2005 The American Society for Nutritional Sciences J. Nutr.

135:1673-1677, July 2005

Human Nutrition and Metabolism

Ascorbate Increases Human Oxaluria and Kidney Stone Risk 1,2

Linda K. Massey3, Michael Liebman* and Susan A. Kynast-Gales

Department of Food Science and Human Nutrition, Washington State University, Spokane, WA
and * Department of Family and Consumer Sciences (Nutrition), University of Wyoming,
Laramie, WY

3
To whom correspondence should be addressed. E-mail: massey@wsu.edu

   ABSTRACT

Currently, the recommended upper limit for ascorbic acid (AA) intake is 2000 mg/d. However,
because AA is endogenously converted to oxalate and appears to increase the absorption of
dietary oxalate, supplementation may increase the risk of kidney stones. The effect of AA
supplementation on urinary oxalate was studied in a randomized, crossover, controlled design in
which subjects consumed a controlled diet in a university metabolic unit. Stoneformers (n = 29;
SF) and age- and gender-matched non-stoneformers (n = 19; NSF) consumed 1000 mg AA
twice each day with each morning and evening meal for 6 d (treatment A), and no AA for 6 d
(treatment N) in random order. After 5 d of adaptation to a low-oxalate diet, participants lived for
24 h in a metabolic unit, during which they were given 136 mg oxalate, including 18 mg 13C2
oxalic acid, 2 h before breakfast; they then consumed a controlled very low-oxalate diet for 24 h.
Of the 48 participants, 19 (12 stoneformers, 7 non-stoneformers) were identified as responders,
defined by an increase in 24-h total oxalate excretion > 10% after treatment A compared with N.
Responders had a greater 24-h Tiselius Risk Index (TRI) with AA supplementation (1.10 ± 0.66
treatment A vs. 0.76 ± 0.42 treatment N) because of a 31% increase in the percentage of oxalate
absorption (10.5 ± 3.2% treatment A vs. 8.0 ± 2.4% treatment N) and a 39% increase in
endogenous oxalate synthesis with treatment A than during treatment N (544 ± 131 A vs. 391 ±
71 µmol/d N). The 1000 mg AA twice each day increased urinary oxalate and TRI for calcium
oxalate kidney stones in 40% of participants, both stoneformers and non-stoneformers.

KEY WORDS: • vitamin C • ascorbic acid • hyperoxaluria • nephrolithiasis • oxalate

The current recommended upper limit for ascorbic acid (AA) 4 is 2000 mg/d (1). A small
percentage (1.5%) of ingested AA is converted in vivo to oxalate (2), which is excreted without
further metabolism quantitatively in the urine over 24 h. It is uncertain whether amounts higher
than typical intakes from foods increase the risk for kidney stones (1). AA supplementation is
widely practiced in the United States; 12.4% of the U.S. adult population (3) and 12–14% of
stoneformers (4) reported taking 500 mg/d. We reported previously (5) that mean 13C2-oxalic
acid absorption was significantly higher in stoneformers (SF) than in non-stoneformers (NSF)
administered AA (treatment A; 10.7 ± 3.2% compared with 7.6 ± 2.6%) but not different between
these subpopulations not given any AA (treatment N; 9.0 ± 2.7% compared with 8.5 ± 2.6%). If
AA supplements are taken, the increased urinary oxalate may increase the risk of calcium
oxalate kidney stones.

1
Contradictory results from previous research evaluating the effect of AA supplementation on
urinary oxalate were attributed primarily to methodology that allowed in vitro degradation of
urinary AA to oxalate (6). However, early case studies suggested that genetic differences
contributed to the variable response to AA supplements (7). Small sample sizes and insufficient
dietary control have limited the identification of a subset of individuals that respond to AA
supplementation with increased urinary oxalate.

This study examined the effect of a divided dose of 2000 mg/d AA on oxalate excretion,
absorption, and endogenous synthesis, as well as the Tiselius Risk Index (TRI) for calcium
oxalate precipitability. The study design included strict control of dietary AA and oxalate. Both SF
and NSF were studied for ascorbate-induced changes in risk; subjects were also characterized
as responders or nonresponders.

   SUBJECTS AND METHODS

 
    Subjects. Individuals (n = 29) with a self-reported history of calcium oxalate stones and 20
age- and gender-matched non-stoneformers were recruited from participants in previous
nephrolithiasis studies, their families, and acquaintances (Table 1). All participants were at least
18 y old and without complicating medical conditions (renal, urinary tract, intestinal, thyroid,
parathyroid, skeletal, or nutritional disorders; uncontrolled hypertension or diabetes), or
medication or supplement use that affect calcium or oxalate metabolism. Nonprescription aspirin,
antacid, and laxative use were prohibited, but prescription medications were allowed if the
dosage had been stable for 3 mo and was the same for both study treatments. Six of the 29 SF
and 3 of the 20 NSF habitually consumed 500 mg of AA supplements several times each week;
they were asked to discontinue AA at least 1 wk before study participation because previous
studies showed that 3 d abstention was sufficient to eliminate the effects of AA on urinary
ascorbate and oxalate (8). Calcium supplements were restricted to 100 mg/d, and other habitual
nutrient supplements were limited to 100% of the Recommended Dietary Allowance during the
study. All participants were screened for normal fasting urinary calcium:creatinine ratio and
normal calcium absorption determined by 4-h urinary calcium excretion after a 1000-mg oral
calcium load [1 package Carnation French Vanilla Instant Breakfast (Nestle Food Company),
240 mL 2% low-fat milk, and 22 mL calcium glubionate syrup (Calciquid, Breckenridge
Pharmaceutical)]. Lean body mass was determined by air displacement plethysmography (Bod
Pod Body Composition System, Life Measurement) or bioelectrical impedance (Model BES
200Z, Bioelectrical Sciences) and used for the determination of completeness of daily urinary
collections by comparing expected creatinine with actual creatinine. Procedures were approved
by the Human Subjects Review Committee at Washington State University and written informed
consent was obtained from participants.

 TABLE 1 Participant characteristics at screening1

Stoneformers Non-stoneformers

n 29 19

2
Gender 19 M, 10 F 8 M, 11 F
Age, y 49.8 ± 14 50.8 ± 14.3
Weight, kg 88.8 ± 17.2 79.4 ± 16.0
BMI, kg/m2 30.5 ± 5.7 29.8 ± 6.7
Urinary calcium, mg/d 217 ± 118 164 ± 78
Urinary oxalate, mg/d 35 ± 8 33 ± 12
TRI 1.3 ± 0.6 0.9 ± 0.5

1
Valuesaremeans±SD.
    Metabolic study design. A randomized crossover design was employed, with each
volunteer participating in two 6-d experimental periods. Figure 1 depicts the experimental
design. During one experimental period (treatment A), they consumed 1000 mg AA
supplement (Nature Made Nutritional Products; no detectible oxalate by direct assay)
with the morning and evening meals during adaptation, and with the oxalate load at 0700
h and the evening meal at 1800 h in the metabolic unit. The alternate 6-d period
(treatment N) was exactly the same but without AA supplementation. Because the
oxaluric effect of AA reaches a plateau after 3 d ( 8), and urinary composition stabilizes
by d 4 and 5 of consuming a controlled diet ( 9,10), 5 d of adaptation were considered
sufficient. Each 6-d experimental period included 2 d of free-living adaptation with
consumption of a self-selected, self-recorded low-oxalate diet (excluding the 10 highest
known oxalate-containing foods: spinach, rhubarb, beets, tea, chocolate, nuts, wheat
bran, berries, parsley, beans, and other legumes), followed by an additional 3 d free-
living adaptation to a controlled low-oxalate diet (37–43 mg oxalate/d) provided by the
investigators, and concluded with 24 h in a metabolic unit consuming a controlled low-
oxalate diet (6–7 mg oxalate/d) (Table 2). Urinary AA levels were determined to verify AA
supplement compliance. In the metabolic unit, a staff member observed meals and
confirmed food, oxalate load, and AA supplement consumption by participants. All foods
were purchased from the same suppliers and lots, and were provided to participants in
weighed portions. The oxalate content of actual lots of all plant foods was measured
directly by oxalate oxidase assay (Trinity Biotech) after acid extraction ( 11). Caffeinated
or decaffeinated coffee was provided in regulated quantities because the oxalate content
was determined to be low, and caffeine does not affect oxalate excretion ( 12). Very low
oxalate varieties of herbal tea, but not regular tea, were also allowed in controlled
amounts. Diets were designed at both 8784 and 10,458 kJ/d to better accommodate
individual energy requirements. The nutrient composition of study diets was determined
by computerized diet analysis using Nutritionist Pro software (version1.3,2002,N-
SquaredComputing).

FIGURE 1 Experimental
design. Urine samples
collected between the
indicated times were
pooled. Ascorbic acid
(1000 mg AA, twice
each day) was given
during treatment A only.

3
 Viewlargerversion (23K):

TABLE 2 Composition of daily study diets at 2 energy levels1

Adaptation diet Metabolic unit diet
n = 20 n = 28 n = 20 n = 28

Energy, kJ 8837 10,460 9351 10,719

Protein, g 60 67 74 79
Ascorbic acid, mg 25 26 21 31
Calcium, mg 740 795 626 670
Magnesium, mg 124 148 163 174
Oxalate, mg 37 43 6 7
Sodium, mg 2969 3315 2728 2970

1
All participants consumed the same amount of food during the 2 treatments, whichever was
most appropriate for their energy expenditure.

At 0700 h on the morning of the metabolic unit stay, after a 12-h fast, participants were given a
136-mg oxalate load [18 mg 13C2-oxalic acid (Cambridge Isotope Laboratories) plus 118 mg
nonlabeled oxalate contained in a gel capsule] with 175 g of unsweetened applesauce and 240 mL
of deionized water. Meals in the metabolic unit were served at 0900, 1300, and 1800 h. The low-
oxalate breakfast consisted of a plain bagel, grape jam, cream cheese, yogurt, and apple juice.
Liberal deionized water intake was encouraged to promote a 24-h urine volume of 2–2.5 L.

During the 5-d adaptation, urine was collected in calibrated jugs containing 100 mL of 3 mmol/L
hydrochloric acid over 24-h periods. In the metabolic unit, urine was collected and pooled at 2-h
intervals for 8 h after the labeled oxalate load, then at two 3-h intervals, and finally after 10 h
overnight for a total of 24 h. All urine collected in the metabolic unit was immediately acidified to

4
pH < 2.0 by the addition of 20 mL of 3 mmol/L HCl at each collection interval to prevent in vitro
AA degradation to oxalate. Urine volumes were recorded, urine was filtered (#2 paper,
Whatman) and aliquots were quickly frozen at –20°C until assay.

    Biochemical analyses. Urine composition was determined as follows: AA by the

dinitrophenylhydrazine method (13); 13C2-oxalic acid by GC-MS (Metabolic Solutions); oxalate,
citrate, and creatinine by the microplate colorimetric oxalate oxidase (Sigma-Aldrich), citrate
lyase (14), and picric acid (15) methods, respectively, using a Sunrise light absorbency
microplate reader (Tecan); and calcium, magnesium, and sodium by inductively coupled plasma
optical emission spectrophotography (Optima 2000 DV, Perkin Elmer Instruments). Oxalate
absorption from the administered oxalate loads was determined by recovery of administered 13C2-
oxalic acid as described previously (5). Endogenous oxalate synthesis for urine samples
collected postoxalate loading was approximated by subtracting the oxalate absorbed [(recovered
13
C2-oxalic acid/administered 13C2-oxalic acid) x oxalate ingested at 0700 h via the oxalate load]
from the total urinary oxalate excretion over the specified time period. TRI for 24-h urine
collections was calculated using the formula by Tiselius (16), which relates the excretion in mmol
of 4 urinary components and urine volume in L as follows:

The TRI is a measure of calcium oxalate saturation, which predicts the risk of its precipitation.

    Statistical analyses. Statistical significance of differences between treatment A and

treatment N, SF and NSF, and between responders (participants with 10% greater oxalate
excretion with AA) and nonresponders, was determined by paired or 2-sample Student’s t test
using Excel software (version 10.3207.3131, 2002, Microsoft). Repeated measures ANOVA was
conducted using Number Cruncher (2001). Differences were considered significant when P
0.05. Values are presented as means ± SD.

   RESULTS

 
All 49 volunteers completed the metabolic study. Data from 1 NSF participant was dropped from
the analysis due to emesis after the combined oxalate and AA load, leaving 29 SF and 19 NSF
(Table 1) for the final analyses. Study diets (Table 2) were consumed per protocol as validated
by sodium excretion for free-living adaptation days. Sodium excretion was 102 ± 6% of
calculated dietary intake during adaptation days and metabolic unit study, and did not differ
between treatments A and N (data not shown). Urinary creatinine excretions during treatments A
and N were 105 and 109% (during adaptation), and 102 and 103% (during the metabolic study)
of expected urinary creatinine based on lean body mass, supporting the completeness of the
urine collections. Urine volumes did not differ between treatments A and N, between SF and
NSF, or between responders and nonresponders during adaptation or the metabolic study.

Ascorbate excretion decreased progressively over adaptation d 1, 3, and 5 for subjects

administered treatment N, and progressively increased over adaptation d 1, 3, and 5 for those
administered treatment A for all subjects (data not shown). Urinary ascorbate did not differ
between SF and NSF, or between responders and nonresponders administered the same
treatment. Oxalate excretion decreased progressively over adaptation d 3–5 in subjects
administered both treatments, and similarly for both SF and NSF (data not shown). Dietary
oxalate was only 40 mg/d during adaptation, less than typical intakes of 150 mg/d (17).

5
In SF, but not NSF, 24-h urinary oxalate was higher during treatment A compared with treatment
N (Table 3). When SF were categorized as clinically hyperoxaluric (mean total oxalate 450
µmol for the 2 screening days) or normooxaluric, the hyperoxaluric SF had significantly higher
oxalate absorption and endogenous synthesis than normooxaluric individuals during treatment N
(Table 4). However, they were nonresponsive to the effects of AA on endogenous synthesis and
absorption, in that ascorbate-induced increases in these values were observed only in the
normooxaluric group.

TABLE 3 Biochemistry of 24-h urine and the risk index of stoneformers and non-stoneformers
when they were (A) or were not (N) administered AA during the metabolic unit study1

Stoneformers (n = 29) Non-stoneformers (n = 19)

N A N A

Volume, L 2.18 ± 0.66 2.13 ± 0.60 2.62 ± 1.17 2.60 ± 1.53

Ca, mmol 3.82 ± 1.63 3.79 ± 1.80 3.04 ± 1.44* 2.76 ± 1.41*
Citrate, mmol 5.85 ± 2.26 5.60 ± 2.23 6.35 ± 2.26* 5.67 ± 1.66
Mg, mmol 3.81 ± 1.15 3.75 ± 1.21 3.92 ± 1.28 3.83 ± 1.07
Oxalate, µmol 566 ± 103 659 ± 139 504 ± 104* 542 ± 173*
TRI 0.94 ± 0.45 1.10 ± 0.60 0.61 ± 0.45* 0.65 ± 0.41*

1
Values are means ± SD.

*
Different from stoneformers administered the same treatment;

different from those not administered AA within each group.

TABLE 4 Biochemistry of 24-h urine of hyperoxaluric and normooxaluric stoneformers when

they were (A) or were not (N) administered AA during the metabolic unit study1
Hyperoxaluric (n = 8) Normooxaluric (n = 21)
N A N A

Total oxalate, µmol 643 ± 90 669 ± 125 536 ± 93* 655 ± 147
Endogenous oxalate, µmol 43 ± 5 44 ± 10 37 ± 7* 44 ± 10
Oxalate absorption, % 10.9 ± 3.1 11.2 ± 3.3 8.2 ± 2.0* 10.6 ± 3.4
TRI 1.11 ± 0.54 1.21 ± 0.90 0.88 ± 0.40 1.06 ± 0.48

1
Values are means ± SD.

*
Different from hyperoxaluric stoneformers administered the same treatment;

6
 different from those not administered AA within each group.

Nineteen of 48 participants were identified as responders, defined by increased 24-h oxalate

excretion >10% after A compared with N administration during the metabolic unit study; 12
responders were SF and 7 were NSF. Responders were slightly older than nonresponders (56 ± 13
compared to 47 ± 13 y, P = 0.02). Gender was not related to oxaluric response to AA. Responders
had higher 24-h TRI with treatment A compared with N (Table 5). The higher total oxalate
excretion in responders with AA supplementation could be attributed to a combination of higher
oxalate absorption and higher endogenous oxalate (Table 5).

TABLE 5 Biochemistry of 24-h urine of responders and nonresponders when they were (A) or
were not (N) administered AA during the metabolic unit study1
Responders (n = 19) Nonresponders (n = 29)
N A N A

Total oxalate, µmol 513 ± 97 707 ± 165* 560 ± 110 551 ± 129
Endogenous oxalate, µmol 391 ± 71 544 ± 131* 420 ± 80 500 ± 114
Oxalate absorption, % 8.0 ± 2.4 10.5 ± 3.2* 9.3 ± 2.7 8.9 ± 3.4
TRI 0.76 ± 0.42 1.11 ± 0.67* 0.84 ± 0.40 0.81 ± 0.49

1
Values are means ± SD.

*
Different from those not administered AA within each group;

different from the responder administered the same treatment.

   DISCUSSION
 
Consumption of 1000 mg AA twice each day resulted in 2 distinctly different oxaluric responses:
40% of individuals, including both SF and NSF, had increases in 24-h urinary oxalate 10%. The
other 60% had essentially no oxaluric response. It is not known what portion of a larger
population would have an AA-induced increase in urinary oxalate; the actual proportion could be
more or less than 40% when careful sampling is done. In an early report, Briggs (7) found only 3
of 67 individuals tested had an increase in urinary oxalate. Examination of individual responses
from 3 published studies in which 1000–2000 mg/d AA supplements were given (18–20) showed
that 7 of the total 19 subjects (38%) had a >10% increase in urinary oxalate, a proportion similar
to ours.

Results of this study concur with those of previous studies in demonstrating mean increases in
total oxalate excretion with AA supplementation. Baxmann et al. (21) reported a 61% urinary
oxalate increase in SF after 1000 mg AA/d, 41% after 2000 mg AA/d in SF, and 56% after 2000
mg AA/d in NSF. Chalmers et al. (22) studied 17 SF and 11 NSF consuming 2000 mg AA. They
found SF excreted 12% more oxalate than NSF without AA and 22% more with AA. Traxer et al.
(23) conducted a similar study with 12 SF and 12 NSF ingesting 1000 mg AA with each morning
and evening meal. Urinary oxalate excretion increased 33% (10 mg oxalate/d) in SF and 20% (6
mg oxalate/d) in NSF. As in our study, Traxer et al. (23) identified responders in both SF and
NSF. Although responders would be at increased risk to form stones with AA supplementation,
SF may not necessarily be responders to AA. Genetic susceptibility in study participants
probably accounts for most of the discordance in response to AA previously reported.
7
In our study, 79% of the AA-induced increase in total urinary oxalate in responders was
attributed to increased endogenous synthesis, and 21% to increased oxalate absorption. Hatch
(24) postulated the existence of 2 kinds of abnormalities leading to increased risk of kidney
stones, i.e., increased endogenous oxalate synthesis and increased oxalate absorption. In our
study population, both seemed to occur together in many individuals.

Of interest was the finding that normooxaluric SF, but not hyperoxaluric SF, exhibited increases
in endogenous oxalate synthesis and oxalate absorption in association with AA supplementation.
This was an unexpected finding because of the supposition that stoneformers with higher urinary
oxalate levels consuming their usual diets would be more sensitive to AA-induced increases in
urinary oxalate. However, a partial explanation may relate to the fact that by virtue of being
normooxaluric, there is more potential for a physiologic effect of AA on endogenous oxalate
synthesis and/or oxalate absorption to be clinically observed as an increase in oxaluria.

If endogenous synthesis of oxalate from AA is 1.5% of supplemental loads (2), increased

urinary oxalate from endogenous synthesis from two 1000-mg doses would be 30 mg or 341
µmol. The actual mean increase in total oxalate observed was 72 µmol for the study group as a
whole, 194 µmol in responders and –9 µmol in nonresponders. The increase is likely to be limited
by saturation of AA absorption and/or tissue uptake at doses lower than the 2000 mg/d used in
this study. This assertion is supported by Baxmann et al. (21) who reported that the increase in
urinary oxalate was no greater with 2000 than with 1000 mg/d in SF. If no more total AA was
absorbed from 2000 than from 1000 mg/d, the 194 µmol response in responders is close to the
170 µmol increase predicted from a 1.5% conversion rate. The remaining increase in urinary
oxalate, 24 µmol, would be from increased absorption. The oxaluric effect of 500 mg AA/d could
be roughly extrapolated from previously reported data from 6 individuals to be 40% less than
that from a 1000-mg dose (25). Because the health benefits of AA supplementation in doses >
500 mg/d are not substantiated (25), 500 mg/d may be considered the maximum dose for
individuals at risk for calcium oxalate kidney stones until further research on lower doses is
completed.

The increase in TRI associated with AA supplementation in this study was mediated primarily
through increased urinary oxalate excretion, with no effect on urinary calcium, magnesium, or
citrate. Baxmann et al. (21) identified increases in TRI and urinary oxalate in 47 SF and 20 NSF
randomly assigned to either 1000 mg AA (500 mg ingested 2 times/d) or 2000 mg AA (1000 mg
ingested 2 times/d) for 3 d. Before d 1 and on d 3, a 24-h urine sample was obtained. The
increase in TRI with administration of 1000 mg AA (0.51) was similar to that for 2000 mg AA
(0.56), suggesting that lower doses of AA than used in the present study may also be lithogenic.

Although urinary oxalate was shown to increase with AA supplementation, a direct association of
AA supplementation with stone incidence is not clear. Taylor et al. (26) recently reported that
1000 mg/d of supplemental vitamin C was associated with a 16% increase in the 14-y incidence
of kidney stones in the Health Professionals Follow-up Study. In contrast, an earlier report on the
women in the Nurses’ Health Study found no association (27). Because supplementation is often
sporadic (3), supplementation data collected at 1 dietary survey may not reflect the intake during
the whole time the individuals were followed for kidney stone occurrence. Also, our data show
that only 40% of our population had an oxaluric response, which would also obscure the risk in a
subset of genetically susceptible people. In our study, 21% of SF and 16% of NSF reported
taking AA supplements before participation. If only 12–20% of the genetically susceptible 40%
were taking supplements, it would be difficult to see an association in an epidemiologic study.

8
In summary, because an individual’s response to AA supplementation is not predictable, high-
dose AA supplementation should be considered cautiously, even for those individuals without a
history of stone formation.

   FOOTNOTES

1
Presented in part at the American Society for Bone and Mineral Research, October 5, 2004,
Seattle, WA [Massey, L., Kynast-Gales, S. & Liebman, M. (2004) Ascorbic acid supplementation,
urinary oxalate and risk of kidney stone disease. J. Bone Miner. Res. 19 (suppl. 1): S465 (abs.)].

2
Supported by a grant from the Vitamin Settlement Fund through the Attorney General’s Office
of Washington State and project 0370 Washington State University Agricultural Research Center.
4

Abbreviations used: AA, ascorbic acid; SF, stoneformers; NSF, non-stoneformers; treatment A,
2000 mg/d ascorbic acid; treatment N, no ascorbic acid supplement; TRI, Tiselius Risk Index.

Manuscript received 31 January 2005. Initial review completed 23 February 2005. Revision
accepted 7 April 2005.

   LITERATURE CITED

1. Food and Nutrition Board, Institute of Medicine. Vitamin C. Reference Dietary Intakes for
Vitamin C, Vitamin E, Selenium and Carotenoids. 2000 National Academies Press Washington,
DC.

2. Urivetzky M., Kessaris D., Smith A. D. Ascorbic acid overdosing: a risk factor for calcium
oxalate nephrolithiasis. J. Urol. 1992;147:1215-1218.[Medline]

3. Radimer K., Bindewald B., Hughes J., Ervin B., Swanson C., Picciano M. F. Dietary
supplement use by US adults: data from the National Health and Nutrition Examination Survey,
1999–2000. Am. J. Epidemiol. 2004;160:339-349.[Abstract/Free Full Text]

4. Wandzilak T. R., D’Andre S. D., Davis P. A., Williams H. E. Effect of high dose vitamin C on
urinary oxalate levels. J. Urol. 1994;151:834-837.[Medline]

5. Chai W., Liebman M., Kynast-Gales S., Massey L. Oxalate absorption and endogenous
oxalate synthesis from ascorbate in calcium oxalate stone formers and non-stone formers. Am.
J. Kidney Dis. 2004;44:1060-1069.[Medline]

6. Simpson G.L.W., Ortwerth B. J. The non-oxidative degradation of ascorbic at physiological

conditions. Biochim. Biophys. Acta. 2000;1501:12-24.[Medline]

9
7. Briggs M. Vitamin C-induced hyperoxaluria [Letter]. Lancet. 1976;1:154.[Medline]

8. Auer B. L., Auer D., Rodgers A. L. The effect of ascorbic acid ingestion on the biochemical
and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin.
Chem. Lab. Med. 1998;36:143-148.[Medline]

9. Massey L. K., Kynast-Gales S. A. Substituting milk for apple juice does not increase kidney
stone risk in most normocalciuric calcium oxalate stoneformers. J. Am. Diet. Assoc.
1998;98:303-308.[Medline]

10. Massey L. K., Kynast-Gales S. A. Both beef and plant protein diets lower risk of calcium
oxalate kidney stones. J. Am. Diet. Assoc. 2001;101:326-331.[Medline]

11. Ohkawa H. Gas chromatographic determination of oxalic acid in foods. J. Assoc. Off. Anal.
Chem. 1985;68:108-111.[Medline]

12. Massey L. K., Sutton R.A.L. Acute caffeine effects on urine composition and calcium kidney
stone formation risk in calcium stone formers. J. Urol. 2004;172:555-558.[Medline]

13. Roe J. H. Ascorbic acid in blood and urine. Seligsen D. eds. Standard Methods of Clinical
Chemistry 3. 1961:35-45 Academic Press New York, NY. .

14. Petrarulo M., Facchini P., Cerelli E., Marangella M., Linari F. Citrate in urine determined with
a new citrate lyase method. Clin. Chem. 1995;41:1518-1521.[Abstract/Free Full Text]

15. Scimone J., Rothstein R. Citrate in urine determined with a new citrate lyase method. Clinical
Chemistry. 1978:56-58 AVI Publishing Company Westport, CT.

16. Tiselius H. G. Aspects on estimation of the risk of calcium oxalate crystallization in urine.
Urol. Res. 1991;47:255-259.

17. Holmes R. P., Kennedy M. Estimation of the oxalate content of foods and daily oxalate
intake. Kidney Int. 2000;57:1662-1667.[Medline]

18. Schwille P. O., Schmiedl A., Herrmann U., Manoharan M., Fan J., Sharma D., Gottlieb D.
Ascorbic acid in idiopathic recurrent calcium urolithiasis in humans—does it have an abettor role
in oxalate, and calcium oxalate crystallization?. Urol. Res. 2000;28:167-177.[Medline]

19. Tiselius H. G., Almgard L.-E. The diurnal urinary excretion of oxalate and the effect of
pyridoxine and ascorbate on oxalate excretion. Eur. Urol. 1977;3:41-46.[Medline]

20. Liebman M., Chai W., Harvey E., Boenisch L. Effect of supplemental ascorbate and orange
juice on urinary oxalate. Nutr. Res. 1997;17:415-425.

21. Baxmann A., Mendonca C., Heilberg I. Effect of vitamin C supplements on urinary oxalate
and pH in calcium stone-forming patients. Kidney Int. 2003;63:1066-1071.[Medline]

22. Chalmers A. H., Cowley D. M., Brown J. M. A possible etiological role for ascorbate in calculi
formation. Clin. Chem. 1986;32:333-336.[Abstract/Free Full Text]

10
23. Traxer O., Huet B., Poindexter J., Pak C., Pearle M. Effect of ascorbic acid consumption on
urinary stone risk factors. J. Urol. 2003;170:397-401.[Medline]

24. Hatch M. Oxalate status in stone-formers. Urol. Res. 1993;21:55-59.[Medline]

25. Levine M., Conry-Cantilena C., Wang Y., Welch R. W., Washko P. W., Dhariwal K. R., Park
J. B., Lazarev A., Graumlich J. F., King J., Cantilena L. R. Vitamin C pharmacokinetics in healthy
volunteers: evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. U.S.A.
1996;93:3704-3709.[Abstract/Free Full Text]

26. Taylor E. N., Stampfer M. J., Curhan G. C. Dietary factors and the risk of incident kidney
stones in men: new insights after 14 years of follow-up. J. Am. Soc. Nephrol. 2004;15:3225-
3232.[Abstract/Free Full Text]

27. Curhan G. C., Willett W. C., Speizer F. E., Stampfer M. J. Intake of vitamins B6 and C and
the risk of kidney stones. J. Am. Soc. Nephrol. 1999;10:840-845.[Abstract/Free Full Text]

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