Abstract
Background: Although caffeine intake may increase urine calcium excretion, caffeine-containing beverages have been associated with a lower risk of nephrolithiasis.
Objective: We sought to determine the association between caffeine intake and the risk of incident kidney stones in 3 large prospective cohorts.
Design: We prospectively analyzed the association between intake of caffeine and incidence of kidney stones in 3 large ongoing cohort studies, the Health Professionals Follow-Up Study (HPFS) and the Nurses’ Health Studies (NHS) I and II. Information on the consumption of caffeine and the incidence of kidney stones was collected by validated questionnaires.
Results: The analysis included 217,883 participants; over a median follow-up of >8 y, 4982 incident cases occurred. After multivariate adjustment for age, BMI, fluid intake, and other factors, participants in the highest quintile of caffeine intake had a 26% (95% CI: 12%, 38%) lower risk of developing stones in the HPFS cohort, a 29% lower risk (95% CI: 15%, 41%) in the NHS I cohort, and a 31% lower risk (95% CI: 18%, 42%) in the NHS II cohort (P-trend < 0.001 for all cohorts). The association remained significant in the subgroup of participants with a low or no intake of caffeinated coffee in the HPFS cohort. Among 6033 participants with 24-h urine data, the intake of caffeine was associated with higher urine volume, calcium, and potassium and with lower urine oxalate and supersaturation for calcium oxalate and uric acid.
Conclusion: Caffeine intake is independently associated with a lower risk of incident kidney stones.
Keywords: caffeine, kidney stones, nutrition, prospective study, coffee
INTRODUCTION
Kidney stones are a common condition, with an estimated prevalence in the United States of 11% for men and 7% for women (1). Previous research highlighted the association between dietary habits and the risk of developing kidney stones; in particular, it was shown that increasing fluid intake would reduce the risk (2) and that the consumption of certain beverages such as coffee and tea may also further reduce the risk (3–5). However, whether the inverse association between such beverages and the risk of developing kidney stones is due to their caffeine content or to other properties of the beverages is not known; of note, an inverse association between the consumption of decaffeinated coffee and incident kidney stones was also reported (3–5). Caffeine intake has been shown to be associated with increased urinary calcium excretion (6) and, as such, could potentially increase the risk of developing kidney stones, although in our previous reports we consistently found an inverse association between consumption of caffeine-containing beverages, such as coffee and tea, and the risk of incident stones. The goal of this study was to analyze the association between caffeine intake and the risk of developing kidney stones in 3 large prospective cohorts. We also analyzed the cross-sectional association between intake of caffeine and 24-h urinary composition in a subgroup of participants with available data.
SUBJECTS AND METHODS
Study population
The Health Professionals Follow-Up Study (HPFS) started in 1986 with the enrollment of 51,529 male health professionals aged 40–75 y, who filled out a questionnaire on lifestyle and medical history. The Nurses’ Health Study (NHS) I started in 1976 with the enrollment of 121,700 female nurses aged 30–55 y, who completed a questionnaire on lifestyle and medical history. A second NHS cohort (NHS II) was enrolled in 1989, consisting of 116,430 female nurses aged 25–42 y. In all 3 cohorts, questionnaires have been sent every 2 y.
Participants with baseline self-reported history of kidney stones and/or cancer (except for nonmelanoma skin cancer) and those with missing baseline caffeine intakes were excluded from the analysis. Participants who developed cancer during the follow-up were censored. These studies were approved by the Partners Health Care institutional review board, which accepts return of the questionnaires as implied consent in these cohorts.
Assessment of caffeine intake and other nutrients
In 1980 (NHS I), 1986 (HPFS), and 1991 (NHS II), participants returned a food-frequency-questionnaire that asked about the average use of >130 foods, beverages, and supplements in the previous year; and dietary information was updated every 4 y. The validity and reliability of the self-reported food-frequency questionnaire were shown in subgroups of the main cohorts (7, 8). For the present analysis, we used data on intakes of calcium, phosphate, sodium, potassium, magnesium, total fructose, oxalate, phytate, total fluid, and vitamins B-6, C, and D. Except for oxalate, nutrient intakes were calculated from USDA data. The oxalate content of foods was measured by capillary electrophoresis as described elsewhere (9). The main contributors of caffeine were coffee (83%), tea (14%), and soda (2%). In our nutrient database, we assigned 95 mg caffeine per cup of caffeinated coffee.
Assessment of kidney stones
Participants who reported an incident kidney stone were asked to complete a supplementary questionnaire asking about the date of occurrence and symptoms such as pain or hematuria from the event. The self-reported diagnosis was shown to be valid in ∼95–98% of self-reported cases who completed the additional questionnaire in separate validation studies (10). Stone composition was analyzed in a subsample of the study population and found to be predominantly calcium oxalate (≥50%) in 86% of participants in the HPFS, 77% of participants in the NHS I, and 79% of participants in the NHS II cohort (10).
Assessment of urinary composition
Urine samples were obtained as part of a study to compare the urine composition of stone formers with non–stone formers as previously described (11). In brief, 24-h urine samples were collected in 2 cycles. In the first cycle, participants were ineligible if they were >70 y of age in the HPFS or >65 y in the NHS I or had a history of cancer or cardiovascular disease. In the second cycle, participants were ineligible if they were >75 y of age or had a history of cancer (other than nonmelanoma skin cancer). An additional third cycle was performed in NHS II non–stone formers, with the following exclusion criteria: age >55 y, non-Caucasian descent, and history of high blood pressure, coronary artery disease or cancer.
The 24-h urine collection procedure used the system provided by Mission Pharmacal (11) for the first 2 waves of collections. The third wave was performed by using the kit from the Litholink Corporation.
To remove participants with likely over- or undercollections, we excluded participants with 24-h urinary creatinine values in the top 1% or bottom 1% of the urinary creatinine distribution of non–stone formers in each cohort. If a participant submitted more than one 24-h urine collection, we used the first sample.
Other covariates
We used data obtained from the questionnaires about the following covariates: age, BMI, use of thiazides, use of calcium supplements, and intake of alcohol. BMI was derived from self-reported weight and height; these data were validated in 2 of the 3 cohorts (12).
Statistical analysis
Age-adjusted incidence rates of kidney stones were computed across quintiles of consumption of caffeine. The HRs and 95% CIs for developing kidney stones in each category of exposure compared with the lowest category were computed in each cohort by using Cox proportional hazards models adjusted for age (continuous), BMI (13 categories), use of thiazides (yes or no), use of calcium supplements (yes or no), intake of alcohol (7 categories), and intakes of dietary calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, and total (food plus supplements) vitamins B-6, C, and D (all quintiles). Missing categories were used for participants with missing covariates. Exposure and covariates were updated every 4 y by using simple updating. Time at risk was 1980–2006 for NHS I, 1986–2006 for HPFS, and 1991–2007 for NHS II.
To assess trends across quintiles of consumption of caffeine and incidence of kidney stones, we evaluated intakes continuously by using the median value of each quintile. We also examined the possible nonlinear relation between caffeine intake and the risk of kidney stones nonparametrically with restricted cubic splines with 4 knots at the quintile cutoffs of the distribution and with the use of the population median as the referent value. Tests for nonlinearity used the likelihood ratio test, comparing the model with only the linear term with the model with the linear and the cubic spline terms. The previously described set of covariates was used for this analysis.
To determine the risk associated with caffeine intake independent of coffee intake, we also analyzed the association in a subgroup of the study population with low or no intake of caffeinated coffee (defined as <1 serving of caffeinated coffee/d).
To assess possible effect modification, the multivariate models were stratified by age (<50 or ≥50 y), BMI (in kg/m2; <25 or ≥25), use of calcium supplements (yes or no), and total fluid intake (<1 or ≥1 L/d). Significance for interaction terms was assessed by using the log-likelihood test.
We analyzed the association between intake of caffeine and 24-h urinary components by using linear regression models with each urinary component as the dependent variable and intake of caffeine in quintiles as the independent variable. We tested for linear trends by using the median intake for each quintile of caffeine intake. Models were adjusted for age, BMI, presence of diabetes, high blood pressure, gout, history of kidney stones, use of thiazides, 24-h urine volume, and all the other urinary components. Multivariate models with supersaturations as dependent variables were not adjusted for any of the other urinary components; log-linear regression models were used to derive percentage changes for supersaturation values. Each regression model was first conducted in cohort-specific subgroups and then merged with random-effects meta-analysis after checking for heterogeneity.
A P value <0.05 was considered significant. Analyses were performed with the use of SAS version 9.3 (SAS Institute).
RESULTS
Association between intake of caffeine and incident kidney stones
After exclusions, a total of 217,883 participants were included in the analysis, contributing 3,032,742 person-years of follow-up. Median follow-up times to an incident kidney stone were 8.3 y for HPFS, 14 y for NHS I, and 8.2 y for NHS II. The overall number of participants who developed a symptomatic incident kidney stone was 4982.
The baseline characteristics of participants by exposure status are shown for each cohort in Tables 1–3. For higher intakes of caffeine, there was a trend toward a decreased intake of calcium and vitamin C and an increased intake of alcohol and total fluid in all the cohorts.
TABLE 1.
Age-standardized baseline characteristics by quintile of caffeine intake in the Health Professionals Follow-Up Study1
| Caffeine intake quintile |
|||||
| First (n = 8351) | Second (n = 8394) | Third (n = 8375) | Fourth (n = 8475) | Fifth (n = 8657) | |
| Caffeine, mg/d | 9.4 ± 8.62 | 61 ± 29 | 157 ± 49 | 339 ± 100 | 568 ± 185 |
| Age,3 y | 55 ± 10 | 54 ± 10 | 55 ± 10 | 54 ± 10 | 53 ± 9 |
| BMI (kg/m2), % | |||||
| <20.0 | 2 | 1 | 1 | 1 | 1 |
| 20.0–24.9 | 38 | 32 | 31 | 29 | 27 |
| 25.0–29.9 | 49 | 53 | 54 | 55 | 57 |
| ≥30.0 | 9 | 11 | 11 | 12 | 13 |
| Thiazide use, % | 8 | 10 | 10 | 9 | 8 |
| Calcium supplement use, % | 20 | 17 | 16 | 14 | 13 |
| Calcium, mg/d | 864 ± 436 | 817 ± 415 | 784 ± 375 | 826 ± 396 | 696 ± 345 |
| Potassium, g/d | 3.5 ± 1.2 | 3.4 ± 1.1 | 3.4 ± 1.1 | 3.6 ± 1.1 | 3.2 ± 1.0 |
| Magnesium, mg/d | 359 ± 131 | 348 ± 123 | 347 ± 118 | 367 ± 121 | 332 ± 110 |
| Vitamin C, mg/d | 496 ± 497 | 445 ± 460 | 422 ± 444 | 393 ± 419 | 345 ± 408 |
| Total fructose, g/d | 27 ± 16 | 27 ± 15 | 26 ± 15 | 26 ± 14 | 20 ± 11 |
| Oxalate, mg/d | 141 ± 148 | 145 ± 144 | 148 ± 166 | 149 ± 127 | 127 ± 109 |
| Phytate, mg/d | 1020 ± 566 | 947 ± 472 | 927 ± 449 | 954 ± 440 | 820 ± 396 |
| Alcohol intake, g/d | 8.4 ± 14.0 | 9.7 ± 13.9 | 12 ± 15 | 15 ± 18 | 13 ± 16 |
| Fluid intake, L/d | 1.6 ± 0.7 | 1.7 ± 0.7 | 1.8 ± 0.7 | 2.2 ± 0.8 | 2.4 ± 0.8 |
Values are standardized to the age distribution of the study population unless otherwise indicated. Values of categorical variables may not sum to 100% because of rounding.
Mean ± SD (all such values).
Values are not age adjusted.
TABLE 2.
Age-standardized baseline characteristics by quintile of caffeine intake: Nurses’ Health Study I1
| Caffeine intake quintile |
|||||
| First (n = 16,801) | Second (n = 16,963) | Third (n = 17,092) | Fourth (n = 17,058) | Fifth (n = 17,055) | |
| Caffeine, mg/d | 54 ± 422 | 210 ± 60 | 367 ± 27 | 521 ± 120 | 802 ± 101 |
| Age,3 y | 52 ± 7 | 52 ± 7 | 53 ± 7 | 53 ± 7 | 52 ± 7 |
| BMI (kg/m2), % | |||||
| <20.0 | 10 | 10 | 10 | 9 | 10 |
| 20.0–24.9 | 45 | 45 | 49 | 47 | 47 |
| 25.0–29.9 | 28 | 28 | 28 | 30 | 31 |
| ≥30.0 | 16 | 15 | 12 | 14 | 12 |
| Thiazide use, % | 13 | 14 | 12 | 12 | 10 |
| Calcium supplement use, % | 56 | 54 | 53 | 52 | 48 |
| Calcium, mg/d | 721 ± 407 | 702 ± 392 | 716 ± 351 | 708 ± 368 | 696 ± 344 |
| Potassium, g/d | 2.4 ± 0.9 | 2.5 ± 0.9 | 2.7 ± 0.8 | 2.8 ± 0.9 | 3.0 ± 0.8 |
| Magnesium, mg/d | 257 ± 95 | 269 ± 95 | 288 ± 84 | 298 ± 97 | 316 ± 87 |
| Vitamin C, mg/d | 350 ± 635 | 309 ± 469 | 283 ± 466 | 271 ± 434 | 255 ± 428 |
| Total fructose, g/d | 23 ± 14 | 23 ± 16 | 20 ± 12 | 21 ± 14 | 18 ± 13 |
| Oxalate, mg/d | 326 ± 347 | 335 ± 346 | 329 ± 326 | 333 ± 341 | 317 ± 335 |
| Phytate, mg/d | 816 ± 419 | 789 ± 353 | 798 ± 365 | 747 ± 311 | 709 ± 315 |
| Alcohol intake, g/d | 4.9 ± 9.5 | 5.7 ± 10.2 | 7.7 ± 11.5 | 6.8 ± 10.6 | 6.6 ± 10.5 |
| Fluid intake, L/d | 0.8 ± 0.5 | 1.2 ± 0.5 | 1.3 ± 0.5 | 1.7 ± 0.5 | 2.0 ± 0.6 |
Values are standardized to the age distribution of the study population unless otherwise indicated. Values of categorical variables may not sum to 100% because of rounding.
Mean ± SD (all such values).
Values are not age adjusted.
TABLE 3.
Age-standardized baseline characteristics by quintile of caffeine intake: Nurses’ Health Study II1
| Caffeine intake quintile |
|||||
| First (n = 18,199) | Second (n = 18,135) | Third (n = 18,106) | Fourth (n = 18,143) | Fifth (n = 18,079) | |
| Caffeine, mg/d | 19 ± 142 | 87 ± 30 | 171 ± 34 | 344 ± 63 | 567 ± 173 |
| Age,3 y | 36 ± 5 | 36 ± 5 | 36 ± 5 | 37 ± 4 | 38 ± 4 |
| BMI (kg/m2), % | |||||
| <20.0 | 14 | 13 | 13 | 12 | 11 |
| 20.0–24.9 | 43 | 41 | 43 | 45 | 44 |
| 25.0–29.9 | 24 | 25 | 24 | 25 | 27 |
| ≥30.0 | 16 | 18 | 17 | 15 | 15 |
| Thiazide use, % | 2 | 2 | 2 | 2 | 2 |
| Calcium supplement use, % | 20 | 18 | 17 | 17 | 16 |
| Calcium, mg/d | 945 ± 435 | 898 ± 403 | 842 ± 374 | 922 ± 383 | 777 ± 364 |
| Potassium, g/d | 2.8 ± 0.9 | 2.8 ± 1.0 | 2.8 ± 0.9 | 3.2 ± 0.9 | 2.9 ± 0.9 |
| Magnesium, mg/d | 311 ± 113 | 306 ± 110 | 301 ± 104 | 335 ± 107 | 306 ± 104 |
| Vitamin C, mg/d | 280 ± 315 | 252 ± 279 | 242 ± 276 | 250 ± 280 | 218 ± 272 |
| Total fructose, g/d | 23 ± 13 | 26 ± 16 | 23 ± 16 | 23 ± 14 | 19 ± 13 |
| Oxalate, mg/d | 122 ± 118 | 130 ± 121 | 137 ± 120 | 147 ± 126 | 128 ± 116 |
| Phytate, mg/d | 784 ± 350 | 774 ± 321 | 757 ± 313 | 831 ± 326 | 730 ± 309 |
| Alcohol intake, g/d | 1.7 ± 4.4 | 2.2 ± 4.9 | 3.1 ± 5.7 | 4.4 ± 7.2 | 4.2 ± 7.0 |
| Fluid intake, L/d | 1.7 ± 0.7 | 1.9 ± 0.7 | 2.0 ± 0.8 | 2.4 ± 0.8 | 2.6 ± 0.9 |
Values are standardized to the age distribution of the study population unless otherwise indicated. Values of categorical variables may not sum to 100% because of rounding.
Mean ± SD (all such values).
Values are not age adjusted.
In age-adjusted analyses, higher intakes of caffeine were associated with a lower risk of developing a stone (P-trend < 0.001 for all cohorts). The association remained significant after multivariate adjustment (P-trend < 0.001 for all cohorts) (Table 4). Participants in the highest quintile of caffeine intake had a 26% (95% CI: 12%, 38%) lower risk of developing stones in the HPFS cohort, a 29% lower risk (95% CI: 15%, 41%) in the NHS I cohort, and a 31% lower risk (95% CI: 18%, 42%) in the NHS II cohort.
TABLE 4.
Age- and multivariate-adjusted HRs of incident kidney stones by quintile of caffeine intake1
| Caffeine intake quintile |
||||||
| First | Second | Third | Fourth | Fifth | P-trend | |
| HPFS | ||||||
| Median caffeine intake, mg/d | 7 | 58 | 152 | 357 | 627 | |
| Cases, n | 330 | 390 | 322 | 285 | 254 | |
| Person-time, y | 108,003 | 109,782 | 110,782 | 114,223 | 119,115 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 1.12 (0.96, 1.30) | 0.92 (0.79, 1.08) | 0.76 (0.65, 0.90) | 0.64 (0.54, 0.76) | <0.001 |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 1.05 (0.91, 1.21) | 0.89 (0.76, 1.03) | 0.81 (0.69, 0.96) | 0.74 (0.62, 0.88) | <0.001 |
| NHS I | ||||||
| Median caffeine intake, mg/d | 31 | 130 | 231 | 376 | 636 | |
| Cases, n | 381 | 372 | 298 | 279 | 259 | |
| Person-time, y | 246,555 | 251,522 | 254,650 | 260,933 | 258,978 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 0.94 (0.81, 1.08) | 0.74 (0.64, 0.86) | 0.68 (0.58, 0.79) | <0.001 | |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 0.94 (0.81, 1.09) | 0.78 (0.66, 0.91) | 0.76 (0.64, 0.89) | 0.71 (0.59, 0.85) | <0.001 |
| NHS II | ||||||
| Median caffeine intake, mg/d | 17 | 83 | 165 | 358 | 536 | |
| Cases, n | 424 | 508 | 356 | 271 | 253 | |
| Person-time, y | 239,435 | 238,667 | 238,963 | 240,811 | 240,323 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 1.20 (1.05, 1.36) | 0.84 (0.73, 0.97) | 0.65 (0.55, 0.75) | 0.61 (0.52, 0.71) | <0.001 |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 1.13 (0.99, 1.29) | 0.86 (0.74, 1.00) | 0.75 (0.63, 0.88) | 0.69 (0.58, 0.82) | <0.001 |
Multivariate Cox regression analysis adjusted for age, BMI, use of thiazides, use of calcium supplements, and intakes of calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, alcohol, and vitamins B-6, C, and D. For illustrative purposes, quintile medians for caffeine were derived from responses to the 1986 (HPFS and NHS I) and 1991 (NHS II) dietary questionnaires. HPFS, Health Professionals Follow-Up Study; NHS, Nurses’ Health Study; Ref, reference.
Figures 1–3 show the association between caffeine intake modeled as a restricted cubic spline and the risk of kidney stones. In all 3 cohorts, there was an inverse association between intake of caffeine and risk of stones (P < 0.001 for linearity in all cohorts), whereas the nonlinear component was significant only in NHS I (P = 0.004) but not in HPFS (P = 0.85) or NHS II (P = 0.20). In the subgroup of participants with a low or no intake of caffeinated coffee, the inverse association between caffeine intake and kidney stones remained consistent in the HPFS cohort but not in the NHS I and NHS II cohorts (Table 5).
FIGURE 1.
Restricted cubic splines of caffeine intake and the risk of kidney stones: Health Professionals Follow-Up Study. The model is adjusted for age, BMI, use of thiazides, use of calcium supplements, and intakes of calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, alcohol, and vitamins B-6, C, and D. The gray-shaded area represents 95% CIs. The lower plot represents the distribution of caffeine intake. P < 0.001 for linearity, P = 0.85 for nonlinearity.
FIGURE 2.
Restricted cubic splines of caffeine intake and the risk of kidney stones: Nurses’ Health Study I. The model is adjusted for age, BMI, use of thiazides, use of calcium supplements, and intakes of calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, alcohol, and vitamins B-6, C, and D. The gray-shaded area represents 95% CIs. The lower plot represents the distribution of caffeine intake. P < 0.001 for linearity, P = 0.004 for nonlinearity.
FIGURE 3.
Restricted cubic splines of caffeine intake and the risk of kidney stones: Nurses’ Health Study II. The model is adjusted for age, BMI, use of thiazides, use of calcium supplements, and intakes of calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, alcohol, and vitamins B-6, C, and D. The gray-shaded area represents 95% CIs. The lower plot represents the distribution of caffeine intake. P < 0.001 for linearity, P = 0.20 for nonlinearity.
TABLE 5.
Age- and multivariate-adjusted HRs of incident kidney stones by quintile of caffeine intake in participants with low or no intake of caffeinated coffee (<1 cup of coffee/d)1
| Caffeine intake quintile |
||||||
| First | Second | Third | Fourth | Fifth | P-trend | |
| HPFS | ||||||
| Median caffeine intake, mg/d | 3 | 18 | 42 | 76 | 162 | |
| Cases, n | 170 | 179 | 213 | 187 | 147 | |
| Person-time, y | 55,964 | 56,542 | 55,858 | 55,668 | 56,371 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 1.05 (0.85, 1.30) | 1.18 (0.96, 1.45) | 1.05 (0.85, 1.29) | 0.77 (0.62, 0.97) | 0.006 |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 1.00 (0.81, 1.24) | 1.07 (0.86, 1.32) | 0.97 (0.78, 1.21) | 0.74 (0.58, 0.94) | 0.004 |
| NHS I | ||||||
| Median caffeine intake, mg/d | 5 | 44 | 95 | 183 | 393 | |
| Cases, n | 176 | 200 | 242 | 191 | 147 | |
| Person-time, y | 122,053 | 135,386 | 144,028 | 159,828 | 165,000 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 1.00 (0.81, 1.22) | 1.10 (0.90, 1.34) | 0.80 (0.64, 1.00) | 0.65 (0.50, 0.84) | <0.001 |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 0.96 (0.78, 1.18) | 1.07 (0.87, 1.31) | 0.82 (0.65, 1.04) | 0.79 (0.58, 1.08) | 0.13 |
| NHS II | ||||||
| Median caffeine intake, mg/d | 6 | 26 | 59 | 113 | 187 | |
| Cases, n | 209 | 222 | 277 | 234 | 213 | |
| Person-time, y | 122,400 | 123,479 | 122,517 | 121,868 | 123,806 | |
| Age-adjusted HR (95% CI) | 1.00 (Ref) | 1.03 (0.85, 1.24) | 1.31 (1.09, 1.57) | 1.10 (0.91, 1.33) | 0.95 (0.78, 1.15) | 0.34 |
| Multivariate-adjusted HR (95% CI) | 1.00 (Ref) | 0.94 (0.78, 1.14) | 1.18 (0.98, 1.42) | 1.02 (0.84, 1.23) | 0.90 (0.73, 1.11) | 0.34 |
Multivariate Cox regression analysis adjusted for age, BMI, use of thiazides, use of calcium supplements, and intakes of calcium, phosphate, sodium, potassium, magnesium, fructose, oxalate, phytate, total fluid, alcohol, and vitamins B-6, C, and D. For illustrative purposes, quintile medians for caffeine were derived from responses to the 1986 (HPFS and NHS I) and 1991 (NHS II) dietary questionnaires. HPFS, Health Professionals Follow-Up Study; NHS, Nurses’ Health Study; Ref, reference.
Among the tested interactions, those with a higher BMI tended to have a larger inverse association, but this was significant only in the NHS II cohort (P-interaction < 0.05). In those participants in NHS II with a BMI <25, the HRs for quintiles of caffeine intake from quintile 2 to quintile 5 compared with the first quintile were 1.26 (95% CI: 1.04, 1.54), 1.00 (95% CI: 0.81, 1.23), 0.94 (95% CI: 0.75, 1.18), and 0.78 (95% CI: 0.61, 1.00), respectively. In those with a BMI ≥25, the HRs for quintiles of caffeine intake from quintile 2 to quintile 5 compared with the first quintile were 1.00 (95% CI: 0.75, 1.33), 0.68 (95% CI: 0.49, 0.93), 0.58 (95% CI: 0.41, 0.82), and 0.58 (95% CI 0.41, 0.82), respectively. Age, use of calcium supplements, and total fluid intake did not modify the association.
Association between intake of caffeine and urine composition
A total of 6033 participants had available data for the analysis. After conducting cohort-specific regression models, the coefficients were pooled by means of random-effects meta-analysis, and the results are presented for all of the cohorts together (Table 6).
TABLE 6.
Differences in 24-h urinary components by quintile of caffeine intake (n = 6033)1
| Caffeine intake quintile |
||||||
| First | Second | Third | Fourth | Fifth | P-trend | |
| Creatinine, mg | ||||||
| Age-adjusted | Ref | 24 (−3.2, 51) | 7.0 (−11, 25) | 32 (−5.9, 69) | 36 (−1.6, 74) | 0.1 |
| Multivariate-adjusted | Ref | 16 (−9.2, 42) | −0.09 (−13, 12) | 7.1 (−14, 28) | 3.9 (−8.5, 16) | 0.99 |
| Calcium, mg | ||||||
| Age-adjusted | Ref | 3.1 (−4.1, 10) | 6.7 (−1.0, 14) | 12 (4.3, 19) | 13 (5.3, 20) | <0.001 |
| Multivariate-adjusted | Ref | 2.4 (−3.7, 8.6) | 6.8 (−0.28, 14) | 7.5 (1.3, 14) | 8.1 (1.9, 14) | 0.004 |
| Oxalate, mg | ||||||
| Age-adjusted | Ref | −0.14 (−1.7, 1.4) | −1.7 (−1.5, 0.11) | −0.47 (−1.3, 0.35) | −0.25 (−1.1, 0.57) | 0.4 |
| Multivariate-adjusted | Ref | −0.50 (−1.5, 0.49) | −0.80 (−1.6, −0.06) | −1.2 (−2.3, −0.08) | −1.2 (−2.2, −0.20) | 0.002 |
| Citrate, mg | ||||||
| Age-adjusted | Ref | −23 (−45, −0.78) | −48 (−70, −26) | −17 (−54, 20) | −6.5 (−49, 36) | 0.99 |
| Multivariate-adjusted | Ref | −25 (−44, −5.6) | −48 (−75, −20) | −36 (−74, 1.6) | −40 (−77, −3.3) | 0.11 |
| Uric acid, mg | ||||||
| Age-adjusted | Ref | 3.1 (−19, 25) | 6.6 (−8.1, 21) | 11 (−48, 70) | 21 (−35, 77) | 0.58 |
| Multivariate-adjusted | Ref | −0.36 (−12, 11) | 11 (−0.52, 22) | 8.0 (−19, 35) | 11 (−7.8, 29) | 0.33 |
| Sodium, mEq | ||||||
| Age-adjusted | Ref | 3.3 (−1.4, 8.0) | 5.9 (1.5, 10) | 3.8 (−2.3, 9.8) | 6.7 (−3.7, 17) | 0.29 |
| Multivariate-adjusted | Ref | 1.4 (−2.2, 5.0) | 3.3 (−0.31, 6.8) | −2.3 (−5.9, 1.3) | −1.8 (−7.4, 3.8) | 0.17 |
| Potassium, mEq | ||||||
| Age-adjusted | Ref | −1.2 (−2.8, 0.36) | −0.45 (−2.0, 1.1) | 2.2 (−1.0, 5.5) | 5.0 (3.2, 6.7) | <0.001 |
| Multivariate-adjusted | Ref | −0.57 (−1.9, 0.80) | −0.13 (−2.5, 2.2) | 0.56 (−1.9, 3.1) | 2.1 (0.12, 4.1) | 0.03 |
| Magnesium, mg | ||||||
| Age-adjusted | Ref | 0.38 (−2.5, 3.3) | −1.8 (−4.7, 1.2) | 2.1 (−0.76, 5.1) | 5.7 (1.0, 10) | <0.001 |
| Multivariate-adjusted | Ref | 1.3 (−1.2, 3.7) | −1.8 (−4.3, 0.66) | −0.77 (−3.3, 1.7) | 1.5 (−6.6, 9.5) | 0.93 |
| Phosphate, mg | ||||||
| Age-adjusted | Ref | 9.9 (−13, 32) | 12 (−11, 34) | 7.2 (−57, 71) | 17 (−44, 77) | 0.74 |
| Multivariate-adjusted | Ref | −3.9 (−21, 13) | 9.5 (−7.7, 27) | −1.5 (−19, 16) | 4.4 (−13, 22) | 0.68 |
| Sulfate, mmol | ||||||
| Age-adjusted | Ref | 0.33 (−0.32, 0.98) | 0.31 (−0.34, 0.96) | 1.5 (0.32, 2.8) | 1.3 (0.02, 2.5) | 0.05 |
| Multivariate-adjusted | Ref | −0.20 (−0.68, 0.28) | −0.40 (−1.3, 0.48) | −0.09 (−0.57, 0.39) | −0.61 (−1.1, −0.13) | 0.09 |
| pH, U | ||||||
| Age-adjusted | Ref | −0.05 (−0.08, −0.01) | −0.02 (−0.07, 0.03) | −0.02 (−0.06, 0.02) | 0.03 (−0.01, 0.07) | 0.07 |
| Multivariate-adjusted | Ref | −0.02 (−0.05, 0.01) | −0.02 (−0.06, 0.02) | −0.04 (−0.07, −0.01) | −0.02 (−0.07, 0.03) | 0.29 |
| Volume, mL | ||||||
| Age-adjusted | Ref | 12 (−44, 67) | 57 (−63, 177) | 241 (116, 366) | 287 (164, 410) | <0.001 |
| Multivariate-adjusted | Ref | 19 (−29, 67) | 41 (−55, 137) | 178 (87, 268) | 188 (111, 266) | <0.001 |
| SS CaOx | ||||||
| Age-adjusted | Ref | 0 (−7, 8) | −2 (−6, 2) | −4 (−11, 3) | −6 (−11, −1) | <0.001 |
| Multivariate-adjusted | Ref | 0 (−6, 6) | −2 (−7, 2) | −5 (−11, 1) | −7 (−11, −2) | <0.001 |
| SS brushite | ||||||
| Age-adjusted | Ref | −1 (−4, 2) | −2 (−5, 1) | −5 (−10, 0) | −3 (−10, 3) | 0.23 |
| Multivariate-adjusted | Ref | −1 (−4, 2) | −1 (−5, 2) | −5 (−8, −2) | −2 (−8, 5) | 0.36 |
| SS uric acid | ||||||
| Age-adjusted | Ref | 4 (−2, 10) | 2 (−6, 10) | −2 (−12, 7) | −8 (−12, −3) | 0.002 |
| Multivariate-adjusted | Ref | 3 (−2, 7) | 2 (−5, 8) | −2 (−10, 7) | −7 (−12, −2) | 0.01 |
Values are βs (95% CIs) with the first quintile of caffeine intake as reference group. The multivariate linear regression model was adjusted for age, BMI, diabetes, high blood pressure, gout, history of kidney stones, use of thiazides, and all of the other urinary components (except for SS values). CaOx, calcium oxalate; Ref, reference; SS, supersaturation.
After full multivariate adjustment, a higher intake of caffeine was positively associated with a slightly higher urinary excretion of calcium. Participants in the highest quintile of caffeine intake had, on average, 8.1 mg/24 h (95% CI: 1.9, 14 mg/24 h) higher calcium excretion than did those in the lowest quintile (P-trend = 0.004). In contrast, participants in the highest quintile of caffeine intake had a lower urinary excretion of oxalate of 1.2 mg/24 h (95% CI: 2.2, 0.2 mg/24 h; P-trend = 0.002), and the excretion of potassium was higher by 2.1 mEq/24 h (95% CI: 0.12, 4.1 mEq/24h; P-trend = 0.03). Furthermore, the intake of caffeine was associated with higher urine volume, with participants in the highest quintile having, on average, 188 mL/24 h (95% CI: 111, 266 mL/24 h) higher urine volume than those in the lowest quintile (P-trend < 0.001). These differences resulted in a net reduction in supersaturation for calcium oxalate, with participants in the highest quintile of caffeine intake having, on average, 7% lower supersaturation (95% CI: 2%, 11%; P-trend < 0.001). Participants in the highest quintile also had significantly lower supersaturation for uric acid, which was, on average, 7% (95% CI: 2%, 12%; P-trend = 0.01). Further adjustment for dietary calcium intake did not change the results (data not shown).
DISCUSSION
In our study, we found a significant inverse independent association between intakes of caffeine and the risk of incident kidney stones in all 3 cohorts. Previous studies focused on the association between sources of caffeine, such as coffee or tea, and the risk of kidney stones and consistently found an inverse association (3–5, 13, 14). However, the fact that such an inverse association was also present for decaffeinated coffee (3–5) suggests that components of those beverages other than caffeine might have beneficial effects on the risk of forming stones. We found that the inverse association between intake of caffeine and the risk of stones was present, at least in 1 of the 3 cohorts, even in those participants consuming no or small amounts of caffeinated coffee, thus suggesting that caffeine per se might be the protective factor.
The effects of caffeine on the kidney have been investigated in a number of studies (6, 15–23). Massey and Wise (24) published a pooled analysis of the experiments performed by their research group on the renal effects of an acute caffeine load in relatively small samples of healthy volunteers. The administration of an average dose of 5.91 mg caffeine/kg resulted in a 23% increase of urine output at 2 h and significantly increased urinary excretion of calcium (78%), magnesium (45%), sodium (74%), potassium (18%), and chloride (69%). With regard to 24-h urine composition and caffeine intake, an association between the intake of caffeine and higher urinary excretion of calcium was reported in the analysis of 2201 stone formers and 1167 non–stone formers from the HPFS and NHS I and II cohorts; after adjustment for potential confounders, participants in the highest quartile of caffeine intake had, on average, a slightly higher urinary excretion of calcium of 10 mg/24 h (95% CI: 2–18 mg/24 h) than did those in the lowest quartile (6). Our present analysis, which was conducted in a larger sample, confirms this finding, showing that participants in the highest quintile of caffeine intake had, on average, 8.1 mg/24 h (95% CI: 1.9, 14 mg/24 h) higher calcium excretion compared with those in the lowest quintile. These values are also similar to previous findings from interventional studies (15, 20).
In our study, we confirm previous findings of an increased urine output; on average, participants in the highest quintile of caffeine intake had 188 mL/24 h (95% CI: 111, 266 mL/24 h) higher urine volume than those in the lowest quintile. The dilution of urine associated with caffeine consumption might contribute to the lower risk of developing stones in our study population.
Despite the increase in urine calcium excretion, the findings from the current study suggest that the net effect of caffeine intake might reduce urinary lithogenicity, as suggested by the significant inverse association between intake of caffeine and urinary supersaturation of calcium oxalate and uric acid.
Our analysis of the association between intakes of caffeine and incident stones in a subgroup of participants with low or no intake of caffeinated coffee shows that, at least in 1 of the 3 cohorts analyzed, the inverse association was still significant. In the other 2 cohorts where the linear trend was not significant, there was a suggestion of lower risk for participants in the highest quintiles of caffeine compared with the lowest. Furthermore, compared with our main analysis, participants in the highest caffeine quintiles in the subgroup study had much lower median intakes of caffeine, which might have affected the significance of our results. In previous studies, we observed a lower risk of kidney stones for caffeinated beverages (coffee and tea) as well as for decaffeinated coffee. Taken together, these findings suggest that the association might be due to caffeine as well as other components of these beverages, which, for instance, were shown to have antioxidant and anti-inflammatory properties (25–28). Our previous finding (5) of a stronger inverse association for caffeinated coffee (HR: 0.74 for the highest compared with lowest quintile) than with decaffeinated coffee (HR: 0.84 for the highest compared with lowest quintile) might indirectly support this hypothesis of an additive effect of caffeine and other substances. Coffee, for instance, is rich in magnesium, which might lower stone risk (29), but the evidence for the association between magnesium intake and stone risk is controversial (30), and we have not previously observed a significant association between magnesium intake and stone risk in these cohorts.
In our study, we found that the association between caffeine intake and risk of stones was modified by BMI in one of our cohorts. The reasons for such a finding are unclear and should be confirmed in other cohorts.
The strengths of our study include the use of 3 large prospective cohorts with well-characterized exposures and outcomes and adjustment for potential confounders that are known to be associated with the risk of developing kidney stones. The large number of participants allowed us to examine the association of interest in a subsample with low or no intake of coffee, enabling us to derive an estimate of the association between caffeine and the risk of stones independent of other potentially active substances present in coffee.
Our study also has limitations. The majority of the study sample consisted of white participants, and race is a known risk factor for stone formation (1). However, to the best of our knowledge, no study reported a differential effect of caffeine on renal function by race-ethnicity. Our study lacks information on stone composition. However, stone composition was predominantly calcium oxalate in a subsample of the study population (10). As for all observational studies, our analysis cannot address the impact on stone risk of a change in caffeine intake. Furthermore, because we included only participants without a history of kidney stones, our results might not apply to recurrent stone formation, even though it might be reasonable to expect similar favorable changes in urinary composition among stone formers. In conclusion, higher caffeine intake is independently associated with a lower risk of incident kidney stones.
Acknowledgments
The authors’ responsibilities were as follows—PMF, ENT, GG, and GCC: designed the research and wrote the manuscript; PMF, ENT, and GCC: conducted the research; PMF: analyzed the data; and PMF and GCC: had primary responsibility for final content. All authors read and approved the final manuscript. GCC was a consultant from Allena Pharmaceuticals, AstraZeneca, and Exponent; received royalties from UpToDate (author and Section Editor); and received honorarium from the American Society of Nephrology (Editor-in-Chief, Clinical Journal of the American Society of Nephrology). None of the other authors had a conflict of interest to disclose.
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