Exposure to Air Pollution and Renal Function-An Underestimated Threat?


 Introduction: Air pollution contributes to the premature death of approximately 428,000 citizens of Europe every year. The adverse effects of air pollution can be observed not only in respiratory, circulatory, and nervous systems but also in renal function.Aim: Our goal was to investigate the hypothesis indicating that we can observe the long-term and also short-term impact of air pollution on kidney function.Methods: We reviewed medical notes of patients hospitalized at Medical University of Bialystok, Poland between 2007-2016. We used linear, log-linear, and logistic regression models to assess the association between renal function and NO2, SO2, and PMs. Results are reported as beta (β) coefficients and odds ratios (OR) for an increase in interquartile range (IQR) concentration with 95% confidence intervals (95%CI). Results: 3,554 patients were included into the final analysis. The median age was 66 (IQR 15) and men were in the majority (53.2%, N=1891). Chronic kidney disease (CKD) was diagnosed in 21.5% (N=764). The long-term increase in annual average concertation of PM2.5 (OR for IQR increase=1.07; 95% CI 1.01 – 1.15, P=0.037) and NO2 (OR for IQR increase=1.05;95% CI 1.01 – 1.10, P=0.047) resulted in an increased number of patients with CKD. In short-term observation the IQR increase in weekly PM2.5 concentration was associated with a 2% reduction in eGFR (OR=0.98, 95%CI 0.97 – 0.99, P=0.03)Conclusions: The effects of air pollution on renal function were observed. Long- and short–term exposure to elevated air pollution levels was associated with a decrease in eGFR. The main pollutant affecting the kidneys was PM2.5.


Introduction
Air quality was put in the spotlight since the severe air pollution event called the Great Smog of London.
Retrospective medical reports in the following weeks estimated that 4,000 people had died as a direct result of the smog and 100,000 more were made ill by the smog's effects on the cardiovascular system and respiratory tract. Since then, it became clear that the adverse effects of air pollution are serious and the reduction of pollution should become a priority in social and health policy.
In recent years it has been established that air pollutants associated with the harmful effect on human health are particulate matter with a diameter of 2.5 mm or less (PM 2.5 ), particulate matter with a diameter of 10 mm or less (PM 10 ), sulfur dioxide (SO 2 ), and nitrogen dioxide (NO 2 ) [1]. Some of these components are formed directly as a result of fuel burning, while others emerge as a result of photochemical reactions that occur under the in uence of ultraviolet radiation in the air.
Regardless of the source, according to the European Environment Agency, particulate matter contributes to the premature death of approximately 428,000 citizens of Europe every year [2]. There is a great deal of evidence in the literature for the short-and long-term adverse effects of air pollution on the cardiovascular and pulmonary systems [3][4][5][6][7][8][9][10][11][12][13]. The exact mechanisms associated with the impact of air pollution on the human body remain unclear. Air pollutants can activate in ammatory cells in the lungs, leading to the release of mediators, and stimulate alveolar receptors which causes an imbalance in the autonomic nervous system and neuroendocrine pathway. The second way is translocating of air pollution via pulmonary epithelium -pollutants enter into the blood circulation and affect the whole organism. The mentioned above processes lead to oxidative stress which is widely acknowledged as a factor for vascular dysfunction [14][15][16].
Although the topic of air pollution has been in the focus of researchers for many years, only a few studies assessing the long-term impact of air pollution on developing chronic kidney disease (CKD) have been reported in the literature [17][18][19][20][21][22]. The lack of major studies evaluating the long-term effects of air pollution on kidney function has led us to analyze this relationship. We also try to carried out to investigate the hypothesis indicating that we can observe not only the long-term but also the short-term impact of air pollution on renal function.

Study participants
We conducted a retrospective cross-sectional study on 26,985 patients referred for elective coronary angiography to the Department of Invasive Cardiology of the Medical University of Bialystok, Bialystok, Poland between 2007 and 2016. We excluded patients with acute coronary syndromes (ACS), coronary artery disease (CAD) and chronic heart failure (CHF) as those diseases affect renal function. Hemodialysis was also the exclusion criterion.
We included 8,288 patients admitted to scheduled coronary angiography for further analysis. The set of extracted variables included residence data, demographic data, medical history, and biochemical test results. In the analysis, we used data from patients registered and residential in the city of Bialystok (id commune 206101). Finally, our study cohort consisted of 3,554 patients [ Figure 1].

CKD recognition was made according to KDIGO 2012 Clinical Practice Guideline for the Evaluation and
Management of Chronic Kidney Disease. CKD was de ned as the presence of kidney damage or an estimated glomerular ltration rate (eGFR) lower than 60 ml/min/1.73 m 2 , persisting for three months or more. The eGFR rate was counted using CKD-EPI formulas [23].

Pollution and weather conditions data
The data of air pollution and gases were obtained from the Voivodeship Inspectorate for Environmental Protection from stations that are representative for the studied city (id commune 206101). In the analysis, we used the concentration of sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), and particulate matter with a diameter of 2.5 mm or less (PM 2.5 ) and 10 mm or less (PM 10 ). The data on the concentrations of gases The daily meteorological data, including mean temperature, the daily level of relative humidity, and mean atmospheric pressure were obtained from the Institute of Meteorology and Water Management. We used the data from station Ciolkowskiego Street (ID 353230295, GPS: 53°10′ N, 23°16′ E). The study material lacked about 3.1% of data. The days with missing data were excluded from the analysis.

Study design and statistical analysis
We analyzed if short-term and long-term air pollution exposure was associated with renal function. To access the impact of air pollution we used lag distributed regression models that have been widely used in environmental epidemiology (detailed description belove). The multivariable logistic regression model was performed to access associations of air pollution and incidence of chronic kidney disease. The number of patients with CKD were de ned as a dependent variable. The independent variables were concentrations of air pollution one year before admission. To control for the long-term trend and seasonal effects, we used a time-strati ed model (simple indicator variables). We adjusted our model for day of the week, public holidays, clinical variables (including obesity, atrial brillation, hyperlipidemia, diabetes mellitus, arterial hypertension), atmospheric pressure, humidity and cubic spline function of mean daily temperature with 4 degrees of freedom. Results are reported for an increase in interquartile range concentration of air pollution and presented as odds ratio (OR) with 95% CI and scatter plots.
Linear regression analysis was performed to identify short-term associations between estimated glomerular ltration rate and concentration of particulate matter and gases. The eGFR CKD -EPI was assessed on admission and was de ned as a dependent variable. The independent variables were concentrations of NO 2 , SO 2 , and PMs at days with LAG from 1 to 6 and mean concertation for week before admission. We estimated two statistical models: unadjusted linear model (without covariates) and linear model controlled for long term and seasonality, also adjusted for weather conditions and clinical variables including age, sex, obesity, atrial brillation, hyperlipidemia, diabetes mellitus, and arterial hypertension. The results are reported as beta coe cients (β) and 95% con dence intervals (CIs) for renal function. We also estimated the log -linear regression model. The eGFR was assessed on admission and was de ned as a dependent variable, the independent variables were weekly before admission concentrations of NO 2 , SO 2 , and PMs. Model was model was adjusted for seasonality and long-time trends, weather conditions: temperature, humidity, atmospheric pressure, age, sex and clinical variables including obesity, atrial brillation, hyperlipidemia, diabetes mellitus, arterial hypertension. Results are reported for an increase in IQR of air pollution and presented as OR with 95% CI and scatter plots. The characteristics od studied population and weather conditions are presented as means with standard deviations (SD) for normally distributed continuous, as medians with interquartile ranges (IQR) for not normally distributed continuous variables and as the number of cases and percentage (for categorical variables). We used the Kolmogorov-Smirnov test to assess the distribution of variables. The correlations between daily air pollutants and eGFR were determined using Person's correlation. Data are presented as rank correlation (R) and scatter plots.
The threshold of statistical signi cance for all tests was set at P< 0.05. All analyses were performed using MS Excel (Microsoft, 2020, version 16.40, Redmond, WA, USA) and XL Stat (Addinsoft, 2020, version 2020.03.01, New York, NY, USA). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, was approved by the ethics committee of the Medical University of Bialystok (R-1-002/18/2019) and registered at ClinicalTrials.gov (Identi er: NCT04541498). Informed consent was obtained from all participants on admission to the hospital.

Results
Out of 26,985 patients admitted to the Department of Invasive Cardiology, a total of 3,554 patients were included into the nal analysis. The median age was 66 (1Q=58; 3Q=73) and men were in the majority (53.2%, N=1891). Hypertension was present in over 80% of study participants (83.5%, N=2966), hyperlipidemia in two thirds (67.5%, N=2399), while diabetes and obesity in a quarter. Patients with atrial brillation accounted for 18.4% (N=653) of the investigated population. Paroxysmal AF was the most frequent form of the analyzed arrhythmia (8.5%, N=303) [ Table 1].
Chronic kidney disease (CKD) was approximately diagnosed in every fourth patient of the study population (21.5%, N=764). The mean CKD -EPI eGFR (mL/min • 1.73 m 2 ) was 75.6 (SD=18.3). The majority of patients were characterized by eGFR in the range 60-90ml/min/1.73m 2 (56.1%, N=1933). The next largest group in terms of quantity were patients with eGFR in the range over 90 ml/min/1.73m 2 , that is 24.1% (N=858). There have been single cases of patients with eGFR under 30 ml/min/1.73m 2 (1.5%, N=54). Detailed characteristics of the kidney function in study subjects are provided in Table 2.

Discussion
To our knowledge, this is the rst study that focuses on the long-and short-term impact of air pollution on renal function. The main ndings are as follows: the long-term effect of PM 2.5 on kidney function was observed. In the short-term analysis, the effects of NO 2 , SO 2 , and PMs were observed and delayed in time up to one week.
Many studies reported geographic variation in the burden of chronic kidney disease. Differences were noted even after adjusting for diabetes mellitus, arterial hypertension, and obesity, which are considered to be major contributors to renal function worsening. This fact suggests that variation in the burden of CKD is likely due to factors other than these traditional risk factors [25]. One of them is air pollution, which was con rmed in our analysis. Similar results were reported in a few studies focused on the association between air pollution and kidney function. In a Taiwanese study increase in annual 10 μg/m 3 concentration of PMs was associated with a 6% higher risk of developing CKD (Hazard Ratio: 1.06, 3), respectively [27]. In a study conducted in Boston (Massachusetts, United States of America) a difference in eGFR level was associated with tra c-related air pollution. Comparing patients living 0.05 km vs. 1 km from a major roadway, the rst group was associated with a 3.9 mL/min/1.73 m2 lower eGFR (95%CI: 1.0-6.7; p=0.007) than the latter one [28]. In a population-based cohort of veterans in the USA, a 10-µg/m 3 increase in PM 2.5 concentration was associated with increased risk of CKD (Hazard ratio=1.21; 95%CI 1.14-1.29) [29].
Potential mechanisms for associations between air pollution and renal function are not clear. In our opinion, long-term effects can be associated with an adverse in uence on the cardiovascular system, peripheral arterial disease, progression of hypertension, and diabetes -mainly glucose intolerance. Decreased insulin sensitivity can negatively in uence kidneys and promote CKD [30][31][32][33][34][35]. Additionally, we speculate that the short-term mechanism of air pollution-related eGFR decrease may be similar to the pathway of cardiovascular diseases induced by air pollution. There are a few ways that inhaled pollutants could affect renal function.
The rst way is a direct impact on the kidneys. Due to the large alveolar surface, air pollutants translocate via pulmonary tract and enter the blood circulation, which leads to oxidative stress. Particulate matter exposure may also progress glomerulosclerosis and tubular damage. In kidneys, pollutions can interact with tissue components to promote pathological effects. The second one explains its in uence via an imbalance in the autonomic nervous system and neuroendocrine pathway. It results in increased systolic blood pressure and pulse rate. Pollutants stimulate alveolar receptors that activate autonomic re ex arcs in uencing kidney vascular homeostasis and provoking pulmonary in ammation, which may then lead to systemic in ammation [36,37]. In the literature, we can nd some indirect evidence supporting this hypothesis. In Miller et al. study, inhaled gold nanoparticles entered the bloodstream via pulmonary alveoli and were detected in the urine after the exposure, which partly proofs the concept of a possible in uence of inhaled air pollution on the kidneys [38]. Those nding lead to one more potential mechanism of eGFR decrease reported in our study. In the mixture of air pollution, there are also various heavy metals and polycyclic aromatic hydrocarbons. Exposure to chemicals directly impairs renal function [39].
The name of the region, in which the analyzed city is located, is widely known as the Green Lungs of Poland. It is situated in the north-eastern part of Poland and owes its name to the surroundings of the national parks and low industrialization. However, despite their unique location, the characteristics of the cities contribute to an increased level of air pollution, with its main origin coming from linear sources, related to vehicles and the transit tra c from Northern and Eastern Europe to Central Europe. Some studies claim that diesel exhausts are the main sources of PM 2.5 -bound PAH. PM 2.5 has various health effects depending on its source. Diesel exhaust particles (DEP) are responsible for the highest generation of intracellular reactive oxygen species (ROS). Additionally, they alter vascular transcription and represent the highest mutagenic activity. Generation of ROS is crucial and can in uences both -long-and shortterm effects of air pollutants on renal function [40][41][42].
This study has several limitations. Cohort participants were Caucasian based in north-eastern Poland; therefore, in our opinion, the ndings may not be applicable to other populations. Secondly, the effect of smoking was not analyzed in our research which may be the main limitation of this study. Smoking is considered to be one of the main risk factors for renal failure and the effect of air pollution may also cover the outcomes of smoking. In our opinion, an additional limitation of our work is also underdeveloped air pollution monitoring system of the study area as well as the lack of constant monitoring of ultra ne PMs and heavy metals.
Regardless of those limitations, we conclude that not only long term but also short-term exposure to air pollutants is associated with lowering of kidney function. However, further studies are required to understand the mechanism of affecting renal function by exposure to air pollution and other environmental factors like soil and water pollutions.

Conclusions
The effects of air pollution on renal function were observed. Long-and short-term exposure to elevated air pollution levels was associated with a decrease in eGFR. The main pollutant affecting the kidneys was PM 2.5. Funding: This research received no external funding.

Declarations
Con icts of Interest: The authors declare no con ict of interest.
Data availability: The data that support the ndings of this study are available from the corresponding author on request.   Abbreviations: CI, con dence interval; NO 2 , nitrogen dioxide; PM 2.5 , particulate matter with a diameter of 2.5 mm or less; PM 10 , particulate matter with a diameter of 10 mm or less; SO 2 , sulfur dioxide