Elsevier

Metabolism

Volume 58, Issue 2, February 2009, Pages 263-269
Metabolism

Oxalic acid excretion after intravenous ascorbic acid administration

https://doi.org/10.1016/j.metabol.2008.09.023Get rights and content

Abstract

Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at −30°C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.

Introduction

Oxalic acid is a major end product of ascorbic acid oxidation, and it has the potential to crystallize as calcium oxalate in the urinary space. An oral dose of 500 mg ascorbic acid modestly increases urinary oxalic acid excretion and could theoretically increase the risk of stone formation in susceptible people [1], [2], [3], [4]. The rate limitation of intestinal ascorbic acid transport makes it unlikely that oral doses greater than 500 mg/d will increase oxalic acid excretion and stone risk proportionately [5], [6], but intravenous administration bypasses this barrier. In an early study, 44% of the radioactivity in an intravenous dose of 14C-ascorbic acid was recovered in the urine as oxalic acid [7]. In the setting of renal dysfunction, acute oxalate nephropathy has been reported after intravenous ascorbic acid administration [8], [9], [10]. Increased urinary oxalic acid excretion has also been reported in connection with parenteral nutrition solutions that included 200 to 500 mg/d of ascorbic acid [11], [12]. Much larger doses than this have been administered therapeutically in recent years [13], [14], [15], [16], but without any information about the associated rate of oxalic acid excretion.

Barriers to the study of oxalic acid formation during ascorbic acid treatment are interference with the analysis by high ascorbic acid concentrations and in vitro conversion of excreted ascorbic acid to oxalic acid in the collection vessel or during storage or analysis [2], [17], [18], [19], [20]. In this study, we overcame these barriers by immediately acidifying urine specimens and promptly storing them at very low temperature and by developing a gas chromatography mass spectrometry (GC-MS) technique that avoids alkaline extraction [21], which oxidizes ascorbic acid to oxalic acid [2]. This method was then used to analyze the pattern of urinary oxalic acid excretion in patients participating in a clinical trial of high-dose intravenous ascorbic acid as cancer therapy.

Section snippets

Study participants and clinical trial design

Urinary oxalic acid excretion was measured in 11 men and 5 women (age, 58 ± 17 years; weight, 69 ± 18 kg; mean ± SD) participating in a phase I clinical trial of intravenous ascorbic acid in advanced cancer [22]. All participants in the trial had good functional status, were biochemically screened for glucose-6-phosphate dehydrogenase deficiency—which is associated with hemolytic episodes after high-dose ascorbic acid infusions [17]—had undergone an abdominal x-ray examination to screen for

Method validation

As shown in Fig. 1, the SIM chromatograms for m/z 261 and 263 were well characterized, and a conventional calibration curve relating amounts of [12C2]- and [13C2]-oxalic acid to the measured intensity ratios of m/z 261 to m/z 263 was easily constructed. Recovery of physiologic amounts of oxalic acid added to 6 normal urine samples was 100% ± 6.9% (mean ± SD). Acid-only extraction, as used here, was compared with the conventional method involving base and acid extraction. Addition of ascorbic

Discussion

This article describes a novel method to analyze oxalic acid accurately in the presence of very high concentrations of ascorbic acid and its use to determine the urinary oxalic acid excretion profiles of patients administered very large intravenous doses of ascorbic acid.

Accurate oxalic acid analysis in the presence of ascorbic acid requires a strongly acid environment and sample storage at low temperature to prevent in vitro oxidation of ascorbic acid to oxalic acid. Acid conditions are also

Acknowledgment

This study was funded by a grant from the Lotte and John Hecht Memorial Foundation and from Research Resource Program Grant PRG-80160 from the Canadian Institutes of Health Research. WHM is a Chercheur National of the Fonds de la Recherche en Santé du Québec. ML is supported by the Intramural Research Program, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

References (38)

  • NasrS.H. et al.

    Secondary oxalosis due to excess vitamin C intake

    Kidney Int

    (2006)
  • Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes

    Dietary reference intakes: vitamin C, vitamin E, selenium, and beta-carotene and other carotenoids

    (2000)
  • JohnstonC.S.

    Biomarkers for establishing a tolerable upper intake level for vitamin C

    Nutr Rev

    (1999)
  • PadayattyS.J. et al.

    Vitamin C pharmacokinetics: implications for oral and intravenous use

    Ann Intern Med

    (2004)
  • McAllisterC.J. et al.

    Renal failure secondary to massive infusion of vitamin C

    JAMA

    (1984)
  • WongK. et al.

    Acute oxalate nephropathy after a massive intravenous dose of vitamin C

    Aust N Z J Med

    (1994)
  • LawtonJ.M. et al.

    Acute oxalate nephropathy after massive ascorbic acid administration

    Arch Intern Med

    (1985)
  • FairholmL. et al.

    Influence of multivitamin regimen on urinary oxalate in home parenteral nutrition patients

    Nutr Clin Pract

    (2003)
  • Pena de la VegaL. et al.

    Urinary oxalate excretion increases in home parenteral nutrition patients on a higher intravenous ascorbic acid dose

    JPEN J Parenter Enteral Nutr

    (2004)
  • Cited by (51)

    • Vitamin C and mitochondrial function in health and exercise

      2023, Molecular Nutrition and Mitochondria: Metabolic Deficits, Whole-Diet Interventions, and Targeted Nutraceuticals
    • Vitamin C supplementation for diabetes management: A comprehensive narrative review

      2023, Free Radical Biology and Medicine
      Citation Excerpt :

      A complicating issue of artefactual assay-related oxalate formation in samples handled and treated in a less than optimal manner may have confounded this relationship in some studies. While many studies in humans with normal renal function have not reported elevated levels of urinary oxalate following high dose vitamin C [2,95], greater uncertainty exists in relation to a safe vitamin C dose that avoids worsening of existing hyperoxaluria and an increased risk of kidney stones in individuals with end stage renal disease [95]. It may therefore be prudent to limit vitamin C supplementation to <500 mg per day in individuals who have end stage renal disease.

    • Fasting and cancer: from yeast to mammals

      2022, International Review of Cell and Molecular Biology
    • Vitamin C

      2020, Present Knowledge in Nutrition: Basic Nutrition and Metabolism
    • A Review of Nonantibiotic Agents to Prevent Urinary Tract Infections in Older Women

      2020, Journal of the American Medical Directors Association
      Citation Excerpt :

      Although found to be used for prevention of UTIs in older women, there have been no appreciable clinical studies generalizable to this population.18 Ascorbic acid therapy carries a risk for hyperoxaluria, and calcium oxalate stones.19–21 Patients who consume more than 1 g of ascorbic acid daily are observed to be at a higher risk for kidney stone formation.

    View all citing articles on Scopus
    View full text