influence of a high oxalate diet on oxalate intestinal absorption

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TOPIC PAPER

Diana J. Zimmermann Albrecht HesseGerd E. von Unruh

Inuence of a high-oxalate diet on intestinal oxalate absorption

Received: 16 September 2005 / Accepted: 4 October 2005 / Published online: 5 November 2005 Springer-Verlag 2005

Abstract Hyperoxaluria is a major risk factor for renalstones. In most cases, it is sustained by increased dietaryloads. In healthy individuals with a normal Western diet,the majority of urinary oxalate is usually derived fromendogenous metabolism. However, up to 50% may bederived from the diet. We were interested in the effect of a high-oxalate diet on oxalate absorption, not merely onthe frequently studied increased oxalate excretion. Instudy I, 25 healthy volunteers were tested with the[13 C 2 ]oxalate absorption test once while following a low-oxalate (63 mg) and once while following a high-oxalate(600 mg) diet for 2 days each. In study II, four volun-teers repeated study I, and afterwards continued with ahigh-oxalate diet (600 mg oxalate/day) for 6 weeks. Inthe last week, the [ 13 C 2 ]oxalate absorption test was re-peated. After 4 weeks of individual normal diet, the

oxalate absorption test with a high-oxalate diet wasperformed again. The results of study I show that themean [ 13 C 2 ]oxalate absorption under low-oxalate dietwas 7.94.0%. In the presence of oxalate-rich food, thepercent absorption for the soluble labelled oxalate al-most doubled (13.76.3%). The results of study II showthat the mean [ 13 C 2 ]oxalate absorption of the four vol-unteers under low-oxalate diet was 7.31.4%. Theabsorption increased to 14.75.2% under 600 mgoxalate. After 6 weeks under a high-oxalate diet, the

[13 C 2 ]oxalate absorption was signicantly decreased(8.21.7%). After the wash-out phase, the absorptionwas again high (14.12.2%) under the 600 mg oxalatechallenge.

Keywords High-oxalate diet Low-oxalate diet Oxalate absorption Oxalobacter formigenes

Introduction

Hyperoxaluria is a major risk factor for calcium oxalateurolithiasis, a disease typically occurring in affluentsocieties. Except for the rare condition of primary hy-peroxaluria, hyperoxaluria appears to be sustained byan increased dietary load. In normal individuals, themajority of urinary oxalate is derived from endogenousmetabolism, while 1020% is generally assumed to bederived from oral ingestion. However, in 2001, Holmeset al. [11] presented evidence that dietary oxalate maycontribute up to 50% of the oxalate excreted in urine.Liebman and Costa [ 15] reported similar results. Thus,dietary oxalate may play a more signicant role in cal-cium oxalate stone formation than what was previouslythought. Oxalate is present in large quantities in food of vegetable origin, cereal grains and some roots. Foodstuff that contain high levels of oxalate include spinach,rhubarb, beetroot, Swiss chard, carambola, black tea,cocoa powder and some nuts [ 9, 10]. The mean oxalate

intake under a Western diet is approximately 100 150 mg/day [ 12]. However, urban diets of the upper in-come group in India were reported to contain 600 mgoxalate per day and seasonal rural diets as much as2,000 mg [ 17]. Unfortunately, knowledge of the extentof gastrointestinal absorption of oxalate, especially theabsorption from high-oxalate diets, is still limited. Apartfrom the amount and chemical form of the oxalate inthe ingested foodstuff, the amount of free oxalate in thegastrointestinal tract, or physiological parameters of the individual, such as intestinal pH and transit time,

D. J. Zimmermann A. HesseDivision of Experimental Urology, Department of Urology,University of Bonn, Sigmund-Freud-Str 25,Bonn, 53105 Germany

D. J. Zimmermann ( & )Diabetes Research Institute, Koelner Platz 1,80804 Munich, GermanyE-mail: [email protected].: +49-89-30793110Fax: +49-89-3081733

G. E. von UnruhDepartment of Internal Medicine I, University of Bonn,Sigmund-Freud-Str 25, Bonn, 53105 Germany

World J Urol (2005) 23: 324329DOI 10.1007/s00345-005-0028-0


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oxalate absorption also depends on the amount of divalent cations, such as calcium and magnesium,simultaneously present in the chyme. These ca-tionsderived from ingested foodstuffs, liquids anddigestive secretionsare able to bind oxalate in the gutand decrease oxalate absorption [ 2, 21, 22].

This study was performed in order to compare andquantify the effect of a short (2 days) low-oxalate diet anda 2-day typical dietary oxalate load (oxalate intake fromspinach) on intestinal oxalate absorption and urinaryoxalate excretion. In a pilot study, the effect of a long-term (6 week) high-oxalate diet was also investigated.

Methods

Subjects

Twenty-ve healthy, non-hospitalised volunteers (13men, 12 women) participated in study I. The mean ageand mean BMI of the subjects were 298.8 years (range2162 years) and 222.5 kg/m 2 (range 1727 kg/m 2 ),respectively. Four of these subjects (two women: vol-unteers 1 and 3; and two men: volunteers 2 and 4)volunteered for study II also. Mean age and mean BMIof the four subjects were 3717 years (range 2662years) and 221.8 kg/m 2 (range 2024 kg/m 2 ),respectively.

Inclusion criteria were: (1) no history of renal stoneformation, (2) no gastrointestinal or renal disease, (3)negative kidney ultrasound, (4) oxalate excretion of


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8.0.0 was used. The results of descriptive statistics aregiven as mean standard deviation (SD). The signi-cance of differences was calculated by the non-para-metric Wilcoxon test for paired samples; P 0.05 wasconsidered signicant.

Results

Study I: The mean [ 13 C 2 ]oxalate absorption of all 25volunteers under low-oxalate diet was 7.94.0% of the50 mg dose of sodium [ 13 C 2 ]oxalate, range 1.818.0%(women 6.93.8%, men 9.04.0%). Owing to theshort-term enrichment of diet with oxalate-rich food,more oxalate (labelled and unlabelled) was absorbed.The percent absorption for the soluble [ 13 C 2 ]oxalate wasalmost twice as high (13.76.3%, range 3.432.7%).There was no statistically signicant gender differencefor the increased [ 13 C 2 ]oxalate absorption (female vol-unteers absorbed 12.34.5% and male volunteers15.27.7% under high oxalate). With low oxalate, themean total (endogenous + unlabelled and labelledexogenous) oxalate excretion was 0.2840.092 mmol/day, range 0.1340.475 mmol/day. With 600 mg oxa-late, the mean total oxalate excretion increased to0.4850.098 mmol/day, range 0.2740.730 mmol/day,an increase of 71%. The mean increase by 0.201 mmoloxalate in the urine consisted of about 0.022 mmol[13 C 2 ]oxalate and 0.179 mmol unlabelled oxalate corre-sponding to approximately 3% of the oxalate ingested

with the spinach. Although men excreted more oxalatethan did women, there was no statistically signicantgender difference for the increased excretion. Femalevolunteers excreted 0.199 mmol/day and male volun-teers an 0.203 mmol/day additional under high oxalate.Figures 1 and 2 show the individual oxalate absorptionsand the individual oxalate excretions for each subject onthe second day of both oxalate absorption tests. Meanand SD values are also indicated.

Both gures illustrate the changes in the absorptiontests under low-oxalate diet compared to those under the

high-oxalate diet as well as the high mean increase in[13 C 2 ]oxalate absorption and total oxalate excretion. Inthree subjects, soluble oxalate absorption decreased.However, this decrease is within the intra-individualstandard deviation for repeated identical tests [ 20].

Table 1 represents the mean values of urinary vol-ume, oxalate, calcium, magnesium, sodium, potassium,citrate and the calculated relative supersaturation withcalcium oxalate on the second day of both oxalateabsorption tests. The baseline (rst oxalate absorptiontest) urinary volume and the excretion of calcium, so-dium and potassium did not differ signicantly from thatof the second test. However, there was a signicant de-cline in the urinary excretion of magnesium and citrate.Oxalate excretion increased and as a result of thesechanges the AP CaOx [18] also increased.

Study II: The mean [ 13 C 2 ]oxalate absorption of thefour volunteers under low-oxalate diet was 7.31.4%.The absorption increased to 14.75.2% with 600 mgoxalate/day on the second of the 2 days. In study I, themean absorption of these four volunteers under 600 mgoxalate/day for 2 days was 14.12.2%. Thus, the short-term effect of the high-oxalate diet was highly repro-ducible. After 6 weeks under high-oxalate diet, the mean[13 C 2 ]oxalate absorption was found to have signicantlydecreased from 14.75.2 to 8.21.7%. The meanabsorption at the end of 6 weeks of high-oxalate diet haddecreased by 40% relative to the beginning of the high-oxalate diet. The two female volunteers showed a drasticincrease and decrease; the two male subjects only amarginal change; none showed an increase in oxalateabsorption at the end of the 6 week high-oxalate diet.After the wash-out phase, the mean [ 13 C 2 ]oxalateabsorption increased again to 14.12.2% under the2 day 600 mg oxalate intake, further demonstrating thehigh reproducibility of the short-term effect of the high-oxalate diet. This sequence is illustrated in Fig. 3. Theconnecting lines allow one to follow the individualchanges more easily. They do not indicate the absorp-tion during the time without measurements between

0

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25

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[13C 2]oxalate absorption tests

oxalate absorption (%)

Fig. 1 [13 C 2 ]oxalate absorption (%) in the 25 volunteers for therst (63 mg oxalate diet) and the second (600 mg oxalate diet)[13 C 2 ]oxalate absorption test. The lines with the error bars representmean SD for the entire group

0.000

0.100

0.200

0.300

0.400

0.500

0.600

0.700

0.800

[13C 2]oxalate absorption tests

oxalate excretion (mmol / d)

Fig. 2 Urinary excretion of oxalate [mmol/day] in the 25 volunteersfor the rst (63 mg oxalate diet) and the second (600 mg oxalatediet) [ 13 C 2 ]oxalate absorption test. The lines with the error barsrepresent mean SD for the entire group

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tests. The two subjects who tested positive for O. for-migenes , one man and one woman, are indicated by aplus sign.

With low oxalate, the oxalate excretion of the fourvolunteers was 0.2830.091 mmol/day, range 0.193 0.387 mmol/day. With 600 mg oxalate, the mean oxalateexcretion increased to 0.4180.093 mmol/day, range0.3300.539 mmol/day. After 6 weeks under high oxalateconditions, the oxalate excretion was 0.4560.131 mmol/day, range 0.3000.613 mmol/day. After thewash-out phase and repeat challenge with the high-oxa-late diet, the mean oxalate excretion was 0.4590.083 mmol/day, range 0.3780.544 mmol/day (Fig. 4).

Discussion

Oxalate intake has an inuence on the pathogenesis of urolithiasis. It is generally known that a high-oxalateintake leads to an increase in oxalate excretion in the

urine [ 11]. However, no study investigating the effect of ahigh-oxalate diet on the oxalate absorption in the guthas been performed to date. The essential nding of study I is that consumption of oxalate-rich food (here:spinach) for 2 days drastically increased the percentoxalate absorption for soluble oxalate as early as on thesecond day. As shown in Figs. 1 and 2, on the secondday of the applied 2 day oxalate-rich diet, absorption of soluble [ 13 C 2 ]oxalate was increased by approximately73% and excretion of total oxalate in urine by approx-imately 71%. Apart from these hard experimental data,several important parameters that are required to fullyunderstand the fate of oxalate in humans could not bemeasured. These parameters can only be estimated.Known important missing parameters include theendogenous synthesis of oxalate, the pH prole of thegastrointestinal tract and the residence time of the diet/chyme in the different pH-compartments, as well as theamount of calcium excreted into the gastrointestinaltract by digestive secretions. For the interpretation of the data we made reasonable assumptions and usedpublished information.

About 7580% of the labelled oxalate that was ab-sorbed was found in the urine collected in the 6 h afteringestion; this excretion pattern was the same as foundpreviously in 120 healthy volunteers [ 20]. As this labelledoxalate was not only absorbed but also excreted in therst 6 h after ingestion, the spinach eaten 6 h after thelabelled oxalate should not have caused the increasedabsorption. We propose the following explanation forthe effect of the rst spinach meal on the absorption of soluble oxalate. The high oxalate absorption was causedby a reduced amount of readily available calcium andmagnesium in the gut. The [ 13 C 2 ]oxalate from the so-dium oxalate-lled capsules of the labelled test dose wasdissolved fully after 20 min. Some of the oxalate fromthe spinach was certainly also dissolved in the gastricjuice, whereas some of it was slowly liberated in theintestinal tract while the spinach cell walls were digested.Calcium in the daily digestive secretionsan amountcomparable to the daily urinary excretion of calcium[5]will be secreted over the entire day. Primarily, this

Table 1 Urinary parameters and AP CaOx (mean SD) of the 25volunteers of study I on the second day of both oxalate absorptiontests

First oxalateabsorption test(63 mg oxalate/day)

Second oxalateabsorption test(600 mg oxalate/day)

P

Volume(l/day)

2.4410.336 2.2880.507 n.s.

Oxalate(mmol/day)

0.2840.092 0.4850.098


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secreted calcium will complex the liberated plant oxalatedirectly in the gut. The oxalate load of the rst day of the test complexes free calcium and magnesium ions inthe gut even on the second day. Therefore, on the secondday, there are less unbound calcium and magnesium ionsin the chyme and a higher amount of ingested solubleoxalate is absorbed. The data only prove that more[13 C 2 ]oxalate from the readily soluble labelled sodiumoxalate was absorbed on the day after the rst spinachmeal. Whether more dietary oxalate was also absorbedcannot be determined from the present data.

To determine the amount of absorbed dietary oxalatein experiments without labelled oxalate from the excretedurinary oxalate, the exact endogenous oxalate synthesismust be known. Methods for the exact measurement of the endogenous oxalate synthesis under normal diet havenot been reported. The best approximations are themethod of oxalate free diet and fasting [ 8, 11]. Bothmethods would give the true endogenous oxalate syn-thesis if no dietary components were metabolised tooxalate in humans. However, this assumption is wrong.The alternative approach involves the calculation of theendogenous synthesis by subtracting the absorbed oxa-late from the excreted oxalate. Liebman and Chai [ 14]derived a formula to calculate the endogenous oxalateproduction from the result of a sodium oxalate load testunder a diet very low in oxalate. They assumed identicalpercentage absorptions for ingested dietary oxalate andsodium oxalate. In reality, the bioavailability of dietaryoxalate is lesser (roughly between one-third and two-thirds) than the bioavailability of sodium oxalate [ 3]. Theerror will be small if a low-oxalate diet is ingested.Multiplication of the amount of ingested dietary oxalateby the measured percent absorption of sodium oxalateyields an upper limit of the amount of exogenous oxalatein the 24 h urine. On each of our test days, exogenousoxalate consisted of the exactly measured labelled oxa-late and absorbed dietary oxalate. Using Liebmans for-mula, a mean endogenous oxalate production of [0.284-0.02923-(0.716 0.079)]=0.198 mmol/day or 17.5 mg/day can be calculated for the 25 volunteers of study I forthe low-oxalate diet. If we made the same calculation,assuming for dietary oxalate a relative bioavailability of 50% of the bioavailability of sodium oxalate, the meanendogenous oxalate synthesis would be 0.226 mmol/dayor 19.9 mg/day.

Assuming constant mean endogenous synthesis of 0.226 mmol/day also under the high-oxalate diet,0.259 mmol oxalate was of exogenous origin. Of theexogenous oxalate, 0.05 mmol was [ 13 C 2 ]oxalate,0.209 mmol was from the dietary oxalate. This calcula-tion indicates that 3% of the oxalate in the spinach wasabsorbed. This amount is within the range of publisheddata of bioavailability of oxalate from spinach [ 4].However, bioavailability of oxalate strongly depends onthe other dietary components as demonstrated by Hesse:oxalate absorption from spinach with cream was 80%less than from leafy spinach [ 6].

The short-term increase of oxalate absorption is ex-tremely important for understanding the occurrence of diet-induced intermittent hyperoxaluria, since oxalateabsorption under a short-term oxalate-rich diet may bemuch higher than expected. The ndings from our studyare consistent with results of Holmes et al. [ 11].Increasing the dietary oxalate from 50 to 250 mg per dayfor several days resulted in a 35% increase of the meanoxalate excretion of 12 healthy volunteers. In our study,the increase of ingested oxalate from 63 to 600 mg raisedthe excretion of soluble oxalate by 71%.

Following our ndings in the short-term (2 day)study, we were curious as to whether the high oxalateabsorption and excretion persisted under a long-termhigh-oxalate diet. Consequently, we performed a pilotstudy with four healthy volunteers from study I andtested the inuence of a short-term as well as a long-termhigh-oxalate diet on the intestinal oxalate absorptionand urinary oxalate excretion. Simultaneously, therepeatability of the short-term effect was assessed andconrmed by the results.

The mean oxalate absorption of these four volunteerson the second day of the high-oxalate diet was exactly of the same order of magnitude as that of their rst short-term study results (14.1 and 14.7%, respectively).However, after 6 weeks under a high-oxalate intake, theabsorption of soluble oxalate was 40% lower than at thestart of the high-oxalate diet. In the two male volunteers,the reduction was minimal; in the two female volunteers,however, it was extreme. The results of this pilot studywith only four subjects allow no denitive conclusions,especially as study I showed no gender differences,conrming earlier results [ 20]. However, they point topreviously unrecognised effects indicating the need forextended studies.

At present, we can only speculate about the reasonsfor this decrease of oxalate absorption under a high-oxalate diet. One plausible explanation would be thegrowth of the oxalate degrading bacterial population inthe gut. We tested faecal samples of the volunteers of study II for the presence of O. formigenes , the mostprominent microorganism capable of oxalate degrada-tion [ 1]. Two volunteers were O. formigenes positive, twowere negative. As can be clearly observed in Fig. 3,presence of O. formigenes cannot be the only explana-tion. However, as can be seen from Fig. 4, the twovolunteers who tested positive for O. formigenes alwaysexcreted less oxalate than the two volunteers who testednegative. We did not test for other microbes known todegrade oxalate [ 13]. Another explanation would be anadaptive increase of the calcium excretion into theintestinal uid driven by the high-oxalate content of thechyme. Whatever the reason for the reduction of theoxalate absorption under long-term high-oxalate diet,this effect is important for people regularly ingesting anoxalate-rich diet, such as vegetarians. This protectiveadaptation was absent after 4 weeks of a normal mixeddiet.

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The nding that on the second day of a high-oxalatediet the absorption of the soluble [ 13 C 2 ]oxalate had in-creased drastically offers an explanation for the puzzlingobservation that only one-third of the recurrent idio-pathic stone formers have been classied as oxalatehyperabsorbers [ 7]. If a small stone exists, a few days of high-oxalate diet may be sufficient to support slowgrowth of the calcium oxalate urolith even in low oxa-late absorbers, as indicated by the increase of theAP CaOx -index (Table 1).

Conclusion

A short-term oxalate-rich diet increases the percentageof intestinal soluble oxalate absorption. Subjects withhigh endogenous synthesis will experience hyperoxalu-ria. Under a long-term oxalate-rich diet, there exists anas-yet unexplained adaptation reducing, though noteliminating, an increase in the percentage of the intesti-nal oxalate absorption. As a high-oxalate load in urineplays a central role in calcium oxalate stone growth,these results stress the necessity to eliminate oxalate-richfood from the diet of calcium oxalate stone formers.

Acknowledgements The study was supported in part by a grant of Deutsche Forschungsgemeinschaft (UN91/3). Skilful technicalassistance by B. Ba r and M. Klo ckner is gratefully acknowledged.Dr. S. Voss measured the oxalate content of the diets and food-stuffs and M.E. Schmidt, MD performed the ultrasound examin-ations.

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8. Hodgkinson A (1978) Evidence of increased oxalate absorptionin patients with calcium-containing renal stones. Clin Sci MolMed 54:291294

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11. Holmes RP, Goodman HO, Assimos DG (2001) Contributionof dietary oxalate to urinary oxalate excretion. Kidney Int59:270276

12. Holmes RP, Assimos DG (2004) The impact of dietary oxalateon kidney stone formation. Urol Res 32:311316

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16. Sidhu H, Allison MJ, Peck AB (1997) Identication and clas-sication of Oxalobacter formigenes strains by using oligonu-cleotide probes and primers. J Clin Microbiol 35:350353

17. Singh PP, Kothari LK, Sharma DC, Saxena SN (1972)Nutritional value of foods in relation to their oxalic acid con-tent. Am J Clin Nutr 25:11471152

18. Tiselius HG (1991) Aspects on estimation of the risk of calciumoxalate crystallization in urine. Urol Int 47:255259

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influence of a high oxalate diet on oxalate intestinal absorption

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