1 Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
2 Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA.
3 Department of Urology, Mayo Clinic, Rochester, MN.
4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Received for publication March 18, 2003; accepted for publication July 21, 2003.
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ABSTRACT |
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carcinoma, renal cell; case-control studies; smoking; urinary tract infections
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio; RCC, renal cell carcinoma; UTI, urinary tract infection.
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INTRODUCTION |
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A history of urinary tract infection (UTI) is currently accepted as an independent risk factor for developing bladder cancer (3), and such a history could also play a role in the development of RCC. To date, however, only a limited number of epidemiologic studies have reported data regarding whether a history of UTI increases the risk of developing RCC. To complicate matters further, the data are inconsistent, with some investigators suggesting a positive association (4, 5) and others suggesting no association (6, 7). To our knowledge, no attempt has been made to address the question of whether other known risk factors for RCC (i.e., smoking, obesity, and hypertension) could modify an association that may exist between a history of UTI and RCC.
In the current study, we estimated the association of a history of UTI with RCC development after adjustment for accepted and other possible risk factors for RCC. In addition, we addressed the issue of whether the effect of a history of UTI on RCC development is modified by other well-known risk factors for RCC including sex, smoking, obesity, and a history of hypertension. To do so, we used data from a population-based case-control investigation conducted in Iowa from 1986 to 1989.
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MATERIALS AND METHODS |
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Controls for this investigation were frequency matched to cases by sex and 5-year age group. Controls younger than age 65 years were randomly selected from computerized state drivers license records, whereas controls aged 65 years or older were selected randomly from listings provided by the US Health Care Financing Administration (HCFA). Each of these selection rosters has been shown to achieve greater than 95 percent coverage of the intended underlying population (10, 11). Similar to the cases enrolled in this study, controls with a history of cancer, except nonmelanoma skin cancer, were excluded. Of the controls younger than age 65 years, we selected 999 eligible subjects from state drivers license listings; 817 (81.8 percent) participated, 66 (8 percent) with an abbreviated telephone interview. Of 2,034 eligible controls aged 65 years or older selected from Health Care Financing Administration listings, 1,615 (79.5 percent) participated, 128 (8 percent) with an abbreviated telephone interview. Of the 2,432 controls sent direct respondent questionnaires, 2,064 questionnaires were completed by the subject, 241 were completed by another person (proxy), and 127 controls were not asked who had completed the form. As for the cases, most of these 127 questionnaires were likely completed by the study subject.
Data collection
Data for this study were collected by using a mailed questionnaire supplemented by a telephone interview. The questionnaire assessed major and proposed RCC risk factors including demographics, anthropometric measures at various times in life, smoking history and status, medical history (including self-report of a physician-diagnosed history of hypertension), reproductive factors, occupational history, usual physical activity (nonoccupational), and family history of cancer. Also included in the questionnaire was a 55-item food frequency section.
Information regarding a history of UTI was ascertained in the health history section of the questionnaire. Subjects were asked to report whether a physician had ever told them that they had a bladder or kidney infection. Subjects were asked not to include diagnoses of UTI that had occurred in the past year. No data were collected on the frequency, severity, or timing of UTI diagnoses.
Statistical analysis
In our analysis, a history of UTI was treated as a dichotomized exposure variable (yes, no). Odds ratios and 95 percent confidence intervals were used to estimate the association of a history of UTI with RCC. We used unconditional logistic regression to estimate both age-adjusted as well as multivariate-adjusted odds ratios. Decisions regarding confounding factors in multivariate analysis were based on 1) whether the covariate is an accepted risk factor for RCC, 2) whether the covariate was associated with a history of UTI (among controls only) and RCC development in our data set, and 3) what effect inclusion of the particular covariate had on the risk estimate for a history of UTI. Covariates considered in the final multivariate model included age (continuous), sex, pack-years of smoking (none, 119, 2039, 40), body mass index (<24 kg/m2, 2430 kg/m2, >30 kg/m2), alcohol consumption (none, <35 g/week,
35 g/week; 35 g/week = median split among users), and history of physician-diagnosed hypertension (yes, no) before the prior year. Tests for interaction with other known risk factors for RCC (sex, body mass index, smoking, and hypertension) were conducted by including interaction terms, along with the appropriate main effects, in logistic regression models and then reporting the Wald chi-square p value for the interaction term. We also assessed the potential for interaction by conducting stratified analysis on each covariate and comparing the resulting risk estimates for UTI.
To address the issue of whether proxy reporting could affect our results, we also conducted a separate analysis in which we removed data provided by any next-of-kin respondents. The results did not differ between the two methods; therefore, in this paper, we report findings including all respondents only. All statistical analyses were performed by using the PROC LOGISTIC procedure in SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina).
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RESULTS |
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DISCUSSION |
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Data regarding the association of a history of UTI with RCC have been reported by investigators from four case-control studies. Comparisons of our data with those from these existing studies should be made with caution since most existing studies report risks associated with infections of the kidney specifically. Using data from a population-based case-control study in Minnesota, McLaughlin et al. (4) reported an increased risk of RCC associated with a history of kidney infection for both males (OR = 2.8, 95 percent CI: 1.3, 5.7) and females (OR = 2.2, 95 percent CI: 1.1, 4.4) after adjustment for age, cigarette smoking, and weight (females only). Similar results of a positive association were reported from a case-control study conducted by using members of a large medical care program in Northern California (5). Both males (OR = 5.5, 95 percent CI: 1.2, 25.7) and females (OR = 2.2, 95 percent CI: 0.3, 15.8) who had a history of kidney infection were at increased risk of RCC. However, because of missing data on approximately 30 percent of the subjects and a low overall prevalence of kidney infections, risk estimates were unstable for both sexes. Studies suggesting no association of kidney infection with RCC also exist. Investigators from a large, international case-control study of RCC reported only limited evidence of an increased risk of RCC for those with a history of kidney infections (OR = 1.2, 95 percent CI: 0.8, 1.5) (6). Similarly, authors of a population-based case-control study in Australia reported no association of a history of kidney infection with RCC but did report evidence of a positive association with cancer of the renal pelvis (7).
Cohort studies of an association of UTI history with RCC are extremely limited. Chow et al. (12) reported on the risk of RCC in a population-based cohort of patients hospitalized for kidney or ureteral stones in Sweden from 1965 to 1983 (n = 61,144). After 25 years of follow-up, standardized incidence ratios did not suggest an increase in risk of RCC for this cohort of patients. Of more interest to our findings, Chow et al. (12) also reported no increase in risk of RCC for the subset of cohort patients who had a UTI at their index visit. Interestingly, the risk of both bladder and renal pelvis cancer was increased for these same patients who were diagnosed with a UTI at their index visit. To our knowledge, no additional data from cohort investigations exist regarding an association of a history of UTI with RCC.
It is well accepted that bacteria are the primary cause of UTIs, with the vast majority (7080 percent) attributed specifically to infection with Escherichia coli (13, 14). To date, the involvement of bacteria in carcinogenesis remains controversial (15) because, in part, of a lack of agreement on potential molecular mechanisms. One theory linking bacterial infection and cancer development suggests that the increased inflammation associated with bacterial infections can generate reactive oxygen and nitrogen intermediates that could lead to direct DNA damage (16, 17). It has also been argued that bacterial infections could be linked to cancer development because such infections are known to promote cell proliferation, produce toxins that directly modulate intracellular signaling pathways, and even suppress apoptosis in host cells. Of particular interest, many uropathogenic E. coli species produce a toxin known as cytotoxic necrotizing factor, which has been shown to induce elevated expression levels of cyclooxygenase-2 in murine fibroblasts (18). The cyclooxygenase-2 enzyme has gained recent interest because it is overexpressed in many human cancers and has been linked to increased tumor invasiveness via overexpression of bcl-2 and suppression of apoptosis. Data from animal and human studies suggest that a portion of RCCs overexpress cyclooxygenase-2 (19, 20). An interesting question, but one we were unable to address, is whether the association of UTI with RCC that we report here is apparent only for RCCs in which overexpression of the cyclooxygenase-2 enzyme is evident.
To our knowledge, our reporting of an interaction between a history of UTI and smoking is novel and will require corroboration. Interestingly, Kantor et al. (21) reported evidence of a similar interaction regarding risk of bladder cancer in a large, population-based case-control study. The authors suggested that persons with a history of bladder infection could be especially prone to tobacco-derived carcinogens in the urine, perhaps through increased penetration into the bladder epithelium. An analogous situation could also exist for smokers with a history of UTI who develop RCC. It has also been reported that persons who experience UTI excrete higher levels of nitrate, a precursor to carcinogenic nitrosamines, in their urine (22, 23). Cigarette smoke is also known to contain nitrosamines (24), and these carcinogens have been linked to RCC development in laboratory animals (25, 26). Therefore, it could be argued that the synergistic effect found in our study for UTI history and smoking is a result of an increase in a nitrosamine-specific pathway for RCC development.
There are alternative explanations for our study findings. The possibility exists that, compared with the relatively healthy controls, cases were more likely to correctly recall a history of UTI. Although this differential misclassification by disease status could indeed result in an artificially positive association, the likelihood that such errors in reporting could be solely responsible for generating risk estimates as strong as we report here is questionable. Furthermore, the modifying effects of sex and smoking status in our data reduce the likelihood that this type of reporting error could fully explain our results. Our lack of data on the timing of UTI precluded us from eliminating the possibility that the occurrence of UTI may have been a consequence of early RCC rather than the cause. Finally, detection bias (or medical surveillance bias) could explain our results given that subjects with recurrent UTI might have had greater contact with the medical system and therefore an increased potential for being diagnosed with RCC, especially subclinical disease. To address this issue, we conducted analysis by stratifying our cases into localized and regional/distant disease using information available from the Surveillance, Epidemiology, and End Results program registry. The magnitude of the effect for history of UTI was greater for localized disease (OR = 2.2, 95 percent CI: 1.6, 3.4) compared with regional/distant disease (OR = 1.7, 95 percent CI: 1.2, 2.2). However, given that the risk remained elevated for regional/distant disease, it would appear that detection bias did not completely explain our observed association.
Strengths of this study include the use of a Surveillance, Epidemiology, and End Results tumor registry to ascertain cases, a randomly selected control population representative of the population at large, and high participation rates among both cases and controls. Additional strengths over previous investigations are our ability to adequately adjust for a wide variety of potential confounding factors and the relatively high prevalence of UTI among study subjects. Limitations include our reliance on self-reported history of physician-diagnosed UTI with no confirmation from medical records. Furthermore, our lack of data on number, timing, and severity of infection prohibited assessment of dose response or issues regarding relevant temporality of the infection. To adequately address this limitation, future investigations should collect information on infection timing and severity. Finally, given the fact that 99 percent of the participants in our study were White, the current results may have limited generalizability to other racial/ethnic groups.
In this population-based case-control investigation, we found evidence of an association of history of UTI with RCC. Our ability to show that this association remained after multivariate adjustment for several confounding factors (i.e., body mass index, hypertension, diet, physical activity, family history, alcohol consumption) strengthens support for a true association. Our data are consistent with those from earlier investigations suggesting that the risk associated with UTI history may be more pronounced for men than wo-men. The interaction with smoking is novel and needs confirmation.
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NOTES |
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REFERENCES |
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