association of air pollution with incident/prevalent CKD, three studies from Taiwan have directly investigated the potential role of air pollution exposure on the progression of CKD. In the first, among 6628 patients with CKD, age 20–90 years, the adjusted HR for progression to kidney failure was 1.19 per 7.8 μg/m^3^ greater PM2.5, with evidence of an exposure-response relationship [57]. In the second, 5301 patients with CKD were followed for a mean duration of 30 months. Over that period, patients with the highest quartile exposure to SO2 and PM2.5 had a significantly higher risk of renal progression than those with the lowest quartile exposure, HR 2.27 and HR 7.58, respectively [58]. A third study involved a cohort of patients with CKD Stage 3b–5 (N = 11 479) from Taichung Veterans General Hospital during January 2006 to December 2020. After adjusting for baseline eGFR stages and other relevant clinical factors, the risk of eGFR deterioration was found to increase with increasing PM2.5 level, especially for those exposed to PM2.5 ≥31.44 μg/m^3^ [59]

To summarize this section, there are generally consistent data that air pollution exposure is associated with an increased risk of incident CKD across the lifespan and, potentially also with accelerated progression of CKD. There are important gaps in this area of study. In particular, most studies treat individuals with CKD homogenously, failing to distinguish among the various causes of kidney disease. Furthermore, the analyses primarily define the exposure period in terms of months or years and do not address the effects of acute changes in pollutant levels. In addition, the majority of the reports focus exclusively on the impact of PM2.5 without any assessment of its components or the effect of multiple, combined pollutant exposures. The HR is in the range of 1.05–1.15 but the effect is modest because this increase in HR is often associated with a 10 μg/m^3^ increase in PM2.5, a degree of change that exceeds the ambient level in many regions around the world including North America and Europe. The increment represents nearly a doubling of exposure levels in most regions of the world where the ambient level is in the range of 10–12 μg/m^3^.

Primary glomerular disease

Membranous nephropathy

Studies have assessed the impact of air pollution on specific types of primary glomerular disease. The first investigations were done in membranous nephropathy (MN). In 2016, Xu et al. [60] examined the trend in the diagnosis made in 71 151 native kidney biopsies obtained at 938 hospitals in China over the period from 2004 to 2014. In addition, the relationship between long-term exposure to PM2.5 with other specific glomerular disease entities was explored. Over the time period, MN was the second most common diagnosis (23%) after immunoglobulin A nephropathy (IgAN) (28%). Interestingly, while the incidence of other glomerulopathies was stable, the incidence of MN increased by 13% per year; each 10 μg/m^3^ increase in PM2.5 concentration was associated with an increased OR 1.14 (95% CI 1.10–1.18) for having MN in regions with high levels of air pollution, namely PM2.5 concentration >70 μg/m^3^. Notably, this level of air pollution is substantially higher than in most other reports from China, North America or Europe. However, in a recent Mendelian randomization study of genes linked to DNA methylation related to air pollution and the diagnosis of MN, there was a causal relationship with exposure to nitrogen oxides but not PM2.5 [61]. Of note, the association between air pollution or its components and MN has not been assessed outside of China. In addition, the impact of air pollution on the clinical course of MN has also not been investigated.

Immunoglobulin A nephropathy

IgAN is the most common primary glomerular disease in the world, especially in Pacific rim countries. However, no studies have examined the association of air pollution and IgAN incidence and only one study examined the link with progression. In a study from China, 1979 patients with IgAN (994 males) with biopsy-proven primary IgAN were recruited at seven kidney disease centers during the period 1998 to 2016. Each 10 μg/m^3^ increase in the annual average concentration of PM2.5 exposure in the year before study entry or time varying PM2.5 exposure after entry was associated with an increased risk of kidney failure, HR 1.14 (95% CI 1.06–1.22) or 1.10 (95% CI 1.01–1.18), respectively. The findings remained significant after adjustment for age, gender, eGFR, proteinuria, anemia, blood pressure, Oxford classification and treatment [62].

Other diagnoses

There are no studies evaluating the impact of air pollution on other forms of primary glomerular disease, including minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). There are studies that report an association of air pollution exposure and relapses or flares of lupus nephritis in adult and pediatric patients. In 2672 adults with lupus nephritis, an IQR increase in PM2.5 and NO2 was associated with an OR of 1.16 and 1.19, respectively, for a kidney flare within 1 month after exposure [63]. It is worth noting that the association between acute exposure and disease activity is stronger epidemiological evidence for an adverse effect of air pollution on kidney health. In another study with 108 repeated measures over a 1-year period in nine children with systemic lupus erythematosus, an IQR increase of 18.12 μg/m^3^ in PM2.5 daily concentration was associated with increased risk of nephritis [64].

Primary glomerular disease as a group

In order to fill the gap in knowledge about the impact of air pollution on the clinical course of patients with primary glomerular diseases, we took advantage of two large-scale prospective observational cohort studies that enrolled participants with these rare disorders. The Nephrotic Syndrome Study Network (NEPTUNE) recruits patients with proteinuria at the time of a diagnostic biopsy or pediatric patients with new-onset nephrotic syndrome. It longitudinally follows patients with a diagnosis of MCD, FSGS or MN [65]. The CureGlomerulonephropathy (CureGN) study enrolls prevalent patients with biopsy-confirmed MCD, FSGS, MN or IgAN within 5 years of diagnosis [66]. We identified a subset of pediatric and adult patients from the two cohorts who were followed for a minimum of 2 years and who had validated census tract data to define air pollution exposure [67]. To estimate ambient air quality, we leveraged a publicly available database (https://sites.wustl.edu/acag/datasets/surface-pm2-5/) of estimated surface PM2.5 concentrations, formed from a fusion of model results with satellite and ground-based observations available in annual and monthly average estimates at a spatial resolution of approximately 1 km × 1 km. We focused on PM2.5, BC and sulfates. Our objectives were to determine (i) higher levels of residential PM2.5 are associated with increased risk of disease progression; and (ii) the level of exposure is associated with the serum concentration of pro-inflammatory biomarkers and with intra-renal inflammatory pathway signaling.

The study cohort was comprised of 925 patients in total, 228 from NEPTUNE and 697 from CureGN. The baseline levels of exposure to the three individual air pollution components were comparable in the two subgroups and were significantly correlated with one another. Patients with exposures to the three pollutants above the median were older, more likely to be Black, and had a lower eGFR at baseline. Moreover, those with exposure above the median for one of the pollutants had higher levels of exposure to the other two pollutants, compared with participants with exposures below the median. This is consistent with reported disparities in exposure to air pollution and related health effects by social determinants of health such as race and socioeconomic status [68].

Overall, 226 out of the 925 participants (24%) experienced disease progression defined as a 40% decline in eGFR or progressed to ESKD. Combining both cohorts, in a model that was fully adjusted for age, baseline eGFR, race and maternal education as a surrogate for socioeconomic status, kidney disease progression was associated with exposure to PM2.5 and BC. Thus, per 1 standard deviation (SD) increment in exposure to PM2.5, the HR was 1.55 (95% CI 1.00–2.38), *P *= .0489, and for BC the HR was 1.43 (95% CI 0.98–2.07), *P *= .0608. These findings were confirmed in a time-to-event analysis. Recognizing that the HR for disease progression was based on a 1 SD increment in exposure, considerably less than a 10 μg/m^3^ increase in much of the environmental sciences literature, this suggests that patients with primary glomerular disorders may have heightened susceptibility to the adverse effects of air pollution.

It has been demonstrated that certain air pollutants trigger not only pulmonary inflammation but can also contribute to a systemic inflammatory state. In our cohort, serum concentration of TNF was directly associated with the degree of exposure to sulfates (r = 0.71, *P *= .003), while the serum concentration of IL-1β was directly related to PM2.5 exposure (r = 0.51, *P *= .03). Moreover, sulfate exposure was positively correlated with scores of gene expression activation of both the TNF and JAK-STAT (Janus kinase/signal transducers and activators of transcription) signaling pathways in both the glomerular and tubular tissue compartments (r = 0.55–0.67, *P *< .01), establishing a link between intra-renal inflammatory markers and subsequent renal disease progression. Overall, our findings provide supportive evidence for the adverse effect of air pollution on disease trajectory in patients with primary glomerular diseases and that the accelerated progression may be mediated, directly or indirectly, in part by activation of inflammatory pathways.

POTENTIAL APPROACHES TO REDUCE EXPOSURE

Individual citizens may find it difficult to limit exposure to air pollution because a significant portions are generated by the industrial sectors and environmental events beyond their control. Legislation to restrict emissions of air pollution is essential to reduce the global health burden and renal consequences of air pollution. Measures have been enacted in many countries with documented improvements in the control of components of air pollution [69, 70]. In the USA, imposition of limits on emissions has been subject to changes in the political environment. As such, strategies such as emission trading that reflect free market activity may have a higher likelihood of successful uptake and implementation [71]. Notably, government actions to address air pollution have met with regional success, e.g. significant reductions in ambient levels of PM2.5 and particulate black smoke in California and Ireland, respectively [72, 73].

Domestic activities also contribute to air pollution, especially indoor, on an individual patient level and are potentially modifiable. The use of gas-burning stoves and wood-burning stoves and fireplaces for heating are associated with worsening air quality and increased levels of toxic particulate matter [74, 75]. Finally, installation of permanent high-quality air filters in homes and other buildings reduces indoor levels of PM2.5. A review of published studies involving filters suggests that they are associated with subclinical cardiovascular health benefits [76]. There is less information regarding the beneficial impact of wearing face masks because they may have limited efficacy in reducing exposure [77]. Nearly all of the reports that address the impact of societal or individual interventions to reduce air pollution exposure focus on cardiovascular/pulmonary health. No clinical studies have been performed to assess whether these maneuvers have a favorable effect on the course of disease in patients with primary glomerular disease or CKD.

FUTURE DIRECTIONS

While the observed associations between air pollution and kidney disease incidence and progression seem plausible, there is a pressing need to delineate the mechanism(s) of injury on kidney structure and function. This may be especially relevant for patients with primary glomerular disorders in whom disease-related mechanisms of injury may interact synergistically with pathways that are activated by air pollution and that may potentially exacerbate the rate of disease progression.

Furthermore, the effects on the relationship of air pollution and CKD of patient age, gender, social determinants of health including level of education, occupation and residential status, type of kidney disease, and genetic factors (e.g. APOL1 high-risk alleles and known genetic modifiers) should be systematically investigated [78]. Methods are needed to disentangle the potential confounding socioeconomic effects of living in areas with high levels of pollution from the effect of pollution itself. Studying the impact of acute as well as chronic exposures on glomerular disease activity would strengthen the evidence in support of the adverse effects of the environmental exposures. The diverse health outcomes related to air pollution exposure in patients with glomerular disorders warrants systematic investigation. Such efforts, summarized in Fig. 3, would likely entail an international collaborative effort to adequately address regional differences in exposure to air pollution and to better understand the interaction with other environmental factors such as ambient temperature and other environmental contaminants [79]. The threat of global warming and emergence of uncontrolled wildfires as an increasingly common event highlight the urgency of defining the full range of adverse effects of air pollution on kidney function in health [80].

Finally, it is important to note that air pollution exposure represents a potentially modifiable risk factor for kidney disease progression. To date, efforts to limit air pollution exposure have mainly focused on public policy initiatives such as imposition of legal restrictions on emissions produced by public and industrial sources. However, altered behavior and implementation of simple maneuvers including masks and air filters in the home and/or workplace may help to attenuate the effects of air pollution exposure and mitigate its adverse effects on kidney health and renal disease progression [81]. The potential benefit of these interventions need to be evaluated in innovative clinical trials of patients with CKD and primary glomerular disorders. We encourage the nephrology community to take the lead in studying the impact of air pollution on health and to collaborate with environmental scientists, policy experts and other health professionals to devise strategies to reduce air pollution globally and develop feasible approaches to reduce the adverse health effects on the individual patient level.