Annals of Oncology Advance Access originally published online on December 8, 2006
Annals of Oncology 2007 18(3):596-600; doi:10.1093/annonc/mdl438
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© 2006 European Society for Medical Oncology
epidemiology |
History of treated hypertension and diabetes mellitus and risk of renal cell cancer
1 S.O.C. Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano (PN)
2 Istituto di Ricerche Farmacologiche "Mario Negri", Milano
3 Servizio di Epidemiologia, Istituto Tumori "Fondazione Pascale", Napoli
4 Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Nazionale Tumori "Regina Elena", Roma
5 Divisione di Anatomia Patologica, Centro di Riferimento Oncologico, Aviano (PN)
6 Unità Operativa di Urologia, Azienda Ospedaliera "Santa Maria degli Angeli", Pordenone, Italy
7 International Agency for Research on Cancer, Lyon, France
8 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milano, Italy
* Correspondence to: Dr A. Zucchetto, Epidemiology and Biostatistics, CRO Aviano, Via Pedemontana Occ. 12, 33081 Aviano (PN), Italy. Tel: +39-0434-659-354; Fax: +39-0434-659-222; E-mail: epidemiology{at}cro.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: An increased risk of renal cell cancer (RCC) has been reported in subjects with hypertension. Whether this association may vary according to sex, smoking, obesity, or RCC clinical presentation is unclear. Results on the link between diabetes mellitus and RCC are inconclusive.
Patients and methods: We conducted an Italian multicenter case–control study, including 767 (494 men, 273 women) incident cases of RCC, under 80 years of age, and 1534 hospital controls, frequency-matched to cases. Multiple logistic regression models, conditioned to center, sex, and age, and adjusted for period of interview, education, smoking, and body mass were used to estimate odds ratios (OR).
Results: Compared with subjects never treated, patients with a history of treated hypertension [OR = 1.7, 95% confidence interval (CI) 1.4–2.1] reported an excess risk of RCC. This pattern was confirmed in different strata of sex, education, smoking habits, body mass, tumor histological type, stage, or grade. The attributable risk of RCC for treated hypertension in this population was 16%. A slight, nonsignificant increased risk was found for history of diabetes mellitus (OR = 1.3, 95% CI 0.9–1.7).
Conclusion: A possible causal role of hypertension in renal cell carcinogenesis is supported by the consistency of the direct association.
Key words: case–control studies, diabetes mellitus, hypertension, renal cell cancer, risk
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The etiology of renal cell cancer (RCC) remains largely undefined. Smoking and elevated body weight are the risk factors most consistently associated with RCC [1–4].
Excess risk for RCC emerged in most studies considering the relation with either hypertension itself or the use of diuretics or other antihypertensive treatments [5–14]; however, the results were somewhat inconsistent across different strata of sex or of other relevant variables. A recent meta-analysis [15], on the basis of 13 case–control studies, including 6964 cases of RCC (2518 with hypertension), estimated a pooled relative risk (RR) of 1.75 [95% confidence interval (CI) 1.61–1.90], consistent among the studies. The association was similar in prospective studies [7, 12, 16].
Diabetes mellitus has been associated with an increased risk of several cancers, but its relation with RCC risk is controversial and indicates a moderate, if any, increased risk [11, 17–19].
Only scanty information is available on RCC risk in patients with hypertension or diabetes according to tumor histological type, stage, or grade, and other established risk factors for RCC. To provide further information on these issues, we carried out a large case–control study in the Italian population.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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We conducted a hospital-based case–control study on RCC, from 1992 to 2004, in four Italian areas: the provinces of Pordenone and Gorizia, the greater Milan area in northern Italy, the province of Latina in central Italy, and the urban area of Naples in southern Italy.
Cases were 767 subjects (494 men and 273 women, median age 62, range 24–79 years) with an incident diagnosis of cancer of the renal parenchyma (International Classification of Diseases-9 = 189.0), admitted to major teaching and general hospitals of the above areas. Histological information on cases included cancer cell type according to the 2004 World Health Organization Classification [20], tumor stage according to tumor–node–metastasis (TNM) classification, and Fuhrman nuclear grade [21]. Patients reporting transplant or chronic kidney diseases, including kidney failure (i.e. relapse in the kidney region) were excluded.
Control subjects were 1534 patients (988 men and 546 women, median age 62, range 22–79 years) admitted to the same network of hospitals for acute non-neoplastic conditions. Among controls, 32% had orthopedic nontraumatic disorders, 26% traumas, 14% surgical conditions, and 28% miscellaneous other illnesses such as eye, ear, nose, throat, dental, or skin disorders. Patients with hormone-related disorders and urinary or genital tract diseases were excluded from the control group. Controls were frequency-matched (2 : 1) to cases according to study center, sex, and age.
A centrally trained staff interviewed all the eligible subjects during their hospital stay. Less than 5% of the approached cases and controls refused the interview. The response rates were similar across hospitals and geographic areas. The structured questionnaire included information on sociodemographic characteristics, anthropometric measures at different ages, lifestyle habits such as smoking, alcohol drinking, physical activity, and diet, and history of cancer in first-degree relatives. Ever smokers were subjects who had smoked at least one cigarette per day for at least one year; otherwise subjects were considered never smokers. Personal history of selected medical conditions, including treated hypertension and diabetes mellitus, was self-reported and included age at first diagnosis.
Risk of RCC was estimated computing odds ratios (OR) and the corresponding 95% CI for history of treated hypertension and diabetes mellitus by multiple logistic regression models [22] conditioned on study center, sex, and age (quinquennia) and adjusted for calendar period of interview (before 1998, 1998 or later); years of education (
6, 7–11, 
12); smoking habits (never smokers, ex-smokers since at least 4 years, current smokers of <20 cigarettes/day, current smokers of 20 cigarettes/day); body mass index (BMI) at age 30 (<20, 20 to <25, 25 to<30, 30 kg/m2); and family history of kidney cancer in first-degree relatives.
Heterogeneity of the ORs across strata of selected variables was tested by a likelihood ratio test, which compared the model including only the main effects to the model also including interaction terms. This statistic was compared with a 
2 distribution with degrees of freedom equal to the number of interaction terms. Heterogeneity of the ORs for cancer histological subtypes, stages, and grades was estimated using polytomous logistic regression models [23]. Population attributable risk was estimated according to Bruzzi et al. [24].
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results |
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Table 1 shows the distribution of cases and controls according to sex, age, and other selected covariates. Compared with controls, cases reported a higher education, were more frequently heavy current smokers (OR = 1.50 for smokers of
20 cigarettes/day, compared with never smokers), had higher BMI in young adulthood (OR = 1.46 for BMI 30, compared with BMI <25), and more frequently had a family history of kidney cancer in first-degree relatives (OR = 3.91, compared with subjects without). In Table 1, the distribution of cases according to histological type, stage, and Fuhrman nuclear grade of cancer is also reported. Among the RCC cases with available information, 73% had clear-cell carcinoma (54% of total cases), 36% a T1 stage (18% of total cases), and 54% a G1 or G2 Fuhrman grade (26% of total cases).
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The association between self-reported history of treated hypertension, diabetes mellitus, and the risk of RCC is reported in Table 2. A significant excess risk emerged for treated hypertension, with an OR of 1.74 (95% CI 1.42–2.12). Compared with patients never treated for hypertension, the ORs were 1.67 (95% CI 1.31–2.14) for those treated for the first time <10 years before the interview, and 1.81 (95% CI 1.39–2.36) for those treated for the first time
10 years before the interview. The ORs were 1.56 (95% CI 1.19–2.03) in patients starting treatment at age 55 years and 1.90 (95% CI 1.48–2.44) in those starting treatment before age 55 years.
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Compared with patients without diabetes, those with a diagnosis of diabetes mellitus had an OR of 1.25 (95% CI 0.91–1.73). The ORs were close to unity also in subgroups of diabetics diagnosed <10 years and
10 years before interview. The results were similar in strata of patients diagnosed with the disease at ages below or above 55 years. The risks of RCC in relation with diabetes mellitus were similar across strata of sex, education, BMI in young adulthood, and smoking and, among cases, across histological type of cancer, stage, and Fuhrman nuclear grade (data not shown).
Table 3 shows ORs for history of treated hypertension by strata of selected covariates. The ORs were 2.08 among women and 1.58 among men, 2.08 among subjects <60 years and 1.62 among patients aged 60 years at interview (nonsignificantly heterogeneous). No heterogeneity of risk was also detected across strata of education or BMI in young adulthood, whereas among never smokers the OR was significantly higher than among ever smokers (2.31 and 1.41, respectively). The OR of RCC in relation with hypertension was 1.73 (95% CI 1.34–2.22) among cases with the clear cell histological type of cancer, and was similar in cases with T1 and T2–T4 tumor stage, and with G1–G2 or G3–G4 Fuhrman nuclear grade.
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Comorbidity for hypertension and diabetes mellitus was reported by 42 (5.5%) cases and 46 (3.0%) controls. Compared with subjects without any of these medical conditions, the OR in those reporting both was 2.07 (95% CI 1.32–3.25).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Consistently with the overall epidemiological evidence from case–control studies [15] and recent prospective ones [5, 7, 12], we observed an excess risk of RCC in patients treated for hypertension. In a cohort of Swedish men, Chow et al. [5] found a direct association between blood pressure and RCC risk, with a significant dose–risk relation. A study from the United States [7] estimated RRs of RCC for hypertension of 1.9 in women and of 1.8 in men, and a Danish prospective study [12] found a RR of 1.6 for use of any antihypertensive treatment. The International renal-cell cancer study [9], the largest case–control study to date, which included 1732 cases, found a RR for hypertension of 1.7 (still significant after adjustment for antihypertensive therapy), though not for untreated hypertension. A large Californian research [11], based on 1204 cases, found elevated risks in hypertensive subjects independently of use of therapy (OR = 2.2).
Our study collected solely information on any history of ‘treated hypertension’; thus, the effect of hypertension and its therapy could not be disentangled. Both hypertension and use of antihypertensive drugs could be independent risk factors for RCC. Being associated with metabolic or functional changes [5, 9], hypertension may induce renal injury or may predispose kidney to carcinogenesis. Antihypertensive treatments could be directly carcinogenic, could elicit or accelerate the effect of other carcinogens, or could impair defense mechanisms [9, 12, 15]. The relation between hypertension and RCC might be mediated by other risk factors, such as obesity, often in copresence with hypertension [7]. Our findings of a similar association of hypertension with RCC risk in subjects with different BMI, however, support an independent effect of hypertension [5, 11]. The issue of causality is still open to discussion, since hypertension may be a consequence rather than a cause of RCC, as early-stage kidney cancer may itself lead to increased blood pressure [6, 7]. In Chow et al. [5] cohort, however, reductions in blood pressure led to reductions in RCC risk. Moreover, in the present study, subjects diagnosed with hypertension earlier than 10 years before the interview showed higher RCC risks than those diagnosed later, supporting the direct causation hypothesis. It is also possible that detection of RCC is more common among treated hypertensives as they are under closer medical supervision than other subjects [10, 13, 15]. Although the similar association of hypertension and RCC risk at different cancer stages and grades did not confirm the hypothesis, surveillance bias cannot be totally excluded.
No information was collected on blood pressure values, severity of hypertension, and type of treatment. Since we considered only treated hypertension, and the mildest forms might have not been treated, our results should be referred purely to the more severe forms of this condition [8, 9]. Moreover, we had no information on use of diuretics or other antihypertensive medications among normotensives, for reasons other than hypertension (i.e. cardiovascular diseases, cardiac failure, weight reduction, or edema). This missing information, however, might have caused an underestimation of risk.
The fraction of RCC cases attributable to treated hypertension in this Italian population was 16% (95% CI 10% to 21%) after adjustment for potential confounders. In a case–control study conducted in Minnesota, the population attributable risk for high blood pressure or use of either diuretics or other antihypertensive drugs was 21% (95% CI 11% to 31%) [25], based on 690 cases, and an OR of 1.7 (95% CI 1.3–2.2).
Smoking habits appear to modify the association between hypertension and RCC. Because a previous study, however, reported no modification [5], these results require further investigation.
In the present study, no evidence of a clear relation between RCC risk and diabetes mellitus and timing of its diagnosis emerged, although a slightly elevated risk cannot be excluded. The epidemiological evidence on this relation is generally reassuring [2], but incomplete, as most studies were based only on few cases. Some case–control studies found no association [11, 26, 27] while others, the International renal-cell-cancer study included, observed borderline or nonsignificant direct associations [14, 19]. Significant increased risks were found in two cohorts of diabetics, with RRs of 
1.3 in men and 1.7 in women [17, 18]; though no increased risk of death emerged in a large cohort of men [28]. Our results are, thus, well comparable with the overall epidemiological evidence. In which measure overweight and obesity can account for this moderate association remains open to discussion. Nonetheless, for diabetics we did not find heterogeneous ORs across strata of BMI in young adulthood, below or above 22.5 kg/m2 (1.03 and 1.34 respectively).
In this study, medical conditions were self-reported. The hospital setting, however, should have reduced eventual differences in recalling personal diseases between cases and controls. Furthermore, recall bias should be unlikely, as both cases and controls were unaware of the possible relation between RCC risk and hypertension or diabetes mellitus. Possible sources of selection bias should also be limited, since cases and controls were drawn from the same catchment areas and participation was almost complete. In addition, allowance for several confounding factors did not alter the risk estimates.
In conclusion, this Italian case–control study further supports the direct association between history of treated hypertension and increased risk of RCC. Moreover, the consistency of the results in strata of relevant covariates or histological type, stage, or grade presentation of RCC, supports the causal role of hypertension in renal carcinogenesis. No major role of diabetes mellitus in RCC etiology emerged, although a slightly increased risk cannot be excluded.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The authors wish to thank L. Mei and I. Calderan for editorial assistance, O. Volpato and R. Cozzi for study coordination, and G. Bessega and L. Zaina, M. Grimaldi and O. Manganelli for their help in data collection. We are deeply thankful to A. Tonini for the revision of histological diagnoses, D. Maruzzi for his support in identifying cancer cases, and to P. Ascierto, G. Chiara, R. Di Lauro, L. Forner, A. Grandi, R. Magri, A. Mele, G. Tosolini, and E. Trevisanutto, for providing hospital control patients. This work was supported by the Italian Association for Cancer Research and the Italian League Against Cancer.
Received for publication July 24, 2006. Revision received October 23, 2006. Accepted for publication October 30, 2006.
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