Introduction

Kidney cancer is the sixth most frequent cancer in men and the 10th in women, representing 5% and 3% of all newly diagnosed cases, respectively1. Globally, kidney cancer accounts for more than 2% of cancer burden2. And the global incidence rate of kidney cancer has been consistently increasing for the past decades3. Most cases of kidney cancer predominantly arise in the renal parenchyma, also known as renal cell carcinoma (RCC)1,3. The most important risk factors related to kidney cancer are age and gender1. And there appears a ratio of men to women from 1.5:1 to 2.0:1 with men predominance1. Only a few modifiable risk factors have been established for potential preventative or detrimental influence on kidney cancer incidence4. Cigarette smoking and obesity have been reported to be positively correlated with kidney cancer risk1. For dietary factors, recent studies have demonstrated the beneficial effects of fruit and vegetable consumption and moderate alcohol intake against kidney cancer5,6,7,8,9.

There is a pressing need to identify additional contributing risk factors for kidney cancer incidence, particularly in regard to dietary risk factors. Tea and coffee are the most commonly consumed beverage worldwide aside from water10. Green tea, particularly, is a popular beverage consumed in Japan, China, and some countries in North Africa and the Middle East10. The protective roles of green tea and coffee on health promotion and cancer prevention have attracted great attention, as established preventive strategies against cancer are limited11,12,13,14,15.

Epidemiological studies have investigated the effects of green tea and coffee drinking in relationship to kidney cancer incidence16,17,18,19,20. For coffee consumption, studies have suggested an inverse relationship between coffee consumption and kidney cancer risk16,17,18. Limited studies focused on the relationship between green tea and the risk of kidney cancer incidence20,21. Most studies involved tea consumption in general, and were mainly in Caucasian populations in Europe or America, with no conclusive results19,20,21,22.The evidence was mostly reported by case–control studies which largely suffered from recall bias and sampling bias, lacking results involving Asian population. Green tea is predominantly consumed in Asian population compared to rest of the world10. Studies that failed to include data from Asia would result in uncertainty of the effects of green tea consumption against kidney cancer incidence. No previous study was conducted in a large Asian cohort to evaluate the association between green tea consumption and the risk of kidney cancer development.

We aimed to evaluate the association between green tea and coffee consumption and the risk of kidney cancer using data from a large prospective cohort study (the Japan Public Health Center-based Prospective Study: JPHC Study) in Japan.

Methods and materials

Study design

The details of the JPHC Study have been reported in previously published papers23,24,25. The study includes two cohorts: Cohort I established in 1990 and Cohort II in 1993. Data from the baseline survey was used in this study, with response rates of 79% in Cohort I and 84% in Cohort II. A total of 140,420 individuals (68,722 men and 71,698 women) aged 40 to 69 years in 11 prefectural public health center areas (PHC) were initially identified. Exclusion criteria for this study included participants from Katsushika-City due to lack of cancer data (n = 7097), ineligibility of non-Japanese nationality, no exist from start, inadequate age, duplicated identification number or refusal for follow-up (n = 284), incorrect response time (n = 113), no response for baseline survey (n = 26,740), incorrect person-years (n = 485), missing information on green tea and coffee consumption (n = 1865) and on body mass index and smoking status (n = 1373). Finally, this resulted in the inclusion of 102,463 participants (48,647 men and 53,816 women). Self-administered questionnaires including items on demographic characteristics, medical history, diet, physical activity, and other lifestyle habits were distributed to all cohort subjects at baseline. All research participants were informed of the study objectives at their enrollment. Informed consent was obtained when participants completed the baseline questionnaire. Incomplete answers were supplemented by telephone interviews.

Follow up

Participants were followed from the time they responded to the baseline survey through December 31, 2013 (December 31, 2012 for Suita-City). Person-years of observation were established as the time from the date of response to the date of kidney cancer diagnosis, the date of moving-out from the study area, or the end date of follow-up, whichever occurred first. Any change in residence or survival status was traced by the residential registry in the study area annually. Loss to follow-up subjects was censored on the last date confirmed of their presence. Information on cause of death was confirmed by examining death certificates, which were provided by the Ministry of Health, Labour, and Welfare with permission from the Ministry of Internal Affairs and Communications24. The information of residency and death registration is requested by law in Japan.

Assessment of exposure

All exposure data was collected from the baseline survey, which included a 44-item food self-administrated food frequency questionnaire (FFQ)26. The questions on measurements of green tea and coffee consumption were the same in Cohort I and Cohort II. Previously published JPHC Study papers were used for reference in determining categories of green tea and coffee consumption27,28. Green tea consumption was divided into five frequency categories: “rarely”, “ < 1 cup/day”, “1–2 cups/day”, “3–4 cups/day” and “ ≥ 5 cups/day”. Coffee consumption was also divided into five frequency categories: “rarely”, “1–2 days/week”, “3–4 days/week”, “1–2 cups/day” and “ ≥ 3 cups/day”. The validity of the FFQ was assessed using dietary records among 201 participants (94 men and 107 women) for 28 or 14 days26. In Cohort I, Spearman rank correlation coefficients between the FFQ and the dietary records were 0.57 for men and 0.63 for women for green tea consumption, whereas for coffee consumption the numbers were 0.42 for men and 0.38 for women26. In Cohort II, the coefficients were 0.37 for men and 0.43 for women for green tea consumption, while for coffee consumption the numbers were 0.59 for men and 0.51 for women28.

Outcome ascertainment

The outcome of kidney cancer incidence as first cancer developed was defined according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), including malignant neoplasm of kidney (C64). The sources of identification of cancer included active patient notifications made by major local hospitals in the study area, data linkage with population-based cancer registries, and death certificate information. Permission was obtained from relevant local governments.

Statistical analysis

Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for kidney cancer incidence were computed using cox proportional hazards regression models. Model 1 considered age (stratified by age groups: 45–49, 50–54, 55–59, 60–64, 65–69 and > 70 years old) and PHC area (10 areas) as covariates; and model 2 considered age, PHC area, smoking (past, current, never, missing), history of hypertension (yes, no, missing), history of diabetes (yes, no, missing), history of renal diseases (yes, no, missing), drinking frequency (rarely, 1–3 days/month, 1–2 days/week, 3–4 days/week, ≥ 5 days/week, missing), body mass index (< 18, 19–22, 23–25, 26–29, > 30, missing), physical activity (rarely, 1–3 days/month, 1–2 days/week, 3–4 days/week, almost daily, missing). Selection of confounding variables was mainly based on a previously published JPHC Study paper investigating the relationship between green tea and kidney cancer mortality27, as well as previous evidence about the relationship between kidney cancer and green tea and coffee intake1,5,6,7,8,9. Supplemental Fig. 1 of a directed acyclic graph (DAG) represents the relationship of variables and kidney cancer risk. The DAG was made via DAGitty version 3.0 with the model by Shrier and Platt29,30. Dummy variables were created to indicate missing information of confounding variables in data analysis. Complete case analysis was done in the sensitivity analysis as an alternative missing data method. Models were mutually controlled for green tea consumption and coffee consumption, and were created for both sexes separately and for the total population with sex added as a confounding variable. As the sex disparity in kidney cancer has been reported widely and was not likely to be fully explained by known risk factors1,31, analyses were done by stratifying sex in this study.

A sensitivity analysis was conducted by limiting kidney cancer cases only with subjective symptoms. Incidental detection of kidney cancer due to the widespread use of testing in addition to screening could lead to potential influence32,33. The detailed definition of subjective symptoms was not provided in this study. Another sensitivity analysis was performed by adjusting for additional variables, green vegetables intake and consumption of miso soup intake in Model 2 to check if the results changed. These two variables are considered as a proxy of healthy lifestyles in Japanese in relation to obesity and hypertension as shown in Supplemental Fig. 132,33. Furthermore, data was right censored by omitting participants who were diagnosed with cancers other than kidney cancer in a sensitivity analysis to reduce potential bias. Stratification analyses were performed by stratifying smoking status (never versus past and current) and by body mass index (< 25 kg/m2 vs. ≥ 25 kg/m2) as previous evidence from the JPHC study has confirmed the increased risk of these two variables related to kidney cancer34,35. The biological mechanism underlying the carcinogenic effects of smoking is generally considered as its promotion to lipid peroxidation and oxygen free radicals’ formation, and that results in renal tubular damage36. Obesity plays a critical role in interlinked hormonal alterations, which could increase cancer incidence and progression37.

The cox proportional hazard assumption for all models was tested using scaled Schoenfeld residuals38. No violation was observed overall. P for trend was tested by treating the green tea and coffee category measures as continuous variables. All statistical analyses were conducted using Stata 16.1 (StataCorp, College Station, TX, USA), with a P value of less than 0.05 considered as statistically significant.

This study has been approved by the Institutional Review Board of the National Cancer Center Japan (approval number: 2015-085) and the Ethics Committee of Graduate School of Medicine, The University of Tokyo (approval number: 2019209NI). All methods were performed in accordance with relevant guidelines and regulations.

Results

Baseline characteristics

Baseline characteristics of participants according to green tea or coffee consumption are shown in Tables 1 and 2. A total of 286 cases of kidney cancer (199 in men, 0.4% in total population, 87 in women 0.2% in total population) were identified during 1,916,421 person-years (mean follow-up period, 19 years). The body mass index (BMI) among the total population were normal in all green tea and coffee consumption categories39. A growing trend in age was observed in participants with increased green tea intake. In contrast, a decreasing trend in age was observed in both men and women with increased coffee intake. Men and women who consumed a high intake of green tea (≥ 5 cups/day) seldom consumed black tea, oolong tea, or coffee. Participants with a high intake of coffee (≥ 3 cups/day) rarely consumed black tea or oolong tea.

Table 1 Baseline characteristics of JPHC Study participants according to green tea consumption (n = 102,463).
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Table 2 Baseline characteristics of JPHC Study participants according to coffee consumption (n = 102,463).
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Green tea consumption and kidney cancer risk

Figure 1 presents the association between the cumulative kidney cancer incidence rates and the frequency of green tea consumption using the Kaplan–Meier method. The cumulative incidence rates were not significantly different among the five groups with different green tea intake frequency (log-rank test, p = 0.20) (Fig. 1). For the total population, after adjusting for potential covariates, there was no statistically significant association between green tea intake and kidney cancer risk found with a p for trend of 0.39 in the multivariable model (Table 3). High green tea consumption, which refers to ≥ 5 cups/day in the study, showed a HR of 0.75 (95% CI: 0.51–1.12) in the total population when adjusted for multivariable, compared to the reference group, those rarely consuming green tea. The relationships were not statistically significant in men, with a multivariable-adjusted HR for the group consumed ≥ 5 cups/day of 0.96 (95% CI: 0.59–1.56). For women, a statistically significant inverse association was found between the highest frequency of green tea intake and kidney cancer risk, with the HR of women who had ≥ 5 cups/day green tea intake of 0.45 (95% CI: 0.23–0.89).

Figure 1
figure 1

Kaplan–Meier survival curves of the cumulative incidence of kidney cancer among JPHC participants with different green tea consumption.

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Table 3 Hazard ratio and 95% confidence interval for kidney cancer incidence according to green tea consumption in Japanese adults.
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Coffee consumption and kidney cancer risk

The association between the cumulative incidence rates of coffee consumption and kidney cancer is presented in Fig. 2. The cumulative kidney cancer incidence rates were significantly different among the groups with different coffee consumption frequency (log-rank test, p = 0.01) (Fig. 2). The associations related to kidney cancer risk were not statistically significant for the total population with a p trend of 0.36 (Table 4). No statistically significant results were observed in both men and women (Table 4). In the total population, individuals who consumed 1–2 cups of coffee per week had a multivariable-adjusted HR of 0.62 (95% CI: 0.43–0.89) compared to those who rarely consumed coffee. Women with the same coffee consumption frequency also had a significant difference (HR: 0.38, 95% CI: 0.18–0.81). No such relationship was found in men.

Figure 2
figure 2

Kaplan–Meier survival curves of the cumulative incidence of kidney cancer among JPHC participants with different coffee consumption.

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Table 4 Hazard ratio and 95% confidence interval for kidney cancer incidence according to coffee consumption in Japanese adults.
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Sensitivity analysis

In the sensitivity analyses adjusting additional variables for green vegetables intake and consumption of miso soup, results were similar when compared to the multivariable-adjusted HRs. No significant associations were detected between green tea intake and kidney cancer in the total population or in men (Supplemental Table 1). In women, a consistent reduced risk was observed in the category of ≥ 5 cups green tea/day (HR: 0.45, 95% CI: 0.22–0.89; p trend = 0.06). Results for coffee consumption did not show statistically significant associations with kidney cancer. The reduced risks in the frequency of 1–2 days/week coffee intake were also found in total population and women, but not in men. In addition, no significant associations between kidney cancer risk and green tea and coffee intake were observed when limiting cases with subjective symptoms (Supplemental Table 2).

In the sensitivity analysis stratified by smoking status, no significant associations between green tea and kidney cancer risk were detected in the total population, in men or in women who never smoked (Supplemental Table 2). A significant inverse relationship between green tea intake and kidney cancer risk was found in women who ever smoked. (p = 0.04). In the sensitivity analysis stratified by BMI, no statistically significant relationships were observed for green tea and coffee consumption (Supplement Table 3).

Results in the complete case analysis were similar to the results using dummy variables (Supplemental Table 4). No statistically significant associations were established between both intakes of green tea and coffee and kidney cancer risk. When using censored data withdrawing participants diagnosed with other cancers, results showed no statistically significant associations between both intakes of green tea and coffee and kidney cancer risk but the same reduced risk in women had ≥ 5 cups green tea/day (Supplemental Table 5).

Discussion

This is the first study, to the best of our knowledge, to evaluate the relationship between green tea intake and risk of kidney cancer development in a large population-based cohort study in Asia. In sum, we found no statistically significant associations between different levels of green tea intake and risk of kidney cancer in the total population. Nonetheless, there might be a decreasing trend between kidney cancer risk and higher green tea intake. The reduced risk shown in women in the highest level of green tea intake further indicated the potential association. For coffee consumption, no statistically significant relationships were established in the total population, in men or in women, which was not consistent with the meta-analysis published in 202216.

Our study indicated a possible decreasing trend between high green tea intake and kidney cancer risk. A recent hospital-based case–control study that investigated the association between green tea intake and clear cell renal cell carcinoma (ccRCC) in a Chinese population proved the inhibitory effect of higher green tea intake (> 500 ml/day) against ccRCC21. The anticarcinogenic effect possibly credited to catechins and theaflavins in green tea is described in evidence from cell or animal studies40,41,42,43. The chemo-preventative action of ( −)-epigallocatechin-3-gallate (EGCG), a type of catechin founded in green tea, has been proven through preservation of gap junction intercellular communication (GJIC) of renal epithelial cells when treated with a renal carcinogen in vitro42,43. This kind of restoration of GJIC indicated the distinguishing feature that green tea has when targeting renal cell tumors. The present study indicated such preventive effects of green tea seemed to exist, especially for women who consume a great amount of green tea. When stratified by smoking status, a statistically significant relationship was found between higher green tea intake and kidney cancer risk in ever-smoked women (p trend = 0.04). The multivariable-adjusted HRs in the group of ≥ 5 cups green tea/day of ever-smoked women (0.06, 95% CI: 0.004–0.79) and never-smoked women (0.57, 95% CI: 0.27–1.18) were similar, indicating there was hardly any difference between women with different smoking statuses. Still, there might be undiscovered effects in ever smoked women, considering the larger HR and the upper limit of 1.18 in the 95% confidence interval in never-smoked women. In the sensitivity analyses stratified by BMI, the HRs in the group of ≥ 5 cups green tea/day of women with BMI < 25 (0.50, 95% CI: 0.28–1.19) and women with BMI ≥ 25 (0.44, 95% CI: 0.14–1.33) were very close. In addition, the results in stratified BMI analysis were similar to the main results, suggesting the same decreasing trend between higher intakes of green tea and kidney cancer risk in women. The insignificant relationship is likely due to the small number of cases in women.

The findings suggest a sex difference in the association between green tea consumption and kidney cancer risk. One possible mechanism could be the different action of sex hormones in women who regularly drank green tea, in particularly related to estrogen metabolism44,45. Estrogen could prevent renal cell carcinoma cell progression by activating estrogen receptor-β46. Studies have shown that intake of green tea was associated with estrogen circulation and metabolism47,48. Further investigation is warranted to discover latent risk factors and mechanisms that may cause the sex discrepancy of the association between green tea intake and kidney cancer risk.

The null relationship between coffee intake and kidney cancer risk was not consistent with the recent meta-analysis by Rhee et al. in 202216. A significant inverse relationship between the highest versus lowest coffee intake and renal cancer risk was established in their meta-analysis of ten identified cohort studies, with a summary relative risk (RR) of 0.88 (95% CI: 0.78–0.99)16. Among the ten cohort studies, four were conducted in the region of North America16. And the summary RR of other regions was 0.93 (95% CI: 0.72–1.21), indicating the difference between geographical regions16. Our results were consistent with results from another cohort study in Japan, the Japan Collaborative Cohort Study (JACC study)49, which was included in the meta-analysis by Rhee et al. The JACC study reported an age-and sex-adjusted HR of 2.69 (95% CI: 0.89–8.10) among participants who drank more than three cups of coffee per day, compared with participants with no coffee intake49. The heterogeneity in results among different studies included in the meta-analysis on coffee may be ascribable to methodological errors. Our results have shown a statistically significant reduced risk in the frequency of 1–2 cups of coffee per week with a HR of 0.62 (95CI%: 0.43–0.89) in the total population. The small number of cases could mask the true effect of a potential inverse relationship between coffee intake and kidney cancer.

The foremost strength of our study was its large-scale prospective design including several public health center areas over Japan, along with a low proportion of loss to follow-up (0.4%). Therefore, the potential of recall bias and selection bias was largely reduced. Furthermore, the data from the comprehensive FFQ, and evaluation from a credible registry system enhanced the accuracy of results. This study has some limitations. First, the main limitation of the study is the low statistical power. The small number of cases and wide CIs due to the small number of cases indicated uncertainty of the results and bias the true effects. The inconsistent results observed in the complete-case analysis also suggested that missing values led to reduced statistical power. Second, the results could be biased due to limitations of FFQ assessment. Changes in dietary patterns were not reflected since only baseline data was used in the analysis. The National Health and Nutrition Survey in Japan50, suggests green tea and coffee consumption remained stable between 2011 and 2018 and it is likely that the trends haven’t changed for decades. Variations of other lifestyle patterns may exist during the follow-up years, which could lead to potential misclassification. The effect of different methods applied in drinking green tea and coffee was not considered due to a lack of questions about brewing process in beverage consumption in the FFQ. Third, residual confounding effects may exist due to the inability to adjust all potential risk factors for kidney cancer based on limited evidence. Possible underlying risk factors include influence of sex hormones51,52 and occupational exposure to heavy metals, gasoline, or diesel engine exhausts53,54. Forth, although the mean follow-up period was long up to 19 years in this study, the small number of kidney cancers detected in each exposure category could lead to uncertainty. Lastly, the moderate correlations between the FFQ and the dietary records of green tea and coffee consumption indicated moderate reproducibility, which could lead to error in estimates when quantifying actual green tea and coffee intake.

In conclusion, our findings suggest that green tea, but not coffee consumption may be inversely related to kidney cancer incidence in Japanese adults, with a significant association observed in Japanese women.