American Journal of Epidemiology Copyright 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved;

; printed in U.S.A.

Vol. 164, No. 3 DOI: 10.1093/aje/kwj173 Advance Access publication June 14, 2006

Original Contribution The Association among Smoking, Heavy Drinking, and Chronic Kidney Disease

Anoop Shankar1, Ronald Klein2, and Barbara E. K. Klein2

1

Division of Epidemiology, Department of Community, Occupational, and Family Medicine, National University of Singapore, Republic of Singapore. 2 Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI. Received for publication August 18, 2005; accepted for publication February 8, 2006.
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Several factors for chronic kidney disease (CKD), including diabetes, hypertension, and obesity, are described consistently in the literature; studies describing modiable lifestyle factors, including smoking and consumption of alcohol, are sparse, sometimes contradictory. The authors examined the factors associated with CKD in a population-based cohort in Wisconsin, with emphasis on smoking and consumption of alcohol. CKD was dened as an estimated glomerular ltration rate of less than 60 ml/minute per 1.73 m2 from serum creatinine. The authors performed two analyses: 1) cross-sectional analysis among 4,898 persons with prevalent CKD (n 324) as the outcome of interest and 2) longitudinal analysis among 3,392 CKD-free persons at baseline, with 5-year incident CKD (n 114) between 1993 and 1995 as the outcome of interest. Smoking and heavy drinking, dened as consumption of four or more servings of alcohol per day, were associated with CKD, independent of several important confounders. Compared with that among never smokers, the odds ratio of developing CKD was 1.12 (95% condence interval (CI): 0.63, 2.00) among former smokers and 1.97 (95% CI: 1.15, 3.36) among current smokers. Heavy drinking was associated with CKD, with an odds ratio of 1.99 (95% CI: 0.99, 4.01). Joint exposure to both current smoking and heavy drinking was associated with almost vefold odds of developing CKD compared with their absence (odds ratio 4.93, 95% CI: 2.45, 9.94). Smoking and consumption of four or more servings of alcohol per day are associated with CKD. alcohol drinking; kidney diseases; smoking

Abbreviations: CI, condence interval; CKD, chronic kidney disease; GFR, glomerular ltration rate; NSAID, nonsteroidal antiinammatory drug; OR, odds ratio.

End-stage renal disease is an important public health problem. There were estimated to be 440,000 patients with endstage renal disease in the United States as of 2003 (1), and based on earlier data an estimated additional 8 million US adults have chronic kidney disease (CKD), dened as a glomerular ltration rate of less than 60 ml/minute per 1.73 m2 (2, 3), who are at risk of progression to end-stage renal disease and its attendant complications (4). Although a number of risk factors for CKD, including diabetes (4, 5), hypertension (3, 4, 6), and obesity (4, 7, 8), have been described consistently in the literature, studies looking at modiable lifestyle factors such as smoking and consumption of alcohol are

sparse and sometimes contradictory (812). In the current paper, we examined the factors associated with CKD in a population-based study in Wisconsin, with particular emphasis on the role of smoking and consumption of alcohol.
MATERIALS AND METHODS Study population

The methods used to identify and describe the population have appeared in previous reports (1315). In brief, a private census of the population of Beaver Dam, Wisconsin, was

Correspondence to Dr. Ronald Klein, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 4th Floor WARF Building, Madison, WI 53726 (e-mail: kleinr@epi.ophth.wisc.edu).

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performed from September 1987 to May 1988 to identify all residents in the city or township of Beaver Dam who were 4384 years of age. Of the 5,924 eligible persons (98 percent Caucasians), 4,926 (83.1 percent) participated in the baseline examination between March 1, 1988, and September 14, 1990. A total of 3,684 persons (81.1 percent) participated in the 5-year follow-up examination between March 1, 1993, and June 14, 1995. Comparisons between participants and nonparticipants at the time of the baseline and 5-year follow-up examinations have appeared elsewhere (13, 14). Both the baseline and follow-up examinations followed a similar protocol. Written, informed consent was obtained from each subject at each examination. The study was approved by the Human Subjects Committee of the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. The current paper presents two sets of analyses: 1) crosssectional analysis with prevalent CKD as the outcome of interest and 2) longitudinal analysis with 5-year incident CKD as the outcome of interest. Of the 4,926 persons who participated in the baseline examination, 4,898 persons with serum creatinine measurements and complete covariate information form the study population for the cross-sectional analysis. Of the 3,984 persons who participated in the baseline and 5-year follow-up examinations, 3,392 persons with serum creatinine measurements taken at both of these examinations form the study population for the longitudinal analysis.
Exposure ascertainment

The baseline examination and the follow-up examination included measuring weight, height, and systolic and diastolic blood pressure by a trained observer and administering a standardized questionnaire that collected information regarding participants demographic characteristics, details regarding cigarette smoking, consumption of alcohol, medical histories and medications taken, including the diagnosis of diabetes or hypertension by a physician, and use of nonsteroidal antiinammatory agents (NSAIDs). Casual blood specimens were obtained for measurement of plasma glucose and serum creatinine. Age was dened as the participants age at the baseline examination. Education was categorized as below high school, high school, or beyond high school. Body mass index was dened as participants weight (kg)/height (m)2. Hypertension was dened as systolic blood pressure of 140 mmHg or higher, diastolic blood pressure of 90 mmHg or higher, or the combination of a self-reported hypertension diagnosis by a physician and use of antihypertensive medications. Persons were dened as having diabetes on the basis of a casual blood sugar measurement of higher than 200 mg/dl (11.1 mmol/liter), or if they had a history of diabetes diagnosis by a physician and were treated with insulin, oral hypoglycemic agents, or diet. History of cardiovascular disease was dened as the presence or absence of a physician-diagnosed episode of myocardial infarction, angina, or stroke. Cigarette smoking status at the time of the baseline examination was determined as follows (15). A subject was classied as a nonsmoker if he/she had smoked fewer than 100 cigarettes in his/her lifetime, as a former smoker if he/

she had smoked this number of cigarettes or more in his/her lifetime but had stopped smoking at least 1 year before the examination, and as a current smoker if he/she had not stopped smoking. The total pack-years smoked was dened as the number of cigarettes smoked per day divided by 20, multiplied by the number of years smoked. Former smokers were queried regarding the years since they stopped smoking. Years since stopped smoking among former smokers were categorized as 15 or more, 514, and less than 5. The examination questionnaire contained questions regarding alcohol consumption (15). Subjects were asked about their average weekly use of beer, wine, and liquor in the previous year. In addition, they were asked about past periods of drinking, including whether or not they ever consumed four or more drinks daily. From these data, a current drinker was dened as a person who had consumed alcoholic beverages within the past year, a former drinker was a person who had consumed alcoholic beverages in the past but not within the previous year, and a nondrinker had never consumed alcoholic beverages. The distribution of alcohol consumption was highly skewed; 51.2 percent of the population consumes alcohol less than weekly or none at all. Alcohol consumption frequency was categorized as none/ less than or equal to one serving per week, 24 servings per week, 56 servings per week, 13 servings per day, and four or more servings per day. To further evaluate heavy drinking, we created the following categories. A current heavy drinker was dened as a person consuming four or more servings of alcoholic beverages daily, a former heavy drinker had consumed four or more servings daily in the past but not in the previous year, and a non-heavy drinker had never consumed four or more servings daily on a regular basis.
Outcome of interestchronic kidney disease

Serum creatinine was measured at the baseline and 5-year follow-up examinations by a modied Jaffe method on a Technicon AutoAnalyzer (Technicon Instruments Corporation, Tarrytown, New York). The referent range in adult females was 0.41.1 mg/dl and in adult males was 0.51.2 mg/dl. The laboratory coefcient of variability was 2.2 percent. Serum creatinine measurements were indirectly calibrated by following a two-step process suggested by Fox et al. (4) adapted to our populations age structure. First, the Third National Health and Nutrition Examination Survey values were calibrated to the standards of the Cleveland Clinic Laboratory, requiring a correction factor of 0.23 mg/dl (20.3 lmol/liter) (16). Then, the mean creatinine values from the Beaver Dam Eye Study by sex-specic 5-year age groups were aligned with the corresponding corrected Third National Health and Nutrition Examination Survey age- and sex-specic means. The preferred measure of kidney function in the current study was the estimated glomerular ltration rate (GFR). This rate was calculated by use of the Modication of Diet in Renal Disease Study equation (17), dened as follows. GFR 186:3 3 serum creatinine mg=dl 3 age
0:203 1:154

3 0:742 for women:

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Estimation of the GFR from serum creatinine by the validated Modication of Diet in Renal Disease Study prediction equation that includes age, sex, race, and body size is recommended to avoid the misclassication of persons on the basis of serum creatinine alone (2, 17). Further, the estimated GFR in the Third National Health and Nutrition Examination Survey was reported to be similar to that from studies of inulin clearance in normal volunteers (2). Chronic kidney disease was dened as an estimated GFR of less than 60 ml/minute per 1.73 m2 on the basis of the National Kidney Foundations Kidney Disease Outcome Quality Initiative working group denition (2). Prevalent CKD (n 324) was dened as the presence of CKD among study participants at the baseline examination. Incident CKD (n 114) was dened as the development of new CKD at the 5-year follow-up examination among study participants who did not have CKD at the baseline examination.
Statistical methods

calculated the population attributable risk of CKD associated with current smoking and heavy drinking using Levins formula as described by Hanley (18). We repeated the analysis for smoking and alcohol consumption in relation to kidney disease using the CockcroftGault formula to estimate creatinine clearance with similar results (19). SAS, version 9.2, statistical software (SAS Institute, Inc., Cary, North Carolina) was used for all analyses.
RESULTS

We performed two sets of analyses: 1) cross-sectional analysis with prevalent CKD as the outcome of interest and 2) longitudinal analysis with 5-year incident CKD as the outcome of interest. In cross-sectional analysis, we examined the relation between various exposures, including age, gender, education, body mass index, current use of NSAIDs, hypertension, diabetes, history of cardiovascular disease, smoking, and alcohol consumption, and prevalent CKD. We examined the relation between smoking and prevalent CKD in detail by rst examining smoking status (never smoker, former smoker, current smoker) and then the dose-response relation as pack-years of smoking (0, <15, 1534, 35 pack-years) and years since stopped smoking among former smokers (15, 514, <5 years). We examined the relation between alcohol and prevalent CKD by examining alcohol consumption status (never drinker, former drinker, current drinker), alcohol consumption frequency (0<1 serving per week, 24 servings per week, 56 servings per week, 13 servings per day, 4 servings per day), and the effect of heavy drinking, that is, four or more servings per day (never heavy drinker, former heavy drinker, current heavy drinker). In longitudinal analysis, we examined selected smoking and alcohol consumption variables found to be strongly associated in the cross-sectional analysis and their relation to incident CKD. We examined the effect of joint exposure to current smoking (absent, present) and current heavy drinking (absent, present) by creating four corresponding categories. Effect modication was formally evaluated by including cross-product interaction terms in the corresponding multivariable models. We were limited by the number of incident CKD cases to do more detailed analyses within different subgroups. For consistency in reporting, for both the cross-sectional and longitudinal analyses, we used multivariable logistic regression models to calculate odds ratios and 95 percent condence intervals. We used two models: the age- and sex-adjusted model and the multivariable-adjusted model additionally adjusting for education, body mass index, current NSAID use, hypertension status, diabetes status, history of cardiovascular disease, smoking status, and heavy drinking. We
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The mean age of study participants at the baseline examination was 62.3 years (range: 4386 years). The mean estimated GFR at the baseline examination of prevalent CKD cases compared with noncases was 51.8 and 98 ml/minute per 1.73 m2, respectively. The mean baseline estimated GFR of those who developed incident CKD compared with those who did not develop CKD was 90.2 and 114 ml/minute per 1.73 m2, respectively. The mean estimated GFR decline was 12 (interquartile range: 16.2) ml/minute per 1.73 m2. In multivariable models (table 1), increasing categories of age, male gender, obese persons, use of NSAIDs, presence of hypertension, diabetes, and history of cardiovascular disease were associated with prevalent CKD. Lower education was associated with prevalent CKD in the age- and sexadjusted model but failed to reach statistical signicance (alpha = 0.05) in the multivariable model. Current smoking was associated with CKD; current alcohol consumption was not associated. We examined the relation between smoking and prevalent CKD in more detail in table 2. Compared with those who never smoked, current smokers had a multivariable odds ratio of 2.2. The analysis of pack-years of smoking showed a strong gradient of association with increasing cumulative dose of smoking. Further, among former smokers, the association with CKD was higher among those with fewer years since stopped smoking compared with 15 or more years since stopping smoking. We examined the relation between alcohol consumption and prevalent CKD in table 3. Taken together, only heavy drinking was associated with CKD. In comparing alcohol consumption frequency, heavy drinking (four or more servings of alcohol per day) was associated with an odds ratio of 1.6. Compared with persons who were never heavy drinkers, both former heavy drinkers (odds ratio (OR) 1.3) and current heavy drinkers (OR 1.8) were more likely to have CKD. Lower levels of alcohol consumption do not appear to be harmful. In subgroup analyses (table 4) by gender, the association between current smoking and CKD appears to be stronger among men (OR 3.3) than among women (OR 1.4). The association between heavy drinking and CKD was present among both women and men but failed to reach statistical signicance (alpha 0.05) among women. In longitudinal analysis (table 5), current smoking and current heavy drinking at baseline were signicantly associated with incident CKD. Furthermore, joint exposure to both current smoking and current heavy drinking (table 6) was associated with a signicantly higher odds ratio of incident CKD than were their respective individual associations.

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TABLE 1. Relation between selected factors and prevalent chronic kidney disease, Wisconsin, 19881995
No. at risk No. of chronic kidney disease cases Prevalence of chronic kidney disease (%) Age- and sex-adjusted odds ratio 95% condence interval Multivariable odds ratio* 95% condence interval

Age (years) 4359 6069 7079 80 Gender Women Men Education Beyond high school High school Below high school Body mass index (kg/m ) 25 2630 >30 Current NSAIDy use Absent Present Hypertension Absent Present Diabetes Absent Present History of cardiovascular diseasez Absent Present Current smoking Absent Present Current alcohol consumption Absent Present 778 4,120 49 275 6.3 6.7 1 1.15 Referent 0.83, 1.59 1 1.09 Referent 0.78, 1.51 3,931 967 178 146 4.5 15.1 1 3.42 Referent 2.68, 4.36 1 2.10 Referent 1.57, 2.81 4,173 725 222 102 5.3 14.1 1 2.59 Referent 2.00, 3.35 1 1.84 Referent 1.39, 2.45 4,458 440 192 132 4.3 30.0 1 5.79 Referent 4.41, 7.61 1 3.58 Referent 2.63, 4.86 3,071 1,827 114 210 3.7 11.5 1 3.22 Referent 2.54, 4.09 1 3.12 Referent 2.46, 3.96 3,331 1,567 190 134 5.7 8.6 1 1.45 Referent 1.14, 1.83 1 1.27 Referent 1.00, 1.62 1,197 1,967 1,734 45 107 172 3.8 5.4 9.9 1 1.34 2.75 Referent 0.94, 1.92 1.96, 3.85 1 1.20 2.50 Referent 0.83, 1.73 1.55, 4.75
2

2,144 1,369 1,032 353 2,744 2,154 1,341 2,121 1,436

39 89 119 77 170 154 79 111 134

1.8 6.5 11.5 21.8 6.2 7.1 5.9 5.2 9.3

1 3.26 5.73 8.70 1 1.27 1 0.89 1.67

Referent 2.21, 4.82 3.92, 8.36 5.62, 13.47 Referent 1.01, 1.58 Referent 0.66, 1.20 1.25, 2.23

1 2.00 4.05 5.38 1 1.25 1 0.89 1.29

Referent 1.31, 3.07 2.72, 6.02 3.22, 8.71 Referent 1.01, 1.55 Referent 0.66, 1.20 0.95, 1.75

* Multivariable logistic regression model adjusted for all the covariates in the table. y NSAID, nonsteroidal antiinammatory agent. z Self-reported history of cardiovascular disease, including myocardial infarction, angina, and stroke.

The population attributable risk of CKD associated with current smoking was 10 percent and with heavy drinking was 4.8 percent. We performed several sets of supplementary analyses. First, we repeated the longitudinal analysis (table 5) with proportional hazards models. Compared with that of never smokers (referent group), the multivariable hazards ratio of incident CKD for former smokers was 1.12 (95 percent condence interval (CI): 0.63, 1.98) and for current smokers

was 1.93 (95 percent CI: 1.15, 3.25). For heavy drinkers, compared with never heavy drinkers (referent group), the multivariable hazards ratio for former heavy drinkers was 1.29 (95 percent CI: 0.65, 2.56) and for current heavy drinkers was 1.80 (95 percent CI: 0.89, 3.66). Second, we performed the longitudinal analysis after excluding 42 additional persons with dipstick proteinuria (dened as urinary protein of 0.3 g/liter) at the baseline examination, as we suspected that such persons either had CKD or were at risk
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TABLE 2. Relation between smoking and prevalent chronic kidney disease, Wisconsin, 19881995
No. at risk No. of chronic kidney disease cases Prevalence of chronic kidney disease (%) Age- and sex-adjusted odds ratio 95% condence interval Multivariable odds ratio* 95% condence interval

Smoking status Never smoker Former smoker Current smoker Pack-years of smoking 0 <15 1534 35 Years since stopped smoking among former smokers 15 514 <5 910 499 328 26 18 56 2.9 3.6 17.1 1 1.05 3.93 Referent 0.55, 2.01 2.32, 6.66 1 0.98 2.09 Referent 0.51, 1.90 1.14, 3.83 2,204 899 866 999 62 46 93 123 2.8 5.1 10.7 12.3 1 1.36 3.37 4.41 Referent 0.89, 2.08 2.39, 4.76 3.20, 6.07 1 1.11 2.57 2.93 Referent 0.71, 1.75 1.79, 3.70 2.08, 4.12 2,194 1,737 967 78 100 146 3.6 5.8 15.1 1 1.43 4.06 Referent 1.05, 1.95 3.03, 5.45 1 1.09 2.18 Referent 0.78, 1.52 1.57, 3.03

* Adjusted for age (years), sex (females, males), education (below high school, high school, beyond high school), body mass index (25, 2630, >30), current nonsteroidal antiinammatory drug use (absent, present), hypertension (absent, present), diabetes (absent, present), history of cardiovascular disease (absent, present), ever heavy drinking (4 servings per day, current or past).

of CKD. Compared with that for never smokers, the multivariable odds ratio of incident CKD for former smokers was 1.12 (95 percent CI: 0.60, 2.07) and for current smokers was

1.89 (95 percent CI: 1.06, 3.39); compared with that for never heavy drinkers, the multivariable odds ratio for former heavy drinkers was 1.10 (95 percent CI: 0.47, 2.56) and for

TABLE 3. Relation between alcohol consumption and prevalent chronic kidney disease, Wisconsin, 19881995
No. at risk No. of chronic kidney disease cases Prevalence of chronic kidney disease (%) Age- and sex-adjusted odds ratio 95% condence interval Multivariable odds ratio* 95% condence interval

Alcohol consumption status Never drinker Former drinker Current drinker Alcohol consumption frequency (servings) 0/1 per week 24 per week 56 per week 13 per day 4 per day Current heavy drinkingy Absent Present Ever heavy drinkingy Never heavy drinker Former heavy drinker Current heavy drinker 4,413 287 198 264 29 31 5.9 10.1 15.7 1 1.63 2.70 Referent 1.08, 2.47 1.78, 4.08 1 1.30 1.77 Referent 0.83, 2.05 1.092.85 4,700 198 293 31 6.2 15.7 1 2.58 Referent 1.71, 3.89 1 1.69 Referent 1.05, 2.72 2,872 743 305 780 198 182 40 21 50 31 6.3 5.4 6.9 6.4 15.7 1 0.83 0.76 0.96 2.31 Referent 0.58, 1.18 0.44, 1.30 0.69, 1.33 1.50, 3.55 1 0.79 0.70 0.87 1.64 Referent 0.55, 1.14 0.40, 1.23 0.62, 1.23 1.01, 2.67 162 616 4,120 9 40 275 5.6 6.5 6.7 1 1.02 1.17 Referent 0.48, 2.18 0.59, 2.32 1 0.99 1.08 Referent 0.47, 2.12 0.54, 2.14

* Adjusted for age (years), sex (females, males), education (below high school, high school, beyond high school), body mass index (25, 2630, >30), current nonsteroidal antiinammatory use (absent, present), hypertension (absent, present), diabetes (absent, present), history of cardiovascular disease (absent, present), and smoking status (never, former, current). y Heavy drinking dened as four or more servings of alcohol per day.

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TABLE 4. Relation among smoking, heavy drinking, and prevalent chronic kidney disease stratied by gender, Wisconsin, 19881995
Men No. at risk No. of chronic kidney disease cases Multivariable odds ratio* 95% condence interval No. at risk No. of chronic kidney disease cases Women Multivariable odds ratio* 95% condence interval

Smoking status Never smoker Former smoker Current smoker Heavy drinking (4 servings per day) Never heavy drinker Former heavy drinker Current heavy drinker 1,809 196 149 107 21 26 1 1.22 1.78 Referent 0.69, 2.18 1.01, 3.14 2,604 91 49 157 8 5 1 1.50 1.39 Referent 0.71, 3.16 0.49, 3.90 593 1,081 480 20 46 88 1 1.07 3.33 Referent 0.62, 1.86 1.95, 5.68 1,601 656 487 58 54 58 1 1.14 1.38 Referent 0.72, 1.82 0.85, 2.24

* Adjusted for age (years), education (below high school, high school, beyond high school), body mass index (25, 2630, >30), current nonsteroidal antiinammatory use (absent, present), hypertension (absent, present), diabetes (absent, present), history of cardiovascular disease (absent, present), smoking status (never, former, current), and ever heavy drinking (4 servings per day, current or past); the stratifying variable (smoking status or heavy drinking) was not adjusted in its corresponding models.

current heavy drinkers was 1.86 (95 percent CI: 0.79, 4.37). Third, we repeated the analysis with an alternate denition of incident kidney disease: reduction in estimated GFR of 50 percent or more over 5 years (n 105); the overall results were similar. Compared with that for never smokers, the multivariable odds ratio of incident CKD for former smokers

was 1.08 (95 percent CI: 0.58, 1.99) and for current smokers was 2.04 (95 percent CI: 1.18, 3.54). Similarly, compared with that for never heavy drinkers, the multivariable odds ratio for former heavy drinkers was 1.19 (95 percent CI: 0.57, 2.48) and for current heavy drinkers was 1.89 (95 percent CI: 0.90, 3.98). Finally, the result for the association

TABLE 5. Relation among smoking, heavy drinking, and incident chronic kidney disease, Wisconsin, 19881995
No. at risk No. of chronic kidney disease cases Age- and sex-adjusted odds ratio 95% condence interval Multivariable odds ratio* 95% condence interval

Current smoking Absent Present Smoking status Never smoker Former smoker Current smoker Current heavy drinkingy Absent Present Ever heavy drinkingy Never heavy drinker Former heavy drinker Current heavy drinker 2,974 255 163 81 12 21 1 1.61 2.84 Referent 0.85, 3.06 1.51, 5.32 1 1.31 1.84 Referent 0.65, 2.63 0.88, 3.88 3,229 163 93 21 1 3.16 Referent 1.76, 5.68 1 1.99 Referent 0.99, 4.01 1,974 810 608 37 32 45 1 1.39 3.20 Referent 0.81, 2.40 1.99, 5.15 1 1.12 1.97 Referent 0.63, 2.00 1.15, 3.36 2,784 608 69 45 1 2.40 Referent 1.58, 3.65 1 1.62 Referent 1.01, 2.59

* Adjusted for age (years), sex (females, males), education (below high school, high school, beyond high school), body mass index (25, 2630, >30), current nonsteroidal antiinammatory use (absent, present), hypertension (absent, present), diabetes (absent, present), history of cardiovascular disease (absent, present), smoking status (never, former, current), and ever heavy drinking (4 servings per day, current or past); the stratifying variable (smoking status or heavy drinking) was not adjusted in its corresponding models. y Heavy drinking dened as four or more servings of alcohol per day.

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TABLE 6. Effect of joint exposure to smoking and heavy drinking, Wisconsin, 19881995
Current smoking Current heavy drinking* No. at risk No. of chronic kidney disease cases Multivariable odds ratioy 95% condence interval

Absent Absent Present Present

Absent Present Absent Present

2,715 69 514 94

62 7 31 14

1 1.24 1.16 4.93

Referent 0.30, 5.16 0.65, 2.08 2.45, 9.94

* Heavy drinking dened as four or more servings of alcohol per day. y Adjusted for age (years), sex (females, males), education (below high school, high school, beyond high school), body mass index (25, 2630, >30), current nonsteroidal antiinammatory use (absent, present), hypertension (absent, present), diabetes (absent, present), and history of cardiovascular disease (absent, present); pinteraction 0.01.

between smoking and alcohol consumption with incident CKD was similar when the CockcroftGault formula was used to estimate creatinine clearance.

DISCUSSION

In a population-based sample consisting predominantly of older adults, smoking was found to be associated with chronic kidney disease independent of body mass index, NSAID use, alcohol consumption, hypertension, diabetes, and other confounders. The association between smoking and CKD was supported by evidence of a dose-response trend. We also found an independent association between heavy drinking (4 servings of alcohol per day) and CKD. Further, joint exposure to smoking and heavy alcohol consumption was associated with almost vefold odds of developing CKD than was their absence. Smoking has been shown to be associated with end-stage renal disease previously (5). The association between smoking and stages of kidney disease earlier in the continuum is increasingly being recognized. Several previous studies have identied smoking as a potential risk factor for CKD among those with diabetes (20, 21). However, similar studies in the general population have not been consistent. Several casecontrol studies failed to detect an association between smoking and CKD (8, 10). In contrast, other case-control (12), cross-sectional (9, 22), and recent longitudinal (4, 23) data support the hypothesis of an association between smoking and CKD. In the current study, the association between smoking and CKD was present in both cross-sectional and longitudinal analyses. The ndings of a higher odds ratio of CKD associated with increasing pack-years of smoking and of the inverse association with years since stopped smoking, taken together, are supportive of a dose-response trend. The magnitude of association between smoking and CKD, its independence from traditional CKD risk factors, evidence of dose-response trend, and the consistency within subgroup analysis by gender all suggest that these ndings are less likely to be due to chance. Further, a number of biologic mechanisms by which smoking can result in kidney damage
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have been identied, including the promotion of renal atherosclerosis (24), alterations in systemic and renal hemodynamics (25), and effects on endothelial function (26). In the current study, consumption of four or more servings of alcohol per day was found to be independently associated with CKD in both cross-sectional and longitudinal analyses. This nding is consistent with results from previous casecontrol studies (10, 27). In another case-control study, CKD was associated only with moonshine consumption, not other alcoholic beverages (8). In a recent prospective study, Schaeffner et al. (11) reported a protective association between moderate alcohol consumption and incident CKD among US male physicians; compared with men who consumed no more than one drink per week, men who consumed at least seven drinks per week had an odds ratio of 0.71 (95 percent CI: 0.55, 0.92). Heavy alcohol consumption was not studied. In our study, moderate alcohol consumption was not harmfully associated with CKD; however, we failed to observe a statistically signicant (alpha 0.05) protective effect. In the current study, joint exposure to both current smoking and heavy drinking was associated with a higher odds ratio of CKD than were their individual effects. It is possible that the biologic mechanisms by which smoking can result in kidney damage may be accentuated by the effect of heavy drinking on the kidney, including alcohol-induced hypertension, rhabdomyolysis, or the direct toxic effects of alcohol (2830). Almost 60 percent of heavy drinkers in our sample were also current smokers. These data indicate that, regarding kidney disease, individual-level interventions aimed at addressing both smoking and heavy alcohol consumption simultaneously may be more benecial. In contrast, at the population level, 10 percent of CKD in the Beaver Dam Township appeared to be related to smoking, and 5 percent appeared to be related to heavy drinking, suggesting population-level interventions targeting smoking to be more benecial. Several study limitations need to be considered when interpreting our results. The relatively homogeneous nature of our cohort (98 percent Caucasians) limits generalizability, particularly to high-risk groups for kidney disease, such as African Americans; however, it reduces confounding. Our

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creatinine measurements were not directly calibrated to Cleveland Clinic standards; studies have shown that the measure of serum creatinine can vary across laboratories and that calibration differences can account for differences in GFR, particularly at higher values (16). However, the incidence and prevalence of kidney disease in our sample are similar to published estimates in other Caucasian studies, including the Framingham Offspring Study for incidence (4) and the non-Hispanic White subgroup of the Third National Health and Nutrition Examination Survey for prevalence (3), suggesting that the CKD estimates from our study are comparable with those from other general population samples. The denition of CKD in the current study differs from the National Kidney Foundations denition (2) in that it excludes kidney damage (no data on albuminuria) and is limited to one visit (no measure of chronicity). Stages 1 and 2 of CKD were not considered in our study as data on albuminuria were not available. A small change in GFR, for example, from 62 to 58 ml/minute per 1.73 m2, could have led to individuals being classied as incident cases. However, because of the prospective nature of the study, the misclassication is likely to be nondifferential and to underestimate the true association. Moreover, the main study results remained essentially similar in a supplementary analysis examining 50 percent or more reduction in estimated GFR as the outcome of interest, suggesting these ndings to be relatively robust. Potential laboratory drift in the measurement of serum creatinine could result in misclassication of incident CKD cases in the longitudinal analysis; this misclassication is likely to be nondifferential and to underestimate the true association. We were limited by our sample size to analyze incident kidney disease in greater detail. Smoking and drinking habits can change with time. Questionnaire-based data collection has the chance of misclassication. However, other reports, such as that by Klein et al. (15), related to smoking and alcohol consumption from our cohort are similar to or have been validated by other studies, suggesting that this population provides reliable reports of smoking and alcohol use. In addition, the prospective method of exposure measurement in our study most likely would lead to random misclassication; resultant bias is potential underestimation of the association among smoking, alcohol consumption, and kidney disease. In summary, in this population-based study, smoking was found to be associated with chronic kidney disease, independent of several important confounders. Similarly, heavy drinking, dened as consumption of four or more servings of alcohol per day, was also associated with chronic kidney disease. Individuals who were both current smokers and heavy drinkers had substantially higher odds of developing kidney disease, suggesting a greater potential benecial effect for simultaneously addressing both of these lifestyle risk factors in the clinical setting.

Blindness, New York, New York (R. K., B. E. K. K., Senior Scientic Investigator Awards). Conict of interest: none declared.

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ACKNOWLEDGMENTS

Supported by National Institutes of Health grant EY06594 (R. K., B. E. K. K.) and, in part, by Research to Prevent

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