Original Investigation Ambient Air Pollutants and Risk of Fatal Coronary Heart Disease Among Kidney Transplant Recipients

Rhonda Spencer-Hwang, DrPH, MPH,1 Synnove Fonnebo Knutsen, PhD, MD, MPH,1 Sam Soret, PhD, MPH,2 Mark Ghamsary, PhD, MS,1 W. Lawrence Beeson, DrPH, MSPH,1 Keiji Oda, MPH,1 David Shavlik, MSPH,1 and Navin Jaipaul, MD, MHS3
Background: There is increasing evidence that specic 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. Study Design: Retrospective cohort. Setting & Participants: This study includes 32,239 nonsmoking adult kidney transplant recipients who underwent transplant in 1997-2003, identied through the US Renal Data System and living in the United States within 50 km of an air pollution monitoring station. Predictor: Long-term ambient pollutant ozone and particulate matter 10 m (PM10), assessed from monthly concentrations of ozone and PM10 calculated from ambient monitoring data by the US Environmental Protection Agency Air Quality System and interpolated to zip code centroids according to patients residence. Outcomes: Outcomes of interest were death from CHD and natural-cause mortality. Results: For the entire transplant cohort, average pollutant levels for ozone and PM10 were 25.5 4.4 parts per billion (ppb) and 25.3 6.4 g/m3, respectively. Correlation between ozone and PM10 values was low, but statistically signicant (P 0.001). There were deaths from CHD (n 267) and natural causes (n 2,076) during the 7-year study period. For each 10-ppb increase in ozone, the risk of fatal CHD increased by 35% (RR, 1.35; 95% CI, 1.04-1.77) in the single-pollutant model and 34% (RR, 1.34; 95% CI, 1.03-1.76) in the 2-pollutant model. No independent association was found between CHD and PM10. No signicant association was identied for PM10 or ozone level and natural-cause mortality (RR, 1.09; 95% CI, 0.99-1.21). Limitations: Exposure assignment based on only residential location. Conclusions: For kidney transplant recipients, ambient ozone levels potentially are associated with higher risk of fatal CHD. These ndings may have implications for regulations governing air pollution and the development of individual CHD risk-reduction strategies. Am J Kidney Dis. 58(4):608-616. 2011 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. INDEX WORDS: Air pollution; coronary heart disease; epidemiology; renal transplantation; survival analysis.

Editorial, p. 506

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ubstantial epidemiologic evidence has identied a potential link between specic ambient air pollutants and a number of adverse cardiovascular health outcomes, including increased rate of hospital admis-

From the Departments of 1Epidemiology and Biostatistics and Environmental and Occupational Health, Loma Linda University; and 3Division of Nephrology, Jerry L. Pettis Memorial VA Medical Center and Loma Linda University School of Medicine, Loma Linda, CA. Received October 28, 2010. Accepted in revised form May 9, 2011. Originally published online July 21, 2011. Address correspondence to Rhonda Spencer-Hwang, DrPH, MPH, Department of Epidemiology and Biostatistics, Loma Linda University, School of Public Health, Nichol Hall, Loma Linda, CA 92354. E-mail: rspencer@llu.edu 2011 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.05.017
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sions for ischemic heart disease, acute myocardial infarction, cardiac arrhythmias, and increased risk of fatal coronary heart disease (CHD).1-10 Both gaseous and particulate pollutants, including ozone and particulate matter, have been identied as adverse risk promoting agents capable of instigating an inammatory response, with some of the greatest risks observed in health-compromised individuals. With most epidemiologic studies to date focused on the general public, the impact that air pollution may have on health outcomes in potentially susceptible populations still needs further research. A few subpopulations with enhanced susceptibility to adverse cardiovascular conditions related to air pollution exposures have been identied. Persons with health conditions associated with states of chronic inammation, such as diabetes and hypertension, have been reported to have an increased risk of adverse cardiovascular events related to air pollution exposures.11-14 Kidney transplant recipients may be another sensitive subgroup. Inammation starts early in the process of kidney disease, and levels of both plasma cytokines and other
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Air Pollutant Risk for Renal Transplant Recipients

inammatory markers have been found to be increased in kidney transplant recipients.15-17 The increase in inammatory marker levels may be caused in part by decreased removal as researchers have identied an association between decreasing glomerular ltration rate and increases in levels of inammatory markers.18 Both traditional (including diabetes and hypertension) and nontraditional risk factors (eg, immunosuppressive medications) are prevalent in kidney transplant recipients.19,20 Presently, one of the major hazards negatively inuencing the survival of kidney transplant recipients is CHD-related mortality. Although epidemiologic data suggest a link between ambient air pollutants and adverse CHD outcomes for the general public and a few sensitive subpopulations, to our knowledge, no study has assessed the potential health effects in organ transplant recipients. Therefore, the goal of this study was to evaluate the association between long-term exposure to the ambient air pollutants ozone and PM10 (particulate matter 10 m) and risk of CHD and death by natural causes in kidney transplant recipients.

time of transplant. Residential zip codes were used to georeference the study population. Using GIS tools, each participant was geographically matched to a centroid (point) location representing his or her residential zip code. Only 1% of the total transplant recipients within the USRDS data set were missing the residential information necessary to geocode addresses, and these were excluded from analysis. Station-specic monthly concentrations across the network throughout the continental United States were calculated for each pollutant. In cases in which more than one monitor was operating at the same location on a particular day, the mean value for the monitors measurements was calculated. Using GIS-based inverse-distanceweighted interpolations (power 2; number of neighbors 3), multiple monthly pollution surfaces were created to predict ozone and PM10 concentrations at each zip code centroid. To minimize errors, the inverse-distanceweighted interpolation parameters were selected by assessing the goodness of t of alternative model congurations through mean prediction error and root-mean-square error.21 Using overlay geoprocessing tools, we linked residential zip code locations with air pollution surfaces containing the zip codespecic exposure estimates modeled from ambient air pollution data. GIS-derived monthly exposure averages were used to cumulate and assign a moving average exposure for each participant from the time of transplant through the follow-up period, with exclusion of the month before death to avoid short-terminduced effects in assigning exposure. Participants were included in the analysis only if they resided within 50 km of an air pollutant monitor.

METHODS
Study Population
Study participants were identied through the US Renal Data System (USRDS), a national data repository containing extensive demographic (including updated residential information), diagnostic, hospital information, and mortality data for persons living with end-stage renal disease (ESRD). Our study population included rst-time kidney transplant recipients 18 years and older who underwent transplant in 1997-2003, with at least 1 year of transplant survival, residing within 50 km of an air pollution monitoring station, and living within the continental United States. Only participants residing within the same zip code during the entire follow-up study period were included in analysis. Participants were followed up until the date of event (CHD and natural-cause mortality) or censoring, which occurred at the end of the study period (October 31, 2003). For CHD mortality analyses, censoring included death from non-CHD causes or the end of the study. For the natural-cause mortality analyses, censoring included the end of the study period. Those who smoked cigarettes (n 2,502) at the time of transplant were excluded. Thus, 38,102 nonsmoking kidney transplant recipients met the inclusion criteria. Of these, 5,863 reported prevalent CHD at the time of transplant, leaving 32,239 with no known heart disease as our study population.

Ascertainment of Deaths
Our 2 main outcomes of interest were death from CHD and death from natural causes. CHD was dened as the primary cause of death if it was coded as such within the USRDS database; this information has been validated previously.22 If the primary cause of death listed was acute myocardial infarction or atherosclerotic heart disease, it was determined that a fatal CHD event had occurred. A natural-cause event was dened as death from natural causes (ie, deaths other than those caused by accident, suicide, or homicide).

Potential Confounding Variables

All identied potential confounders available within the USRDS database were assessed for confounding in the base model by adding and removing each potential confounder one at a time to the base model and determining if they individually changed the air pollution main effect by 10% (Table 1). The potential confounders investigated included sex (men/women); race (white, black, and other); body mass index category ( 18.5, 18.5-29.9, and 30 kg/m2); duration of pretransplant dialysis treatment (months); causes of kidney failure (diabetes, hypertension, primary glomerulonephritis, polycystic kidney disease, miscellaneous factors, and unknown factors); United Network for Organ Sharing region (11 regions total); serum creatinine level before posttransplant hospital discharge (0.1-1.2, 1.3-1.7, 1.7-2.7, and 2.8 mg/dL); hypertension independent of the cause of kidney failure (yes/no); diabetes independent of the cause of kidney failure (yes/no); educational level at the time of transplant (high school or less and college or more); pretransplant blood transfusion (yes/no); delayed transplant function, dened as the need for dialysis within the rst week posttransplant or lack of urine output in the rst 24 hours after transplant (yes/no); total number of kidney transplants performed throughout the follow-up period (1 only and 2); organ donor type (deceased/living); organ donor age ( 30, 30-44, 44-60, and 60 years); and organ donor sex. Immunosuppressant medication was evaluated on an intention-to-treat basis and included the following variables: cyclosporine (yes/no), tacrolimus (yes/no), other (rapa609

Pollution Exposure Assignment

Air pollution statistics collected over the national ambient monitoring network in 1997-2003 and the geographic coordinates of each xed monitoring station were extracted from the US Environmental Protection Agency Air Quality System. Hourly ozone and PM10 data were collected for each monitoring location and were used to create monthly average values for each site. ArcGIS 9.3 (ESRI, www.esri.com) was used for all spatial data manipulations and implementation of exposure models to estimate air pollutant concentrations for each participant. Estimates of monthly concentrations of ambient ozone and PM10 were created for each study participant according to residential address at the
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Table 1. Assessment of Potential Confounding Variables
Model RR (95% CI) % Changea

Basicb Model 2 basic cause of ESRD Model 3 basic dialysis Model 4 basic hypertension Model 5 basic diabetes Model 6 basic obesity Model 7 basic education Model 8 basic total no. of transplants Model 9 basic creatinine level Model 10 basic delayed transplant function Model 11 basic transfusion Model 12 basic UNOS region Model 13 basic donor type Model 14 basic donor age

1.41 (1.08-1.84) 1.34 (1.02-1.75) 1.42 (1.09-1.85) 1.45 (1.11-1.89) 1.41 (1.08-1.84) 1.46 (1.04-2.05) 1.33 (0.98-1.80) 1.41 (1.08-1.83) 1.54 (1.18-2.02) 1.44 (1.03-2.01)

Reference 4.96 0.71 2.84 0.00 3.55 5.67 0.00 9.22 2.13

1.38 (1.02-1.88) 1.42 (1.09-1.86) 1.41 (1.08-1.84) 1.42 (1.08-1.87)

2.13 0.71 0.00 0.71

Models Including Immunosuppressive Medications Model 15 basic donor sex Model 16 basic azathioprine Model 17 basic mycophenolate mofetil Model 18 basic steroid Model 19 basic cyclosporine Model 20 basic tacrolimus Model 21 basic other medication (rapamycin, leunomide, deoxyspergualin) 1.42 (1.09-1.86) 1.38 (1.06-1.81) 1.39 (1.06-1.82) 1.39 (1.06-1.81) 1.37 (1.05-1.80) 1.37 (1.05-1.79) 1.4 (1.07-1.84) 0.71 2.13 1.42 1.42 2.84 2.84 0.71

using t test, 2 test, or analysis of variance for univariate analysis. Correlation of air pollutants was estimated using Pearson correlation coefcient. The 2 specic health outcomes analyzed included death from CHD and natural-cause deaths, as previously dened. Participants were followed up from the time of transplant until event or censoring, as previously dened. Cox proportional hazard models were used to estimate the effect of ambient air pollutants on risk of CHD and natural-cause death using attained age as the time variable. We further adjusted for change in air pollutant compositions over time by adding year of transplant as a covariate. A basic model was developed that included the air pollutant, sex, race, age, and year of transplant. All potential confounders available within the USRDS database were assessed for confounding in this base model. None of the candidate variables changed the main effect by 10% (Table 1). However, because of the strong predictive effect of primary cause of kidney disease and length of dialysis therapy before transplant on mortality in kidney transplant patients, these were added to the nal model. Tests of interactions between the various patient demographics and air pollutants were assessed using the log likelihood ratio 2 test comparing the reduced Cox model (without interaction terms) with the full Cox model (with interaction terms). None of the interaction terms was statistically signicant. All variables in the nal model were assessed with respect to meeting the requirements of proportional hazard assumptions by checking the log [log(survival)] curves against the log time variable, and all met the assumption. Additionally, all variables were assessed for multicollinearity. Results are reported per 10- g/m3 increase for PM10 and 10-parts per billion (ppb) increase for ozone. A sandwich variance estimate was added to the nal model to adjust for potential correlation that might exist between observations within a localized area.23 Finally, a sensitivity analysis was conducted in which participants with prevalent CHD were included in analyses and prevalent CHD was added as a covariate to the model. Additional sensitivity analyses were conducted that included only participants residing within 30 km of the nearest monitor to compare with overall study results. All analyses were performed using SAS, version 9.2 (SAS Institute, www.sas.com).

RESULTS
Study Population The transplant population for this study consisted of individuals from across the entire continental United States (Fig 1). A total of 267 CHD deaths and 2,076 natural-cause deaths occurred in the 32,239 individuals studied (230.2 CHD deaths/100,000 person-years) during the 7-year study period. A combined total of 115,983.5 person-years was contributed by cohort participants during the follow-up period. Deaths from CHD accounted for 12.9% of the total 2,076 naturalcause deaths. For those with death from CHD, median time from transplant to death was 36.2 (mean, 37.6 17.8) months. A comparison of cases with noncases indicated differences in several baseline demographic and other variables. CHD mortality cases and naturalcause death cases tended to be older at the time of transplant, more likely to have diabetes or hypertension as the primary cause of ESRD, less likely to have received an organ from a living donor, and more likely to have experienced initial delayed transplant function after transplant.
Am J Kidney Dis. 2011;58(4):608-616

Abbreviations: CI, condence interval; ESRD, end-stage renal disease; RR, relative risk; UNOS, United Network for Organ Sharing. a (RR RRbasic)/RRbasic 100. b Includes ozone adjusted for sex, race (white, black, and Asian/other), age, and year of transplant (1997-2003).

mycin, leunomide, and deoxyspergualin; yes/no), azathioprine (yes/no), mycophenolate mofetil (yes/no), steroid (prednisone, methylprednisolone, and dexamethasone; yes/no).

Statistical Analysis
Comparisons of baseline and follow-up demographics between cases (CHD or natural-cause deaths) and noncases were made
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Figure 1. Locations of individuals included in study cohort (US kidney transplant recipients aged transplant in 1997-2003).

18 years who underwent

Across the ozone categories, a number of baseline characteristic differences were observed for this study cohort (Table 2). Within the highest ozone category ( 32 ppb), differences included a lower proportion of black transplant recipients, a greater proportion with a diagnosis of hypertension independent of cause of ESRD, and a greater proportion with lower creatinine levels (0.1-1.2 mg/dL) at the time of hospital discharge posttransplant. From the lowest to the highest ozone category, there was an increase in proportion of kidney transplant recipients with ESRD attributed to diabetes. For the entire transplant cohort, average pollutant levels for PM10 and ozone were 25.3 6.4 g/m3 and 25.5 4.4 ppb, respectively. Correlation between ozone and PM10 was low, but statistically signicant (P 0.001). Risk of Fatal CHD Single-Pollutant Models In the multivariable-adjusted model (Table 3), an increase in ozone of 10 ppb was associated with a 35% increased risk of fatal CHD (relative risk [RR], 1.35; 95% condence interval [CI], 1.04-1.77). This effect was unchanged when adjusting the multivariAm J Kidney Dis. 2011;58(4):608-616

able model for potential autocorrelation, although the CIs slightly widened. Inclusion of participants with prevalent CHD at the time of transplant slightly reduced the strength of association between ozone level and CHD mortality, but the association remained statistically signicant. As also listed in Table 3, no association was found between ambient PM10 levels and risk of CHD mortality in either the age- or multivariable-adjusted models. The estimates were virtually the same when adjusting for potential autocorrelation or inclusion of participants with prevalent CHD at the time of transplant.
Two-Pollutant Models

Compared with the single-pollutant model, the association between ozone level and fatal CHD was virtually unchanged in both age- and multivariableadjusted models after adjustment for PM10 (Table 4), with RR of 1.34 (95% CI, 1.03-1.76). Inclusion of participants with prevalent CHD at the time of transplant slightly reduced the strength of the association between ozone level and CHD mortality, although the association remained statistically signicant.
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Table 2. Baseline Characteristics of the Study Population by Ozone Exposure
Total 32,239) <19 ppb (n 2,135) 19-<25 ppb (n 11,345) 25-<32 ppb (n 16,724) >32 ppb (n 2,035)

Characteristics

(N

Age at transplant (y) Sex Men Women Race White Black Asian/Indian/other BMI category 18.5 kg/m2 18.5-29.9 kg/m2 30 kg/m2 Primary cause of ESRD Primary GN Diabetes Hypertension PKD Miscellaneous Unknown factor Hypertension (independent of ESRD) Yes No Time on dialysis 0-12 mo 13-24 mo 24 mo SCr level at discharge 0.1-1.2 mg/dL 1.3-1.7 mg/dL 1.8-2.7 mg/dL 2.8 mg/dL Donor type Deceased Living Delayed transplant function Yes No Pretransplant blood transfusion Yes No PM10 20 203040 g/m3 30 g/m3 40 g/m3 g/m3

46.4

12.3

45.4

12.6

46.6

12.3

46.4

12.3

46.2

12.5a

18,503 (57.4) 13,735 (42.6)

1,193 (55.9) 942 (44.1)

6,491 (57.2) 4,854 (42.8)

9,639 (57.6) 7,084 (42.4)

1,180 (58.0) 855 (42.0)

22,148 (68.7) 7,983 (24.8) 2,099 (6.5)

1,209 (56.6) 681 (31.9) 242 (11.3)

7,088 (62.5) 3,280 (28.9) 971 (8.6)

12,111 (72.4) 3,846 (23.0) 767 (4.6)

1,740 (85.5) 176 (8.6)b 119 (5.8)

9,148 (28.4) 16,924 (52.5) 6,113 (19.0)

708 (33.2) 1,114 (52.2) 313 (14.7)

3,239 (28.6) 5,896 (52.0) 2,156 (19.0)

4,622 (27.6) 8,847 (52.9) 3,255 (19.5)

579 (28.5) 1,067 (52.4)b 389 (19.1)

9,045 (28.1) 6,352 (19.7) 5,903 (18.3) 3,714 (11.5) 4,970 (15.4) 2,255 (7.0)

623 (29.2) 364 (17.0) 496 (23.2) 180 (8.4) 294 (13.8) 178 (8.3)

3,090 (27.2) 2,109 (18.6) 2,378 (21.0) 1,224 (10.8) 1,687 (14.9) 857 (7.6)

4,734 (28.3) 3,388 (20.3) 2,780 (16.6) 2,077 (12.4) 2,650 (15.8) 1,095 (6.5)

598 (29.4) 491 (24.1) 249 (12.2)b 233 (11.4) 339 (16.7) 125 (6.1) 1,059 (52.0)b 976 (48.0)

14,625 (45.4) 17,614 (54.6)

757 (35.5) 1,378 (64.5)

4,706 (41.5) 6,639 (58.5)

8,103 (48.5) 8,621 (51.5)

13,846 (42.9) 5,924 (18.4) 12,469 (38.7)

902 (42.2) 355 (16.6) 878 (41.1)

4,727 (41.7) 2,051 (18.1) 4,567 (40.3)

7,287 (43.6) 3,134 (18.7) 6,303 (37.7)

930 (45.7) 384 (18.9)b 721 (35.4)

7,614 (23.6) 7,770 (24.1) 7,000 (21.7) 9,064 (28.1)

460 (21.5) 449 (21.0) 421 (19.7) 707 (33.1)

2,549 (22.5) 2,543 (22.4) 2,406 (21.2) 3,502 (30.9)

4,019 (24.0) 4,254 (25.4) 3,744 (22.4) 4,398 (26.3)

586 (28.8) 524 (25.7)b 429 (21.1) 457 (22.5)

19,084 (59.2) 13,155 (40.8)

1,246 (58.4) 889 (41.6)

6,800 (59.9) 4,545 (40.1)

9,898 (59.2) 6,826 (40.8)

1,140 (56.0) 895 (44.0) 304 (14.9)b 1,199 (58.9)

6,012 (18.6) 18,486 (57.3)

485 (22.7) 1,240 (58.1)

2,314 (20.4) 6,661 (58.7)

2,909 (17.4) 9,386 (56.1)

8,342 (25.9) 18,137 (56.3)

592 (27.7) 1,222 (57.2)

2,901 (25.6) 6,414 (56.5)

4,314 (25.8) 9,279 (55.5)

535 (26.3) 1,222 (60.0)

5,823 (18.1) 20,774 (64.4) 4,676 (14.5) 966 (3.0)

197 (9.2) 1,278 (59.9) 2,105 (29.0) 41 (1.9)

1,749 (15.4) 7,145 (63.0) 619 (18.6) 346 (3.0)

3,515 (21.0) 11,264 (67.4) 1,582 (9.5) 363 (2.2)

362 (17.8) 1,087 (53.4) 370 (18.2) 16 (10.6)

Note: Continuous variables expressed as mean standard deviation; categorical variables, as number (column percentage). For continuous outcomes, comparison using analysis of variance. For categorical outcomes, comparison using 2 test. Some columns do not add to 100% because of missing data. Conversion factor for SCr in mg/dL to mol/L, 88.4. Abbreviations: BMI, body mass index; ESRD, end-stage renal disease; GN, glomerulonephritis; PKD, polycystic kidney disease; PM10, particulate matter 10 m; ppb, parts per billion; SCr, serum creatinine. a P 0.01; bP 0.001.

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Table 3. Single-Pollutant Models of Relative Risks of Fatal CHD
Age Adjusted (n 267) Multivariable Adjusteda (n 261) Multivariable Adjustedb (n 261) Multivariable Adjustedc (n 373)

Pollutant

Increment

PM10 O3

10 g/m3 10 ppb

0.98 (0.81-1.18) 1.30 (1.00-1.69)

0.93 (0.77-1.13) 1.35 (1.04-1.77)

0.93 (0.74-1.17) 1.35 (1.01-1.81)

0.96 (0.82-1.12) 1.28 (1.02-1.60)

Note: Values shown are relative risk (95% condence interval). Abbreviations: CHD, coronary heart disease; O3, ozone; PM10, particulate matter 10 m; ppb, parts per billion. a Multivariable model is adjusted for the following variables: sex, race (white, black, and other), age, year of transplant (1997-2003), primary cause of end-stage renal disease (diabetes, hypertension, primary glomerulonephritis, polycystic kidney disease, miscellaneous, and unknown factor), and length of pretransplant dialysis (months). b Multivariable model with inclusion of sandwich variance estimate to adjust for potential spatial autocorrelation. c Multivariable model with inclusion of participants with prevalent CHD at the time of transplant.

The null ndings from the single-pollutant model for PM10 were virtually unchanged in the 2-pollutant models with adjustment for ozone level, as well as including participants with prevalent CHD. Risk of Natural-Cause Mortality Single-Pollutant Models In the multivariable-adjusted model, an increase in ozone level of 10 ppb was associated with a 10% increase in risk of natural-cause death (Table 5), although results were not statistically signicant (RR, 1.10; 95% CI, 0.99-1.21). This effect was unchanged when adjusting the multivariable model for potential autocorrelation, although CIs slightly widened. No association was found between ambient PM10 level and risk of natural-cause death in either the ageor multivariable-adjusted models. Estimates were virtually the same when adjusting for potential autocorrelation or inclusion of participants with prevalent CHD at the time of transplant.
Two-Pollutant Models

participants with prevalent CHD at the time of transplant slightly reduced the association between ozone level and natural-cause death. The null ndings from the single-pollutant model for PM10 level were virtually unchanged in the 2-pollutant models with adjustment for ozone level, as well as including participants with prevalent CHD. Sensitivity Analyses Risk estimates for ozone were virtually the same when limiting analyses to include only participants residing within 30 km from the nearest air pollutant monitor compared with those residing within 50 km. The same was true for the lack of association with PM10 level.

Compared with the single-pollutant model, the association between ozone level and natural-cause death was similar in both age- and multivariable-adjusted models after adjustment for PM10 level (Table 6), although results were not statistically signicant with an RR of 1.09 (95% CI, 0.99-1.21). Inclusion of

DISCUSSION To our knowledge, no other study has assessed the impact of ambient air pollution on organ transplant recipients. Findings from this cohort study provide support for the hypothesis that air pollution exacerbates the atherosclerotic process and increases the risk of fatal CHD in kidney transplant recipients. Most studies of the effect of ambient air pollution on risk of CHD have found a clear and harmful effect of particulate matter, especially PM2.5 (particulate matter 2.5 m), but usually little effect of ozone.10,24-27 Our results differ from previous studies in that we found a

Table 4. Two-Pollutant Models of Relative Risks of Fatal CHD

Age Adjusted (n 267) Multivariable Adjusteda (n 261) Multivariable Adjustedb (n 261) Multivariable Adjustedc (n 373)

Pollutant

Increment

Adjusted

PM10 O3

10 g/m3 10 ppb

O3 PM10

1.00 (0.83-1.20) 1.30 (0.99-1.69)

0.95 (0.79-1.15) 1.34 (1.03-1.76)

0.95 (0.77-1.18) 1.34 (1.01-1.79)

0.98 (0.84-1.14) 1.27 (1.02-1.60)

Note: Values shown are relative risk (95% condence interval). Abbreviations: CHD, coronary heart disease; O3, ozone; PM10, particulate matter 10 m; ppb, parts per billion. a Multivariable model is adjusted for the following variables: sex, race (white, black, and other), age, year of transplant (1997-2003), primary cause of end-stage renal disease (diabetes, hypertension, primary glomerulonephritis, polycystic kidney disease, miscellaneous, and unknown factor), and length of pretransplant dialysis (months). b Multivariable model with inclusion of sandwich variance estimate to adjust for potential spatial autocorrelation. c Multivariable model with inclusion of participants with prevalent CHD at the time of transplant. Am J Kidney Dis. 2011;58(4):608-616 613

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Table 5. Single-Pollutant Models of Relative Risks of Natural-cause Mortality
Age Adjusted (n 2,076) Multivariable Adjusteda (n 2,049) Multivariable Adjustedb (n 2,049) Multivariable Adjustedc (n 2,748)

Pollutant

Increment

PM10 O3

10 g/m3 10 ppb

1.02 (0.96-1.09) 1.05 (0.95-1.15)

0.97 (0.91-1.04) 1.10 (0.99-1.21)

0.97 (0.88-1.08) 1.10 (0.96-1.25)

0.98 (0.93-1.04) 1.08 (0.99-1.18)

Note: Values shown are relative risk (95% condence interval). Abbreviations: O3, ozone; PM10, particulate matter 10 m; ppb, parts per billion. a Multivariable model is adjusted for the following variables: sex, race (white, black, and other), age, year of transplant (1997-2003), primary cause of end-stage renal disease (diabetes, hypertension, primary glomerulonephritis, polycystic kidney disease, miscellaneous, and unknown factor), and length of pretransplant dialysis (months). b Multivariable model with inclusion of sandwich variance estimate to adjust for potential spatial autocorrelation. c Multivariable model with inclusion of participants with prevalent CHD at the time of transplant.

signicant effect of ozone on risk of fatal CHD, and this effect was stronger than the nonsignicant association found for PM10. Unfortunately, there were limited numbers of PM2.5 monitors during follow-up of this study, and thus we were unable to assess the effect of ne PM. Because PM2.5 is smaller in diameter than PM10, it is anticipated that stronger associations will be found for PM2.5 because smaller particles more easily penetrate biological defense mechanisms. We found a consistent and signicant increased risk of fatal CHD with increasing levels of ambient ozone across the models from age- to multivariable-adjusted models and in both single- and 2-pollutant models. The increased risk of fatal CHD associated with ozone level was stable and ranged from 30% in the ageadjusted single- and 2-pollutant models to 34%-35% in both the single- and 2-pollutant multivariableadjusted models. The consistent association between ozone level and CHD mortality across all models suggests that ozone level may be a risk factor for CHD mortality in kidney transplant recipients with and without prevalent CHD at the time of transplant. We found a slight increase in risk between ozone level and natural-cause mortality in the single-pollutant multivariable-adjusted model, and although results did not reach statistical signicance, they still may have clinical implications. In general, long-term cohort studies of ambient air pollutants and related adverse health events typically

have selected participants from the general public, with few from potentially sensitive subpopulations. One of the few long-term cohort studies, the Adventist Health and Smog Study (AHSMOG) by Abbey et al,24 found a slight increase in risk of cardiopulmonary mortality in a study conducted on Adventists residing in Southern California. The increased risk was found for both ozone and PM10, but results did not reach statistical signicance. In a later study from the same cohort, Chen et al10 found no association between ozone level and fatal CHD, but found a statistically signicant association with PM2.5 level. Results from Pope et al25 recorded a slight increase in risk for ozone level and cardiopulmonary mortality; however, they did not attain statistical signicance. Recently, Jerrett et al26 identied an association between cardiopulmonary mortality and ozone level in single-pollutant models, but it disappeared after adjustment for PM2.5 level. The differences in ndings between these cohort studies and ours may be that our study participants are kidney transplant recipients who, because of their decrease in kidney function and associated increased risk factors, may experience aggravated responses to air pollutants. There is limited evidence about which sensitive subgroups of the general public are more susceptible to adverse effects of ambient air pollution. However, studies of hospital admissions and mortality research have implicated diabetes, obesity, and hypertension as

Table 6. Two-Pollutant Models of Relative Risks of Natural-Cause Mortality

Age Adjusted (n 2,076) Multivariable Adjusteda (n 2,049) Multivariable Adjustedb (n 2,049) Multivariable Adjustedc (n 2,748)

Pollutant

Increment

Adjusted

PM10 O3

10 g/m3 10 ppb

O3 PM10

1.03 (0.96-1.10) 1.05 (0.95-1.16)

0.98 (0.92-1.05) 1.09 (0.99-1.21)

0.98 (0.89-1.09) 1.09 (0.96-1.24)

0.99 (0.93-1.04) 1.07 (0.99-1.17)

Note: Values shown are relative risk (95% condence interval). Abbreviations: O3, ozone; PM10, particulate matter 10 m; ppb, parts per billion. a Multivariable model is adjusted for the following variables: sex, race (white, black, and other), age, year of transplant (1997-2003), primary cause of end-stage renal disease (diabetes, hypertension, primary glomerulonephritis, polycystic kidney disease, miscellaneous, and unknown factor), and length of pretransplant dialysis (months). b Multivariable model with inclusion of sandwich variance estimate to adjust for potential spatial autocorrelation. c Multivariable model with inclusion of participants with prevalent CHD at the time of transplant. 614 Am J Kidney Dis. 2011;58(4):608-616

Air Pollutant Risk for Renal Transplant Recipients

groups with enhanced vulnerability to the effects of ambient air pollution.11-15,28 Many of these conditions are highly prevalent in kidney transplant recipients. A review by Ojo19 reported in kidney transplant recipients prevalences of hypertension, hypercholesterolemia, and diabetes of 80%, 60%, and 55%, respectively, potentially making them one of the highest risk sensitive subpopulations for air pollutionassociated cardiovascular effects. Cottone et al17 conducted a study of kidney transplant recipients and found that compared with healthy controls, levels of C-reactive protein and other inammatory markers were signicantly increased. Transplant recipients have additional CHD risk factors as a result of the use of immunosuppressive medications. These medications have been associated with hyperlipidemia, hypertension, and new onset of diabetes posttransplant.29,30 Together, these various factors may enhance vulnerability in kidney transplant recipients. The biological mechanisms through which the gaseous air pollutant ozone works to promote adverse cardiovascular effects is not fully understood. Inhalation of both particulates and gaseous ambient air pollutants has been found to cause a pulmonary inammatory response that may promote a systemic inammatory response either directly or indirectly through triggering a cascade of events, ultimately setting in motion systemic inammatory processes.31,32 Evidence is accumulating that ozone inuences a number of blood inammatory markers, including oxidative stress, coagulation factors, and C-reactive protein, all of which ultimately increase the risk of cardiovascular disease and mortality.32,33 Our study design has several strengths, as well as limitations. By using the USRDS database, we have a nationally representative sample of more than 79,500 rst-time kidney transplant recipients who underwent transplant in 1997-2003. This large number of transplants gives access to large number of events, providing sufcient strength in determining whether these patients are vulnerable with respect to risk of CHD in an environment with higher air pollution levels. Our study has a few limitations that merit discussion. As with other studies of health effects of air pollution, only ambient pollution concentrations at the place of residence were available, which potentially could cause exposure misclassication. However, it is unlikely that there is a directional bias with only cases experiencing misclassication of exposure assignment. Additionally, we did not have information about ambient levels of PM2.5. Adjusting for this pollutant potentially could alter the effects of ozone even if adding PM10 in 2-pollutant models did not change the effect of ozone. However, a number of both animal and human laboratory studies have found
Am J Kidney Dis. 2011;58(4):608-616

harmful effects of ozone independent of PM2.5.34-36 Last, the low number of CHD deaths in kidney transplant recipients in this study may indicate that CHD deaths have been assigned a different cause of death within the database, possibly with a cardiovascular disease other than CHD. Further analysis of the association between ambient air pollutant levels and other cardiovascular-related deaths are warranted. In summary, we have presented the rst epidemiologic evidence that long-term ambient levels of ozone air pollution may potentially increase the risk of fatal CHD in kidney transplant recipients. More research is needed to conrm these ndings and determine whether patients with decreased kidney function in general have an increased risk of fatal CHD associated with ambient air pollution. There may be more than 5 million people living in the United States with some form of decreased kidney function, and the risk of CHD may be progressive from the onset of decreased kidney function through kidney transplant.37 Potentially, any changes in ambient air pollution could have important ramications for the health of an increasing segment of the population. Ultimately, ndings from our study may have implications for air pollution regulations and the development of health information guidelines about exposure reduction targeting this potentially vulnerable population.

ACKNOWLEDGEMENTS
The authors thank Rebekah Spencer, DMD (Oregon Health and Science University), for valuable comments with drafting of the manuscript. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an ofcial policy or interpretation of the US government. Support: This study was in part funded by Environmental Protection Agency grant CR830547010. Financial Disclosure: The authors declare that they have no relevant nancial interests.

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