Thomas LDK, Elinder C, Tiselius H, Wolk A, Åkesson A. Ascorbic Acid Supplements and Kidney Stone Incidence Among Men: A Prospective Study. JAMA Intern Med. 2013;173(5):386-388. doi:10.1001/jamainternmed.2013.2296
Author Affiliations: Institute of Environmental Medicine, Division of Nutritional Epidemiology (Ms Thomas and Drs Wolk and Åkesson), and Department of Clinical Science, Intervention, and Technology, CLINTEC, (Drs Elinder and Tiselius), Karolinska Institutet, Stockholm, Sweden.
Urinary oxalate is an important determinant of calcium oxalate kidney stone formation.1 Vitamin C is excreted in urine both in its unmetabolized form and as oxalate; however, there remains considerable uncertainty over the kidney stone risk that may be associated with ascorbic acid supplement use.2
We examined whether ascorbic acid supplements (approximately 1000 mg) were associated with kidney stones in a population-based, prospective cohort of men.
The Cohort of Swedish Men (COSM) has been described elsewhere.3 In brief, 48 850 men, aged 45 to 79 years at baseline, were recruited in 1997 (response rate, 49%). Detailed diet and lifestyle data were collected at baseline using a self-administered questionnaire. Based on validated questions, men reported their use of ascorbic acid (sensitivity = 67% and specificity = 93%)4 and of 20 other supplement types. We excluded those with incorrect national registration numbers, implausible energy intake, prebaseline cancer diagnosis, and missing supplement use data and those diagnosed as having kidney stones prior to baseline, based on registry (n = 1612) and self-reported (n = 5898) data, because these men may have changed their diet or supplement use based on medical advice. We also excluded users of supplements other than ascorbic acid as this may be a significant source of confounding (n = 12 873). For comparison, we repeated the analysis for multivitamin (only) users.
First incident cases of kidney stones (International Statistical Classification of Diseases, 10th Revision code N20) were ascertained from January 1, 1998, to December 31, 2009, using registry data.
We estimated hazard ratios (hereafter, relative risks [RRs]) with Cox proportional hazards regression models using attained age as the timescale. Follow-up was censored at date of kidney stone diagnosis, death, or end of follow-up, whichever occurred first. The Schoenfeld residual test indicated no violation of the proportional hazard assumption.
Dose-response was assessed using the frequency-of-use data, which were available for 91.5% of ascorbic acid users. The linear trend across categories was tested using the median tablet usage within each group as a continuous variable.
Ethical approval was granted by the regional ethical review board in Stockholm, Sweden, and return of the completed questionnaire was considered to imply informed consent.
During 11 years of follow-up we ascertained 436 first incident cases of kidney stones. Ascorbic acid use was associated with a statistically significant 2-fold increased risk (Table). In contrast, multivitamin use was not associated with kidney stone risk (RR, 0.86 [95% CI, 0.62-1.19]).
Users of only ascorbic acid taking fewer than 7 (median) and 7 or more tablets per week showed increased risks of RR, 1.66 (95% CI, 0.99-2.79) and RR, 2.23 (95% CI, 1.28-3.88), respectively, compared with supplement nonusers in the full multivariate-adjusted model (P value for trend = .001).
The strengths of this study include the large population-based prospective cohort design, validated exposure data, and virtually complete follow-up of the study population through linkage to high-quality registers. Furthermore, analysis of kidney stone material collected from 3176 men, treated with extracorporeal shockwave lithotripsy in Stockholm County, found calcium oxalate to be the dominant component in 92.6% (H.-G.T., unpublished data). It could thus be assumed that at least 90% of the kidney stones in our study population were composed primarily of calcium oxalate.5
Our results may not be generalizable to women, who typically have a much lower kidney stone risk. Because the risk associated with ascorbic acid may depend both on the dose and on the combination of nutrients with which the ascorbic acid is ingested, our findings should not be translated to dietary vitamin C. Data on the brand of supplement used were not available, and we were not, therefore, able to fully characterize the dose taken. However, previous studies have demonstrated that ascorbic acid preparations available on the Swedish market typically contain 1000 mg of ascorbic acid per tablet.6 Supplement users may be more health conscious and therefore more likely to seek medical help; however, given the severe pain associated with kidney stones, this is unlikely to explain our findings. It is also not supported by our null results for multivitamin use. We cannot rule out the possibility of residual confounding.
The rate difference was 147 of 100 000 for first incident cases; however, the recurrent nature of kidney stones implies that the absolute risk increase, for this modifiable risk factor, is potentially higher. Our findings need to be confirmed by other studies but may have important implications for the clinical advice given to kidney stone formers. Currently there are no well-documented benefits of high-dose ascorbic acid supplement use,7 and, therefore, it seems prudent to advise that high-dose preparations be avoided, particularly by those with a history of kidney stones.
In conclusion, our results indicate that high-dose ascorbic acid supplements—one of the most commonly used vitamin preparations—are associated with a dose-dependent 2-fold increased risk of kidney stone formation among men.
Correspondence: Dr Åkesson, Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, 171 77 Stockholm, Sweden (Agneta.Akesson@ki.se).
Published Online: February 4, 2013. doi:10.1001/jamainternmed.2013.2296
Author Contributions: Dr Thomas and Åkesson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Thomas, Wolk, and Åkesson. Acquisition of data: Wolk. Analysis and interpretation of data: Thomas, Elinder, Tiselius, Wolk, and Åkesson. Drafting of the manuscript: Thomas and Åkesson. Critical revision of the manuscript for important intellectual content: Thomas, Elinder, Tiselius, Wolk, and Åkesson. Statistical analysis: Thomas. Obtained funding: Wolk and Åkesson. Administrative, technical, and material support: Tiselius and Wolk. Study supervision: Elinder and Åkesson.
Conflict of Interest Disclosures: None reported.
Funding/Support: The research was funded by the Swedish Research Council/Research Infrastructures (grant No. 2008-5947) and Karolinska Institutet KID funding (PhD funding awarded to Ms Thomas).
Role of the Sponsors: The funders had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Previous Presentation: This study was presented as a conference poster, “Vitamin C Supplementation and Kidney Stone Incidence Among Men: A Population-Based Prospective Cohort Study,” at the International Conference on Diet and Activity Methods, Food and Organisation; May 15, 2012; Rome, Italy.