Abstract
Background
Cross-sectional studies suggest that coffee drinking is associated with better renal function. However, to our knowledge, no prospective study has examined its relation with the risk of end-stage renal disease (ESRD).
Objective
We examined the relations between coffee, tea, soda, and total caffeine consumption and the risk of ESRD among middle-aged and older Chinese in Singapore.
Methods
We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women aged 45–74 y at recruitment from 1993 to 1998. Baseline information on the consumption of caffeinated coffee and other caffeinated beverages (tea and sodas), habitual diet, medical history, and lifestyle factors was obtained via in-person interviews. The standard serving size of 1 cup was assigned as 237 mL in the questionnaire. Incident ESRD cases were identified via linkage with the nationwide registry. We used multivariable Cox regression models to estimate HRs and 95% CIs of ESRD risk associated with the consumption of caffeinated beverages, with adjustment for potential confounders.
Results
After a mean follow-up of 16.8 y, 1143 cohort subjects developed ESRD. Compared with those who drank coffee less than daily, the HR (95% CI) was 0.91 (0.79, 1.05) for those who drank 1 cup of coffee/d and 0.82 (0.71, 0.96) for those who drank ≥2 cups/d (P-trend = 0.012). When stratified by sex, this association was observed in men but not in women. Compared with those who drank less than daily, the HR (95% CI) for drinking ≥2 cups/d was 0.71 (0.57, 0.87) among men and 0.97 (0.78, 1.19) among women (P-interaction = 0.03). Conversely, intakes of tea, soda, or total caffeine were not associated with the risk of ESRD in multivariable models.
Conclusion
The consumption of ≥2 cups of coffee/d may reduce the risk of ESRD in the general population, especially among men. This study was registered at http://www.clinicaltrials.gov as NCT03356340.
Keywords: coffee, end-stage renal disease, tea, caffeine, Chinese
Introduction
End-stage renal disease (ESRD), defined as kidney failure requiring dialysis or kidney transplantation, is an increasing public health threat globally associated with high morbidity and mortality and has major social and economic consequences (1). The rates of ESRD in the United States rank among the highest in the world. According to the US Renal Data System, ∼12,400 incident cases of ESRD were reported in 2015, with a prevalence of nearly 500,000 patients receiving dialysis treatment and >200,000 living with a kidney transplant (2). Over the past 20 y, the incidence of treated ESRD in Singapore has also increased by >50%, and in the latest US Renal Data System Annual Data Report, Singapore has the sixth highest incidence of treated ESRD in the world (2).
Coffee is one of the most widely consumed beverages in the world. Coffee consumption is the highest in European countries, followed by North America and Asia. However, Asia has been experiencing dynamic growth in coffee consumption since 1990 and consumption is expected to increase to levels on par with those of Western countries with time (3). Several meta-analyses of observational studies have suggested that moderate habitual consumption of coffee may reduce the risks of all-cause and cardiovascular disease–related mortality (4–8). Specifically, coffee consumption was nonlinearly associated with cardiovascular disease risk in 1 meta-analysis, with the lowest risk among those drinking 3–5 cups/d (9). In contrast, in a dose-response meta-analysis on the association between coffee intake and hypertension risk, an inverse J-shaped association was observed, with a small (9%) but significant increase in hypertension risk for those who drank 1–3 cups of coffee/d, but no association for those who drank less than daily or who drank >3 cups of coffee/d (10). Comparatively, coffee consumption was inversely associated with the risk of type 2 diabetes in a dose-response manner (11).
Because hypertension, diabetes, and cardiovascular disease are known comorbid risk factors for chronic kidney disease (CKD) (12–16) and ESRD (17–21), habitual coffee consumption may reduce the risk of ESRD via its effects on reducing the risk of these comorbid risk factors. Polyphenols in coffee have been shown to exert anti-inflammatory, antithrombotic, and vasodilatory effects beneficial to the prevention of cardiometabolic disease (22), and these bioactive chemicals in coffee may also have a similar beneficial effect on renal function. Indeed, previous cross-sectional studies have shown that habitual coffee drinking is associated with higher estimated glomerular filtration rate (eGFR) (23–27). However, to the best of our knowledge, no prospective study has examined the relation of regular coffee consumption with ESRD risk.
In this prospective study, we examined the association between the consumption of coffee and the risk of ESRD in a population-based cohort of middle-aged and elderly Singapore Chinese men and women. In addition, caffeine is a major biologically active ingredient of coffee, and probably one of the first components in coffee to be studied for its direct and indirect effects on the vascular tissue by different mechanisms of action and on a wide range of molecular targets (28). Hence, we also studied the association of other caffeinated beverages, such as tea and sodas, and total caffeine intake with the risk of ESRD.
Methods
Study population
The Singapore Chinese Health Study (SCHS) is a population-based cohort of 63,257 Chinese adults, aged 45–74 y during recruitment from April 1993 to December 1998 (29). The study participants were recruited from government housing estates, which are facilities in which ∼86% of Singaporeans resided in during the recruitment period. The participants were from 2 major dialect groups in Singapore, the Hokkiens and Cantonese, who originated from Fujian and Guangdong provinces in Southern China, respectively. At recruitment, trained interviewers obtained informed consent before conducting in-person interviews in participants’ homes with the use of a structured questionnaire that ascertained information on demographic characteristics, height, weight, tobacco use, physical activity, and medical history. The present study was approved by the Institutional Review Board of the National University of Singapore. This study was registered at http://www.clinicaltrials.gov as NCT03356340.
Assessment of diet and covariates
Habitual diet in the preceding 1 y, which included beverage items, was captured with the use of a semiquantitative 165-item FFQ specifically developed for this study population. This questionnaire was subsequently validated by using two 24-h dietary recall interviews and repeat administration of the FFQ among a subset of 810 cohort participants, and most mean pairs for energy and nutrients were within 10% deviation from each other by the 2 different methods (29).
Before we embarked on the study, we first conducted a pilot study in 200 representative adults to obtain 24-h dietary recalls for the development of the structured FFQ. From the 24-h recall data, we predetermined the categories of beverage consumption in the questionnaire for ease of reporting by the participants and to cover the range of consumption. For beverages, the participants were instructed to select the frequency of consuming a standard serving from 1 of the predefined categories: never or hardly ever, 1–3 times/mo, 1 time/wk, 2–3 times/wk, 4–6 times/wk, 1 time/d, 2–3 times/d, 4–5 times/d, and ≥6 times/d. The standard serving size was described as “1 cup” for coffee and “1 glass” for tea or sodas and assigned as 237 mL in the questionnaire.
The frequencies of drinking instant, freshly brewed, and 3-in-1 preparation coffee consumption were asked in separate questions. The 3-in-1 preparation coffee is an instant coffee beverage widely consumed in Singapore and other parts of Asia. It is a mixture of coffee powder, nondairy creamer, and refined cane sugar packed in individual packs, and the contents of each pack dissolves in hot water to make a cup of coffee.
The dietary nutrients of the food items were derived from the Singapore Food-Composition Database, and caffeine intake was estimated from the self-reported intakes of coffee, tea, and other caffeinated beverages and food items. The caffeine concentrations were between 53 and 58 mg/100 g for brewed coffee, ∼30 mg/100 g for instant coffee, ∼20 mg/100 g for both green and black teas, and ∼10 mg/100 g for caffeinated sodas. Coffee and tea were the 2 major sources of caffeine in this population, accounting for 83% and 13% of total caffeine intake, respectively (30). Green tea and other caffeinated food sources such as soda, cocoa drinks, and chocolate-related food items were minor contributors (4%) to caffeine intake in this population (30). Because decaffeinated coffee or tea was rarely consumed in our study population at the time of recruitment, all coffee and tea consumed were assumed to be caffeinated in this study.
Incident ESRD cases and CKD mortality cases
ESRD cases were identified by linking our cohort database with the population-based Singapore Renal Registry, which has been shown to be comprehensive in its recording of ESRD cases since 1999 (31). The registry uses multiple sources to identify ESRD cases, including laboratory records, hospital records, and listing of patients on dialysis. Since 2011, notifications of ESRD have been made compulsory under the National Registry of Diseases Act in Singapore.
The registry defines ESRD as meeting ≥1 of the following criteria: 1) serum creatinine concentration ≥880 µmol/L (10 mg/dL), 2) eGFR of <15 mL ⋅ min−1 ⋅ 1.73 m−2 [based on either the Modification of Diet in Renal Disease Study equation, the Cockcroft Gault equation, or 24-h creatinine clearance], 3) undergoing hemodialysis or peritoneal dialysis, or 4) having undergone kidney transplant. Consistent with international guidelines, criteria 1 to 3 have to be persistent for >3 mo to qualify as ESRD (31, 32). Information on date and cause of death was obtained through linkage analysis with the nationwide registry of birth and death in Singapore. The primary cause of death was coded according to the International Classification of Diseases, Ninth Revision, and CKD deaths referred to codes 585.0–586.9.
As of 31 December 2014, only 47 participants (0.07%) from our cohort were known to be lost to follow-up due to migration out of Singapore or for other reasons. This suggests that emigration among these participants was negligible. Thus, the follow-up via linkage with nationwide registries can be considered to be virtually complete. The current analysis included data from 63,147 participants, after excluding 110 participants who were diagnosed with ESRD at baseline.
Statistical analysis
The primary outcome was defined as incident ESRD, and the secondary outcome referred to additional cases with CKD coded as the primary cause of death. Person-years for each participant were calculated from the date of the baseline interview to the date of reported ESRD, loss to follow-up, or death or 31 December 2014, whichever occurred first. The differences in baseline characteristics by coffee intake were examined by using the chi-square test for categorical variables and t test for continuous variables. We studied the frequencies of the intake categories from the questionnaire data and created categories for the analysis on the basis of cutoff values that were logical and which offered sufficient statistical power, such as by integrating categories with low frequencies. For the intake of coffee, 29.7% of our participants drank less than daily, 36.1% drank 1 cup/d, 30.3% drank 2–3 cups/d, and only 3.9% drank ≥4 cups/d. Hence, to maximize statistical power, we created 3 categories and defined the highest amount as “≥2 cups/d.” Following this rationale, the intake of coffee was analyzed in the following groups: “none to <1 cup/d,” “1 cup/d,” and “≥2 cups/d.” The intake of tea was analyzed in the following groups: “none to less than weekly,” “weekly to <1 cup/d,” “1 cup/d,” and “≥2 cups/d.” The intake of soda was analyzed in the following groups: “none to <1 glass/mo,” “monthly to <1 glass/wk,” “weekly to <1 glass/d,” and “≥1 glass/d.” Caffeine intake was categorized into “0–<100 mg/d,” “100 to <200 mg/d,” “200 to <300 mg/d,” and “≥300 mg/d.” Cox proportional hazards regression was used to calculate the HR and its 95% CI for developing ESRD compared with the respective lowest category. The proportional hazards assumption was met, and no significant interactions with time were observed for the variables of interest in our study.
The selection of potential confounders was based primarily on previous consideration of their associations with the risk of ESRD in this population. Model 1 (a basic model) included age (years), sex, year of recruitment (1993–1995, 1996–1998), dialect (Hokkien or Cantonese), and educational level (no formal education, primary school, or secondary school or higher). Model 2 included all variables in model 1 and the following variables: lifetime smoking status (never or ever), alcohol consumption (none, occasionally, weekly, or daily), BMI (kg/m2; <20.0, 20.0–23.9, 24.0–27.9, or ≥28.0), physical activity (defined as any weekly moderate or vigorous activity or sports lasting ≥30 min), red meat intake, and total protein intake. In model 3, on top of all variables in model 2, we also included self-reported histories of physician-diagnosed hypertension, diabetes, coronary artery disease, and stroke (yes or no for each disease), because these diseases are established comorbid risk factors for ESRD, and coffee has been shown to affect the risk of these comorbidities (4–11). Finally, we included a fourth model (model 4) that included all of the variables in model 3 and the consumption of coffee, black tea, green tea, and soda.
We further stratified analysis by sex, smoking status (never or ever), and self-reported history of diabetes and other comorbid conditions. Tests for trend were performed by using the ordinal values in the intake categories as continuous variables in the Cox regression models. The heterogeneity of the coffee-ESRD associations by different factors was tested by including an interaction term (product between coffee intake categories and interaction factor) in the Cox model. With the use of the mediation analysis method described by Buis (33), we decomposed the total association between coffee intake and ESRD risk into direct and indirect associations (diabetes as mediator) with the use of bootstrapping to calculate SEs. For sensitivity analysis, we repeated our analysis on participants with >4 y of follow-up in order to minimize the potential confounding effect of subclinical disease on the observed coffee-ESRD association. To examine how changes in enforceability for ESRD with the commencement of the National Registry of Diseases Act since 2011 would have affected the results, we also repeated the analysis by including only cases notified before the Act and setting the censoring date as 31 December 2010.
All of the analyses were performed by using SAS version 9.2 (SAS Institute, Inc.), and significance was based on 2-sided probability of 0.05.
Results
Approximately 70.3% of participants in this study were daily coffee drinkers, and 34.2% drank ≥2 cups of coffee/d. In contrast, only 22.3% were daily drinkers of either black or green tea. Compared with participants who drank coffee less than daily, those who drank ≥2 cups of coffee/d were more likely to be men, ever smokers, weekly or daily drinkers of alcohol, less educated, and less physically active. They were also less likely to self-report physician-diagnosed history of hypertension, diabetes, coronary artery disease, and stroke (Table 1).
TABLE 1.
Baseline characteristics of cohort participants by frequency of coffee consumption1
| Frequency of coffee intake | |||
|---|---|---|---|
| None to <1 cup/d | 1 cup/d | ≥2 cups/d | |
| Participants, n | 18,778 | 22,757 | 21,612 |
| ESRD cases, n | 390 | 419 | 334 |
| Age at recruitment, y | 56.6 ± 8.32 | 56.8 ± 8.0 | 56.2 ± 7.7 |
| Male, n (%) | 7988 (43) | 8647 (38) | 11,261 (52) |
| Dialect, n (%) | |||
| Cantonese | 8950 (48) | 10,711 (47) | 9571 (44) |
| Hokkein | 9828 (52) | 12,046 (53) | 12,041 (56) |
| Secondary school or higher, n (%) | 6239 (33) | 5993 (26) | 5618 (26) |
| Ever smoker, n (%) | 4320 (23) | 6053 (27) | 8928 (41) |
| Physical activity,3n (%) | 6872 (37) | 7113 (31) | 6779 (31) |
| BMI, kg/m2 | 23.2 ± 3.3 | 23.2 ± 3.3 | 23.0 ± 3.3 |
| Hypertension, n (%) | 4831 (26) | 5770 (25) | 4371 (20) |
| Coronary artery disease, % | 958 (5) | 901 (4) | 728 (3) |
| Stroke, n (%) | 382 (2) | 325 (1) | 239 (1) |
| Diabetes, n (%) | 2036 (11) | 2100 (9) | 1535 (7) |
| Total protein intake, g/d | 58.4 ± 23.6 | 57.2 ± 23.2 | 61.9 ± 25.3 |
| Total red meat intake, g/d | 28.6 ± 23.3 | 28.9 ± 22.5 | 33.9 ± 26.4 |
| Alcohol intake, n (%) | |||
| Nondrinkers | 17,102 (91) | 20,246 (89) | 18,489(86) |
| Weekly drinkers | 1211 (7) | 1698 (7) | 2196 (10) |
| Daily drinkers | 465 (3) | 813 (4) | 927 (4) |
| Caffeine, mg/d | 55.7 ± 61.5 | 115.0 ± 48.2 | 262.3 ± 85.9 |
| Green tea consumption, cups/mo | 11.8 ± 28.4 | 9.1 ± 23.4 | 7.9 ± 21.9 |
| Black tea consumption, cups/mo | 10.5 ± 21.2 | 5.3 ± 13.1 | 5.3 ± 14.5 |
| Soda consumption, glasses/wk | 0.5 ± 2.0 | 0.5 ± 1.9 | 0.7 ± 2.3 |
1 n = 63,147. The standard serving size of 1 cup or 1 glass was assigned as 237 mL. P values were based on chi-square test for categorical variables and 1-factor ANOVA for continuous variables (all P values <0.0001). ESRD, end-stage renal disease.
2Mean ± SD (all such values).
3Physical activity was defined as any weekly moderate activity, vigorous activity, or strenuous sports lasting ≥30 min (yes or no).
After a mean ± SD follow-up of 16.8 ± 5.1 y, there were 1143 incident ESRD cases among the 63,147 participants (1,061,149 person-years). Increased intake of coffee was associated with a decreased risk of ESRD in a dose-dependent manner (Table 2). In a multivariable model that adjusted for age, sex, education, lifestyle, and dietary factors, compared with participants who drank coffee less than daily, the risk of ESRD was decreased by 15% in those who drank 1 cup of coffee/d (HR: 0.85; 95% CI: 0.74, 0.97) and by 30% in those who drank ≥2 cups of coffee/d (HR: 0.70; 95% CI: 0.62, 0.82). This dose-dependent reduction in risk with increasing level of coffee consumption was significant (P-trend < 0.0001). Adjustment for existing comorbidities attenuated the dose-dependent inverse association but it remained significant (P-trend = 0.013), and the HR (95% CI) for those who drank ≥2 cups of coffee/d was 0.83 (0.71, 0.96) (Table 2).
TABLE 2.
Association between ESRD incidence and the different types of caffeinated beverages in the Singapore Chinese Health Study1
| HR (95% CI)2 | ||||||
|---|---|---|---|---|---|---|
| Intake | Cases, n | Person-years | Model 1 | Model 2 | Model 3 | Model 4 |
| Coffee | ||||||
| None to <1 cup/d | 390 | 311,888 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 1 cup/d | 419 | 383,245 | 0.85 (0.74, 0.98) | 0.85 (0.74, 0.97) | 0.91 (0.80, 1.05) | 0.91 (0.79, 1.05) |
| ≥2 cups/d | 334 | 366,016 | 0.70 (0.61, 0.81) | 0.70 (0.62, 0.82) | 0.83 (0.71, 0.96) | 0.82 (0.71, 0.96) |
| P-trend | <0.0001 | <0.0001 | 0.013 | 0.012 | ||
| Black tea | ||||||
| None to less than weekly | 828 | 759,127 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| Weekly to <1 cup/d | 190 | 182,607 | 1.04 (0.88, 1.22) | 1.04 (0.88, 1.22) | 1.04 (0.88, 1.22) | 1.02 (0.87, 1.20) |
| 1 cup/d | 93 | 87,682 | 1.06 (0.85, 1.31) | 1.07 (0.86, 1.33) | 1.06 (0.85, 1.31) | 1.02 (0.82, 1.27) |
| ≥2 cups/d | 32 | 31,734 | 0.94 (0.66, 1.35) | 0.95 (0.67, 1.36) | 0.92 (0.65, 1.31) | 0.88 (0.62, 1.26) |
| P-trend | 0.79 | 0.73 | 0.86 | 0.83 | ||
| Green tea | ||||||
| None to less than weekly | 783 | 748,722 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| Weekly to <1 cup/d | 199 | 182,640 | 1.12 (0.96, 1.31) | 1.09 (0.93, 1.27) | 0.96 (0.82, 1.12) | 0.95 (0.81, 1.11) |
| 1 cup/d | 156 | 124,025 | 1.26 (1.06, 1.50) | 1.18 (0.99, 1.40) | 1.02 (0.85, 1.21) | 1.01 (0.84, 1.20) |
| ≥2 cups/d | 5 | 5762 | 0.89 (0.37, 2.15) | 0.83 (0.34, 2.01) | 0.72 (0.30, 1.74) | 0.69 (0.28, 1.71) |
| P-trend | 0.01 | 0.09 | 0.85 | 0.71 | ||
| Soda | ||||||
| None to less than monthly | 923 | 799,752 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| Monthly to <1 glass/wk | 85 | 103,106 | 0.80 (0.64, 1.00) | 0.79 (0.63, 0.98) | 0.98 (0.78, 1.23) | 0.98 (0.78, 1.22) |
| Weekly to <1 glass/d | 104 | 124,297 | 0.85 (0.70, 1.05) | 0.84 (0.69, 1.03) | 1.04 (0.84, 1.28) | 1.04 (0.85, 1.28) |
| ≥1 glass/d | 31 | 33,994 | 0.91 (0.64, 1.31) | 0.92 (0.64, 1.32) | 1.08 (0.75, 1.55) | 1.08 (0.75, 1.55) |
| P-trend | 0.07 | 0.05 | 0.67 | 0.65 | ||
1 n = 63,147. The standard serving size of 1 cup or 1 glass was assigned as 237 mL. ESRD, end-stage renal disease; ref, reference.
2Model 1 adjusted for age at recruitment, sex, dialect group, year of recruitment, and education; model 2 adjusted for variables in model 1 plus BMI, smoking status, physical activity, alcohol consumption, red meat intake, and total protein intake; model 3 adjusted for all variables in model 2 plus self-reported history of diabetes, hypertension, stroke, and cardiovascular heart disease; model 4 adjusted for all variables in model 3 plus consumption of other caffeine-containing beverages (coffee, black tea, green tea, and soda).
We further conducted analysis for the composite of both primary and secondary outcomes, which was the sum of 1143 incident ESRD cases and 130 CKD deaths within the cohort. Similarly, an almost 20% decrease in the risk of ESRD- or CKD-related mortality (HR: 0.81; 95% CI: 0.70, 0.93) was observed in those who drank ≥2 cups of coffee/d compared with those who drank less than daily in a model that adjusted for age, sex, education, lifestyle and dietary factors, and comorbidities (model 3), and the dose-dependent reduction in risk with increasing level of coffee consumption was significant (P-trend = 0.003). Conversely, the consumption of black tea, green tea, or soda was not significantly associated with risk of ESRD (Table 2).
When we examined the association of caffeine intake with ESRD, higher caffeine intake was initially associated with lower ESRD risk in the model that included age, sex, education, lifestyle, and dietary factors. However, this inverse association was attenuated and no longer significant after adjustment for pre-existing comorbid conditions. Compared with the referent group with <100 mg of caffeine intake/d, the HR (95% CI) of those consuming ≥300 mg caffeine/d was 0.93 (0.73, 1.18), and there was no significant dose-dependent association between total caffeine intake and ESRD risk (P-trend = 0.16) in the final model (Table 3).
TABLE 3.
Association between caffeine intake and ESRD risk in the Singapore Chinese Health Study1
| HR (95% CI)2 | |||||
|---|---|---|---|---|---|
| Caffeine intake, mg/d | Cases, n | Person-years | Model 1 | Model 2 | Model 3 |
| 0 to <100 | 524 | 446,481 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 100 to <200 | 264 | 256,120 | 0.90 (0.78, 1.05) | 0.89 (0.77, 1.04) | 0.93 (0.80, 1.07) |
| 200 to <300 | 276 | 279,333 | 0.82 (0.71, 0.95) | 0.83 (0.71, 0.96) | 0.89 (0.77, 1.03) |
| ≥300 | 79 | 79,215 | 0.83 (0.66, 1.06) | 0.82 (0.65, 1.05) | 0.93 (0.73, 1.18) |
| P-trend | 0.008 | 0.008 | 0.16 | ||
1 n = 63,147. The standard serving size of 1 cup or 1 glass was assigned as 237 mL. ESRD, end-stage renal disease; ref, reference.
2Model 1 adjusted for age at recruitment, sex, dialect group, year of recruitment, and education; model 2 adjusted for variables in model 1 plus BMI, smoking status, physical activity, alcohol consumption, red meat intake, and total protein intake; model 3 adjusted for all variables in model 2 plus self-reported history of diabetes, hypertension, stroke, and cardiovascular heart disease.
We further stratified the analysis by sex, smoking status, and presence or absence of diabetes, hypertension, stroke, and coronary artery disease. When stratified by sex, we noted that the significant inverse relation between coffee consumption and ESRD risk was observed in men but not in women, and the heterogeneity by sex was significant (P-interaction = 0.03). In men, compared with those who drank coffee less than daily, the HR (95% CI) was 0.81 (0.66, 1.00) for men who drank 1 cup of coffee/d and 0.71 (0.57, 0.87) for those who drank ≥2 cups of coffee/d (P-trend = 0.001). In contrast, the corresponding values in women were 1.01 (0.84, 1.21) for 1 cup/d and 0.97 (0.78, 1.19) for ≥2 cups/d (P-trend = 0.75) (Supplemental Table 1). On the other hand, the association between coffee drinking and the risk of ESRD was not modified by smoking status or history of comorbid conditions (Supplemental Table 1). In the mediation analysis with diabetes as mediator, the total inverse association for ≥2 cups of coffee/d was decomposed to a direct 0.81 (95% CI: 0.70, 0.94) and an indirect 0.88 (95% CI: 0.86, 0.90) association. Accordingly, the size of the indirect association through diabetes was ∼37.2% of the total association.
In a lag-time analysis conducted by including a subcohort of participants with >4 y of follow up, the inverse association between coffee consumption and ESRD risk remained essentially unchanged. When compared with drinking coffee less than daily in this subcohort, drinking ≥2 cups of coffee/d was associated with a 19% lower risk of ESRD (HR: 0.81; 95% CI: 0.69, 0.96), and the stepwise reduction in risk with increasing amount of coffee drinking was significant (P-trend = 0.01) (Supplemental Table 2). The interaction between coffee consumption and sex on ESRD risk also remained present and significant in this subcohort. Among men, the HR for ≥2 cups of coffee/d was 0.70 (95% CI: 0.56, 0.88), whereas the corresponding HR among women was 0.96 (95% CI: 0.76, 1.20; P-interaction = 0.038).
Finally, we repeated the analysis by setting 31 December 2010 as the censor date to include only cases that were registered before enforcement of the National Registry of Diseases Act, and the results remained essentially the same. The HR (95% CI) was 0.85 (0.71, 1.01) for those who drank ≥2 cups of coffee/d, compared with less than daily, in a model adjusted for age, sex, education, lifestyle, dietary factors, and existing comorbidities.
Discussion
In this prospective, population-based cohort study, we observed that the habitual consumption of ≥2 cups of coffee/d was associated with a lower risk of ESRD, especially among men. We did not observe any association with the consumption of tea, soda, or total caffeine.
Epidemiologic evidence suggests that habitual coffee consumption, caffeinated or decaffeinated, may reduce the risk of cardiometabolic diseases, notably type 2 diabetes (11, 34) and cardiovascular diseases (9, 35–37). We have shown in previous analyses with the use of data from the SCHS that habitual coffee consumption was associated with a lower risk of diabetes (38), which concurred with findings from 2 large meta-analyses that both caffeinated and decaffeinated coffees were associated with a linear dose-dependent reduction in the risk of diabetes (11, 34). Data from 3 large prospective cohorts in the United States showed that both caffeinated and decaffeinated coffees showed significant inverse associations with cardiovascular disease mortality (9), and more recently, a multiethnic cohort study from Hawaii and Los Angeles also observed inverse associations between coffee consumption and deaths related to heart disease and stroke (8). In addition, the authors of the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) observed an inverse relation between coffee consumption and deaths from both circulatory and cerebrovascular diseases (6). A recent study in 3042 healthy adults in the ATTICA study also showed the protective effect of drinking moderate quantities of coffee (equivalent to ∼1–2 cups/d) against cardiovascular incidents (39). For all-cause mortality, a recent meta-analysis of 20 prospective cohort studies concluded that coffee consumption of ≥2 cups/d was associated with a reduced risk of total mortality (40), and this was further confirmed by recent observations from both a multiethnic nonwhite cohort from the United States (8) and by the observations from the EPIC cohort (6). Similarly, data from this Singapore Chinese cohort showed that, among never-smokers, there was an inverse dose-response association between a higher amount of coffee intake and all-cause mortality (41).
To the best of our knowledge, although coffee intake has been associated with a reduced risk of mortality related to kidney disease (8), our study is the first prospective study to show the association between coffee consumption and ESRD risk. Our stratified analysis also showed that the association between coffee and the risk of ESRD was similar between those who were generally healthy and those who had diabetes or other comorbid conditions, suggesting that coffee could have a protective effect on renal function even in those with pre-existing comorbid risk factors. Furthermore, our mediation analysis showed that diabetes only accounted for 37% of the association between coffee and the risk of ESRD.
Authors of a recent meta-analysis on the risk of CKD in individuals who drink a significant amount of coffee compared with nondrinkers searched through MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from inception until April 2016 and found only 4 cross-sectional studies that fit their inclusion criteria: 2 studies in Italy and Korea that reported a protective association and 2 studies in Japan that reported a null association. The pooled analysis showed a nonsignificant reduction in the risk of CKD in individuals who consume coffee daily (RR: 0.71; 95% CI: 0.47, 1.08) (42). Among these 4 studies, the Italian study investigated coffee drinking and a renal resistive index, a hallmark of renal arterial stiffness associated with renal insufficiency among patients with early-stage CKD, and reported a significant inverse relation between the renal resistive index and the number of coffee cups habitually consumed (43). The large cross-sectional study in Korean women also reported that the OR of developing impaired renal function (defined as eGFR <60 mL ⋅ min−1 ⋅ 1.73 m−2) in women who habitually drank ≥2 cups of coffee/d was reduced by 40%, compared with those who drank 1 cup of coffee/d (27). Conversely, in the 2 cited Japanese studies, no significant association was found between daily coffee consumption and the risk of CKD defined as eGFR <60 mL ⋅ min−1 ⋅ 1.73 m−2 (25, 44). Nevertheless, in 1 of the studies, the authors reported that healthy Japanese adults who habitually drank ≥1 cup of coffee/d still had an almost 3 times higher odds of having normal functioning kidneys (defined as eGFR ≥90 mL ⋅ min−1 ⋅ 1.73 m−2) compared with nonhabitual coffee drinkers (25). A Dutch study also found that, compared with drinking less than daily, drinking coffee daily was associated with a higher eGFR, with a positive dose-dependent response between the number of cups consumed per day and eGFR (P-trend = 0.01) (23).
In contrast, the previously mentioned Dutch study and a study in Guangzhou that investigated the association between tea consumption and changes in renal function did not yield a significant association (23, 45), although the study in Guangzhou reported a positive, albeit weak, association between black tea consumption and eGFR (β-coefficient = 0.037, P = 0.013) in men but not in women (β-coefficient = −0.002, P = 0.856) (45). A crossover trial conducted in Japan also found that that short-term consumption of coffee resulted in a higher eGFR, but green tea consumption did not have any effect (26).
In our study, we did not observe an association between total caffeine intake and ESRD risk, suggesting that the renoprotective effect of coffee may not be due to caffeine or its diuretic effect but to other chemicals present in coffee. Similarly, other studies have differentiated between caffeinated and noncaffeinated coffee and showed similar effects for both types of coffee against cardiovascular disease (9), diabetes (11, 34), and all-cause mortality (6). Collectively, all of these studies and ours support the hypothesis that other active ingredients in coffee, and not caffeine, could be responsible for the beneficial effect of coffee on cardiometabolic and chronic kidney diseases. One possible candidate may be chlorogenic acid, a phenolic compound with antioxidative properties (46, 47). In addition to its antioxidative effects, chlorogenic acid has also been shown to reduce blood glucose concentration by inhibiting intestinal glucose absorption and decreasing the release of liver glycogen stores (48), hence reducing the risks of overt nephropathy and microalbuminuria (49). Other biologically active classes of phytochemicals in the coffee beverage, such as the melanoidins, trigonelline, the diterpenes, cafestol, and kahweol, have been shown, at least in vitro, to possess antioxidant, antihypertensive, hypoglycemic, and antiglycative activities, all of which may also be responsible for its renoprotective effects (50).
In our study, we noted that the renoprotective association of habitual coffee consumption with the risk of ESRD was stronger in men than in women. The predominance of data in humans also suggests that the course of both diabetic and nondiabetic kidney disease is more aggressive in men than in women (51). Animal studies also showed that estrogen replacement in female rat models may protect the kidney in female rats from hypertension-associated renal disease by attenuating injury-induced superoxide production (52), or from age-related renal disease by decreasing renal inflammation through the downregulation of NO production (53). Hence, we postulate that trigonelline, a phytoestrogen found in coffee beans (54), may be a possible candidate that could similarly offer protection from renal injury by attenuating inflammation from superoxide or NO production. Because men have lower concentrations of estrogen than women, this effect may therefore be more prominent in men than in women. However, our novel finding could also be attributed to chance, and future efforts should be made to validate if such a sex difference does exist.
The strengths of this study include the high rate of follow-up, robust data obtained through face-to-face interviews, the use of a comprehensive FFQ that was specific to this population, and a cohort with a wide variation in coffee, black tea, and green tea consumption, which allowed us to simultaneously examine the association between these different beverages and ESRD risk. The identification of incident ESRD cases through the Singapore Renal Registry was comprehensive, with a minimal loss-to-follow-up rate in this study. Our computation of caffeine consumption was from the intake of commonly consumed caffeine-containing beverages in this population, and the caffeinated beverage items in our FFQ should be sufficient to capture total intake because our population did not have many other sources of caffeine that were not accounted for, such as over-the-counter products or dietary supplements or energy shots.
A weakness of our study is that we only used the dietary information at baseline and the frequency of coffee and tea consumption may change over time. The other covariates were also self-reported and may have resulted in some misclassification and residual confounding. However, such misclassifications are likely to be nondifferential in nature and may only lead to underestimation of the risk estimates. Nevertheless, in a follow-up interview that was conducted, on average, 12.7 y after the baseline interview, the majority of our participants retained their status as daily or nondaily drinkers of coffee (72.3%), black tea (85.6%), and green tea (85.2%). Because decaffeinated coffee or tea was rarely consumed in our study population at the time of recruitment, we were unable to differentiate the effects between caffeinated and decaffeinated coffee. Finally, we did not measure kidney function at recruitment and hence we were unable to establish the temporal relation between coffee and deteriorating renal function with certainty. However, we have repeated our analysis in participants with >4 y of follow-up in order to minimize the potential confounding effect of subclinical disease on the observed coffee-ESRD association, and the results remained consistent.
In conclusion, drinking ≥2 cups of coffee/d significantly reduced the risk of ESRD, especially among men, in the SCHS cohort. Because coffee is widely consumed globally, this finding has noteworthy clinical and public health implications and provides further impetus to determine the components of coffee that are responsible for its renoprotective effects. However, it is too early to recommend the consumption of coffee as a renoprotective agent until more thorough data from clinical trials can be obtained.
Supplementary Material
Acknowledgments
We thank Siew-Hong Low of the National University of Singapore for supervising the fieldwork of the SCHS and Renwei Wang for the maintenance of the cohort study database. Finally, we acknowledge the founding Principal Investigator of the SCHS, Mimi C Yu. The authors’ responsibilities were as follows—Q-LJL and THJ: contributed to the conception and design of the study; AJ: contributed to the data analysis; J-MY: participated in acquisition of data; W-PK: was in charge of the conception and design of the study, acquisition of data and data analysis, and took responsibility for the integrity of the work as a whole; and all authors: were involved in the interpretation of data and drafting of intellectual content and read and approved the final manuscript.
Notes
Supported by the NIH (R01 CA144034 and UM1 CA182876). W-PK is supported by the National Medical Research Council, Singapore (NMRC/CSA/0055/2013).
Author disclosures: Q-LJL,THJ, AJ, J-MY, and W-PK, no conflicts of interest.
Supplemental Tables 1 and 2 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/.
Abbreviations used:
- CKD
chronic kidney disease
- eGFR
estimated glomerular filtration rate
- ESRD
end-stage renal disease
- SCHS
Singapore Chinese Health Study
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