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Absence of Effect of Allopurinol on Oxalate Excretion by Stone Patients on Random and Controlled Diets
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Vcl. 144, July Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1990 by AMERICAN
UROLOGICAL ASSOCIATION) INC.
ABSENCE OF EFFECT OF ALLOPURINOL ON OXALATE EXCRETION BY STONE PATIENTS ON RANDOM AND CONTROLLED DIETS MORTON URIVETZKY, SUSAN BRAVERMAN, JAY A. MOTOLA
AND
ARTHUR D. SMITH
From the Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York
ABSTRACT
After 1 year of allopurinol treatment in 36 patients with a history of uric acid and/ or calcium oxalate lithiasis and hyperuricosuria, we observed that in addition to the desired decreases in uric acid there were apparently significant decreases in urinary oxalate levels: 37 ± 3 mg. per day (mean ± standard error) before therapy and 31 ± 4 mg. per day after a mean decrease of 16% (p <0.05) with an equivalent decrease in the supersaturation (calcium oxalate) of the urine. However, the decrease in oxalate could have been related to changes in dietary habits rather than to any specific effects of allopurinol on oxalate metabolism. Therefore, we recruited 26 of the patients for a study in which dietary factors were controlled. Each participant was assigned to 1 of 3 diet groups: low or high protein, or a customary diet. Each patient collected a urine specimen while on allopurinol and again after the medication was discontinued. With analytical procedures that we ascertained to be free of any significant methodological bias, we observed no significant changes in urinary oxalate excretion that could be attributed to allopurinol. There were significant differences in oxalate excretion on versus off allopurinol between the low and high protein groups, with higher oxalate levels found for the latter group. Our results indicate that allopurinol does not have a specific effect on oxalate metabolism or oxaluria. (J. Ural., 144: 97-98, 1990) Does allopurinol decrease urinary oxalate excretion? The drug, which is an inhibitor of xanthine oxidase, is used to decrease endogenous production of uric acid in patients with hyperuricosuria or hyperuricosemia. Most patients who are treated with the allopurinol at our clinic and at many other stone clinics have a history of uric acid and/ or calcium function lithiasis and have uricosuria before therapy. Because xanthine oxidase is 1 of 3 endogenous enzymes capable of catalyzing the oxidation of glyoxylate to oxalate, allopurinol also could have the potential to decrease urinary oxalate levels. Indeed, studies claiming that allopurinol therapy was able to decrease urinary oxalate levels or the recurrence of calcium oxalate stones have been reported previously. 1 - 3 There also are reports that have contradicted these claims. 4 - 6 The conflicting data and conclusions might be attributable to differences in environmental factors and/or methodologies used by the respective investigators. 6 With methods that did not introduce analytical bias, we studied the effect of allopurinol on oxaluria in stone patients while they were on customary as well as on controlled low or high protein diets.
imum total purine intake of 300 mg. per day. For both groups the maximum daily intake of oxalate and ascorbate was 120 and 100 mg., respectively. Each patient collected a 12-hour urine specimen beginning at 8 p.m. on day 3 of 2 test periods, the first while the patient was on allopurinol (1 morning dose) and the second 3 weeks after the drug had been discontinued. Group 3 consisted of 7 patients who remained on their own customary diet regimens for the first (on allopurinol) and second test periods. Analyses of the diet records showed 2,210 ± 105 KCal. protein (mean± 2 standard deviations) accounting for 16 ± 33% of total caloric intake, carbohydrate 60 ± 10%, ascorbate 120 ± 10 mg. per day, oxalate 160 ± 20 mg. per day and purines 240 ± 40 mg. per day. The patients in all 3 groups were requested to follow the same daily diet plans for the 3 days of each test period. All urine specimens were collected with ethylenediaminetetraacetic acid to stabilize ascorbate and oxalate, and kept at 4C until assay. 7 Analyses. Urine specimens that were to be analyzed for oxalate were treated with sodium nitrite to remove any ascorbate. 8 Oxalate then was determined by the Sigma enzymatic method as modified by Kasidas and Rose, 8 and by Crider and Curran. 9 Calcium and magnesium were determined by atomic absorption spectrophotometry and uric acid with uricase at 293 nM.; all other constituents were assayed by accepted clinical methodologies. In our hands the oxalate analysis has interassay and intrassay coefficients of variation of 5.6 and 1.8%, respectively, when urinary oxalate concentrations are between 20 and 40 mg./1. Urinary purine levels (as added guanosine) as high as 500 mg.fl. do not affect the results and uric acid levels as high as 600 mg./1. cause a maximum positive error of 4.7% (unpublished data). The statistical significance of the results was analyzed by the paired Student t test.
MATERIALS AND METHODS
Patients. The 36 adult outpatients whose blood and urine were monitored before and 1 year after the start of 300 mg. per day allopurinol therapy included 22 men 24 to 58 years old and 14 women 27 to 60 years old, all of whom had hyperuricosuria before treatment and normal urinary calcium levels. Of the patients 26 had a history of uric acid stones, 2 of calcium oxalate stones and 8 of uric acid plus calcium oxalate calculi. Of these patients 26 then participated in a 3-day study of diet effect. Group 1 consisted of 10 patients who consumed a low protein diet in which 12% of the total caloric intake (2,000 KCal.) was protein of high biological value, 65% was carbohydrate and the maximum purine intake was 200 mg. per day. Group 2 consisted of 9 patients matched to group 1 according to sex and stone history who consumed 25% of the total 2,000 KCal. intake as protein and 50% as carbohydrate with a max-
RESULTS
For the 36 patients who were tested on their customary diets before and 1 year after the start of allopurinol therapy we observed a 40% mean decrease in uric acid excretion and a 16% decrease in urinary oxalate excretion (table 1). In addition to the changes in uric acid and oxalate, the increases in urinary
Accepted for publication February 26, 1990.
97
98
URIVETZKY AND ASSOCIATES TABLE
1. Urinary constituents before and after 1 year of allopurinol in 36 patients Before* 826 37 147 928 83 154 5.62 2.05 2.84
Uric acid (mg./24 hrs.) Oxalate (mg./24 hrs.) Calcium (mg./24 hrs.) Phosphorus (mg./24 hrs.) Magnesium (mg./24 hrs.) Sodium (mEq./24 hrs.) pH Vol. (1/24 hrs.) Concentration product ratio of calcium oxalate
± ± ± ± ± ± ± ± ±
42 3 16 105 11 16 .10 .25 .28
After*
% Change
Significance (p value)t
± ± ± ± ± ± ± ± ±
-40.8 -16.2 0 5.6 15.7 -2.6 8.0 6.3 16.9
<0.005 <0.05 Not significant Not significant Not significant Not significant <0.005 Not significant <0.05
489 31 148 980 96 150 6.10 2.18 2.36
26 4 13 100 12 14 .11 .21 .24
* Mean ± standard error. t Paired t test.
Urine oxalate excretion on low protein (group 1), high protein (group 2) and customary (group 3) diets, and effect of allopurinol
TABLE 2.
Group
mMol. oxalate/mo!. creatinine: On allopurinol Off allopurinol Concentration product ratio of calcium oxalate: On allopurinol Off allopurinol
1
2
3
20 ± 3.8 24 ± 3.0
33 ± 4.2 35 ± 3.9
28 ± 3.0 30 ± 4.0
2.16 ± 0.25 2.18 ± 0.30
2.31 ± 0.30 2.27 ± 0.22
2.30 ± 0.28 2.31 ± 0.29
Values are mean ± standard error.
pH and volume (although the latter was not significant) contributed to the over-all decrease in the saturation of the urine with calcium oxalate. The 3 diet groups showed that there were no significant changes in the amounts of oxalate excreted that could be related to the discontinuation of allopurinol (table 2). A significantly greater amount of oxalate was excreted on or off allopurinol by the subjects on the high protein diet (group 2) than by those on the low protein diet (group 3) (p <0.05). The differences between group 1 or 2 and group 3 were not significant. DISCUSSION
Among the 36 stone patients who had received 1 year of allopurinol therapy there were, in addition to the predicted decreases in uric acid excretion, decreases in oxalate excretion content and the supersaturation of the urine with respect to calcium oxalate. These findings would be consistent with a decrease in the potential for calcium oxalate lithiasis and are in accord with those reported by other investigators. 1- 3 However, conflicting data and conclusions also have been published, perhaps attributable to environmental or methodological variables.4-6 For example, the decreases in urinary oxalate and in supersaturation we observed could have been the result of changes in the dietary habits. When we start our patients on allopurinol therapy they are advised to restrict the daily consumptions of protein of high biological value and, particularly when there is a history of calcium oxalate lithiasis or urinary oxalate levels of more than 30 mg. per day, foods with a high oxalate content. The observed decrease in oxaluria could, thus, have reflected changes in dietary habits rather than any specific effects of allopurinol on oxalate metabolism. Evidence has been presented, for example by Morris and associates, 6 that methodological factors also could have contributed to the conflicting results. In the analytical procedure we used oxalate and ascorbate were stabilized during collection, with any ascorbate present being removed by degradation be-
fore analysis. With recovery controls we ascertained that the amounts of purines and uric acid present in the analyzed specimens did not introduce a significant error in measured oxalate values. Thus, the methodology was of adequate specificity and reliability, and the comparisons of the data obtained in our studies should be valid. In the controlled diet studies the patients in each group (low or high protein, or customary diets) were instructed to follow the same daily diet plan during the 2 (on and off allopurinol) test periods. The diets of the patients in the low and high protein groups also were restricted with respect to the contents of oxalate, ascorbate and purines. With the conditions of diet and methodology described, we did not find any significant differences in the oxalate levels of specimens collected on versus off allopurinol for any diet, including the random diet. This was most likely attributable to the repetition of diet plans before urine collections. The only significant differences for urinary oxalate were those found between group 2 (high protein with the higher oxalate level) and group 1 (low protein) on and off the drug. We conclude that allopurinol does not alter oxalate metabolism. Thus, any decreases seen during drug therapy are, in the absence of methodological bias, attributable to diet or environmental factors and not allopurinol. REFERENCES
1. Scott, R., Paterson, P. J., Smith, M. and Mathieson, A.: Reduction in urinary oxalate values by allopurinol. Urology, 12: 212, 1978. 2. Tomlinson, B., Cohen, S. L., Al-Khader, A., Kasidas, G. P. and Rose, G. A.: Further reduction of oxalate excretion by allopurinol in stone formers on a low purine diet. In: Urolithiasis and Related Clinical Research. Edited by P. 0. Schwille, L. H. Smith, W. G. Robertson and W. Vahlensieck. New York: Plenum Press, pp. 513-517, 1985. 3. Ettinger, B., Tang, A., Citron, J. T., Livermore, B. and Williams, T.: Randomized trial of allopurinol in the prevention of calcium oxalate calculi. New Engl. J. Med., 315: 1386, 1986. 4. Fellstrom, B.: Allopurinol treatment in urolithiasis. In: Urolithiasis and Related Clinical Research. Edited by P. 0. Schwille, L. H. Smith, W. G. Robertson and W. Vahlensieck. New York: Plenum Press,pp. 505-512, 1985. 5. Pena, J. C., Monforte, M. F. and Briceno, A.: The role of oxalate and calcium oxalate activity and formation product ratio in patients with renal stones before and during treatment. J. Urol., 138: 1137, 1987. 6. Morris, G. S., Simmonds, H. A., Toseland, P.A., Van Acker, K. J., Davies, P. M. and Stuchbury, J. H.: Urinary oxalate levels are not affected by dietary purine intake or allopurinol. Brit. J. Urol., 60: 292, 1987. 7. Chalmers, A.H., Cowley, D. M. and McWhinney, B. C.: Stability of ascorbate in urine; relevance to analyses for ascorbate and oxalate. Clin. Chem., 31: 1703, 1985. 8. Kasidas, G. P. and Rose, G. A.: Removal of ascorbate from urine prior to assaying with a commercial kit. Clin. Chim. Acta, 164: 215, 1987. 9. Crider, Q. E. and Curran, D. F.: Simplified method for enzymatic urine oxalate assay. Clin. Biochem., 17: 351, 1984.
Vcl. 144, July Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1990 by AMERICAN
UROLOGICAL ASSOCIATION) INC.
ABSENCE OF EFFECT OF ALLOPURINOL ON OXALATE EXCRETION BY STONE PATIENTS ON RANDOM AND CONTROLLED DIETS MORTON URIVETZKY, SUSAN BRAVERMAN, JAY A. MOTOLA
AND
ARTHUR D. SMITH
From the Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York
ABSTRACT
After 1 year of allopurinol treatment in 36 patients with a history of uric acid and/ or calcium oxalate lithiasis and hyperuricosuria, we observed that in addition to the desired decreases in uric acid there were apparently significant decreases in urinary oxalate levels: 37 ± 3 mg. per day (mean ± standard error) before therapy and 31 ± 4 mg. per day after a mean decrease of 16% (p <0.05) with an equivalent decrease in the supersaturation (calcium oxalate) of the urine. However, the decrease in oxalate could have been related to changes in dietary habits rather than to any specific effects of allopurinol on oxalate metabolism. Therefore, we recruited 26 of the patients for a study in which dietary factors were controlled. Each participant was assigned to 1 of 3 diet groups: low or high protein, or a customary diet. Each patient collected a urine specimen while on allopurinol and again after the medication was discontinued. With analytical procedures that we ascertained to be free of any significant methodological bias, we observed no significant changes in urinary oxalate excretion that could be attributed to allopurinol. There were significant differences in oxalate excretion on versus off allopurinol between the low and high protein groups, with higher oxalate levels found for the latter group. Our results indicate that allopurinol does not have a specific effect on oxalate metabolism or oxaluria. (J. Ural., 144: 97-98, 1990) Does allopurinol decrease urinary oxalate excretion? The drug, which is an inhibitor of xanthine oxidase, is used to decrease endogenous production of uric acid in patients with hyperuricosuria or hyperuricosemia. Most patients who are treated with the allopurinol at our clinic and at many other stone clinics have a history of uric acid and/ or calcium function lithiasis and have uricosuria before therapy. Because xanthine oxidase is 1 of 3 endogenous enzymes capable of catalyzing the oxidation of glyoxylate to oxalate, allopurinol also could have the potential to decrease urinary oxalate levels. Indeed, studies claiming that allopurinol therapy was able to decrease urinary oxalate levels or the recurrence of calcium oxalate stones have been reported previously. 1 - 3 There also are reports that have contradicted these claims. 4 - 6 The conflicting data and conclusions might be attributable to differences in environmental factors and/or methodologies used by the respective investigators. 6 With methods that did not introduce analytical bias, we studied the effect of allopurinol on oxaluria in stone patients while they were on customary as well as on controlled low or high protein diets.
imum total purine intake of 300 mg. per day. For both groups the maximum daily intake of oxalate and ascorbate was 120 and 100 mg., respectively. Each patient collected a 12-hour urine specimen beginning at 8 p.m. on day 3 of 2 test periods, the first while the patient was on allopurinol (1 morning dose) and the second 3 weeks after the drug had been discontinued. Group 3 consisted of 7 patients who remained on their own customary diet regimens for the first (on allopurinol) and second test periods. Analyses of the diet records showed 2,210 ± 105 KCal. protein (mean± 2 standard deviations) accounting for 16 ± 33% of total caloric intake, carbohydrate 60 ± 10%, ascorbate 120 ± 10 mg. per day, oxalate 160 ± 20 mg. per day and purines 240 ± 40 mg. per day. The patients in all 3 groups were requested to follow the same daily diet plans for the 3 days of each test period. All urine specimens were collected with ethylenediaminetetraacetic acid to stabilize ascorbate and oxalate, and kept at 4C until assay. 7 Analyses. Urine specimens that were to be analyzed for oxalate were treated with sodium nitrite to remove any ascorbate. 8 Oxalate then was determined by the Sigma enzymatic method as modified by Kasidas and Rose, 8 and by Crider and Curran. 9 Calcium and magnesium were determined by atomic absorption spectrophotometry and uric acid with uricase at 293 nM.; all other constituents were assayed by accepted clinical methodologies. In our hands the oxalate analysis has interassay and intrassay coefficients of variation of 5.6 and 1.8%, respectively, when urinary oxalate concentrations are between 20 and 40 mg./1. Urinary purine levels (as added guanosine) as high as 500 mg.fl. do not affect the results and uric acid levels as high as 600 mg./1. cause a maximum positive error of 4.7% (unpublished data). The statistical significance of the results was analyzed by the paired Student t test.
MATERIALS AND METHODS
Patients. The 36 adult outpatients whose blood and urine were monitored before and 1 year after the start of 300 mg. per day allopurinol therapy included 22 men 24 to 58 years old and 14 women 27 to 60 years old, all of whom had hyperuricosuria before treatment and normal urinary calcium levels. Of the patients 26 had a history of uric acid stones, 2 of calcium oxalate stones and 8 of uric acid plus calcium oxalate calculi. Of these patients 26 then participated in a 3-day study of diet effect. Group 1 consisted of 10 patients who consumed a low protein diet in which 12% of the total caloric intake (2,000 KCal.) was protein of high biological value, 65% was carbohydrate and the maximum purine intake was 200 mg. per day. Group 2 consisted of 9 patients matched to group 1 according to sex and stone history who consumed 25% of the total 2,000 KCal. intake as protein and 50% as carbohydrate with a max-
RESULTS
For the 36 patients who were tested on their customary diets before and 1 year after the start of allopurinol therapy we observed a 40% mean decrease in uric acid excretion and a 16% decrease in urinary oxalate excretion (table 1). In addition to the changes in uric acid and oxalate, the increases in urinary
Accepted for publication February 26, 1990.
97
98
URIVETZKY AND ASSOCIATES TABLE
1. Urinary constituents before and after 1 year of allopurinol in 36 patients Before* 826 37 147 928 83 154 5.62 2.05 2.84
Uric acid (mg./24 hrs.) Oxalate (mg./24 hrs.) Calcium (mg./24 hrs.) Phosphorus (mg./24 hrs.) Magnesium (mg./24 hrs.) Sodium (mEq./24 hrs.) pH Vol. (1/24 hrs.) Concentration product ratio of calcium oxalate
± ± ± ± ± ± ± ± ±
42 3 16 105 11 16 .10 .25 .28
After*
% Change
Significance (p value)t
± ± ± ± ± ± ± ± ±
-40.8 -16.2 0 5.6 15.7 -2.6 8.0 6.3 16.9
<0.005 <0.05 Not significant Not significant Not significant Not significant <0.005 Not significant <0.05
489 31 148 980 96 150 6.10 2.18 2.36
26 4 13 100 12 14 .11 .21 .24
* Mean ± standard error. t Paired t test.
Urine oxalate excretion on low protein (group 1), high protein (group 2) and customary (group 3) diets, and effect of allopurinol
TABLE 2.
Group
mMol. oxalate/mo!. creatinine: On allopurinol Off allopurinol Concentration product ratio of calcium oxalate: On allopurinol Off allopurinol
1
2
3
20 ± 3.8 24 ± 3.0
33 ± 4.2 35 ± 3.9
28 ± 3.0 30 ± 4.0
2.16 ± 0.25 2.18 ± 0.30
2.31 ± 0.30 2.27 ± 0.22
2.30 ± 0.28 2.31 ± 0.29
Values are mean ± standard error.
pH and volume (although the latter was not significant) contributed to the over-all decrease in the saturation of the urine with calcium oxalate. The 3 diet groups showed that there were no significant changes in the amounts of oxalate excreted that could be related to the discontinuation of allopurinol (table 2). A significantly greater amount of oxalate was excreted on or off allopurinol by the subjects on the high protein diet (group 2) than by those on the low protein diet (group 3) (p <0.05). The differences between group 1 or 2 and group 3 were not significant. DISCUSSION
Among the 36 stone patients who had received 1 year of allopurinol therapy there were, in addition to the predicted decreases in uric acid excretion, decreases in oxalate excretion content and the supersaturation of the urine with respect to calcium oxalate. These findings would be consistent with a decrease in the potential for calcium oxalate lithiasis and are in accord with those reported by other investigators. 1- 3 However, conflicting data and conclusions also have been published, perhaps attributable to environmental or methodological variables.4-6 For example, the decreases in urinary oxalate and in supersaturation we observed could have been the result of changes in the dietary habits. When we start our patients on allopurinol therapy they are advised to restrict the daily consumptions of protein of high biological value and, particularly when there is a history of calcium oxalate lithiasis or urinary oxalate levels of more than 30 mg. per day, foods with a high oxalate content. The observed decrease in oxaluria could, thus, have reflected changes in dietary habits rather than any specific effects of allopurinol on oxalate metabolism. Evidence has been presented, for example by Morris and associates, 6 that methodological factors also could have contributed to the conflicting results. In the analytical procedure we used oxalate and ascorbate were stabilized during collection, with any ascorbate present being removed by degradation be-
fore analysis. With recovery controls we ascertained that the amounts of purines and uric acid present in the analyzed specimens did not introduce a significant error in measured oxalate values. Thus, the methodology was of adequate specificity and reliability, and the comparisons of the data obtained in our studies should be valid. In the controlled diet studies the patients in each group (low or high protein, or customary diets) were instructed to follow the same daily diet plan during the 2 (on and off allopurinol) test periods. The diets of the patients in the low and high protein groups also were restricted with respect to the contents of oxalate, ascorbate and purines. With the conditions of diet and methodology described, we did not find any significant differences in the oxalate levels of specimens collected on versus off allopurinol for any diet, including the random diet. This was most likely attributable to the repetition of diet plans before urine collections. The only significant differences for urinary oxalate were those found between group 2 (high protein with the higher oxalate level) and group 1 (low protein) on and off the drug. We conclude that allopurinol does not alter oxalate metabolism. Thus, any decreases seen during drug therapy are, in the absence of methodological bias, attributable to diet or environmental factors and not allopurinol. REFERENCES
1. Scott, R., Paterson, P. J., Smith, M. and Mathieson, A.: Reduction in urinary oxalate values by allopurinol. Urology, 12: 212, 1978. 2. Tomlinson, B., Cohen, S. L., Al-Khader, A., Kasidas, G. P. and Rose, G. A.: Further reduction of oxalate excretion by allopurinol in stone formers on a low purine diet. In: Urolithiasis and Related Clinical Research. Edited by P. 0. Schwille, L. H. Smith, W. G. Robertson and W. Vahlensieck. New York: Plenum Press, pp. 513-517, 1985. 3. Ettinger, B., Tang, A., Citron, J. T., Livermore, B. and Williams, T.: Randomized trial of allopurinol in the prevention of calcium oxalate calculi. New Engl. J. Med., 315: 1386, 1986. 4. Fellstrom, B.: Allopurinol treatment in urolithiasis. In: Urolithiasis and Related Clinical Research. Edited by P. 0. Schwille, L. H. Smith, W. G. Robertson and W. Vahlensieck. New York: Plenum Press,pp. 505-512, 1985. 5. Pena, J. C., Monforte, M. F. and Briceno, A.: The role of oxalate and calcium oxalate activity and formation product ratio in patients with renal stones before and during treatment. J. Urol., 138: 1137, 1987. 6. Morris, G. S., Simmonds, H. A., Toseland, P.A., Van Acker, K. J., Davies, P. M. and Stuchbury, J. H.: Urinary oxalate levels are not affected by dietary purine intake or allopurinol. Brit. J. Urol., 60: 292, 1987. 7. Chalmers, A.H., Cowley, D. M. and McWhinney, B. C.: Stability of ascorbate in urine; relevance to analyses for ascorbate and oxalate. Clin. Chem., 31: 1703, 1985. 8. Kasidas, G. P. and Rose, G. A.: Removal of ascorbate from urine prior to assaying with a commercial kit. Clin. Chim. Acta, 164: 215, 1987. 9. Crider, Q. E. and Curran, D. F.: Simplified method for enzymatic urine oxalate assay. Clin. Biochem., 17: 351, 1984.