Micronutrients and the risk of renal cell cancer: A case-control study from Italy
The role of various micronutrients on the risk of renal cell cancer (RCC) was examined in a multicentric case-control study from Italy, in which information on dietary habits were collected using a validated food-frequency questionnaire. Cases were 767 patients (494 men and 273 women) with incident, histologically confirmed RCC; controls were 1,534 subjects (988 men and 546 women) admitted to the same hospitals as cases for a wide spectrum of acute, nonneoplastic conditions. After allowing for energy and other major covariates, a significant inverse association was found for vitamin E (odds ratio, OR, for the highest quintile of intake versus the lowest one 0.56, 95% confidence interval, CI 0.41–0.75), and vitamin C (OR = 0.72, 95% CI = 0.54–0.96), although the trend in risk for vitamin C was of borderline significance. No significant trend of decreasing risk was found for other micronutrients analyzed, although for most of them the risk estimates were below unity for intakes above the lowest. The ORs for the upper quintile of intake when compared with the lowest one were 0.80 (95% confidence interval, CI = 0.59–1.08) for retinol, 0.82 (95% CI = 0.61–1.10) for α-carotene, 0.90 (95% CI = 0.68–1.20) for β-carotene, 0.94 (95% CI = 0.73–1.21) for β-criptoxanthin, 0.85 (95% CI = 0.63–1.14) for lutein/zeaxanthin, 0.76 (95% CI = 0.57–1.01) for vitamin D, 0.75 (95% CI = 0.55–1.01) for thiamine, 0.88 (95% CI = 0.66–1.19) for riboflavin, 0.85 for vitamin B6 (95% CI = 0.64–1.13), 0.85 (95% CI = 0.64–1.12) for folate and 0.80 (95% CI = 0.60–1.07) for niacin. No meaningful associations emerged for lycopene (OR = 1.11). The present findings support a possible beneficial effect of vitamin E and C on RCC. © 2006 Wiley-Liss, Inc.
Renal cell cancer (RCC) accounts for about 80–85% of all malignant tumors of the kidney in adults, and for about 2% of new cancer cases and deaths worldwide. It has been related to tobacco smoking, overweight and obesity, hypertension and family history of the disease.1, 2, 3, 4 Among dietary habits, inverse relations were reported with vegetable and fruit intake, while direct associations were suggested with milk, dairy products and meat, although the issue is still open to discussion.5, 6, 7, 8, 9, 10
With reference to dietary intake of micronutrients, the epidemiological evidence is scanty and inconsistent. A case-control study from the USA11 on 495 cases reported a small decrease in the risk of RCC for carotene (odds ratio, OR, for the highest level of intake 0.8) and vitamin C (OR = 0.7) for men only, and no association for retinol. Similarly, another US case-control study12 on 203 incident and 207 prevalent cases found a nonsignificant reduced RCC risk for β-carotene (OR = 0.6), but not for retinol intake. A decreased risk was seen with increasing intake of vitamin C (OR = 0.62) in a case-control study from Germany including 277 RCC patients.7 A multicentric case-control study6 based on 1,185 RCC from Australia, Sweden, Denmark and the US showed no meaningful association with β-carotene and retinol, nor with vitamin C and vitamin E. A significant inverse relation was however observed for vitamin C in nonsmokers (OR = 0.6), and for vitamin E in subjects in the upper quartile of intake when compared with those in the lowest decile (OR = 0.7). Conversely, in a case-control study conducted in Los Angeles9 on 1,204 cases of RCC, significant inverse associations were reported with various carotenoids, including α-carotene (OR = 0.6), and β-carotene (OR = 0.7), but not with lycopene and vitamin A, and a nonsignificant inverse association was found with vitamin C (OR = 0.8). The only cohort study providing data on micronutrients and RCC—the Iowa Women's Health study cohort, including 35,192 postmenopausal women, and 62 RCC cases13—showed a reduced risk for the highest intake of vitamin E (relative risk = 0.7), but not of vitamin A, carotene, vitamin C, nor of selected other nutrients.
The role of various micronutrients on the risk of RCC was further examined in a multicentric case-control study from Italy, in which information on dietary habits were collected using a validated food-frequency questionnaire (FFQ).
Material and methods
A case-control study on RCC was conducted between 1992 and 2004 in 4 Italian areas, including greater Milan and the provinces of Pordenone and Gorizia in northern Italy, the province of Latina in central Italy and the urban area of Naples in southern Italy.14 Cases were 767 patients (494 men and 273 women; median age: 62 years, range: 24–79 years) with incident, histologically confirmed RCC (ICD-IX 189.0), admitted to major teaching and general hospitals of the study areas. Cancers of the renal pelvis and ureter (ICD-IX 189.1-189.2) were excluded. Controls were 1,534 subjects (988 men and 546 women; median age: 62 years, range: 22–79 years) admitted to the same hospitals as cases for a wide spectrum of acute, nonneoplastic conditions, unrelated to known or potential risk factors for RCC, nor to long-term diet modifications. Controls were matched with cases by study centre, sex, and quinquennia of age, with a case to control ratio of 1:2. Twenty-six percent of controls were admitted for traumas, 32% for other orthopaedic disorders, 14% for surgical conditions and 27% for other various illnesses. Less than 5% of both cases and controls contacted refused to participate.
Cases and controls were interviewed during their hospital stay by trained interviewers using a structured questionnaire. This included information on socio-demographic characteristics, anthropometric measures, lifestyle habits, such as tobacco smoking and alcohol drinking, personal medical history, and family history of cancer in first-degree relatives.
The subjects' usual diet during the 2 years before cancer diagnosis or hospital admission (for controls) was assessed using an interviewer-administered FFQ, including 78 foods and beverages as well as a range of the most common Italian recipes. Subjects were asked to indicate the average weekly frequency of consumption for each dietary item; intakes lower than once a week, but at least once a month, were coded as 0.5 per week. To estimate total energy and nutrient intake, an Italian food composition database, integrated with other sources when needed, was used.15, 16 Losses due to cooking were subtracted for the computation of vitamin content when appropriate, except for specific carotenoids, where such information was not available. The FFQ showed satisfactory validity17 and reproducibility.18 Quintiles were computed both directly on the nutrients and on the residuals of the regression of the nutrient on energy.19 Since both analyses yielded similar results, only the latter were presented.
Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were calculated using conditional multiple logistic regression models,20 conditioned on study centre, sex, and quinquennia of age, and adjusted for period of interview, years of education, body mass index (BMI), tobacco smoking, alcohol drinking and family history of kidney cancer in first-degree relatives.
Table I shows the distribution of 767 cases of RCC and 1,534 controls, according to sex, age and other selected covariates. By design, cases and controls had the same sex and age distribution. Cases were more educated than controls, had a higher BMI, were more frequently heavy smokers, and reported more often first-degree relatives with kidney cancer. Cases and controls were comparable in terms of alcohol consumption and total energy intake.
Table I. Distribution of 767 Renal Cell Carcinomas and 1,534 Controls According to Selected Covariates. Italy, 1992–2004
|Body mass index (kg/m2)1|
| 1–19 cigarettes/day||109||14.3||277||18.1|
| ≥20 cigarettes/day||126||16.5||189||12.3|
| Never drinkers||131||17.1||231||15.1|
| Ex drinkers||63||8.2||114||7.4|
| Current drinkers|
| <21 drinks/week||231||47.1||720||46.9|
| ≥21 drinks/week||114||27.6||469||30.6|
|Family history of kidney cancer3|
|Total calorie intake (kcal/day)|
Table II gives the mean daily intake of various micronutrients among controls, and the ORs of RCC cancer according to energy-adjusted quintiles of intake. A significant inverse association was found for vitamin E (odds ratio, OR, for the highest quintile of intake versus the lowest one 0.56, 95%, CI 0.41–0.75), and vitamin C (OR = 0.72, 95% CI = 0.54–0.96), although the trend in risk for vitamin C was of borderline significance. No significant trend in risk was found for other micronutrients analyzed. However, for most of them risk estimates were below unity for intakes above the lowest quintile. The ORs for subjects in the upper quintile of intake when compared with those in the lowest one were 0.80 (95%, CI = 0.59–1.08) for retinol, 0.82 (95% CI = 0.61–1.10) for α-carotene, 0.90 (95% CI = 0.68–1.20) for β-carotene, 0.94 (95% CI = 0.73–1.21) for β-criptoxanthin, 0.85 (95% CI = 0.63–1.14) for lutein/zeaxanthin, 0.76 (95% CI = 0.57–1.01) for vitamin D, 0.75 (95% CI = 0.55–1.01) for thiamine, 0.88 (95% CI = 0.66–1.19) for riboflavin, 0.85 for vitamin B6 (95% CI = 0.64–1.13), 0.85 (95% CI = 0.64–1.12) for folate, 0.80 (95% CI = 0.60–1.07) for niacin and 0.72 (95% CI = 0.54–0.96) for vitamin C. No meaningful associations emerged for lycopene (OR = 1.11).
Table II. Odds Ratio (OR) of Renal Cell Carcinoma, and Corresponding 95% Confidence Intervals (CI) According to Energy-Adjusted Quintile of Intake of Selected Micronutrients. Italy, 1992–2004
|Upper cutpoint||805.31 (1062.11)||171.92||332||470.43||1729.04||–|| || |
|Cases/controls|| ||136/306||179/308||160/306||155/307||137/307|| || |
|95% CI|| || ||0.63–1.18||0.49–1.00||0.60–1.15||0.59–1.08||0.25||0.63–1.06|
|Upper cutpoint||703.85 (653.78)||231.33||445.37||705.43||1057.23||–|| || |
|Cases/controls|| ||159/307||155/306||165/308||143/307||145/306|| || |
|95% CI|| || ||0.74–1.30||0.74–1.29||0.68–1.21||0.61–1.10||0.17||0.74–1.16|
|Upper cutpoint||4434.56 (2713.55)||2884.76||3743.65||4573.45||5754.69||–|| || |
|Cases/controls|| ||159/306||170/308||148/306||127/307||163/307|| || |
|95% CI|| || ||0.66–1.14||0.63–1.10||0.53–0.95||0.68–1.20||0.24||0.67–1.03|
|Upper cutpoint||310.47 (365.22)||94.76||196.26||304.7||311.75||–|| || |
|Cases/controls|| ||153/306||174/308||156/306||131/308||153/306|| || |
|95% CI|| || ||0.79–1.38||0.62–1.10||0.30–1.49||0.73–1.21||0.45||0.74–1.17|
|Upper cutpoint||4539.99 (2531.11)||2698.27||3793.93||4774.99||6099.51||–|| || |
|Cases/controls|| ||159/306||162/308||169/307||117/306||160/307|| || |
|95% CI|| || ||0.75–1.30||0.65–1.16||0.51–0.94||0.63–1.14||0.06||0.69–1.09|
|Upper cutpoint||7217.16 (3809.51)||4893.24||6304.38||7566.46||9371.12||–|| || |
|Cases/controls|| ||145/306||160/307||148/308||153/307||161/306|| || |
|95% CI|| || ||0.82–1.45||0.76–1.35||0.87–1.53||0.83–1.47||0.42||0.87–1.37|
|Vitamin D (μg)|
|Upper cutpoint||3.16 (1.38)||2.18||2.72||3.26||4.08||–|| || |
|Cases/controls|| ||163/307||150/306||157/307||152/308||145/306|| || |
|95% CI|| || ||0.58–1.01||0.58–1.01||0.65–1.13||0.57–1.01||0.16||0.63–0.98|
|Vitamin E (mg)|
|Upper cutpoint||14.48 (6.31)||11.9||13.47||15.17||17.51||–|| || |
|Cases/controls|| ||182/307||142/306||169/308||153/307||121/306|| || |
|95% CI|| || ||0.68–1.18||0.59–1.04||0.51–0.91||0.41–0.75||<0.0001||0.58–0.91|
|Upper cutpoint||0.89 (0.26)||0.77||0.86||0.92||1.01||–|| || |
|Cases/controls|| ||142/308||172/305||168/307||155/307||130/307|| || |
|95% CI|| || ||0.89–1.54||0.75–1.33||0.77–1.36||0.55–1.01||0.04||0.79–1.25|
|Upper cutpoint||1.56 (0.52)||1.26||1.45||1.62||1.81||–|| || |
|Cases/controls|| ||134/307||161/306||204/308||119/306||149/307|| || |
|95% CI|| || ||0.75–1.32||0.81–1.42||0.76–1.35||0.66–1.19||0.52||0.79–1.24|
|Vitamin B6 (mg)|
|Upper cutpoint||1.94 (0.56)||1.71||1.87||2.01||2.18||–|| || |
|Cases/controls|| ||156/307||165/306||149/307||153/308||144/306|| || |
|95% CI|| || ||0.87–1.48||0.67–1.18||0.61–1.07||0.64–1.13||0.04||0.74–1.14|
|Total folate (μg)|
|Upper cutpoint||272.56 (82.86)||231.58||257.05||282||314.04||–|| || |
|Cases/controls|| ||149/307||155/306||168/307||142/308||153/306|| || |
|95% CI|| || ||0.58–1.00||0.57–1.00||0.59–1.03||0.64–1.12||0.30||0.63–0.98|
|Upper cutpoint||18.63 (5.29)||15.96||17.74||19.31||21.25||–|| || |
|Cases/controls|| ||168/306||159/307||146/307||140/307||154/307|| || |
|95% CI|| || ||0.76–1.31||0.54–0.96||0.58–1.03||0.60–1.07||0.03||0.66–1.03|
|Vitamin C (mg)|
|Upper cutpoint||140.28 (76.36)||89.41||115.45||142.78||185.67||–|| || |
|Cases/controls|| ||168/307||158/306||152/307||148/307||141/307|| || |
|95% CI|| || ||0.50–0.88||0.54–0.95||0.58–1.02||0.54–0.96||0.09||0.58–0.89|
The ORs of RCC according to vitamin D, E, C and total folate intake for subjects in the upper 4 energy-adjusted quintiles of intake when compared with the lowest one across strata of selected covariates are given in Table III. Although there was no systematic heterogeneity across strata of sex, age, BMI and smoking habit, the associations were somewhat stronger for women, younger subjects (less than 60 years) and those overweight (BMI ≥25 kg/m2). Moreover, the inverse relation with vitamin D was limited to never smokers, while those for vitamin E and folate were stronger in ever smokers.
Table III. Odds Ratio (OR) of Renal Cell Carcinoma and Corresponding 95% Confidence Intervals (CI) for Subjects in the Upper Four Energy-Adjusted Quintiles of Consumption of Selected Micronutrients when Compared to those in the Lowest One. Italy, 1992-2004
In the present study, based on a large dataset and with extensive information on major sources of vitamins and micronutrients in the Italian population, an inverse relation was observed between vitamin E and vitamin C intake and RCC risk. For most other micronutrients, including retinol, various carotenoids and vitamins, no significant trend of decreasing risk was found, although subjects with an intake above the first quintile had ORs below unity. Thus, only low intakes of micronutrients appeared to have a detrimental effect on RCC in this population.
The beneficial effect of dietary vitamin E on RCC reported in this study is consistent with the results of a few other investigations.6, 13, 21 Moreover, a case-control study from Canada10 on 1,279 RCC reported a significant inverse association with long-term supplementation with vitamin E. Other 2 case-control studies,22, 23 however, did not report any meaningful association, and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study,24 a randomized trial on 29,133 male smokers from Finland, did not find a reduction in the incidence of RCC in subject who received long-tem supplementation (5–8 years) with α-tocopherol (50 mg/day). The number of RCC cases (102) in that randomized trial was however limited.
The antioxidant properties of vitamin E can explain its protective effect on RCC, observed also on other cancers.25 The major source of vitamin E in the Italian population is olive oil.26 Thus, the beneficial effect of vitamin E may reflect a more general favorable effect of olive oil, found to be inversely associated to the risk of various neoplasms in Mediterranean populations.27 Alternatively, vitamin E may represent an indirect indicator of a diet rich in vegetables, which are usually consumed with olive oil in this population, and have been related to a reduced risk of RCC.5, 8, 14
We found no evidence that preformed vitamin A has a protective effect against RCC, consistent with most previous studies.6, 9, 11, 12, 13, 23 No strong protective effect was also found for various vitamin A precursors (including α-carotene, β-carotene, β-criptoxanthin, lutein/zeaxanthin) and for other carotenoids with antioxidant activity, such as lycopene, although our results are compatible with a weak protective effect reported by some,9, 10, 11, 12, 21, 22 but not all,6, 13, 23 previous studies.
The present study supports a weak beneficial effect of vitamin C on RCC.7, 11, 21 The evidence of the role of vitamin C on RCC is however inconsistent, with various studies reporting no meaningful relations.6, 9, 10, 13, 22, 23
For other micronutrients, such as vitamin D, folates and B-complex vitamins, no clear indication of a role on RCC appears from our investigation, and the evidence from previous studies is scanty.13, 23
Among the possible limitations of the present study, there is the use of hospital controls, whose dietary habits may differ from those of the general population.20 However, we took great care in excluding from the control group all diagnoses that might have been associated to tobacco smoking or involved long-term modifications of diet. Further, in the present study dietary intake was very similar across the 4 major diagnostic categories of controls (i.e., traumas, other orthopaedic, surgical and miscellaneous conditions). Moreover, the similar interview setting and catchment areas, and the almost complete participation of cases and controls are reassuring against any relevant selection and recall bias. Another limitation may be the problem of multiple comparisons, which can lead to chance findings. Among the strengths of the study, there are the large sample and the use of a validated17 and reproducible18 FFQ, which allowed a comprehensive assessment of major micronutrient sources in the Italian diet. Further, total energy intake, as well as major potential confounding factors—including tobacco smoking, BMI, and education—were carefully accounted for in all the analyses.
In conclusion, the present findings suggest a possible beneficial effect of vitamin E and on RCC. It however confirms the difficulty to identify micronutrients responsible for the protection found for vegetables, and possibly fruit, on RCC. Thus, it is possible that, as for other common neoplasms, the favourable effect of plant food may be due to other still unidentified compounds, or to the complex action of several micronutrients combined.
The authors thank Ms M. P. Bonifacino for editorial assistance, Mrs O. Volpato for study coordination and Ms G. Bessega, L. Zaina, Dr M. Grimaldi and S. Desicato for their help in data collection. They are also deeply thankful to Dr R. Mele, A. Grandi, P. Ascierto, R. Magri, R. Di Lauro and I. Forner for providing hospital control patients.