Association of Ambient Fine Particulate Matter Air Pollution With Kidney Transplant Outcomes

This cohort study investigates the association of exposure to ambient fine particulate matter air pollution with kidney transplant outcomes.


Introduction
Increased levels of ambient air pollution (ie, fine particulate matter 2.5 μm or less in aerodynamic diameter [PM 2.5 ]) are associated with an increased risk of detrimental health outcomes, including cardiovascular disease, diabetes, and all-cause mortality. [1][2][3][4][5][6] The underlying mechanisms for these associations may include associations of inhaled particulate matter with increased sympathetic vascular modulation, intravascular thrombosis, and promotion of atherosclerosis. 7,8 A dose-response association has also been reported. 9 Furthermore, Dockery et al 10 found that improvements in air quality, with decreases in PM 2.5 levels, were associated with a decrease in mortality risk.
In the field of kidney disease, epidemiological studies from 2016 to 2020 [11][12][13] have found that increased levels of PM 2.5 are associated with increased risk for decline in kidney functions, including decreased estimated glomerular filtration rate (eGFR) and increased rates of chronic kidney disease (CKD) and end-stage kidney disease. The etiology of kidney disease may be mediated by an increase in systemic inflammation and oxidative stress associated with air pollutants. 14,15 It also has been found that particulate matter inhaled through the respiratory tract and cleared by the kidney may be associated with direct damage to renal tissue. 16 Furthermore, air pollutants and PM 2.5 are associated with insulin resistance, 17,18 attenuated flow-mediated arterial dilation, 19 and systemic hypertension, [20][21][22] which are important factors that may be associated with kidney function.
Despite the existing evidence for an association between PM 2.5 levels and health outcomes, few studies have examined the association between PM 2.5 levels and the outcomes of solid organ transplantation. Among patients with lung transplants, Bhinder et al 23 found that increased PM 2.5 levels were associated with an increased risk of chronic lung allograft dysfunction and overall mortality. Similar findings have been observed among individuals with heart transplants. 24 Among individuals with kidney transplant (KT), studies 25,26 found that exposure to air pollutants was associated with an increased risk of cardiovascular mortality, but associations of PM 2.5 levels with other important transplant outcomes have not been examined to date, to our knowledge. With the identified knowledge gap in the association of PM 2.5 levels with KT outcomes, this study aimed to determine whether PM 2.5 concentration is an independent risk factor associated with kidney rejection, graft failure, or overall mortality among patients with KTs.

Methods
Exemptions for study approval and informed consent were obtained for this cohort study from the Washington University in St. Louis School of Medicine Institutional Review Board because the study was secondary analyses of deidentified data. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

Study Design and Data
A retrospective cohort of patients who received KTs from 2004 to 2016 was obtained from the Organ Procurement and Transplantation Network (OPTN). Transplant outcomes were followed up until March 2021. Detailed descriptions of OPTN data were described elsewhere. 27,28 Briefly, the All tests were 2-sided, and results were considered statistically significant at α = .05 or when 95% CIs did not cross 1 for odds ratios and hazard ratios. All statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute) and R statistical software version 4.0.2 (R Project for Statistical Computing). Zip code-level PM 2.5 concentration was computed using ArcGIS Pro software version 2.7.0 (Esri). Data were analyzed from April 2020 through July 2021.

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To account for variations in city characteristics that could confound the association, sensitivity analyses for all 3 outcomes were conducted using multilevel models and adapting city-adjusted and within-city models. These models were detailed elsewhere. 5,11 Cities were defined as core-based (including metropolitan and micropolitan) statistical areas, which were obtained from the US Census Bureau 33 and linked to patient residential zip codes. Additionally, for the acute kidney rejection outcome, multivariable logistic regression was performed adjusting for city clustering.

Results
Among 214 Figure 1A-B) demonstrated a similar pattern.

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In multivariable analyses (Figure 2), compared with quartile 1 of baseline PM 2.5 level (Figure 2A all-cause death: aHR per 10 μg/m 3 increase, 1.21; 95% CI, 1.14-1.28) (Figure 2B left) with increased levels of PM 2.5 over 12 μg/m 3 is presented in Figure 4. The burden increased with the darkness of the color, and the areas with gray color indicate that no patients in the analytic cohort resided in those areas at the time of their KTs. In sensitivity analyses adjusting for variations in city characteristics, we found that, compared with quartile 1 of the baseline PM 2.5 level, increased baseline PM 2.5 level quartiles were associated with increased risk of acute kidney rejection, graft failure, and all-cause death (eTable in the Supplement).

Discussion
This cohort study is one of the first studies, to our knowledge, to assess the association of ambient fine particulate matter air pollution with outcomes among recipients of KTs. Using annual mean PM 2.5 concentration during post-KT follow-up or in the year before KT (by quartile or quantity), our study consistently found that PM 2.5 concentration was an independent risk factor associated with acute rejection, death-censored graft failure, and all-cause mortality among recipients of KTs. These results were robust when different statistical models (with or without adjustment for city variations) were used. We also found linear exposure response associations between baseline PM 2.5 concentration and risks for death-censored graft failure and all-cause death. These findings suggest that consistent exposure to fine particulate matter air pollution is associated with increased risk of worse transplant outcomes among recipients of KTs, including kidney rejection, kidney graft failure, and all-cause death.
The geographic distribution of the burden of graft failure associated with increased levels of Survival curves were adjusted for recipients' age, sex, race and ethnicity, dialysis status and duration, and area deprivation index. PM 2.5 indicates fine particulate matter air pollution. One highlight of this study is the finding that increased PM 2.5 concentration was associated with increased risk of kidney graft failure. This finding is consistent with those in previous reports finding increased risks for CKD and ESRD among individuals with native kidneys. 11,13,43 Additionally, using multiple definitions of exposures, Bowe et al 11 found an association between exposure to PM 2.5 and risk for incident CKD and ESRD in a cohort of US veterans. In an earlier study, Mehta et al 13 found that

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1-year exposure to increased PM 2.5 concentration was associated with an annual decrease in kidney function. Globally, it was estimated that PM 2.5 concentration is associated with 3.3 million cases of incident CKD and 122.4 million cases of prevalent CKD. 43 However, our finding is not supported by the finding in a Feng et al, 44  Kidney graft rejection is a major risk factor associated with graft loss. [45][46][47] We found a 13% increase in odds of rejection within the first year of KT among recipients residing in areas with the fourth quartile of baseline PM 2.5 levels, compared with the first quartile. This finding is consistent with that in Feng et al 44 and suggests an alloimmune etiology as a possible pathway for rejection that  may be associated with increased risk of graft loss. The exact mechanism of increased risk of rejection with PM 2. 5 has not yet been elucidated. We hypothesize that this could be associated with increased systemic inflammation and activation of the innate and adaptive immune systems. This hypothesis is based on a growing body of literature suggesting that the organic compounds, free radicals, and transition metals contained in PM 2.5 are associated with increased oxidative stress, as well as the gene and protein expression of proinflammatory mediators, such as tumor necrosis growth factor α, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, interleukin 6, interleukin 1β, and interleukin 8. 15,48 Studies have also found that PM 2.5 is associated with increased expression of adhesion molecules like vascular cellular adhesion molecule 1 and the adhesion of monocyte cells to endothelial cells. 49,50 In lung transplant, aryl hydrocarbon receptor is considered as a pathway to changing naive T cells to inflammatory T helper 17 cells and promoting chronic inflammation and chronic rejection. 51 Our study found a 21% increase in mortality risk among individuals with KTs for every 10 ug/m 3 increase in PM 2.5 level, similar to the finding of Feng et al (15% increase per 10 ug/m 3 increase in PM 2.5 level). 44 Prior studies among recipients of KTs have found increased risk of cardiovascular mortality from exposure to air pollutants. 25,26 The increased mortality risk has also been reported among individuals with heart transplants: 26% to 43% increases in mortality risk per 10 ug/m 3 increase in time-dependent PM 2.5 concentration. 24 In patients with lung transplants, the increase in mortality risk was not statistically significant, as reported by Bhinder and colleagues, 52 possibly associated with the exposure definition (ie, mean annual PM 2.5 concentration from 1996-2010) and a smaller sample size (ie, approximately 400 individuals). As for mortality among patients with CKD, it was estimated at 211 019 deaths associated with CKD associated with PM 2.5 exposure globally. 43 However, similar to the situation in the general nontransplant population, it is likely that most of these deaths are associated with detrimental cardiovascular outcomes of PM 2.5 exposure. 14,53

Strengths and Limitations
This study has several strengths. First, to our knowledge, it is one of the first studies on the association of PM 2.5 levels with acute rejection, graft failure, and death in a large national cohort of individuals with KTs. Second, our analyses benefited from merges of multiple databases to comprehensively account for potential confounding, including patient, donor, and transplant factors, as well as contextual characteristics (eg, ADI and population density). Third, multiple exposure definitions were used to ensure the robustness of study findings. Fourth, the robustness of the findings was strengthened by sensitivity analyses adjusting for city variations. We note that PM 2.5 concentration generally decreased over time. As a consequence, using time-dependent exposure is particularly important to capture the association of decreasing PM 2.5 levels over time with transplant outcomes. Furthermore, this trend was associated with changes in included recipient and donor characteristics, transplant factors, and contextual factors, as well as transplant outcomes when recipients were grouped by baseline PM 2.5 level quartiles, as presented in the Table. Patients receiving KTs in earlier years were more likely to be in the fourth quartile, while patients receiving KTs in more recent years were more likely to be in the first quartile. To account for these differences, we used multivariable time-to-event analyses with all relevant factors (including year of KT) included as covariates. We then chose to report the results using time-dependent exposure as the main findings, supplemented with results using baseline exposures.
Nonetheless, this study has several limitations that should be noted. First, like most retrospective studies, the results rely on the accuracy of the recorded data from multiple databases.
Second, although time-dependent analyses allowed for capturing the exposure after KT, the most updated annual mean PM 2.5 concentration was available up to 2018 at the time of the study, limiting follow-up time. Nonetheless, we were able to include a follow-up of 2 to 15 years. Third, the most up-to-date residential zip codes for recipients of KTs were recorded at the time of KT. Timedependent analyses may be biased if the patients moved to another zip code area after KT. However, this bias may be decreased if patients who moved after KT were not systematically more likely to move to areas with higher or lower levels of PM 2.5 compared with their area of residence at KT.
Fourth, composition and toxic content of PM 2.5 may change over time and by geography; consequently, use of PM 2.5 level alone may underestimate risk. 54 Fifth, indoor air pollution was not accounted for in this study. Sixth, although we controlled for as many covariates as possible and adjusted for city variations, residual confounding may remain, which could bias the estimated association.

Conclusions
To our knowledge, this is one of the first studies in a national cohort of recipients of KTs that found that increased levels of PM 2.5 were independently associated with increased risk of acute rejection, graft loss, and death. Our findings suggest that efforts toward cleaner air may be associated with decreased burden of adverse outcomes after KT. In clinical practice, suggesting that recipients of KTs reside in areas with lower levels of PM 2.5 concentration may be associated with improved transplant outcomes.