Can vitamin c supplements cause kidney stones

This old story hit the newspapers this week due to a study of several thousand people that found that those taking high dose vitamin CWhat it does: Strengthens immune system – fights infections. Makes collagen, keeping bones, skin and joints firm and strong. Antioxidant, detoxifying pollutants and protecting against… had double the risk of developing kidney stones. However, those also taking other supplements such as multivitamins showed no increased risk.

The age old concern about vitamin CWhat it does: Strengthens immune system – fights infections. Makes collagen, keeping bones, skin and joints firm and strong. Antioxidant, detoxifying pollutants and protecting against… causing kidney stones stems from studies in the ‘90’s that reported raised oxalic acid levels in the urine of people supplementing vitamin C. Oxalic acid is a key component of calciumWhat it does: Promotes a healthy heart, clots blood, promotes healthy nerves, contracts muscles, improves skin, bone and dental health, relieves aching muscles and bones,… oxalate stones – 70% of all kidney stones contain this substance. Obviously, an elevated urinary oxalic acid level is undesirable. However, while metabolic conversion does indeed take place, it is insignificant.

The apparently higher levels of oxalic acid in the urine that have been previously reported arise from the fact that ascorbic acid which is excreted in the urine undergoes a chemical conversion to oxalic acid while it is in a test -tube prior to analysis. This was proven several years ago by research at the Kidney Stone Research Laboratory of the University of Cape Town where they conducted a controlled trial in which 10 volunteer subjects were required to ingest 4g of Vit C per day for 5 days. Urines (24h) were collected before, during and after the ingestion period. Unlike the earlier studies they simply put a preservative in our urine collection bottles to prevent this conversion in the test tube. Previous studies failed to take this precaution and hence reported erroneously high oxalic acid levels in their urine. These were rigorously analysed for a host of independent physicochemical risk factors, all of which are regarded as powerful indicators of the risk of kidney stone formation.

The results showed that these risk factors were not significantly altered. They concluded that ingestion of large doses of Vitamin C does not increase the risk of forming kidney stones. The results of this study were published internationally. I asked Professor Allen Rodgers from the University of Cape Town, one of the world’s leading experts on kidney stones, if vitamin C could cause kidney stones and he said “The answer is simply no.” On the basis of this research the official position of the Food Standards Agency in the Uk is that vitamin C doesn’t increase kidney stone risk, So why this apparent small increased risk in those just taking high dose vitamin C? In real terms the apparent increased risk was small – the difference in risk being three more cases in every two thousand people. The authors also point out that ‘we cannot rule out the possibility of residual confounding (factors)’ due to the anomaly that those taking high dose vitamin C with multivitamins showed no such risk. Also, according to the authors ‘our results may not be generalizable to women, who typically have a much lower kidney stone risk.’

The authors appear not to be fans if vitamin C saying “Currently there are no well-documented benefits of high-dose ascorbic acid supplement use” somehow ignoring the evidence that high dose vitamin C reduces severity and duration of infections, lowers cholesterol, as well as blood pressure, according to a meta-analysis of 29 studies published last year. There is certainly more reason to take high dose vitamin C, at a rate of 1 to 2 grams a day, than not to. Whether or not there is any real increased risk of kidney stones remains questionable.

doi: 10.1681/ASN.V104840.

Affiliation

• 1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [email protected]

Pietro Manuel Ferraro, MD,1,2 Gary C. Curhan, MD, ScD,2 Giovanni Gambaro, MD, PhD,1 and Eric N. Taylor, MD2,3

Pietro Manuel Ferraro

1Division of Nephrology, Department of Medical Sciences, Columbus-Gemelli University Hospital, Catholic University of the Sacred Heart, Rome, Italy

2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

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Gary C. Curhan

2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

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Giovanni Gambaro

1Division of Nephrology, Department of Medical Sciences, Columbus-Gemelli University Hospital, Catholic University of the Sacred Heart, Rome, Italy

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Eric N. Taylor

2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

3Division of Nephrology and Transplantation, Maine Medical Center, Portland, USA

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Author information Copyright and License information Disclaimer

1Division of Nephrology, Department of Medical Sciences, Columbus-Gemelli University Hospital, Catholic University of the Sacred Heart, Rome, Italy

2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

3Division of Nephrology and Transplantation, Maine Medical Center, Portland, USA

Corresponding author: Pietro Manuel Ferraro, MD, MSc, Division of Nephrology – Renal Program, Department of Medical Sciences, Columbus-Gemelli University Hospital, Catholic University of the Sacred Heart, 00168, Rome, Italy, [email protected]

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Abstract

Background

Previous studies of vitamin C and kidney stones were conducted mostly in men and either reported disparate results for supplemental and dietary vitamin C or did not examine dietary vitamin C.

Study Design

Prospective cohort analysis.

Setting & Participants

156,735 women in the Nurses’ Health Study (NHS) I and II and 40,536 men in the Health Professionals Follow-up Study (HPFS).

Predictor

Total, dietary and supplemental vitamin C intake, adjusted for age, BMI, thiazide use, and dietary factors.

Outcomes

Incident kidney stones

Results

During median follow-up of 11.3–11.7 years, 6,245 incident kidney stones were identified. After multivariable adjustment, total vitamin C intake (<90 [reference], 90–249, 250–499, 500–999 and ≥1,000 mg/d) was not significantly associated with the risk of kidney stones among women, but was among men (HRs of 1.00 [reference], 1.19 [95% CI, 0.99–1.46], 1.15 [95% CI, 0.93–1.42], 1.29 [95% CI, 1.04–1.60] and 1.43 [95% CI, 1.15–1.79], respectively; p for trend = 0.005). Median total vitamin C intake for the 500–999 mg/d category was about 700 mg/d. Supplemental vitamin C intake (no use [reference], <500, 500–999, and ≥1,000 mg/d) was not significantly associated with the risk of kidney stones among women, but was among men (HR, 1.19 [95% CI, 1.01–1.40] for ≥1,000 mg/d; p for trend = 0.001). Dietary vitamin C intake was not associated with stones among men or women, although few participants had dietary intakes >700 mg/d.

Limitations

Nutrient intakes derived from food-frequency questionnaires, lack of data on stone composition for all the cases.

Conclusions

Total and supplemental intake of vitamin C was significantly associated with a higher risk of incident kidney stones in men, but not among women.

Keywords: kidney disease, nutrition, diet, supplements, urolithiasis, vitamin C, ascorbic acid, kidney stone formation, incident kidney stone, calcium oxalate, urinary oxalate excretion, food-frequency questionnaire (FFQ), gender difference, risk factor

Kidney stones are common, with a lifetime prevalence of about 10% in the US population. Diet is thought to play an important role in the development of kidney stones, particularly intakes of calcium,1–3 sodium,1,3 fructose,4 water and other beverages5–8. Ascorbic acid, or vitamin C, is an essential nutrient acting as a cofactor in several enzymatic pathways, the main dietary sources of which are fresh fruits and vegetables. Ingested vitamin C is partly converted to oxalate and excreted in the urine, thus potentially increasing the risk of calcium oxalate stone formation.9,10 In a metabolic study in 24 individuals, 2 grams daily of ascorbic acid increased urinary oxalate excretion by about 22%.11

Two previous epidemiologic studies have addressed kidney stone risk associated with vitamin C intake in men. In a prospective cohort study of men in the Health Professionals Follow-Up Study (HPFS), 1,000 mg/d or more of total vitamin C intake was associated with a 41% higher risk of stones compared with 90 mg/d or less after adjusting for age, body mass index (BMI), use of thiazide diuretics, and dietary factors.12 Recently, another study also reported a positive association between supplemental vitamin C intake and kidney stones in a cohort of 23,355 Swedish men; the multivariable adjusted relative risk associated with supplemental use of vitamin C was almost double compared with no use.13 To date, the only study in women was performed in the Nurses’ Health Study (NHS) I cohort and found no association between intake of vitamin C and risk of stones.14

However, the relationship between vitamin C intake and kidney stone formation remains unclear. First, the different results for men and women warrant further investigation. Dietary risk factors for kidney stones may vary by sex.3,12,15 Second, the risk associated with a higher intake (≥1,000 mg/d) of supplemental vitamin C in the previous study in HPFS was of borderline statistical significance (hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.97–1.39; p for trend = 0.01).12 Finally, interpretation of urinary oxalate excretion rates after vitamin C loading in metabolic studies may be complicated by ex vivo non-enzymatic conversion of urinary vitamin C into oxalate.16

To examine the independent associations of total, supplemental and dietary vitamin C and risk of kidney stones in women, we analyzed data from a large prospective cohort, the NHS II. We also updated our previous analyses of the NHS I and the HPFS cohorts to include 12 years of additional follow-up for each cohort, which provided greater statistical power.

Methods

Study Population

The NHS I enrolled 121,700 female nurses aged 30–55 years in 1976; NHS II enrolled 116,430 female nurses aged 25–42 years in 1989; HPFS enrolled 51,529 male health professionals aged 40–75 years in 1986. Participants were asked to complete biennial questionnaires with information on medical history, lifestyle and medications; information from the questionnaires was updated every 2 years, or every 4 years for the food frequency questionnaires (FFQs). For the current analysis, participants who reported a history of kidney stones prior to the start of time at risk were excluded from the analysis. Similarly, those with a history of cancer (except for non-melanoma skin cancer) prior to baseline were excluded from the analysis, and those who developed cancer during follow-up were censored, as this condition might have affected their dietary or other behaviors. These studies were approved by the Partners HealthCare institutional review board. Return of completed baseline and biennial questionnaires was accepted by the institutional review board as implied informed consent.

Assessment of Vitamin C Intake and Other Nutrients

In 1986 (NHS I and HPFS) and 1991 (NHS II), participants were asked to complete a FFQ that asked about the average use of more than 130 foods and 22 beverages in the previous year; dietary information was updated every four years. Validation studies have demonstrated the reliability of the FFQ.17,18 The intake of dietary factors was calculated from the reported frequency of consumption of each specified unit of food and, except for oxalate, from US Department of Agriculture data on the content of the relevant nutrient in specified portions. The oxalate content of most foods on the FFQ, as well as of frequently consumed foods written in, was measured by capillary electrophoresis as previously described.19 The FFQ also inquires about vitamin and mineral supplements. Users of multivitamins and vitamin C supplements are asked to name the specific brand and to provide the amount and frequency of use. Our database contains the composition of over 1000 brands of multivitamins and calculates the amount of vitamin C (and other vitamins and minerals) as the frequency of intake multiplied by composition. The same method is used for individual vitamin C supplements. For the current analysis, we used data from the FFQ for total vitamin C (dietary plus supplement sources); intake of alcohol; dietary intake of calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein, and total fluids; and calcium supplements. All nutrients were energy-adjusted.

Assessment of Kidney Stones

Participants who reported an incident kidney stone were asked to complete a supplementary questionnaire about the date of occurrence and associated signs and symptoms such as pain or hematuria. A kidney stone associated with pain or hematuria was the study outcome. Medical record validation studies confirmed the kidney stone diagnosis in more than 95% of cases among participants who submitted the supplementary questionnaire.20 Stone composition was available in a subsample of the cases and found to be ≥50% calcium oxalate in 77% of NHS I, 79% of NHS II and 86% of HPFS participants.20

Assessment of Other Covariates

Updated information from the questionnaires was used for the following variables: age, BMI, and use of thiazide diuretics. Self-reported weight, from which BMI was calculated, was validated in the NHS I and HPFS cohorts.21

Statistical Analysis

The study design was prospective; information on diet was collected before the diagnosis of the kidney stone. We analyzed the association between total vitamin C and risk of stones using categories of vitamin C of <90, 90–249, 250–499, 500–999 and ≥1,000 mg/day. We selected these cutpoints based on our previous study in men.12 We updated exposure and covariates every four years. We allocated person-time contributed by each participant during follow-up to the respective category of vitamin C intake and calculated incidence rates of kidney stones for each category. Age- and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for stones in each category of vitamin C intake were computed separately in each cohort with Cox proportional hazards regression models. We adjusted for age, BMI (13 categories), use of thiazides (yes/no), supplemental calcium intake (no use, <100, 100–499, ≥500 mg/d), intake of alcohol (7 categories), and dietary intakes of calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein and fluid (all quintiles). We further analyzed the association using quintiles of total vitamin C intake and repeated the analyses in the NHS I and NHS II cohorts with a referent category of total vitamin C intake of <75 mg/d, which is the recommended daily allowance (RDA) for women. Linear trends were evaluated using mid-points for categories of vitamin C intake and median values of vitamin C intake for quintiles; non-linear relations were explored with models that included total vitamin C intake using restricted cubic splines with knots at quintiles. Finally, we constructed models of dietary and supplemental vitamin C intake separately with the following categories: <90, 90–249 and ≥250 mg/d for dietary intake and no use, <500 mg/d, 500–999 mg/d, and ≥1,000 mg/d for supplemental intake. Also in these analyses, midpoints for each category were used to test for linear trends across categories. Time at risk was 1986–2006 for NHS I, 1991–2011 for NHS II and 1986–2010 for HPFS.

Estimates obtained from the NHS I and NHS II cohorts were pooled with random-effects meta-analysis after evaluation of heterogeneity. Pooled results are presented for the two cohorts. For descriptive tables, variables were age-standardized using direct standardization to the overall age distribution (in 5-year age categories) in the study population.

Results

The analysis included 197,271 participants, with 2,494,789 person-years of follow-up. During a median follow-up of 11.7 years for NHS I, 11.5 years for NHS II, and 11.3 years for HPFS, 6,245 incident kidney stone events occurred. Baseline characteristics of the study cohorts are reported in Tables 1 to ​to3.3. In all the cohorts, the use of calcium supplements as well as intakes of potassium, magnesium, oxalate and phytate tended to be higher across vitamin C categories. Among NHS I participants, age and intake of dietary calcium tended to be higher across total vitamin C categories. Among NHS II participants, BMI tended to be lower across total vitamin C categories.

Table 1

Age-standardized baseline characteristics by intake of total vitamin C: NHS I

Total Vitamin C<90 mg/d90–249 mg/d250–499
mg/d500–999 mg/d≥1,000 mg/dVitamin C, mg/d67.8(15.8)162(43)337(67)700(129)1,405(343)Age, y*51.1(7.1)52.7(7.2)53.6(7.1)53.9(7.1)54.1(6.9)BMI, kg/m225.6(5.1)25.4(4.8)25.2(4.7)24.8(4.5)24.9(4.7)Thiazide use1113151313Calcium supplement use3248667986Dietary calcium, mg/d662(273)718 (250)733(249)739 (251)743(273)Potassium, mg/d2,547(508)3,015(531)3,272(662)3,179(665)3,284(724)Magnesium, mg/d252(53)290(58)321(72)322(74)339(84)Total fructose, g/d15.1(9.4)20.8(7.6)25.4(9.5)23.2(9.6)23.7(10.3)Oxalate, mg/d88.4(64.1)113(80)135(116)130(104)141(117)Phytate, mg/d621(235)692(245)727(278)751(300)793(335)Animal protein, g/d53.5(14.8)54.9(13.4)54.5(14.2)54.8(14.0)55.3(15.4)Alcohol intake, g/d*1.1 [0–7.5]1.8[0–7.6]1.8[0–7.4]1.8[0–7.8])1.8[0–7.8]Fluid volume, L/d1.84(0.73)1.98(0.69)2.13(0.74)2.10(0.75)2.06(0.73)

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Note: Values for categorical variables are given as percentage and those for continuous variables, as mean ± standard deviation or median [interquartile range], and are standardized to age distribution of study population, except where otherwise specified. Nutrient intakes are energy-adjusted.

BMI, body mass index; NHS, Nurses’ Health Study

*Value is not age adjusted;

Table 3

Age-standardized baseline characteristics by intake of total vitamin C: HPFS

Total vitamin C<90 mg/d90–249 mg/d250–499 mg/d500–999 mg/d≥1,000 mg/dVitamin C, mg/d67.0(15.9)164(43)343(69)716(126)1,530(389)Age, y *51.5(9.1)53.7(9.8)54.4(9.9)55.0(9.8)54.3(9.5)BMI, kg/m225.8(3.4)25.6(3.4)25.4(3.4)25.2(3.1)25.1(3.3)Thiazide use89999Calcium supplement use511254457Dietary calcium, mg/d746(325)798(301)815(292)813(303)814(314)Potassium, mg/d2,850(550)3,338(588)3,645(718)3,619(787)3,744(834)Magnesium, mg/d302(64)337(67)370(81)381(89)404(103)Total fructose, g/d17.8(10.9)23.8(9.5)28.9(11.4)27.9(12.7)27.9(12.7)Oxalate, mg/d103(75)138(144)157(139)152(129)168(160)Phytate, mg/d812(335)905(358)973(399)1,009(417)1,068(451)Animal protein, g/d67.6(18.0)68.1(17.2)66.7(17.7)67.1(18.4)67.9(18.8)Alcohol intake, g/d*6.0[0–17.1]6.0[1.0–15.4]5.3[0.9–13.9]6.0[0.9–15.0]5.8[0.9–15.0]Fluid volume, L/d1.93(0.81)1.92(0.77)1.99(0.80)1.99(0.81)1.91(0.78)

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Note: Values for categorical variables are given as percentage and those for continuous variables, as mean ± standard deviation or median [interquartile range], and are standardized to age distribution of study population except where otherwise specified. Nutrient intakes are energy-adjusted.

BMI, body mass index; HPFS, Health Professionals Follow-up Study

*Value is not age adjusted

Results of age-adjusted and multivariable adjusted analyses for total vitamin C intake are shown in Table 4. For the NHS cohorts, the age-adjusted HR for total vitamin C intake of ≥1,000 compared with <90 mg/d was 0.76 (95% CI, 0.69–0.82; p for trend = 0.001). After multivariable adjustment, the HR for the same comparison was 0.99 (95% CI, 0.90–1.09; p for trend = 0.1). The analysis of quintiles of total vitamin C intake yielded similar results: the adjusted HR for the highest quintile compared with the lowest was 1.05 (95% CI, 0.92–1.20; p for trend = 0.6). The multivariable adjusted HR for total vitamin C intake of ≥1,000 mg/d compared with taking less than the RDA of 75 mg/d was 1.04 (95% CI, 0.93–1.17).

Table 4

HRs of incident kidney stones by categories of total vitamin C intake in NHS I and II and HPFS cohorts

Total Vitamin CP for
trend

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Note: Multivariable analysis adjusted for age; body mass index; thiazide use; supplemental calcium intake; intake of dietary calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein, and total fluid; and alcohol intake. For illustrative purposes, medians for total vitamin C were derived from responses to the 1986 (NHS I, HPFS) and 1991 (NHS II) dietary questionnaires. However, total vitamin C intake was updated throughout the study. CI, confidence interval; HPFS, Health Professionals Follow-up Study; HR, hazard ratio; NHS, Nurses’ Health Study

For HPFS, the age-adjusted HR for total vitamin C intake of ≥1,000 compared with <90 mg/d was 0.98 (95% CI, 0.80–1.20; p for trend = 0.6). After multivariable adjustment, the HR was 1.43 (95% CI, 1.15–1.79; p for trend = 0.005). The association between total vitamin C and higher risk was statistically significant only for the highest two categories of intake, and the median total vitamin C for the 500–999 mg/d intake category averaged approximately 700 mg/d over the course of the study. The analysis of quintiles of total vitamin C intake yielded similar results: the multivariable adjusted HR for the highest quintile compared with the lowest was 1.22 (95% CI, 1.04–1.43; p for trend = 0.01).

Among NHS I participants, the change in point estimates from the age-adjusted to the multivariable-adjusted model for total vitamin C was due predominantly to inclusion of BMI and calcium and potassium intakes into the regression models. Among NHS II participants, the change in point estimates from the age-adjusted to the multivariable-adjusted model was due predominantly to inclusion of BMI and intakes of alcohol, total fluid, calcium and potassium. Among HPFS participants, the change in point estimates from the age-adjusted to the multivariableadjusted model was due predominantly to inclusion of potassium intake into the regression models, and to a lesser extent to BMI and intake of calcium.

Results of age-adjusted and multivariable-adjusted analyses for supplemental vitamin C intake are shown in Table 5. The multivariable-adjusted HR for those taking the highest amount of supplemental vitamin C (≥1,000 mg) compared with those not taking any supplemental vitamin C was 0.90 (95% CI, 0.79–1.04; p for trend = 0.5) in the NHS cohorts and 1.19 (95% CI, 1.01–1.40; p for trend = 0.001) in the HPFS cohort.

Table 5

HRs of incident kidney stones by categories of supplemental intake of vitamin C in NHS I and II and HPFS cohorts

Supplemental Vitamin C IntakeP for
trend

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Note: Multivariable analysis adjusted for age; body mass index; thiazide use; supplemental calcium intake; intake of dietary vitamin C, calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein, and total fluid; and alcohol intake. For illustrative purposes, medians for supplemental vitamin C were derived from responses to the 1986 (NHS I, HPFS) and 1991 (NHS II) dietary questionnaires. However, supplemental vitamin C intake was updated throughout the study. CI, confidence interval; HPFS, Health Professionals Follow-up Study; HR, hazard ratio; NHS, Nurses’ Health Study; supp, supplemental

Restricted cubic splines analysis confirmed no significant association between intake of total vitamin C and risk of stones in the NHS cohorts (Figure 1). In HPFS, the p-value for non-linearity for the cubic spline was 0.4 (Figure 2). By inspection, the risk became statistically significant at total vitamin C intakes of 700–800 mg/d. The HPFS participants with total vitamin C intake >700 mg/d in general consumed vitamin C supplements: few men had dietary vitamin C intakes of 700 mg/d or more. Splines for dietary and supplemental intakes are reported in Figures S1–S4 (provided as online supplementary material).

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Figure 1

Restricted cubic spline of total vitamin C intake and risk of incident kidney stones: Nurses’ Health Studies I and II

Model adjusted for age, BMI, thiazide use, use of calcium supplements, intake of calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein, total fluid and alcohol.

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Figure 2

Restricted cubic spline of total vitamin C intake and risk of incident kidney stones: Health Professionals Follow-up Study

Model adjusted for age, BMI, thiazide use, use of calcium supplements, intake of calcium, sodium, potassium, magnesium, fructose, oxalate, phytate, animal protein, total fluid and alcohol.

There was no association between intake of dietary vitamin C and incident kidney stones in any cohort (Table S1): the multivariableadjusted HR for dietary vitamin C intake of ≥250 compared with <90 mg/d was 0.92 (95% CI, 0.68–1.24; p for trend = 0.3) in the NHS cohorts and 0.95 (95% CI, 0.75–1.19; p for trend = 0.7) in the HPFS cohort.

Discussion

We found no association between intake of total, dietary or supplemental vitamin C and risk of incident kidney stones in 2 large cohorts of women. We also confirmed the previously reported positive association in a cohort of men, with increased statistical power and precision.

Vitamin C intake has been proposed as a risk factor for kidney stone formation because vitamin C may increase urinary oxalate excretion.10,11 However, it is possible that this finding might be due to non-enzymatic ex vivo conversion of vitamin C into oxalate in the collection vessel.16 When urine specimens were treated with immediate acidification at a pH of 2 and frozen at −30°C, intravenous administration of large amounts of vitamin C up to 1.5 g per kilogram of body weight resulted in oxalate conversion of less than 0.5% of the vitamin C load.22 In contrast, urine sample handling, storage and analysis without acidification and immediate freezing resulted in up to 25-fold increase in urine oxalate after intravenous administration of vitamin C.22

Two previous population-based studies have assessed the association between intake of vitamin C and incidence of kidney stones in men. In the prior study of HPFS, intake of 1,000 mg/d or more of total vitamin C was associated with a 41% (95% CI, 11%–80%) increased risk of developing a first stone, after multivariable adjustment for other risk factors.12 In that study, the higher risk associated with supplemental intake of vitamin C was not statistically significant; the significant association between higher risk and supplemental vitamin C intake in the current, updated study is likely due to higher statistical power resulting from 12 years of additional follow-up and >25% more cases. A recent analysis of over 23,000 Swedish men showed an increased risk associated with use of supplemental vitamin C (multivariable-adjusted HR, 1.92; 95% CI, 1.33–2.77) compared with no use.13 Although data on supplemental vitamin C dose was not available, a dose-response relation was suggested, with HRs of 1.66 (95% CI, 0.99–2.79) for intakes of less than 7 vitamin C capsules per day and of 2.23 (95% CI, 1.28–3.88) for intakes of 7 vitamin C capsules or more per day when compared with no use.13 In that study, no data were presented for dietary or total vitamin C intake.

The reason for the disparate results between men and women is unclear. However, we previously reported differential associations by sex for several dietary risk factors for stones, including animal protein, sucrose, potassium, sodium and phytate.3,12,15 It is possible that the effect of vitamin C on kidney stone risk is different in men and women, and some data suggest the potential for sex differences in vitamin C metabolism.23,24

We did not find any association between dietary vitamin C intake and risk of stones in the HPFS cohort. However, this finding might be due to the relative low number of participants with very high intakes of dietary vitamin C: the median intake for the highest quintile of dietary vitamin C was 266 mg/d. Visual inspection of spline curves suggests that the risk would significantly increase at values of of 700–800 mg/d (Figure 2); in the HPFS cohort there were few participants with that level of dietary intake.

Our study has limitations. First, the possibility of unmeasured or residual confounding factors cannot be excluded. It is possible that the disparate results between dietary and supplemental vitamin C in men indicate unknown differences between supplement and non-supplement users that affected our results. Second, nutrient intakes were derived from FFQs, although they were validated. Third, we did not have stone composition reports or 24-hour urine data for most of the participants in our study. Although the majority of kidney stones in these cohorts were likely the calcium oxalate type, we would not expect to see associations between vitamin C intake and other types of kidney stones. Fourth, it is possible that much higher levels of vitamin C intake than we observed in our study might increase risk of kidney stones in women. Finally, our cohorts were predominantly white, and the results of our study might not be generalizable to different races.

In conclusion, higher total and supplemental vitamin C intakes were not associated with risk of incident kidney stones in two large cohorts of women, whereas they were associated with higher risk in a large cohort of men. Dietary vitamin C was not associated with risk in any cohort. We advise that male calcium oxalate stone formers abstain from supplemental but not dietary vitamin C. Future studies are needed to examine associations between vitamin C, oxalate metabolism, and kidney stone formation and to explore the possible effects of sex on the relationship between vitamin C intake and kidney stone risk.

​

Table 2

Age-standardized baseline characteristics by intake of total vitamin C: NHS II

Total Vitamin C<90 mg/d90–249 mg/d250–499 mg/d500–999 mg/d≥1000 mg/dVitamin C, mg/d68.5(15.1)154(43)333(67)699(136)1,492(460)Age, y *36.4(4.6)36.5(4.7)36.4(4.7)37.3(4.6)37.8(4.5)BMI, kg/m225.1(5.8)24.6(5.2)24.3(5.1)23.9(4.8)23.9(5.1)Thiazide use22222Calcium supplements use1130545967Dietary calcium, mg/d815(313)895(300)911(303)910(312)909(311)Potassium, mg/d2,538(456)2,963(477)3,162(583)3,091(591)3,137(620)Magnesium, mg/d268(54)314(65)344(80)352(89)377(110)Total fructose, g/d19.1(13.5)22.6(9.6)26.7(11.1)24.9(10.9)25.4(11.6)Oxalate, mg/d98.1(72.0)134(108)158(139)158(136)180(184)Phytate, mg/d725(217)782(232)813(252)825(268)870(293)Animal protein, g/d64.1(16.7)64.8(16.0)62.2(17.3)63.0(17.6)61.7(19.4)Alcohol intake, g/d*0.9 [0–3.1]0.9 [0–3.5]0.9 [0–3.3]1.0 [0–4.0]1.0 [0–3.9]Fluid volume, L/d1.97(0.80)2.13(0.81)2.21(0.86)2.19(0.88)2.11(0.85)

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Note: Values for categorical variables are given as percentage and those for continuous variables, as mean ± standard deviation or median [interquartile range], and are standardized to age distribution of study populati except where otherwise specified. Nutrient intakes are energy-adjusted.

BMI, body mass index; NHS, Nurses’ Health Study

*Value is not age adjusted;

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Acknowledgements

Support: This study was supported by research grants from the National Institutes of Health: DK094910, DK91417, CA186107, CA176726 and CA167552. The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

Dr Curhan: consultant, Allena Pharmaceuticals, AstraZeneca, Exponent; royalties, UpToDate (author and section editor); honorarium, American Society of Nephrology (Editor-in-Chief, Clinical Journal of the American Society of Nephrology). Dr Ferraro: Consultant, BioHealth Italia.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Financial Disclosure: The other authors declare that they have no other relevant financial interests.

Contributions: Research idea and study design: PMF, ENT, GG, GCC; data acquisition: ENT, GCC; data analysis/interpretation: PMF, ENT, GCC; statistical analysis: PMF; supervision or mentorship: ENT, GCC, GG. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. PMF takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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