Keywords

1 Introduction

Air pollution is becoming an ever more serious problem due to rapid urban industrialization and modernization (Chen 2007; Power et al. 2018). The World Health Organization (WHO) reports that 90% of the world’s population suffers from the polluted environment, while almost seven million deaths from air pollution every year are caused by exposure to fine particles (an annual average PM2.5 concentration above 10 μg/m3) (World Health Organization 2018a, b, c). Air pollutants are composed of gaseous substances, volatile substances, semi-volatile substances, and particulate matter (PM) mixture (Zanobetti et al. 2009). PMs with diameters that are generally 2.5 μm and smaller (e.g., PM2.5) have been found to have a greater impact on human health (Brunekreef and Holgate 2002; Costa et al. 2014). More than half of the global population is exposed to very low quality air (PM2.5 concentration > 35 μg/m3) (World Development Indicators 2017). After enrichment in PM2.5, the above substances can be deposited in the alveoli through respiration, and can even enter the blood circulation through the gas–blood barrier, thus reaching other tissues and organs, and causing damage to many systems such as respiration, circulation, and so on (Martinelli et al. 2013; Dominici et al. 2006; Zhu et al. 2015; World Health Organization 2018a, b, c).

Over recent years, the epidemiological studies have shown an obvious upward trend in the incidence of CKD. The global prevalence rate is about 11–13% and the incidence of adult CKD in China is around 10.8% (Zhang et al. 2012; Hill et al. 2016). Thus, the prevention and treatment of CKD are becoming vital public health problems faced by the whole world. The presence of some comorbidities such as cardiovascular disease(CVD), hypertension, and diabetes is a potential predictor of the rapid aggravation from CKD to the end-stage renal disease (ESRD). The increasing number of studies have shown that air pollution may be a new risk factor for CKD (Tonelli et al. 2012; Blum et al. 2020; Lin et al. 2020; Wu et al. 2020).

As an important organ involved in hemofiltration and toxin excretion, kidneys can be easily affected by air pollutants in blood, which is why the effect of PM2.5 exposure on kidney disease should not be ignored. In this review, we summarized the epidemiological evidence of kidney disease being associated with PM2.5 exposure, as well as the findings about the effects of PM2.5 on the progression of kidney disease. At the same time, we also discussed the possible mechanisms of kidney injury caused by PM2.5 exposure. Based on these findings, we developed a hypothesis that exposure to PM2.5 and CKD is interrelated and there are many biological mechanisms involved in this process.

2 Method

We searched on the World Wide Web for combinations of keywords such as fine particulate matter pollution, PM2.5, source apportionment of fine PM, constituents of PM2.5, PM2.5, and chronic kidney disease (CKD), PM2.5 and end-stage renal disease, PM2.5 and proteinurian in PubMed, Web of Science and Google Scholar. We selected 350 peer-reviewed articles published from 1998 to 2020 containing information on fine PM and related CKD. Among the articles searched, only articles that met the following criteria were included in the review: (1) Geographical location: Journals from all over the world were considered for the literature review; (2) Sample size: Sample size was not considered in the screening process; (3) Study methodology and statistical analysis: Research methods and the associated statistical analysis were not considered during the screening process; (4) Discussion of health effect: health effects using human or animal subjects. For global and country specific variations in fine PM, databases from government organizations like the National Clean Air Program (NCAP) in India, United States Environmental Protection Agency (US EPA) in the USA, European Environment Agency (EEA) for Europe, and World Health Organization (WHO) for global database were also screened (National Clean Air Programme 2019; European Environment Agency 2019; The U.S. Environmental Protection Agency 2012; World Health Organization 2018a, b, c). This review has selected 133 papers, of which PM2.5 and CKD related studies were distributed in the following countries (number of papers): China (34), Taiwan, China (5), India (3), Japan (2), South Korea (1), East Asia (1), USA (20), Canada (5), South Africa (1), United Arab Emirates (1), New Zealand (2), France (3), the UK (4), The Netherlands (2), Germany (1), Spain (1), Denmark (1), Greece (1), Europe (3), Global (8).

3 The Compositions of PM2.5

PM2.5 is one of the main components of air pollution and a major risk factor for the global disease burden (Cohen et al. 2017; Monn and Becker 1999). PM2.5 is not a simple pollutant, but a mixture of many substances (Harrison et al. 2004). It often derives from different outdoor emission sources and also has different chemical compositions. Chemical components include trace heavy metals (Cd, Cr, Cu, Mn, Ni, Pb, V, and Zn), organic compounds (volatile components and polycyclic aromatic hydrocarbons), carbonaceous aerosols (elemental carbon and organic carbon), inorganic mineral dust, sea salt and water-soluble inorganic ions (NO3−,SO42−,Cl−,F−,NO2−,Br−,NH4+, Na+, K+, Ca2+, Mg2+) (Tao et al. 2016; Feng et al. 2006; Morakinyo et al. 2016). To be specific, PM2.5 can also originate from indoor sources. Particles of indoor origin include components derived from biological sources. Biological components include pollen, microorganisms (fungi, bacterias, and virus) and organic compounds derived from microorganisms (endotoxin, metabolites, toxins, and other microbial fragments), many of which are known allergens (Douwes et al. 2003). The biological aerosol accounts for 5–34% of the indoor pollutants which may trigger the immune response, inflammation response, infectious disease, cancer, and other toxicity (Pollution Issues 2006; Air Quality Direct 2007; Douwes et al. 2000; Fung and Hughson 2003; Samake et al. 2017; Srikanth et al. 2008).

The wide distribution of heavy metals (metallic elements that have a relatively high density compared to water) and carbonaceous aerosols in PM2.5 results in severe biological problems (Zhang et al. 2016; Gadi et al. 2019). The combustion elements such as EC (elemental carbon) and combustion sources such as biomass burning (potassium, as the main trace element) have been shown to be strongly associated with mortality, compared to other components (Achilleos et al. 2017). Typical fuel oils contain Iron (Fe), Nickel (Ni), Vanadium (V), and Zinc (Zn) and they are reflected in the composition of fly ash produced from fossil-fuel combustion (Vouk and Piver 1983). The exposure to zinc may interfere with the vasoconstriction and vasodilation that increase the risk of CVD and upregulate the expression of cytokines and stress proteins (Graff et al. 2004). The exposure to vanadium and chromium potentially has a major role in inducing oxidative DNA damage (Sørensen et al. 2005). Sulfate, ammonium, and nitrate carried in PM2.5, usually found in coal combustion and vehicle emissions, are the main contributors to the haze in China, which can rapidly dissolve in the well-buffered lining fluids of the respiratory system (Harrison and Yin 2000). Polycyclic aromatic hydrocarbons (PAHs) in PM2.5 are formed by incomplete combustion and pyrolysis of organic substances such as coal, oil, natural gas, and wood, which can lead to carcinogenesis and gene mutation (Bandowe et al. 2014; Lundstedt et al. 2007; Yunker et al. 2002).The US Environmental Protection Agency reports that the acute exposure to PAHs may be harmful to human health (The U.S. Environmental Protection Agency 2012). However, the PAH levels in the atmosphere in China are generally higher than those in foreign countries (Farmer et al. 2003; Lee et al. 2005; Sharma et al. 2007; Wang et al. 2015).

In addition, studies from many institutions in different countries have shown that the concentration, characteristics, and toxicity of PM2.5 vary with time, season, location, and climate (Bell et al. 2008; Kim et al. 2019; Lee et al. 2019). Fine PM levels and exceedance of national and international standards were several times higher in Asian countries (Mukherjee and Agrawal 2017). The monitoring data of PM2.5 in 45 major cities around the world in 2013 showed that, as a result of the rapid expansion of cities and rapid economic growth, the highly polluted megacities were concentrated in east-central China and the Indo-Gangetic Plain, among which the most polluted areas were Delhi in India, Cairo in Egypt, and Tianjin in China with the highest annual average PM2.5 concentration (89 to 143 μg/m3) (Cheng et al. 2016). The satellite data evaluation model from 2004 to 2014 showed that the estimated value of 10-year average PM2.5 in the Beijing-Tianjin metropolitan region (including Beijing, Tianjin, and Hebei) was generally no less than 100 μg/m3. The 10-year average concentration of PM2.5 in Sichuan Basin and Yangtze River Delta is generally no less than 85 μg/m3, and it is no less than 55 μg/m3 in Pearl River Delta (Ma et al. 2015). PM2.5 levels vary greatly in different regions of the same country. It is worth noting that a recent study found that China’s average annual PM2.5 concentrations have dropped by 30% and 50% overall (Zhai et al. 2019). PM concentrations collected by the newest air quality monitoring network of the Ministry of Environmental Protection in 190 major cities in China between April 2014 and April 2015 show that the concentration of PM2.5 has a significant seasonal variation, which is highest in winter and lowest in summer (Zhang and Cao 2015). Although PM2.5 levels in China have gradually decreased in recent years, the incidence of CKD is still very high. The reason for this is probably that PM2.5 levels are still higher than the WHO guidelines recommend. In addition, the damage to the kidney caused by long-term exposure to PM2.5 is not transient, but usually has a sequelae effect.

Mounting evidence implicates the components of PM2.5 can translocate from the lungs into the circulation, are filtered and excreted by the kidneys. Although currently limited, data on the link between air pollution and kidney injury or disease in humans and in animal models are also now beginning to emerge.

4 PM2.5 and CKD: Epidemiological Studies

A large cohort study of 100, 629 non-CKD Taiwanese residents aged 20 or over found that long-term exposure to environmental PM2.5 was associated with an increased risk of CKD developing. For every 10 μg/m3 increase in PM2.5 concentration, the risk of CKD increased by 6% (HR:1.06, 95% CI:1.02, 1.10) (Chan et al. 2018). Of note, in this study a single measurement of eGFR <60 mL/min/1.73 m2 was used to define CKD while it might be due to acute kidney disease or other diseases; thus, some participants might have been misclassified as having CKD based on this criterion. Currently, a large number of studies have confirmed the epidemiological evidence of the relationship between renal disease and PM2.5 exposure. A large cohort of 2,482,737 veterans in the USA revealed that long-term exposure to PM2.5 was associated with an increased risk of CKD during a median follow-up of 8.52 years. For every 10 μg/m3 increase in PM2.5 concentration, the risk of developing CKD increased by 27% (HR, 1.27; 95% CI, 1.17 to 1.38) (Bowe et al. 2017, 2018). However, the study included only US veterans who were mostly older, white men. Therefore, the findings might not be generalizable to other populations. Furthermore, a median exposure to PM2.5 of the air quality in the USA is 10–11 μg/m3, which is better than most countries. A study of 71,151 native biopsies from 938 hospitals in China found that higher PM2.5 exposure was associated with the risk of membranous nephropathy. In areas with PM2.5 > 70 ug/m3, each 10 μg/m3 increase in PM2.5 concentration was associated with 14% higher odds for membranous nephropathy (odds ratio, 1.14; 95% CI, 1.10 to 1.18) (Xu et al. 2016). There were some limitations of this study. First, the study included only patients from whom renal biopsy samples were taken and not the general population. Furthermore, information on patient residence were limited to the city level, where levels of PM2.5 were generally higher than in other regions and might have led to an underestimation of the effect of PM2.5. It is of great clinical significance to studying the dose–response relationship between PM2.5 and the development and progression of CKD across a wide range of exposure levels. Bowe and his colleagues recently quantitated the global burden of CKD attributable to ambient air pollution in 2016 and found that more than 30% of disability-adjusted life years of CKD were related to PM2.5 exposure globally (Bowe et al. 2019). The study used the Global Burden of Disease study data and provided a quantitative analysis of the global burden of CKD attributable to PM2.5. Although its explanations and conclusions based on a raw analysis, the results provided an intuitive way to translate from the relative risk into attributable burden of CKD due to PM pollutants. Although its explanations and conclusions were based on raw analysis, the results provided an intuitive way to translate from the relative risk into attributable burden of CKD due to PM pollutants (Table 1).

Table 1 Summary of epidemiological studies on the association between fine particulate matter and chronic kidney disease
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There is a strong reason to believe that PM2.5 may be a novel environmental risk factor for CKD. Associations between long-term PM2.5 exposure and death were modified by many factors, such as other air pollutants like ozone and mercury (Lelieveld et al. 2019; Stojan et al. 2019), meteorological factors like temperature, resultant wind, relative humidity and barometric pressure, epidemiological and social factors like wealth gap between rich and poor (Kioumourtzoglou et al. 2016). However, in the same environment, some people are more likely than others to develop kidney disease. This may be due to susceptibility of the population.

Previous studies suggested that elderly people and children were especially susceptible to the harmful effects of PM2.5 exposure (Mehta et al. 2016; Bowe et al. 2017, 2018). These studies may be influenced by the aging of the population in Europe and the USA and the mean age of onset of CKD (Risk factor for CKD: age 60 or older) (Inker et al. 2014). In fact, vascular endothelial dysfunction worsens with age, and the vascular endothelium is more sensitive to pollutants and more vulnerable to injury in older people. Also, children and infants are susceptible to harm from inhaling PM2.5 because they inhale more air per pound of body weight than do adults – they breathe faster, spend more time outdoors, and have smaller body sizes. In addition, children’s immature immune systems may cause them to be more susceptible to PM2.5 than healthy adults. Moreover, the gender differences may exist in the effect of PM2.5 exposure on CKD. A study of 47,204 Chinese adults aged 18 years or older found that every 10 μg/m3 increase in PM2.5 was positively associated with the prevalence of chronic kidney disease (odds ratio [OR] 1.33, 95% CI 1.25–1.41, p < 0.001). Sex-stratified analyses showed that risk in men (OR 1.42, 95% CI 1.29–1.57) was slightly higher than in women (1.26, 1.17–1.36) (Li et al. 2020). The above-mentioned analyses cannot be generalized. Susceptibility of population is also affected by differences in age and genetic factors in various regions of the world. Therefore, more global longitudinal studies are needed in the future to directly compare the effects of PM2.5 on CKD.

5 PM2.5 and CKD: Progression and Prevention

In addition to increasing risk of kidney disease, exposure to PM2.5 has also been associated with an increased risk of CKD progression. A prospective cohort study of 669 veterans in the Boston area from the Veterans Affairs Normative Aging Study Institution revealed that every 2.1 μg/m3 increase in the concentration of PM2.5 results in 1.73 m2 decreases in eGFR (95%CI:2.99 to 0.76) and 0.60 mL/min/1.73m2 decrease in renal function per year (95%CI:0.79 to 0.40). It should be emphasized that the exposure level of PM2.5 in the study population met the environmental air quality requirements of 13.5% in the USA (Standard for 13.0 μg/m3). Thus, it can be speculated that the higher levels of PM2.5 exposure can significantly increase the rate of the renal dysfunction in the exposed patients (Mehta et al. 2016). Other studies have shown that for every 10 mg/m3 increase of PM2.5 concentration, the risk of eGFR decline ≤30% increases by 28% (HR, 1.28; 95% CI:1.18 to 1.39), and the risk of ESRD increases by 26% (HR, 1.26;95% CI:1.17 to 1.35) (Bowe et al. 2017, 2018). Road traffic emissions are one of the main sources of PM2.5, which has extensive cyto- and genotoxic effects, which in turn can affect the physiology, development, and mortality of a broad subset of the species that encounter roads (Pérez et al. 2010; Leonard and Hochuli 2017). A study of 1,103 patients with acute ischemic stroke in the Boston-area between 1999 and 2004 showed that eGFR levels decreased in patients living closer to major roadway, indicating a decline in renal function. The eGFR levels of patients who live 50 m away from the main road are 3.9 mL/min/1.73m2 lower than in those who live 1,000 m away (95%CI: 1.0–6.7; P = 0.007). The decrease of renal function in patients living 50 m away from the main road is equal to the decrease of natural physiological renal function with the increase of age by 4 years (Lue et al. 2013).

A cross-sectional study of 317 patients with acute pulmonary edema complicated with stage 5 nondialysis chronic nephropathy (CKD 5-ND) in Taiwan found that a high PM2.5 level was associated with an increased risk of acute lung edema in patients with CKD 5-ND. High ambient temperature in hot seasons and low ambient temperature in cold seasons were also associated with increased risk (Chiu et al. 2018). There is an approximate linear correlation between the relative changes of albuminuria over a one-year interval and the risk of CKD; and the presence of albuminuria may be a predictor of the CKD aggravation (Sumida et al. 2017). A study of 812 patients with T2DM in Taiwan found that the albumin-to-creatinine ratio (ACR) in patients with exposure to high-level PM2.5 increased 3.96 m g/g, while in patients with low-level it increased 3.17 mg/g, indicating that the exposure to higher levels of PM2.5 and CO can increase albuminuria in patients with T2DM (Chin et al. 2018). Another clinical cohort study of patients with SLE living on Montreal Island showed that the levels of PM2.5 exposure are associated with the anti-dsDNA and the tubular cell type, reflecting severe renal inflammation (Bernatsky et al. 2010). It has been shown that kitchen fumes contain high concentrations of PM2.5. By comparing the levels of exposure to PM2.5, VOC and PAH from the working environment and burden of these toxic substances on the body in 94 chefs and controls, cross-sectional study revealed that PM2.5 may result in the microalbuminuria in kitchen workers (Singh et al. 2016). Smoking is also an important source of indoor PM2.5. A cross-sectional analysis of 15,179 participants in the third National Health and Nutrition Survey in the USA found that in passive smokers, who were grouped by a quartile of serum cotinine levels, the risk of microalbuminuria in highest group was 1.41 times higher than that in the lowest group (Hogan et al. 2007).

Although there is some evidence that CKD progression is associated with PM2.5 pollution, it is manifested in an increased risk of progression to ESRD, increase in albuminuria, decrease in eGFR levels, and the emergence of complications such as pulmonary edema. Current data were based on a few cohort studies and were limited to some countries, lacking globally large-scale and long-term cohort studies.

6 PM2.5 and CKD: Mechanisms

The toxic mechanisms underlying the relationship between PM2.5 and CKD still remain unclear. A large amount of researches from clinical and animal experiments have confirmed the association between exposure to PM2.5 and CVD (Combes and Franchineau 2019). Meanwhile, various risk factors of CVD, such as smoking, obesity, hypertension, and diabetes mellitus, are still the risk factors of CKD (Gansevoort et al. 2013; Parikh et al. 2006; Papademetriou et al. 2016). A current study shows that PM2.5 can easily enter the circulatory system through alveolar epithelial cells and can eventually damage the cardiovascular system, thereby causing damage to the kidneys (Milojevic et al. 2014). Therefore, we speculate that part of the pathogenic mechanism of the PM2.5-related CKD may be similar to the PM2.5-related CVD (Fig. 1).

Fig. 1
figure 1

Plausible biological pathways linking fine particulate matter exposure with chronic kidney disease (CKD). The 6 generalized intermediary pathways and the subsequent specific biological responses that could be capable of instigating CKD events are shown. eGFR estimated glomerular filtration rate, PI3K phosphatidylinositol-3-kinase, Akt protein kinase B, mTOR mammalian target of rapamycin, FGF fibroblast growth factor, FGFRs fibroblast growth factor receptors, MAPK mitogen-activated protein kinase, VEGF vascular endothelial growth factor, JAK Janus kinase, STAS spread through air spaces, Bax Bcl-2 associated X, Bcl-2 B cell lymphoma-2, LC3 light chain 3, TNFRs tumor necrosis factor receptors, TACE TNF-α converting enzyme, NF-κB nuclear factor kappa-B, IκB inhibitor of NF-κB, IL-18 Interleukin-18, COX2 cyclooxygenase 2, ROS reactive oxygen species, iRhom2 inactive rhomboid protein 2, Ang II angiotensin II, SOD seminal plasma enzymes, GCLC glutamate-cysteine ligase catalytic, GSR glutathione reductase, TAC total antioxidant capacity, GSH glutathione, MDA malondialdehyde, Nrf2 nuclear factor-erythroid 2-related factor 2, RAGE advanced glycation end, IFN interferon, PLA2R phospholipase A2 receptor

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Oxidative Stress

Numerous studies have shown that the oxidative stress induced by PM2.5 has an important role in the PM2.5-mediated toxicity (Li et al. 2008; Weichenthal et al. 2016; Crobeddu et al. 2017). iRHOM2(RHBDF2), a member of the rhomboid family with proteolytic activity, has been explored in the pathogenic mechanism of CKD (Liu et al. 2018; Herrlich and Kefaloyianni 2018). It has been observed that PM2.5 promotes the production of ROS and iRhom2 in mice exposed to PM2.5, thus resulting in the blocking of Nrf2 signaling pathway, the activation of JNK MAPK signaling pathway and the damage of podocyte, and eventually in the chronic renal injury (Xu et al. 2018; Ge et al. 2018). It has also been observed that the production of ROS induced by PM2.5 inhibits the Nrf2 signaling pathway and the activity of downstream genes SOD1, Gclc and GSR in human embryonic stem cells. Meanwhile, N-acetylcysteine (NAC) can restore partial antioxidant stress by scavenging ROS (Jin et al. 2019). NOX4, which is a member of NADPH oxidase family, is considered as the main source of ROS production in the kidneys (Gorin et al. 2005; He et al. 2016). After the intratracheal exposure to the PM2.5, the expression of NOX4 and the content of H2O2 in the kidneys (the mainly direct metabolite of NOX4) significantly increase while the expression of antioxidant enzyme SOD-1 significantly decreases in the BALB/c mice. Furthermore, the renin–angiotensin system (RAS) in mice can be activated by the PM2.5 exposure. It has been reported that Ang-II is one of the most important stimuli to promote the oxidative stress, showing that the renal damage by PM2.5 may be induced via activation of RAS, which in turn induces oxidative stress and inflammation (Zhang et al. 2018; Chabrashvili et al. 2003).

Inflammatory Response

As mentioned above, PM2.5 has an important role in the unhealthy effect induced by the inflammatory response (Bekki et al. 2016; Bo et al. 2016). In the type 1 DM rat model induced by STZ, the levels of the cytokines involved in the inflammatory response including IL-6 and fibrinogen significantly increase after exposure to low concentrations (close to the current air quality standards) and low-enriched PM2.5. Also, the histopathologic studies show that exposure to PM2.5 results in glomerulosclerosis and proximal tubular injury (Yan et al. 2014). PM2.5 promotes the activation of inflammatory associated TNF-α invertase/TNF-α receptor (TACE/TNFRs) signaling pathway and α/nuclear factor κB (IκBα/NF- κB) signaling pathways in the renal cell lines (including HEK-293, MPC5 and HK-2) from the PM2.5 exposed mice (Ge et al. 2018).

Vascular Injury

PM2.5 may induce endothelial injury through systemic inflammation, oxidative stress, and atherosclerosis, resulting in glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis, and eventually chronic kidney diseases (Rui et al. 2016; Bo et al. 2016; Liang et al. 2019). Previous studies have shown that the diesel exhaust particulate (DEP) is the main source of PM2.5 and ultrafine particles found in cities (Cho et al. 2004; Pérez et al. 2008). Exposure to DEP aggravates renal vascular injury in the CKD rats induced by adenine, resulting in tubular dilatation, tubular necrosis, tubular type, and decreased renal blood flow (RBF) (Nemmar et al. 2009). AngII can induce endothelial injury by activating NADPH oxidase system (Niazi et al. 2017). After intratracheal instillation of PM2.5, increasing levels of circulating AngII are observed in rats, which may be due to the activation of the branches of IRE1 α/XBP1s on the unfolded protein-reactive (UPR) (Xu et al. 2017).

Immune Response

Previous studies have shown that environmental pollution may break the immune balance and increase the incidence of chronic diseases (Lee and Lawrence 2018). Some of the autoimmune responses have an important role in the occurrence of a series of nephritis (Clynes et al. 1998; Chang et al. 2011; Lau et al. 2010). Idiopathic membranous nephropathy is also an autoimmune disease characterized by the formation of circulating autoantibodies against secretory phospholipase A2 receptor (PLA2R) (Beck Jr. et al. 2009). Existing studies have shown that exposure to fine particles can promote the formation of autoantibodies and immune complexes (Brown et al. 2003, 2004; Pfau et al. 2004). The deposition of IgG immune complexes has been found in the kidneys of C57Bl/6 mice after exposure to fine particles, while the presence of abnormal glomeruli and tubules suggested the occurrence of glomerulonephritis (Pfau et al. 2008).

Cell Apoptosis and Autophagy

Cell apoptosis and autophagy can be induced by PM2.5-exposure (Wang et al. 2017a, b; Ding et al. 2017). The activation of PI3K-Akt/mTOR signaling pathway, FGF/FGFR/MAPK/VEGF signaling pathway, and JAK-STAT signaling pathway can be promoted by PM2.5, which induces the cell apoptosis and autophagy (Zheng et al. 2017; Wang et al. 2016). A recent study has revealed that the sections of renal tissue from the C57BL/6 mice and the 293 T cells exposed to the Arsenic(As) or SO2 show severe diffuse sclerosing glomerulonephritis. Meanwhile, it has also been found the key members of Caspase family, and the expression of Bax, the indicator of Caspase Pathway, are up-regulated in the 293 T cells, while the expression of Bcl-2 is down-regulated (Ji et al. 2019). It has been reported that a large amount of Cd2+ accumulation is found in the kidneys of residents living near industrial areas. Cd2+ can significantly reduce the survival rate of renal tubular epithelial cells (HK2) and have a key role in renal injury (Kuang 2018; Thomaidis et al. 2003). The increase of LC3-II and the decrease of p62, which are both markers of cell autophagy, can be observed in the renal tubular ductal epithelial cells (NRK-52E) from the rats exposed to Cadmium for 1 h. This suggests that the short-term exposure to cadmium can rapidly activate cell autophagy and thereby counteract the damage (Lee et al. 2017).

Omics

Currently, omics has been widely used in clinical research and it has become a new tool for exploration of the biomarkers in renal disease. After the intratracheal exposure to PM2.5, a metabolomics test of the urine shows a significant increase in levels of cresol sulfate and p-cresol glucuronide of the uremic toxins from the exposed rats. Both of these are derivatives of p-cresol in phenylalanine metabolites. Furthermore, the levels of glucuronide acidification of acetaminophen decrease, indicating that PM2.5 inhibits the kidney detoxification (Zhang et al. 2017). A global analysis of the circulating miRNA genome from people exposed to traffic-related air pollutants has shown that the expression of miR-148a-3p, which is highly expressed in the kidneys, increases after the exposure to higher levels of pollution. Also, the levels of miR-148b-3p in serum have been described as one of the potential non-invasive biomarkers for the diagnosis of IgA nephropathy (Krauskopf et al. 2018).

Podocyte Injury

Recent studies have revealed that exposure to PM2.5 can mediate the podocyte injury through a variety of mechanisms, which in turn lead to renal injury (Santana et al. 2016; Yang et al. 2018). As mentioned earlier, the PAHs in PM2.5 can lead to carcinogenesis and mutagenicity, and the content of PAHs in the air of China is generally higher compared to foreign countries (Bandowe et al. 2014; Lundstedt et al. 2007; Yunker et al. 2002). The highest content of PAHs of PM2.5 was benzo fluoranthene (BbF) observed in the atmosphere in Zhengzhou City (Wang et al. 2017a, b). Based on this, we established a mouse model of co-culture glomerular podocytes and alveolar epithelial cells, and found that the expression of Nephrin protein and Podocin protein decreased and the expression of Desmin protein increased with the increase of the concentration and exposure time to BbF (P < 0.05), indicating increasing of podocyte injury. Also, the number of autophagy corpuscles decreased and the expression of Beclin-1 protein and LC3B protein decreased (P < 0.05) with the increase of the concentration and time of the exposure, suggesting the decreased levels of autophagy in podocytes. Therefore, we speculate that the inhibition of autophagy pathway may be one of the mechanisms underlying glomerular podocyte injury induced by PAHs of PM2.5, which may lead to renal disease. The specific mechanism needs to be further clarified (Zhang et al. 2020).

Toxic exploration of PM2.5 is an extremely important issue. Oxidative stress, inflammation, endothelial injury, apoptosis, autophagy, and immune response are the main potential mechanisms in PM2.5-induced kidney disease progression. The research findings of in vitro cell and in vivo animal investigations have provided vital insights into the mechanisms of PM2.5 exposure in kidney disease progression. Better understandings of the mechanisms associated with PM2.5 will allow the development of new strategies to decrease the harmful effects of PM2.5 on the pathogenesis of various diseases. Despite all accumulating data regarding pollution and its adverse health effects, there are still gaps that have to be recognized. The pathogenesis is still not fully understood. These studies were almost based on animal models. In the future, we need to characterize which components of PM2.5 are primarily responsible for specific disease processes. Moreover, human subject researches need to be more developed (Table 2).

Table 2 Summary of in vivo and in vitro studies on kidney effects of PM2.5
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7 Global Implication of Polices and Measurements

The reduction of PM2.5 in general requires concerted action by public authorities, industry, and individuals at national, regional, and even international levels. Since the harmful effect of PM2.5 on human health, and especially the kidneys, has been confirmed by many studies, the effective management of PM2.5 is necessary to reduce health risks to a minimum. In 2005, WHO announced that the recommended concentration of PM2.5 was less than 10 μg/m3 for an annual average and less than 24 μg/m3 for a 24-h average. However, these are hard to achieve. Thus, WHO gave a three-tier interim goal (World Health Organization 2006). The Non-Communicable Diseases (NCDs) represent the largest and fastest growing threat to human health (World Health Organization 2014). Traditionally, WHO introduced the association as 4 × 4 model: four main NCDs included cardiovascular diseases, cancer, chronic respiratory diseases, and four main modifiable risk factors included tobacco use, unhealthy diet, physical inactivity, and harmful use of alcohol. The UN Political Declaration of 2018 on NCDs added air pollution as the fifth risk factor, rebranding a more comprehensive “5 × 5” model for NCDs management and control (Renshaw et al. 2019).

Many countries around the world have taken various measures to reduce PM2.5. In some relatively clean countries, such as the USA, fine particulate pollution decreased 25% on average across the country between 2010 and 2016 (Clay and Muller 2019). The US administration has taken steps to weaken air quality and climate regulations for this. The US EPA strengthened the nation’s air quality standards for fine particle pollution to improve public health protection by revising the primary annual PM2.5 standard to 12 μg/m3 (The U.S. Environmental Protection Agency 2012). Most member states in Europe would reach PM2.5 levels close to or even below the WHO guideline value (of 10 μg/m3), and well below the current EU target value (which will be transformed into a limit value in 2015) of annual 25 μg/m3. In 2017, Estonia, Finland, and Norway did not report any concentrations above the WHO air quality guidelines for PM2.5 by EEA Report (European Environment Agency 2019). In addition to using clean energy, green technology, reduction in emissions, and lower population density, the European Environment Agency’s (EEA) European Air Quality Index provides citizens with a tool for checking the air quality in their city and supports public engagement in efforts to reduce air pollution. At the same time, India’s air quality does still not show an optimistic picture as one of the most polluted countries in the world. 11 of the 12 cities with the highest levels are located in India when looking at the database’s ranking of particulate pollution in cities from WHO (World Health Organization 2018a, b, c). The Indian government launched the National Clean Air Program (NCAP), a five-year action plan to curb air pollution, build a pan-India air quality monitoring network, and improve citizen awareness (National Clean Air Programme 2019). The programme focuses on 102 polluted Indian cities and aims to reduce PM2.5 levels by 20–30% over the next 5 years. By 2017, Beijing’s PM2.5 pollution ranking in the world’s cities dropped from the previous 40th to 187th. PM2.5 pollution in 62 other cities in China also fell by 30% between 2013 and 2017(Greenstone 2018). Moreover, targeted measures should be taken to prevent the PM2.5 pollution, such as using air filtration devices, air anion nebulizers and wearing professional dust masks. Meanwhile, kitchen fumes should be controlled and the indoor smoking should be eliminated. Recently, some scholars have suggested taking Vitamin B as an effective way to resist the PM2.5 pollution. They found that Vitamin B can reduce the DNA methylation changes induced by PM2.5, and that it has an important role in the inflammation and the oxidative stress (Zhong et al. 2017).

8 Conclusions

Fine particulates are important risk factors for kidney disease, especially in developing countries in which environmental pollution is prevalent. The causes of CKD and the toxic mechanisms of most environmental nephrotoxins remain to be elucidated. This paper discussed a number of large cohort studies and cross-sectional studies that associate PM2.5 and CKD, as well as the potential mechanisms of PM2.5 exposure in kidney disease progression. As mentioned earlier, CKD cases from countries such as America and Asia are estimated to be attributable to long-term exposure to PM2.5, and PM2.5 may accelerate the progression of CKD to ESRD. In addition, studies on the pathogenic mechanisms of PM2.5 involve some molecular biological networks and cellular signaling pathways. In order to understand the causal relationship between PM2.5 exposure and CKD, it is important to study the toxic effects of various components in PM2.5, as well as the effects of temperature, season and regional distribution on them. In terms of mechanisms, most studies have focused on the effects of certain specific components in PM2.5 in relation to oxidative stress, inflammatory response, immune response, and other general pathways. Lack of specific mechanisms of action and the pathogenesis still need to be fully elucidated. More detailed longitudinal studies and experimental designs are needed to prove which components of PM2.5 are responsible for CKD processes and the dose-response relationship between PM2.5 and the development and progression of CKD.

In short, PM2.5 is an important risk factor for kidney disease. A database of PM2.5 and chronic kidney disease should be globally developed. The data from different regions should be released every year or quarter to provide a new perspective at PM2.5. This new angle might help to promote the prevention and control of chronic kidney diseases in various countries around the world. In the exploration of relevant mechanisms, from the epigenetics, genomics, proteomics, metabolomics and other levels exploring the impact of PM2.5 on CKD, impact mechanisms might provide experimental basis for the prevention and treatment of CKD.

We believe that via joint efforts of various countries around the world, the environmental pollution might not only be improved, but the prevention and control of CKD could also be raised to a new level.