Air Pollution and Coronary Risk in Kidney Transplant Recipients

Abstract

Related Article, p. 608This issue of the American Journal of Kidney Diseases contains a novel study on the association between ambient air pollution and cardiovascular disease in kidney transplant recipients.1Spencer-Hwang R. Knutsen S.F. Soret S. et al.Ambient air pollutants and risk of fatal coronary heart disease among kidney transplant recipients.Am J Kidney Dis. 2011; 58: 608-616Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar While numerous studies exist on the effects of air pollution on health-related outcomes in the general population or certain subpopulations, this appears to be the first such study in patients with kidney disease. In this commentary, we review the important principles of air pollution and related biomedical research for the nonexpert reader and why the impact on patients with kidney disease from air pollution might be particularly relevant.Ambient air pollution is produced from multiple sources, including transportation, stationary combustion sources, industrial processes, forest fires, wind-blown dust, and secondary atmospheric reactions. The US Environmental Protection Agency (EPA) routinely monitors 6 components of air pollution under the National Ambient Air Quality Standards (NAAQS). These include particulate matter with a median diameter <10 μm (PM10) and <2.5 μm (PM2.5), nitrogen dioxide (NO2) and other nitrogen oxides, ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), and lead (Pb). Particulate matter includes both solid particles and liquid droplets. PM10, or “inhalable particles,” arise predominantly from road dust, fires, and industrial processes. The particles emitted from combustion sources (eg, automobiles, industries, and power plants) are mainly in the smaller size fraction, PM2.5. These particles penetrate deeper into the lung and are thus considered to be the most detrimental to health. NO2 and other nitrogen oxides are gases that arise from the combustion of fossil fuels in motor vehicles and from fixed sources such as power plants. The predominant source of SO2 is industrial sources, including the combustion of coal and crude oil. Ground-level O3 originates from industrial or traffic-related emissions (eg, NO2 and volatile organic compounds) that react with sunlight in the atmosphere and is the primary constituent of smog in urban areas. Historically, the primary source of Pb emissions in the air was motor vehicles. However, since the removal of lead in gasoline, the major sources of Pb emissions are ore and metals processing and aviation fuels.2US Environmental Protection AgencySix common air pollutants.http://www.epa.gov/airquality/urbanairGoogle ScholarLong- and short-term exposures to these constituents of air pollution have been associated with a variety of morbidity and mortality outcomes, including but not limited to coronary heart disease.3Pope III, C.A. Dockery D.W. Health effects of fine particulate air pollution: lines that connect.J Air Waste Manag Assoc. 2006; 56: 709-742Crossref PubMed Scopus (3970) Google Scholar, 4Brunekreef B. Health effects of air pollution observed in cohort studies in Europe.J Expo Sci Environ Epidemiol. 2007; 17: S61-S65Crossref PubMed Scopus (75) Google Scholar The pathophysiological mechanisms that are thought to mediate air pollution–inflicted injury are complex, including changes in autonomic function, oxidative stress, systemic inflammation leading to endothelial dysfunction, thrombosis, or atherosclerosis.3Pope III, C.A. Dockery D.W. Health effects of fine particulate air pollution: lines that connect.J Air Waste Manag Assoc. 2006; 56: 709-742Crossref PubMed Scopus (3970) Google Scholar, 5Pope III, C.A. Burnett R.T. Thurston G.D. et al.Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease.Circulation. 2004; 109: 71-77Crossref PubMed Scopus (2068) Google Scholar, 6Donaldson K. Stone V. Seaton A. MacNee W. Ambient particle inhalation and the cardiovascular system: potential mechanisms.Environ Health Perspect. 2001; 109: 523-527PubMed Google Scholar, 7Utell M.J. Frampton M.W. Zareba W. Devlin R.B. Cascio W.E. Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing.Inhal Toxicol. 2002; 14: 1231-1247Crossref PubMed Scopus (143) Google Scholar, 8Gurgueira S.A. Lawrence J. Coull B. Murthy G.G. Gonzalez-Flecha B. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation.Environ Health Perspect. 2002; 110: 749-755Crossref PubMed Scopus (422) Google ScholarThe US Clean Air Act requires EPA to set NAAQS (listed in Title 40, Part 50 of the Code of Federal Regulations) for pollutants considered harmful to public health and the environment. There are 2 types of national air quality standards: primary standards that set limits to protect public health, including the health of “sensitive” populations such as asthmatics, children, and the elderly; and secondary standards that set limits to protect public welfare, including protection against decreased visibility, damage to animals, crops, vegetation, and buildings.9US Environmental Protection AgencyNational Ambient Air Quality Standards (NAAQS).http://www.epa.gov/air/criteria.htmlGoogle Scholar A variety of groups, including the National Research Council10National Research CouncilResearch Priorities for Airborne Particulate Matter: IV Continuing Research Progress. National Academy Press, Washington, DC2004Google Scholar have specifically discussed the need to identify potentially susceptible subpopulations.In this issue of the American Journal of Kidney Diseases, Spencer-Hwang et al1Spencer-Hwang R. Knutsen S.F. Soret S. et al.Ambient air pollutants and risk of fatal coronary heart disease among kidney transplant recipients.Am J Kidney Dis. 2011; 58: 608-616Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar identify kidney transplant recipients as a novel subpopulation susceptible to ambient air pollution. They identified transplant recipients (1997-2003) from the US Renal Data System (USRDS), and determined mortality from coronary heart disease and natural causes through October 2003. Monthly exposure to O3 and PM10 were predicted for each individual's residential zip code centroid using inverse distance-weighted interpolations of the ambient monitoring data. A moving average exposure from the time of transplant through the follow-up period, excluding the month before death, was calculated for each subject. For each 10-ppb increase in O3, risk of fatal coronary heart disease increased by 34% (95% confidence interval, 3%-76%) in models adjusted for sex, race, age, year of transplant, primary cause of kidney failure, months of pretransplant dialysis, and PM10. While the analysis was conducted using standard methods of environmental health research, it should be noted that most studies of O3 use measurements from the summer months only. Thus, using a running average of O3 exposure from transplant may induce some misclassification, most likely resulting in a bias towards the null. However, contrary to their study's findings for O3, Spencer-Hwang et al did not identify any independent associations with cardiovascular risk for PM10. In the general air pollution/cardiovascular literature, PM2.5 has been identified as the more relevant size fraction of particulate matter compared with PM10. Therefore, it is too early to determine whether or not particulate air pollution may play a role in the observed association.To date, the majority of the research on the adverse effects of exposure to O3 has been in short-term time-series studies. In 4 meta-analyses summarizing the effects of this literature, there is consistent evidence of adverse effects on mortality, including cardiovascular disease.11Bell M.L. Dominici F. Samet J.M. A meta-analysis of time-series studies of ozone and mortality with comparison to the national morbidity, mortality, and air pollution study.Epidemiology. 2005; 16: 436-445Crossref PubMed Scopus (461) Google Scholar, 12Ito K. De Leon S.F. Lippmann M. Associations between ozone and daily mortality: analysis and meta-analysis.Epidemiology. 2005; 16: 446-457Crossref PubMed Scopus (320) Google Scholar, 13Levy J.I. Chemerynski S.M. Sarnat J.A. Ozone exposure and mortality: an empiric Bayes metaregression analysis.Epidemiology. 2005; 16: 458-468Crossref PubMed Scopus (257) Google Scholar, 14Gryparis A. Forsberg B. Katsouyanni K. et al.Acute effects of ozone on mortality from the “air pollution and health: a European approach” project.Am J Respir Crit Care Med. 2004; 170: 1080-1087Crossref PubMed Scopus (357) Google Scholar There has only been one other study of long-term exposures to O3 and mortality risk—in the general population–based American Cancer Society (ACS) Study.15Jerrett M. Burnett R.T. Pope III, C.A. et al.Long-term ozone exposure and mortality.N Engl J Med. 2009; 360: 1085-1095Crossref PubMed Scopus (987) Google Scholar Using the average O3 concentrations from April to September, Jerrett and colleagues observed an increased risk of death from respiratory causes of 4% for each 10-ppb increase in O3 after controlling for PM2.5. There was no elevation for cardiovascular disease mortality specifically. Similar to the Spencer-Hwang analysis, a recent analysis addressed the association of O3 and mortality in potentially susceptible subpopulations (individuals with diabetes, congestive heart failure, prior myocardial infarction, or chronic obstructive pulmonary disease).16Zanobetti A, Schwartz J. Ozone and survival in four cohorts with potentially predisposing diseases [published online ahead of print June 23, 2011]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201102-0227OC.Google Scholar They observed stronger associations with all-cause mortality than those observed in the ACS study.The overarching question addressed by the present study is whether kidney transplant recipients should be considered a susceptible subpopulation when assessing the associations of chronic air pollution exposure and mortality. There are certainly reasons why they may be at increased risk: it is widely accepted that patients with chronic kidney disease, including those requiring dialysis, experience states of increased inflammation and oxidative stress.17Muntner P. Hamm L.L. Kusek J.W. Chen J. Whelton P.K. He J. The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.Ann Intern Med. 2004; 140: 9-17Crossref PubMed Scopus (352) Google Scholar, 18Himmelfarb J. Linking oxidative stress and inflammation in kidney disease: which is the chicken and which is the egg?.Semin Dial. 2004; 17: 449-454Crossref PubMed Scopus (114) Google Scholar It is plausible that these states make patients with kidney disease particularly susceptible to air pollution–inflicted injury. Patients who live with a functioning kidney transplant are a special case because of the long-term immunosuppressive therapy they receive. Immunosuppression per se may alter the response to noxious pollutants and it is not clear whether subsequent health risks are increased or reduced as a consequence. Clearly, further work is needed in this area to understand if transplant recipients are actually at higher risk than the general population. Related Article, p. 608 Related Article, p. 608 Related Article, p. 608 This issue of the American Journal of Kidney Diseases contains a novel study on the association between ambient air pollution and cardiovascular disease in kidney transplant recipients.1Spencer-Hwang R. Knutsen S.F. Soret S. et al.Ambient air pollutants and risk of fatal coronary heart disease among kidney transplant recipients.Am J Kidney Dis. 2011; 58: 608-616Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar While numerous studies exist on the effects of air pollution on health-related outcomes in the general population or certain subpopulations, this appears to be the first such study in patients with kidney disease. In this commentary, we review the important principles of air pollution and related biomedical research for the nonexpert reader and why the impact on patients with kidney disease from air pollution might be particularly relevant. Ambient air pollution is produced from multiple sources, including transportation, stationary combustion sources, industrial processes, forest fires, wind-blown dust, and secondary atmospheric reactions. The US Environmental Protection Agency (EPA) routinely monitors 6 components of air pollution under the National Ambient Air Quality Standards (NAAQS). These include particulate matter with a median diameter <10 μm (PM10) and <2.5 μm (PM2.5), nitrogen dioxide (NO2) and other nitrogen oxides, ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), and lead (Pb). Particulate matter includes both solid particles and liquid droplets. PM10, or “inhalable particles,” arise predominantly from road dust, fires, and industrial processes. The particles emitted from combustion sources (eg, automobiles, industries, and power plants) are mainly in the smaller size fraction, PM2.5. These particles penetrate deeper into the lung and are thus considered to be the most detrimental to health. NO2 and other nitrogen oxides are gases that arise from the combustion of fossil fuels in motor vehicles and from fixed sources such as power plants. The predominant source of SO2 is industrial sources, including the combustion of coal and crude oil. Ground-level O3 originates from industrial or traffic-related emissions (eg, NO2 and volatile organic compounds) that react with sunlight in the atmosphere and is the primary constituent of smog in urban areas. Historically, the primary source of Pb emissions in the air was motor vehicles. However, since the removal of lead in gasoline, the major sources of Pb emissions are ore and metals processing and aviation fuels.2US Environmental Protection AgencySix common air pollutants.http://www.epa.gov/airquality/urbanairGoogle Scholar Long- and short-term exposures to these constituents of air pollution have been associated with a variety of morbidity and mortality outcomes, including but not limited to coronary heart disease.3Pope III, C.A. Dockery D.W. Health effects of fine particulate air pollution: lines that connect.J Air Waste Manag Assoc. 2006; 56: 709-742Crossref PubMed Scopus (3970) Google Scholar, 4Brunekreef B. Health effects of air pollution observed in cohort studies in Europe.J Expo Sci Environ Epidemiol. 2007; 17: S61-S65Crossref PubMed Scopus (75) Google Scholar The pathophysiological mechanisms that are thought to mediate air pollution–inflicted injury are complex, including changes in autonomic function, oxidative stress, systemic inflammation leading to endothelial dysfunction, thrombosis, or atherosclerosis.3Pope III, C.A. Dockery D.W. Health effects of fine particulate air pollution: lines that connect.J Air Waste Manag Assoc. 2006; 56: 709-742Crossref PubMed Scopus (3970) Google Scholar, 5Pope III, C.A. Burnett R.T. Thurston G.D. et al.Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease.Circulation. 2004; 109: 71-77Crossref PubMed Scopus (2068) Google Scholar, 6Donaldson K. Stone V. Seaton A. MacNee W. Ambient particle inhalation and the cardiovascular system: potential mechanisms.Environ Health Perspect. 2001; 109: 523-527PubMed Google Scholar, 7Utell M.J. Frampton M.W. Zareba W. Devlin R.B. Cascio W.E. Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing.Inhal Toxicol. 2002; 14: 1231-1247Crossref PubMed Scopus (143) Google Scholar, 8Gurgueira S.A. Lawrence J. Coull B. Murthy G.G. Gonzalez-Flecha B. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation.Environ Health Perspect. 2002; 110: 749-755Crossref PubMed Scopus (422) Google Scholar The US Clean Air Act requires EPA to set NAAQS (listed in Title 40, Part 50 of the Code of Federal Regulations) for pollutants considered harmful to public health and the environment. There are 2 types of national air quality standards: primary standards that set limits to protect public health, including the health of “sensitive” populations such as asthmatics, children, and the elderly; and secondary standards that set limits to protect public welfare, including protection against decreased visibility, damage to animals, crops, vegetation, and buildings.9US Environmental Protection AgencyNational Ambient Air Quality Standards (NAAQS).http://www.epa.gov/air/criteria.htmlGoogle Scholar A variety of groups, including the National Research Council10National Research CouncilResearch Priorities for Airborne Particulate Matter: IV Continuing Research Progress. National Academy Press, Washington, DC2004Google Scholar have specifically discussed the need to identify potentially susceptible subpopulations. In this issue of the American Journal of Kidney Diseases, Spencer-Hwang et al1Spencer-Hwang R. Knutsen S.F. Soret S. et al.Ambient air pollutants and risk of fatal coronary heart disease among kidney transplant recipients.Am J Kidney Dis. 2011; 58: 608-616Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar identify kidney transplant recipients as a novel subpopulation susceptible to ambient air pollution. They identified transplant recipients (1997-2003) from the US Renal Data System (USRDS), and determined mortality from coronary heart disease and natural causes through October 2003. Monthly exposure to O3 and PM10 were predicted for each individual's residential zip code centroid using inverse distance-weighted interpolations of the ambient monitoring data. A moving average exposure from the time of transplant through the follow-up period, excluding the month before death, was calculated for each subject. For each 10-ppb increase in O3, risk of fatal coronary heart disease increased by 34% (95% confidence interval, 3%-76%) in models adjusted for sex, race, age, year of transplant, primary cause of kidney failure, months of pretransplant dialysis, and PM10. While the analysis was conducted using standard methods of environmental health research, it should be noted that most studies of O3 use measurements from the summer months only. Thus, using a running average of O3 exposure from transplant may induce some misclassification, most likely resulting in a bias towards the null. However, contrary to their study's findings for O3, Spencer-Hwang et al did not identify any independent associations with cardiovascular risk for PM10. In the general air pollution/cardiovascular literature, PM2.5 has been identified as the more relevant size fraction of particulate matter compared with PM10. Therefore, it is too early to determine whether or not particulate air pollution may play a role in the observed association. To date, the majority of the research on the adverse effects of exposure to O3 has been in short-term time-series studies. In 4 meta-analyses summarizing the effects of this literature, there is consistent evidence of adverse effects on mortality, including cardiovascular disease.11Bell M.L. Dominici F. Samet J.M. A meta-analysis of time-series studies of ozone and mortality with comparison to the national morbidity, mortality, and air pollution study.Epidemiology. 2005; 16: 436-445Crossref PubMed Scopus (461) Google Scholar, 12Ito K. De Leon S.F. Lippmann M. Associations between ozone and daily mortality: analysis and meta-analysis.Epidemiology. 2005; 16: 446-457Crossref PubMed Scopus (320) Google Scholar, 13Levy J.I. Chemerynski S.M. Sarnat J.A. Ozone exposure and mortality: an empiric Bayes metaregression analysis.Epidemiology. 2005; 16: 458-468Crossref PubMed Scopus (257) Google Scholar, 14Gryparis A. Forsberg B. Katsouyanni K. et al.Acute effects of ozone on mortality from the “air pollution and health: a European approach” project.Am J Respir Crit Care Med. 2004; 170: 1080-1087Crossref PubMed Scopus (357) Google Scholar There has only been one other study of long-term exposures to O3 and mortality risk—in the general population–based American Cancer Society (ACS) Study.15Jerrett M. Burnett R.T. Pope III, C.A. et al.Long-term ozone exposure and mortality.N Engl J Med. 2009; 360: 1085-1095Crossref PubMed Scopus (987) Google Scholar Using the average O3 concentrations from April to September, Jerrett and colleagues observed an increased risk of death from respiratory causes of 4% for each 10-ppb increase in O3 after controlling for PM2.5. There was no elevation for cardiovascular disease mortality specifically. Similar to the Spencer-Hwang analysis, a recent analysis addressed the association of O3 and mortality in potentially susceptible subpopulations (individuals with diabetes, congestive heart failure, prior myocardial infarction, or chronic obstructive pulmonary disease).16Zanobetti A, Schwartz J. Ozone and survival in four cohorts with potentially predisposing diseases [published online ahead of print June 23, 2011]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201102-0227OC.Google Scholar They observed stronger associations with all-cause mortality than those observed in the ACS study. The overarching question addressed by the present study is whether kidney transplant recipients should be considered a susceptible subpopulation when assessing the associations of chronic air pollution exposure and mortality. There are certainly reasons why they may be at increased risk: it is widely accepted that patients with chronic kidney disease, including those requiring dialysis, experience states of increased inflammation and oxidative stress.17Muntner P. Hamm L.L. Kusek J.W. Chen J. Whelton P.K. He J. The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.Ann Intern Med. 2004; 140: 9-17Crossref PubMed Scopus (352) Google Scholar, 18Himmelfarb J. Linking oxidative stress and inflammation in kidney disease: which is the chicken and which is the egg?.Semin Dial. 2004; 17: 449-454Crossref PubMed Scopus (114) Google Scholar It is plausible that these states make patients with kidney disease particularly susceptible to air pollution–inflicted injury. Patients who live with a functioning kidney transplant are a special case because of the long-term immunosuppressive therapy they receive. Immunosuppression per se may alter the response to noxious pollutants and it is not clear whether subsequent health risks are increased or reduced as a consequence. Clearly, further work is needed in this area to understand if transplant recipients are actually at higher risk than the general population. Financial Disclosure: The authors declare that they have no relevant financial interests. Ambient Air Pollutants and Risk of Fatal Coronary Heart Disease Among Kidney Transplant RecipientsAmerican Journal of Kidney DiseasesVol. 58Issue 4PreviewThere is increasing evidence that specific ambient air pollutants are associated with coronary heart disease (CHD) morbidity and mortality. Because kidney transplant recipients have prevalent traditional and nontraditional risk factors, they may constitute a sensitive subgroup. Full-Text PDF