Pediatric Case Report High-dose Supplementation With Vitamin Ceinduced Pediatric Urolithiasis: The First Case Report in a Child and Literature Review Xuehua Chen, Luming Shen, Xiaojian Gu, Xinjuan Dai, Li Zhang, Yan Xu, and Ping Zhou High dose of vitamin C intake could increase urine oxalate excretion and hence the risk of calcium stone formation. We report a case of left ureteral stone in a 9-year-old boy with an extremely high urine oxalate excretion. Besides, he had a habit of taking high-dose supplementation of vitamin C since the age of 3 years. After vitamin C intake prohibited without other therapy and change of dietary intake, the urine oxalate excretion was decreased to normal level and no recurrence of urolithiasis was present during the 3-year follow-up. Thus, high-dose supplementation with vitamin C for years in a child could induce the urinary stones. UROLOGY 84: 922e924, 2014. 2014 Elsevier Inc.
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itamin C (ascorbic acid, ascorbate) is an essential micronutrient involved in many biological and biochemical functions, acting as an electron donor or a reducing agent in chemical reactions. Its supplementation is widely practiced in many countries, such as China. Besides, vitamin C is also a precursor of oxalate. As a result, high dose of vitamin C supplements increases urinary oxalate excretion1 and subsequently may increase the risk of calcium oxalate kidney stones.2-4 However, there is no case report about this association. We report a case of pediatric urolithiasis, which may have been induced by high intake of vitamin C.
CASE REPORT In April 2011, a 9-year-old boy was admitted to our hospital with intermittent left colic pain, hematuria, mild nausea, and vomiting for 1 month. Left ureteral stone (arrow in figure) was diagnosed by plain x ray of the kidneys, ureters, and bladder (Fig. 1). Physical examination showed percussion pain in the left renal region. No family history of urolithiasis was found. Xuehua Chen and Luming Shen contributed to the work equally and should be regarded as co-first authors. Financial Disclosure: Luming Shen is a member of the Foundation of Jiangsu Province Hospital of Traditional Chinese Medicine. The other authors declare that they have no relevant financial interests. Funding Support: This study was supported by the grant from the Foundation of Jiangsu Province Hospital of Traditional Chinese Medicine (Y13033), Jiangsu Province, P.R. China. From the Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China Reprint requests: Xiaojian Gu, Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, 155 Hanzhong Road, Nanjing 210029, P.R. China. E-mail: [email protected] Submitted: April 2, 2014, accepted (with revisions): July 7, 2014
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ª 2014 Elsevier Inc. All Rights Reserved
Metabolic evaluation was performed to determine the metabolic disorders in this child. Blood chemistry studies included the determination of serum calcium, phosphorus, sodium, potassium, chloride, blood urea nitrogen, urate, creatinine, and parathyroid hormone levels. They were all in the normal range. Urinalysis showed 14 red blood cells/high power field (hpf) (normal range, 0-12 red blood cells/hpf), 15 white blood cells/hpf (normal range 0-12 white blood cells/hpf), 2þ vitamin C (normal range: negative), and protein negative. The levels of calcium, phosphorus, sodium, potassium, magnesium, creatinine, oxalate, and citrate were measured in a 24-hour urine collection. Results showed that the excretion of oxalate in urine was extremely high, reaching up to 278 mg/24 h, whereas the excretion of citrate was only 150.39 mg/24 h. Ureteral stone of the child was treated by shock wave lithotripsy with Dornier Compact S II (Dornier MedTech, Germany). Two days after shock wave lithotripsy, stone fragments were spontaneously passed. Stone was composed of calcium oxalate dehydrate and calcium oxalate monohydrate, determined by infrared spectroscopy (Fig. 2). On further questioning, his parents did mention the habit of taking about 3 g per day of vitamin C effervescent tablets since the age of 3 years to avoid colds and flu. To decide the effect of vitamin C on the urine oxalate excretion in this patient, vitamin C supplementation was prohibited, and no other therapy or change of dietary intake was performed. Three months later, no stone was found by ultrasonography, and the excretion of oxalate and citrate in 24hour urine was tested again. The result showed that the excretion of oxalate and citrate was 12.62 mg/24 h and 162.20 mg/24 h, respectively. Subsequently, a 3-year http://dx.doi.org/10.1016/j.urology.2014.07.021 0090-4295/14
Figure 1. Plain x ray of the kidneys, ureters, and bladder (KUB) acquired in our patient before shock wave lithotripsy. KUB shows an approximately 7-mm stone (arrow) in the left ureter. (Color version available online.)
Figure 2. Infrared spectrogram of the urinary stone in our patient. The spectrogram determined that the stone was composed of calcium oxalate dehydrate and calcium oxalate monohydrate.
follow-up was performed. Vitamin C supplementation was prohibited. The excretion of oxalate ranged from 10.3 to 20.4 mg/24 h, whereas that of citrate ranged from 159.7 to 180.5 mg/24 h. No urinary stones were found by ultrasonography during this period.
COMMENT As described by Ralli et al5 in the 1930s, vitamin C is excreted by kidneys through filtration and active tubular reabsorption. The metabolism of vitamin C to oxalate was later described in the 1960s by other investigators.6,7 Most of the oxalate in urine is produced endogenously as a metabolic end product of glyoxylic acid (50%-70%) and ascorbic acid (30%-50%), with minor contributions by UROLOGY 84 (4), 2014
gelatin, tryptophan, phenylalanine, and so on.8 In recent years, more and more evidences support that high dose of vitamin C intake could significantly increase urine oxalate excretion in healthy people and urinary stone patients, and hence, the risk of calcium stone formation.9,10 Nevertheless, till now, no literature has reported a direct relation between high-dose supplementation of vitamin C and the formation of calcium oxalate stone. In our patient, extremely high hyperoxaluria was found. The extremely high excretion of oxalate in urine may be the major pathogenic factor in this child. First, the extremely high excretion of oxalate may indicate the primary hyperoxaluria. Both primary hyperoxaluria type I and II usually present during childhood 923
with early stone formation, tissue deposition of oxalate, and renal failure due to nephrocalcinosis. Death often occurs before the age of 20 years in untreated patients.11 However, in this case, the stone formation was present in childhood, but only single ureteral stone of about 8 mm was found, without family history of urolithiasis. Thus, primary hyperoxaluria was not the first diagnosis considered. Second, enteric hyperoxaluria was also excluded because of no history of enteric diseases and surgeries. Finally, hyperoxaluria could occur as a result of dietary intake or drugs such as vitamin C. Thus, high-dose supplementation with vitamin C was considered as the major reason of hyperoxaluria in our patients. After prohibiting the supplementation with vitamin C for months, the urine oxalate excretion decreased to normal range, and no stone formation was presented in the 3-year follow-up. In conclusion, our study first reported that the highdose supplementation with vitamin C for years could induce high urine excretion of oxalate and subsequently cause the formation of the urinary stone in a child. References 1. Williams HE, Wandzilak TR. Oxalate synthesis, transport and the hyperoxaluric syndromes. J Urol. 1989;141:742-747.
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2. Trinchieri A, Mandressi A, Luongo P, et al. The influence of diet on urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone formers. Br J Urol. 1991;67:230-236. 3. Urivetzky M, Kessaris D, Smith AD. Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis. J Urol. 1992;147: 1215-1218. 4. Trinchieri A, Ostini F, Nespoli R, et al. Hyperoxaluria in patients with idiopathic calcium nephrolithiasis. J Nephrol. 1998;11(Suppl 1):70-72. 5. Ralli EP, Friedman GJ, Rubin SH. The mechanism of the excretion of vitamin C by the human kidney. J Clin Invest. 1938;17: 765-770. 6. Takenouchi K, Aso K, Kawase K, et al. On the metabolites of ascorbic acid, especially oxalic acid, eliminated in urine, following the administration of large amounts of ascorbic acid. J Vitaminol (Kyoto). 1966;12:49-58. 7. Takiguchi H, Furuyama S, Shimazono N. Urinary oxalic acid excretion by man following ingestion of large amounts of ascorbic acid. J Vitaminol. 1966;12:307-312. 8. Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 1997;41:269-282. 9. Massey LK, Liebman M, Kynast-Gales SA. Ascorbate increases human oxaluria and kidney stone risk. J Nutr. 2005;135:16731677. 10. Baxmann AC, De O G Mendonc¸a C, Heilberg IP. Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients. Kidney Int. 2003;63:1066-1071. 11. Hockaday T, Clayton JE, Frederick EW, et al. Primary hyperoxaluria. Medicine (Baltimore). 1964;43:315-346.
UROLOGY 84 (4), 2014
V
itamin C (ascorbic acid, ascorbate) is an essential micronutrient involved in many biological and biochemical functions, acting as an electron donor or a reducing agent in chemical reactions. Its supplementation is widely practiced in many countries, such as China. Besides, vitamin C is also a precursor of oxalate. As a result, high dose of vitamin C supplements increases urinary oxalate excretion1 and subsequently may increase the risk of calcium oxalate kidney stones.2-4 However, there is no case report about this association. We report a case of pediatric urolithiasis, which may have been induced by high intake of vitamin C.
CASE REPORT In April 2011, a 9-year-old boy was admitted to our hospital with intermittent left colic pain, hematuria, mild nausea, and vomiting for 1 month. Left ureteral stone (arrow in figure) was diagnosed by plain x ray of the kidneys, ureters, and bladder (Fig. 1). Physical examination showed percussion pain in the left renal region. No family history of urolithiasis was found. Xuehua Chen and Luming Shen contributed to the work equally and should be regarded as co-first authors. Financial Disclosure: Luming Shen is a member of the Foundation of Jiangsu Province Hospital of Traditional Chinese Medicine. The other authors declare that they have no relevant financial interests. Funding Support: This study was supported by the grant from the Foundation of Jiangsu Province Hospital of Traditional Chinese Medicine (Y13033), Jiangsu Province, P.R. China. From the Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China Reprint requests: Xiaojian Gu, Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, 155 Hanzhong Road, Nanjing 210029, P.R. China. E-mail: [email protected] Submitted: April 2, 2014, accepted (with revisions): July 7, 2014
922
ª 2014 Elsevier Inc. All Rights Reserved
Metabolic evaluation was performed to determine the metabolic disorders in this child. Blood chemistry studies included the determination of serum calcium, phosphorus, sodium, potassium, chloride, blood urea nitrogen, urate, creatinine, and parathyroid hormone levels. They were all in the normal range. Urinalysis showed 14 red blood cells/high power field (hpf) (normal range, 0-12 red blood cells/hpf), 15 white blood cells/hpf (normal range 0-12 white blood cells/hpf), 2þ vitamin C (normal range: negative), and protein negative. The levels of calcium, phosphorus, sodium, potassium, magnesium, creatinine, oxalate, and citrate were measured in a 24-hour urine collection. Results showed that the excretion of oxalate in urine was extremely high, reaching up to 278 mg/24 h, whereas the excretion of citrate was only 150.39 mg/24 h. Ureteral stone of the child was treated by shock wave lithotripsy with Dornier Compact S II (Dornier MedTech, Germany). Two days after shock wave lithotripsy, stone fragments were spontaneously passed. Stone was composed of calcium oxalate dehydrate and calcium oxalate monohydrate, determined by infrared spectroscopy (Fig. 2). On further questioning, his parents did mention the habit of taking about 3 g per day of vitamin C effervescent tablets since the age of 3 years to avoid colds and flu. To decide the effect of vitamin C on the urine oxalate excretion in this patient, vitamin C supplementation was prohibited, and no other therapy or change of dietary intake was performed. Three months later, no stone was found by ultrasonography, and the excretion of oxalate and citrate in 24hour urine was tested again. The result showed that the excretion of oxalate and citrate was 12.62 mg/24 h and 162.20 mg/24 h, respectively. Subsequently, a 3-year http://dx.doi.org/10.1016/j.urology.2014.07.021 0090-4295/14
Figure 1. Plain x ray of the kidneys, ureters, and bladder (KUB) acquired in our patient before shock wave lithotripsy. KUB shows an approximately 7-mm stone (arrow) in the left ureter. (Color version available online.)
Figure 2. Infrared spectrogram of the urinary stone in our patient. The spectrogram determined that the stone was composed of calcium oxalate dehydrate and calcium oxalate monohydrate.
follow-up was performed. Vitamin C supplementation was prohibited. The excretion of oxalate ranged from 10.3 to 20.4 mg/24 h, whereas that of citrate ranged from 159.7 to 180.5 mg/24 h. No urinary stones were found by ultrasonography during this period.
COMMENT As described by Ralli et al5 in the 1930s, vitamin C is excreted by kidneys through filtration and active tubular reabsorption. The metabolism of vitamin C to oxalate was later described in the 1960s by other investigators.6,7 Most of the oxalate in urine is produced endogenously as a metabolic end product of glyoxylic acid (50%-70%) and ascorbic acid (30%-50%), with minor contributions by UROLOGY 84 (4), 2014
gelatin, tryptophan, phenylalanine, and so on.8 In recent years, more and more evidences support that high dose of vitamin C intake could significantly increase urine oxalate excretion in healthy people and urinary stone patients, and hence, the risk of calcium stone formation.9,10 Nevertheless, till now, no literature has reported a direct relation between high-dose supplementation of vitamin C and the formation of calcium oxalate stone. In our patient, extremely high hyperoxaluria was found. The extremely high excretion of oxalate in urine may be the major pathogenic factor in this child. First, the extremely high excretion of oxalate may indicate the primary hyperoxaluria. Both primary hyperoxaluria type I and II usually present during childhood 923
with early stone formation, tissue deposition of oxalate, and renal failure due to nephrocalcinosis. Death often occurs before the age of 20 years in untreated patients.11 However, in this case, the stone formation was present in childhood, but only single ureteral stone of about 8 mm was found, without family history of urolithiasis. Thus, primary hyperoxaluria was not the first diagnosis considered. Second, enteric hyperoxaluria was also excluded because of no history of enteric diseases and surgeries. Finally, hyperoxaluria could occur as a result of dietary intake or drugs such as vitamin C. Thus, high-dose supplementation with vitamin C was considered as the major reason of hyperoxaluria in our patients. After prohibiting the supplementation with vitamin C for months, the urine oxalate excretion decreased to normal range, and no stone formation was presented in the 3-year follow-up. In conclusion, our study first reported that the highdose supplementation with vitamin C for years could induce high urine excretion of oxalate and subsequently cause the formation of the urinary stone in a child. References 1. Williams HE, Wandzilak TR. Oxalate synthesis, transport and the hyperoxaluric syndromes. J Urol. 1989;141:742-747.
924
2. Trinchieri A, Mandressi A, Luongo P, et al. The influence of diet on urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone formers. Br J Urol. 1991;67:230-236. 3. Urivetzky M, Kessaris D, Smith AD. Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis. J Urol. 1992;147: 1215-1218. 4. Trinchieri A, Ostini F, Nespoli R, et al. Hyperoxaluria in patients with idiopathic calcium nephrolithiasis. J Nephrol. 1998;11(Suppl 1):70-72. 5. Ralli EP, Friedman GJ, Rubin SH. The mechanism of the excretion of vitamin C by the human kidney. J Clin Invest. 1938;17: 765-770. 6. Takenouchi K, Aso K, Kawase K, et al. On the metabolites of ascorbic acid, especially oxalic acid, eliminated in urine, following the administration of large amounts of ascorbic acid. J Vitaminol (Kyoto). 1966;12:49-58. 7. Takiguchi H, Furuyama S, Shimazono N. Urinary oxalic acid excretion by man following ingestion of large amounts of ascorbic acid. J Vitaminol. 1966;12:307-312. 8. Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 1997;41:269-282. 9. Massey LK, Liebman M, Kynast-Gales SA. Ascorbate increases human oxaluria and kidney stone risk. J Nutr. 2005;135:16731677. 10. Baxmann AC, De O G Mendonc¸a C, Heilberg IP. Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients. Kidney Int. 2003;63:1066-1071. 11. Hockaday T, Clayton JE, Frederick EW, et al. Primary hyperoxaluria. Medicine (Baltimore). 1964;43:315-346.
UROLOGY 84 (4), 2014
