Editorial

Does Vitamin C Cause Kidney Stones? Rekindling the Debate

It has frequently been claimed that ingestion of large doses of vitamin C can increase the risk of developing kidney stones, because vitamin C is converted in part to oxalate. While these claims have largely been refuted, two new observational studies have rekindled the debate by finding that higher intake of vitamin C was associated with an increased risk of kidney stones. This new research will be discussed at the end of this editorial.

A number of studies have indeed found an increase in urinary oxalate excretion after supplementation with large doses of vitamin C. However, the hyperoxaluria associated with high-dose vitamin C was due primarily to a laboratory artifact resulting from the conversion of vitamin C to oxalate ex vivo (i.e., after it has left the body, while it is in the collection bottle).¹ If there is a small increase in urinary oxalate resulting from ingestion of large doses of vitamin C, that increase might be counterbalanced by other effects of the vitamin. For example, ascorbic acid binds calcium in the urine, potentially reducing the formation of calcium oxalate crystals; produces a small increase in urinary acidity, thereby increasing calcium oxalate solubility; and possibly decreases urinary stasis by promoting diuresis.² In addition, vitamin C reversed some potentially lithogenic metabolic abnormalities (such as hyperinsulinemia and poor urine acidification) following a high-carbohydrate, high-calcium meal in men with recurrent calcium oxalate kidney stones.³

Practitioners who have routinely used large doses of vitamin C have not observed kidney stones as a side effect.⁴ Abraham Hoffer, a pioneer in the field of orthomolecular psychiatry, prescribed 2 to 10 g per day of vitamin C for more than 20 years to more than 3000 patients and did not see any calcium oxalate kidney stones.⁵ Robert Cathcart treated more than 11,000 patients over a 14-year period with large doses of vitamin C. He reported that vitamin C did not cause kidney stones, and actually seemed to prevent stones in patients who had had them previously.⁶ Jackson et al. administered nearly 8000 high-dose intravenous vitamin C infusions over a 16-year period to 273 patients, and none of them developed a kidney stone.⁷

Until recently, observational studies also failed to support the suggestion that vitamin C causes kidney stones. In a 6-year prospective study of 51,529 male health professionals (published in 1996), the risk of developing a kidney stone was 22% lower in men consuming 1500 mg per day or more of vitamin C than in those consuming less than 250 mg per day.⁸ A 14-year prospective study of 85,557 female nurses (published in 1999) found that higher intake of vitamin C (≥ 1500 mg per day) was not associated with an increased risk of kidney stones.⁹ However, a prospective cohort study of 48,850 Swedish men (published in 2013) found a significant increase in incidence of kidney stones among men taking vitamin C supplements.¹⁰ In addition, prospective cohort studies (published in 2016) of 156,735 female nurses and 40,536 male health professionals found that, in multivariate analysis, there was a significant trend toward a higher incidence of kidney stones with higher vitamin C intake in men, but not in women.¹¹

How does one reconcile the conflicting findings from observational studies? With regard to the Swedish study, the results may have been influenced by selection bias, since men taking supplements other than vitamin C were excluded from the analysis. It is possible that men who take only vitamin C supplements have differences in diet, lifestyle, and health compared with men who take other supplements as well; and that those differences (rather than vitamin C supplementation) were responsible for the observed increase in stone risk. In the 2016 study of female nurses and male health professionals, when the analysis was adjusted only for age, there was actually a lower incidence of kidney stones with higher vitamin C intake in both women and men. This trend was statistically significant in the women, but not in the men. The analysis that adjusted only for age was not emphasized by the researchers. Instead, they focused on the multivariate analysis, which adjusted for many factors including age, supplemental calcium intake, and dietary intake of magnesium, calcium, sodium, potassium, and fructose. It is not clear whether the assumptions upon which the adjustments were made are valid. For example, the multivariate analysis would presumably adjust stone risk upward for people with high intake of magnesium or low intake of sodium. It is possible that the model “overadjusted” the data, leading to spurious elevations of stone risk in people who, for example, eat broccoli (which is high in both vitamin C and magnesium and low in sodium). Overall, the observational studies cited in this article do not provide any clear evidence that high vitamin C intake increases the risk of kidney stones.

It is possible that, in rare cases, genetic abnormalities render a person susceptible to vitamin C-induced kidney stones. In a case report, a Chinese boy developed a calcium oxalate ureteral stone at the age of 9 years, after having taken 3 g per day of vitamin C for 6 years. Urinary oxalate (measured correctly, to avoid laboratory artifact) was markedly elevated, but returned to normal after vitamin C was discontinued.¹² There is anecdotal evidence that vitamin C-induced elevations of urinary oxalate can be minimized by vitamin B6 (pyridoxine) supplementation. In addition, magnesium supplementation would presumably reduce the risk of stone formation associated with a vitamin C-induced increase in urinary oxalate.¹³

Alan R. Gaby, MD

Notes

1. Wandzilak TR et al. Effect of high dose vitamin C on urinary oxalate levels. J Urol. 1994;151:834–837.

2. Ringsdorf WM Jr, Cheraskin E. Nutritional aspects of urolithiasis. South Med J. 1981;74:41–44.

3. Schwille PO et al. Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: attenuation by ascorbic acid supplementation of a test meal. Urol Res. 1997;25:49–58.

4. Poser E. Large ascorbic acid intake. N Engl J Med. 1972;287:412.

5. Hoffer A. Vitamin C and infertility. Lancet. 1973;2:1146.

6. Cathcart RF. Vitamin C: the nontoxic, nonrate-limited, antioxidant free radical scavenger. Med Hypotheses. 1985;18:61–77.

7. Jackson JA et al. Sixteen-year history with high dose intravenous vitamin C treatment for various types of cancer and other diseases. J Orthomol Med. 2002;17:117–119.

8. Curhan GC et al. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155:1847–1851.

9. Curhan GC et al. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10:840–845.

10. Thomas LD et al. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Intern Med. 2013;173:386–388.

11. Ferraro PM et al. Total, dietary, and supplemental vitamin C intake and risk of incident kidney stones. Am J Kidney Dis. 2016;67:400–407.

12. Chen X et al. High-dose supplementation with vitamin C-induced pediatric urolithiasis: the first case report in a child and literature review. Urology. 2014;84:922–924. (Note: The method of testing urinary oxalate was clarified in a personal communication from Gu X.)

13. Johansson G et al. Effects of magnesium hydroxide in renal stone disease. J Am Coll Nutr. 1982;1:179–185.