- Email: [email protected]
Urinary Metabolic Evaluations in Normal and Stone Forming Children
Urinary Metabolic Evaluations in Normal and Stone Forming Children William DeFoor,* John Asplin,† Elizabeth Jackson, Chad Jackson, Pramod Reddy, Curtis Sheldon, Michael Erhard and Eugene Minevich From the Children’s Hospital Medical Center, Cincinnati, Ohio, Nemours Children’s Clinic, Jacksonville, Florida, and University of Chicago, Chicago, Illinois
Purpose: Urinary stone disease is relatively rare in children and urinary metabolic evaluations have been the standard in our practice. We have previously reported a high rate of urinary metabolic abnormalities in stone forming children. We compared urinary chemistry values in normal and stone forming children. Material and Methods: A prospective study was performed to assess urinary metabolic profiles in children with no history or a family history of urinary calculi. The 24-hour urine collections were performed and evaluated at an outside central laboratory. Urine chemistry studies were adjusted for creatinine. The data were compared to those on a historical cohort of calcium stone forming children. Results: A total of 58 samples from normal children and 142 from stone forming children were evaluated. Mean age was 10 years in normal children and 12 years in stone forming children. of the normal and stone forming children 45% and 51%, respectively, were female. Supersaturation levels of calcium oxalate as well as calcium to creatinine levels were significantly higher in children with stones. No data confounding by age or sex was identified by stratification. Conclusions: There are significant differences in urinary metabolic evaluations between normal and stone forming children. This may allow more precise treatment to prevent recurrent stone episodes. We continue to perform metabolic evaluations in all children with documented urolithiasis. Key Words: urinary calculi, calcium oxalate, metabolism
rinary stone disease in children is relatively rare but often associated with metabolic abnormalities that can lead to recurrent stone episodes.1–5 Urinary supersaturation indexes have been suggested as more precise predictors of stone recurrence and they are commonly reported in stone risk assessments.6,7 We have previously reported the results of abnormal urinary supersaturation indexes in a pediatric stone forming population.8 We recently evaluated urinary supersaturation in normal children compared to normal adults.9 We compared urinary metabolic indexes in normal children with those in a cohort of stone forming children.
U
MATERIALS AND METHODS After obtaining approval from the Institutional Review Board a prospective cohort study was performed to assess urinary metabolic profiles in normal children. Informed consent was obtained from the parents of each enrolled subject. Inclusion criteria were healthy, toilet trained children 18 years or younger. They were recruited from children presenting to a pediatric urology clinic with conditions unrelated to stone disease, eg inguinal hernia, hydrocele or low grade vesicoureteral reflux. Asymptomatic siblings were Study received institutional review board approval CCHMC 01-726X. * Correspondence and reprint requests: William DeFoor, Division of Pediatric Urology, Cincinnati Children’s Hospital Medical Center, 3333 Burnett Ave., Cincinnati, Ohio 45229-3039 (telephone: 513-6366758; FAX: 513-636-6753; e-mail: [email protected]). † Financial interest and/or other relationship with Litholink.
0022-5347/06/1764-1793/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
also invited to participate. Exclusion criteria were an active or previous history of urolithiasis as well as a family history positive for stone disease. In addition, patients with obstructive uropathy, renal insufficiency or a reconstructed lower urinary tract requiring intermittent catheterization were excluded. Subjects were given an order for a metabolic stone evaluation to be performed at home. Two 24-hour urine collections were collected at home and mailed to an outside central laboratory. The evaluation included standard urinary indexes, such as volume, creatinine, calcium, oxalate, citrate, pH and uric acid, as well as urinary calcium oxalate, calcium phosphate and uric acid supersaturation. Urine supersaturation or the proximate free energy to crystallization was calculated as the ratio of the concentration of dissolved salt to its solubility in urine. Supersaturation ratios were calculated using the iterative computer program EQUIL 2. Urine chemistry studies, such as calcium, citrate, uric acid and oxalate, were adjusted for urine creatinine. Urine pH, and calcium oxalate, calcium phosphate and uric acid supersaturation were assessed but did not require correction using creatinine excretion. Samples from children that were believed to be under collected (less than 9 mg creatinine per kg body weight) were excluded from analysis. Pediatric normal control data were then compared to those on a historical cohort of calcium stone forming children from 2 institutions. Stones were diagnosed clinically and confirmed in all cases by radiographic imaging, such as plain abdominal radiography, excretory urography, ultrasonography and/or computerized tomography. Stone analysis was assessed if available. Pre-evaluation medical management
1793
Vol. 176, 1793-1796, October 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(06)00607-0
1794
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN TABLE 1. Patient demographics
No. pts No. samples Mean age (yrs) Age range (yrs): 0–5 6–10 11–15 16–18 % Female
Normal
Stones
33 58 9.5
71 142 12.4
4 17 9 3 45
6 19 27 19 51
Analysis of a scatterplot of calcium oxalate supersaturation vs age did not reveal a significant trend in normal or stone forming children (fig. 1). Standard indexes, such as calcium, oxalate, uric acid and citrate, were also analyzed by linear regression and they showed no significant trends with age (data not shown). When stratified by age into prepubertal and postpubertal patients, the significant difference seen in calcium oxalate supersaturation between normal and stone forming children was maintained (fig. 2). No differences were seen in the data when stratified by sex (data not shown). DISCUSSION
was not controlled but in general patients were advised to increase fluid intake and decrease added table salt. The mean of the 2 samples per patient were averaged and included as a single sample in the final database. The mean ⫾ SD was then calculated for each of the indexes in the 2 groups. Univariate analysis between mean values was performed using the 2-tailed t test for normally distributed data and confirmed by the nonparametric Wilcoxon rank sum test using StatView® 5.0.1 with a statistically significant difference considered at p ⬍0.05. To assess for confounding by age the data were stratified into children older and younger than 12 years (arbitrary age at puberty) for t test analysis. In addition, linear regression was performed of the various indexes plotted by patient age and R2 was calculated to assess trend. The data were also stratified by sex to assess confounding. RESULTS A total of 142 samples from stone forming children and 58 from normal children were evaluated (table 1). Six normal samples were excluded due to a suggestion of under collection in 2 and missing data in 4. No stone forming children were excluded. Mean age in normal and stone forming children was 9.5 and 12.4 years, respectively. The difference in mean age was statistically significant (p ⫽ 0.001). The 2 groups were similar in sex, in that 45% of normal and 51% of stone forming children were female. Stone composition was available in 29 of 71 patients (41%). The majority of the stones were calcium oxalate dihydrate or monohydrate. Of these patients 64% had increased calcium oxalate supersaturation. One stone was identified as calcium phosphate and this patient was found to have increased calcium phosphate supersaturation. No elements of uric acid epitaxy were documented in patients with calcium oxalate stones and no pure uric acid stones were identified. Table 2 lists mean urinary chemistry values ⫾ SD. All results significant by the 2-tailed t test were also significant by nonparametric testing with the Wilcoxon rank sum test. There were significant differences noted between mean calcium oxalate supersaturation and the mean calcium-to-creatinine ratio in normal and stone forming children. Urinary volume as well as urine pH was higher in normal children. Citrate was lower in stone forming children but this did not quite achieve statistical significance (p ⫽ 0.06). Oxalate was actually somewhat higher in the normal group but the mean in each group was essentially within normal limits. Uric acid was not significantly different between the 2 groups but none of the stone forming children had radiolucent stones.
Urinary stone disease in children is relatively rare but it may be increasing in frequency.1 Metabolic abnormalities are commonly found in the pediatric stone forming population and a full metabolic evaluation is often performed after the first stone episode.2– 4,10,11 Supersaturation indexes are believed to accurately predict stone composition and they may be a more precise predictor of response to therapy.6,7 We have previously reported urine chemistry values in a cohort of children from 2 pediatric institutions who were diagnosed with urolithiasis.8 We subsequently performed a prospective trial to assess normal urinary supersaturation in children.9 In this study we compared results in stone forming children with those in normal control children. In this study calcium excretion was higher in calcium stone forming children when values were adjusted for creatinine excretion. Calcium oxalate supersaturation was also found to be higher in stone formers. The urinary excretion of citrate, a commonly known stone inhibitor, was found to be lower in stone forming patients, although the trend just missed statistical significance. Other investigators have reported that hypocitruria is the most important risk factor for calcium lithiasis in children.5,10 The standard metabolic evaluation has been used for many years in adults and children, and it has accepted pediatric reference ranges.12 While normal reference ranges for calcium oxalate supersaturation have not been precisely determined, our previous study suggested that they are similar to those in normal adults.9 Larger studies in normal children may be necessary to establish precise reference ranges for all supersaturation indexes. Currently adult reference ranges for urinary supersaturation are used in our clinical practice. The usefulness of supersaturation indexes
TABLE 2. Urinary metabolic indexes in stone forming children and normal controls
Vol (ml/kg/hr) Supersaturation: Calcium oxalate Calcium phosphate Uric acid Calcium/creatinine (mg/gm/day) Oxalate/creatinine (mg/gm/day) Citrate/creatinine (mg/gm/day) Uric acid/creatinine (mg/gm/day) Urine pH
Mean Normal ⫾ SD
Mean Stones ⫾ SD
p Value
25 ⫾ 7
21 ⫾ 12
0.09
8.2 ⫾ 4 2.5 ⫾ 1 0.58 ⫾ 0.4 168 ⫾ 89
12.1 ⫾ 4.4 2.8 ⫾ 1 0.98 ⫾ 0.7 214 ⫾ 109
⬍0.0001 0.2 0.003 0.04
43 ⫾ 20
36 ⫾ 19
0.08
587 ⫾ 256
479 ⫾ 274
0.06
622 ⫾ 156
526 ⫾ 217
0.03
6.45 ⫾ 0.3
6.20 ⫾ 0.4
0.003
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN
1795
FIG. 1. Linear regression of calcium oxalate supersaturation (SS) vs patient age
in the evaluation of pediatric urolithiasis has been confirmed by other investigators.13 However, in 1 series it was not believed to add appreciable information to the standard evaluation.14 A limitation of the current study is the relatively small number of normal samples in this pilot study compared to the stone forming cohort. Furthermore, mean age in the 2 groups was not quite matched since the stone forming group contained more adolescents. This was a concern because it is known that some indexes change with age. Further enrollment of normal subjects is planned in an upcoming National Institutes of Health trial of pediatric urolithiasis with emphasis on enrolling more adolescents in the control group. Moreover, due to the difficulty in obtaining a 24-hour urine collection in nontoilet trained children the groups did not include infants or children younger than 5 years. In addition, since this was not a clinical trial, there was no control of treatment effects in the stone forming population. In the period between presenting and being treated for the stone episode, and metabolic evaluation certain empirical treatments are generally recommended to patients. They generally include increasing oral fluid intake and decreasing added table salt but not empirical use of thiazides or potassium citrate until the metabolic evaluation is performed. However, these nonspecific therapies would only have biased the stone forming group toward the null hypothesis,
which is that there was no metabolic difference between the 2 groups. In our previous study we found significant differences in the urinary metabolic indexes between children and adults.9 This leads to the assumption that these indexes can change with increasing age. In the current study we were not able to determine a trend of changes toward adult values in the pediatric age ranges that were studied but this analysis may have been limited by the small number of subjects. Further investigation of metabolic changes with age may be helpful for counseling patients and their families regarding the findings of the evaluation.
CONCLUSIONS Despite the small numbers of patients in this pilot study there are significant differences in the urinary metabolic evaluations between normal and stone forming children. This may allow more precise treatment to prevent recurrent stone episodes. We continue to perform metabolic evaluations in all children with documented urolithiasis. Continued enrollment of normal children will be performed to develop pediatric reference ranges for supersaturation indexes as well as assess age related trends toward adult values.
FIG. 2. Stratification of calcium oxalate supersaturation (SS) by patient age
1796
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN
ACKNOWLEDGMENTS
7.
Evaluation of 24-hour urine collections was done at Litholink®.
8.
REFERENCES
9.
1. 2.
3.
4. 5.
6.
Kroovand, R. L.: Pediatric urolithiasis. Urol Clin North Am, 24: 173, 1997 Pietrow, P. K., Pope, J. C. T., Adams, M. C., Shyr, Y. and Brock, J. W., 3rd: Clinical outcome of pediatric stone disease. J Urol, 167: 670, 2002 Perrone, H. C., dos Santos, D. R., Santos, M. V., Pinheiro, M. E., Toporovski, J., Ramos, O. L. et al: Urolithiasis in childhood: metabolic evaluation. Pediatr Nephrol, 6: 54, 1992 Drach, G. W.: Metabolic evaluation of pediatric patients with stones. Urol Clin North Am, 22: 95, 1995 Tekin, A., Tekgul, S., Atsu, N., Sahin, A., Ozen, H. and Bakkaloglu, M.: A study of the etiology of idiopathic calcium urolithiasis in children: hypocitruria is the most important risk factor. J Urol, 164: 162, 2000 Asplin, J., Parks, J., Lingeman, J., Kahnoski, R., Mardis, H., Lacey, S. et al: Supersaturation and stone composition in a network of dispersed treatment sites. J Urol, 159: 1821, 1998
10.
11.
12. 13.
14.
Parks, J. H., Coward, M. and Coe, F. L.: Correspondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Int, 51: 894, 1997 Battino, B. S., DeFoor, W., Coe, F., Tackett, L., Erhard, M., Wacksman, J. et al: Metabolic evaluation of children with urolithiasis: are adult references for supersaturation appropriate? J Urol, 168: 2568, 2002 Defoor, W., Asplin, J., Jackson, E., Jackson, C., Reddy, P., Sheldon, C. et al: Results of a prospective trial to compare normal urine supersaturation in children and adults. J Urol, 174: 1708, 2005 Tefekli, A., Esen, T., Ziylan, O., Erol, B., Armagan, A., Ander, H. et al: Metabolic risk factors in pediatric and adult calcium oxalate urinary stone formers: is there any difference? Urol Int, 70: 273, 2003 Erbagci, A., Erbagci, A. B., Yilmaz, M., Yagci, F., Tarakcioglu, M., Yurtseven, C. et al: Pediatric urolithiasis— evaluation of risk factors in 95 children. Scand J Urol Nephrol, 37: 129, 2003 Bartosh, S. M.: Medical management of pediatric stone disease. Urol Clin North Am, 31: 575, 2004 Hoppe, B., Jahnen, A., Bach, D. and Hesse, A.: Urinary calcium oxalate saturation in healthy infants and children. J Urol, 158: 557, 1997 Lande, M. B., Varade, W., Erkan, E., Niederbracht, Y. and Schwartz, G. J.: Role of urinary supersaturation in the evaluation of children with urolithiasis. Pediatr Nephrol, 20: 491, 2005
Purpose: Urinary stone disease is relatively rare in children and urinary metabolic evaluations have been the standard in our practice. We have previously reported a high rate of urinary metabolic abnormalities in stone forming children. We compared urinary chemistry values in normal and stone forming children. Material and Methods: A prospective study was performed to assess urinary metabolic profiles in children with no history or a family history of urinary calculi. The 24-hour urine collections were performed and evaluated at an outside central laboratory. Urine chemistry studies were adjusted for creatinine. The data were compared to those on a historical cohort of calcium stone forming children. Results: A total of 58 samples from normal children and 142 from stone forming children were evaluated. Mean age was 10 years in normal children and 12 years in stone forming children. of the normal and stone forming children 45% and 51%, respectively, were female. Supersaturation levels of calcium oxalate as well as calcium to creatinine levels were significantly higher in children with stones. No data confounding by age or sex was identified by stratification. Conclusions: There are significant differences in urinary metabolic evaluations between normal and stone forming children. This may allow more precise treatment to prevent recurrent stone episodes. We continue to perform metabolic evaluations in all children with documented urolithiasis. Key Words: urinary calculi, calcium oxalate, metabolism
rinary stone disease in children is relatively rare but often associated with metabolic abnormalities that can lead to recurrent stone episodes.1–5 Urinary supersaturation indexes have been suggested as more precise predictors of stone recurrence and they are commonly reported in stone risk assessments.6,7 We have previously reported the results of abnormal urinary supersaturation indexes in a pediatric stone forming population.8 We recently evaluated urinary supersaturation in normal children compared to normal adults.9 We compared urinary metabolic indexes in normal children with those in a cohort of stone forming children.
U
MATERIALS AND METHODS After obtaining approval from the Institutional Review Board a prospective cohort study was performed to assess urinary metabolic profiles in normal children. Informed consent was obtained from the parents of each enrolled subject. Inclusion criteria were healthy, toilet trained children 18 years or younger. They were recruited from children presenting to a pediatric urology clinic with conditions unrelated to stone disease, eg inguinal hernia, hydrocele or low grade vesicoureteral reflux. Asymptomatic siblings were Study received institutional review board approval CCHMC 01-726X. * Correspondence and reprint requests: William DeFoor, Division of Pediatric Urology, Cincinnati Children’s Hospital Medical Center, 3333 Burnett Ave., Cincinnati, Ohio 45229-3039 (telephone: 513-6366758; FAX: 513-636-6753; e-mail: [email protected]). † Financial interest and/or other relationship with Litholink.
0022-5347/06/1764-1793/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
also invited to participate. Exclusion criteria were an active or previous history of urolithiasis as well as a family history positive for stone disease. In addition, patients with obstructive uropathy, renal insufficiency or a reconstructed lower urinary tract requiring intermittent catheterization were excluded. Subjects were given an order for a metabolic stone evaluation to be performed at home. Two 24-hour urine collections were collected at home and mailed to an outside central laboratory. The evaluation included standard urinary indexes, such as volume, creatinine, calcium, oxalate, citrate, pH and uric acid, as well as urinary calcium oxalate, calcium phosphate and uric acid supersaturation. Urine supersaturation or the proximate free energy to crystallization was calculated as the ratio of the concentration of dissolved salt to its solubility in urine. Supersaturation ratios were calculated using the iterative computer program EQUIL 2. Urine chemistry studies, such as calcium, citrate, uric acid and oxalate, were adjusted for urine creatinine. Urine pH, and calcium oxalate, calcium phosphate and uric acid supersaturation were assessed but did not require correction using creatinine excretion. Samples from children that were believed to be under collected (less than 9 mg creatinine per kg body weight) were excluded from analysis. Pediatric normal control data were then compared to those on a historical cohort of calcium stone forming children from 2 institutions. Stones were diagnosed clinically and confirmed in all cases by radiographic imaging, such as plain abdominal radiography, excretory urography, ultrasonography and/or computerized tomography. Stone analysis was assessed if available. Pre-evaluation medical management
1793
Vol. 176, 1793-1796, October 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(06)00607-0
1794
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN TABLE 1. Patient demographics
No. pts No. samples Mean age (yrs) Age range (yrs): 0–5 6–10 11–15 16–18 % Female
Normal
Stones
33 58 9.5
71 142 12.4
4 17 9 3 45
6 19 27 19 51
Analysis of a scatterplot of calcium oxalate supersaturation vs age did not reveal a significant trend in normal or stone forming children (fig. 1). Standard indexes, such as calcium, oxalate, uric acid and citrate, were also analyzed by linear regression and they showed no significant trends with age (data not shown). When stratified by age into prepubertal and postpubertal patients, the significant difference seen in calcium oxalate supersaturation between normal and stone forming children was maintained (fig. 2). No differences were seen in the data when stratified by sex (data not shown). DISCUSSION
was not controlled but in general patients were advised to increase fluid intake and decrease added table salt. The mean of the 2 samples per patient were averaged and included as a single sample in the final database. The mean ⫾ SD was then calculated for each of the indexes in the 2 groups. Univariate analysis between mean values was performed using the 2-tailed t test for normally distributed data and confirmed by the nonparametric Wilcoxon rank sum test using StatView® 5.0.1 with a statistically significant difference considered at p ⬍0.05. To assess for confounding by age the data were stratified into children older and younger than 12 years (arbitrary age at puberty) for t test analysis. In addition, linear regression was performed of the various indexes plotted by patient age and R2 was calculated to assess trend. The data were also stratified by sex to assess confounding. RESULTS A total of 142 samples from stone forming children and 58 from normal children were evaluated (table 1). Six normal samples were excluded due to a suggestion of under collection in 2 and missing data in 4. No stone forming children were excluded. Mean age in normal and stone forming children was 9.5 and 12.4 years, respectively. The difference in mean age was statistically significant (p ⫽ 0.001). The 2 groups were similar in sex, in that 45% of normal and 51% of stone forming children were female. Stone composition was available in 29 of 71 patients (41%). The majority of the stones were calcium oxalate dihydrate or monohydrate. Of these patients 64% had increased calcium oxalate supersaturation. One stone was identified as calcium phosphate and this patient was found to have increased calcium phosphate supersaturation. No elements of uric acid epitaxy were documented in patients with calcium oxalate stones and no pure uric acid stones were identified. Table 2 lists mean urinary chemistry values ⫾ SD. All results significant by the 2-tailed t test were also significant by nonparametric testing with the Wilcoxon rank sum test. There were significant differences noted between mean calcium oxalate supersaturation and the mean calcium-to-creatinine ratio in normal and stone forming children. Urinary volume as well as urine pH was higher in normal children. Citrate was lower in stone forming children but this did not quite achieve statistical significance (p ⫽ 0.06). Oxalate was actually somewhat higher in the normal group but the mean in each group was essentially within normal limits. Uric acid was not significantly different between the 2 groups but none of the stone forming children had radiolucent stones.
Urinary stone disease in children is relatively rare but it may be increasing in frequency.1 Metabolic abnormalities are commonly found in the pediatric stone forming population and a full metabolic evaluation is often performed after the first stone episode.2– 4,10,11 Supersaturation indexes are believed to accurately predict stone composition and they may be a more precise predictor of response to therapy.6,7 We have previously reported urine chemistry values in a cohort of children from 2 pediatric institutions who were diagnosed with urolithiasis.8 We subsequently performed a prospective trial to assess normal urinary supersaturation in children.9 In this study we compared results in stone forming children with those in normal control children. In this study calcium excretion was higher in calcium stone forming children when values were adjusted for creatinine excretion. Calcium oxalate supersaturation was also found to be higher in stone formers. The urinary excretion of citrate, a commonly known stone inhibitor, was found to be lower in stone forming patients, although the trend just missed statistical significance. Other investigators have reported that hypocitruria is the most important risk factor for calcium lithiasis in children.5,10 The standard metabolic evaluation has been used for many years in adults and children, and it has accepted pediatric reference ranges.12 While normal reference ranges for calcium oxalate supersaturation have not been precisely determined, our previous study suggested that they are similar to those in normal adults.9 Larger studies in normal children may be necessary to establish precise reference ranges for all supersaturation indexes. Currently adult reference ranges for urinary supersaturation are used in our clinical practice. The usefulness of supersaturation indexes
TABLE 2. Urinary metabolic indexes in stone forming children and normal controls
Vol (ml/kg/hr) Supersaturation: Calcium oxalate Calcium phosphate Uric acid Calcium/creatinine (mg/gm/day) Oxalate/creatinine (mg/gm/day) Citrate/creatinine (mg/gm/day) Uric acid/creatinine (mg/gm/day) Urine pH
Mean Normal ⫾ SD
Mean Stones ⫾ SD
p Value
25 ⫾ 7
21 ⫾ 12
0.09
8.2 ⫾ 4 2.5 ⫾ 1 0.58 ⫾ 0.4 168 ⫾ 89
12.1 ⫾ 4.4 2.8 ⫾ 1 0.98 ⫾ 0.7 214 ⫾ 109
⬍0.0001 0.2 0.003 0.04
43 ⫾ 20
36 ⫾ 19
0.08
587 ⫾ 256
479 ⫾ 274
0.06
622 ⫾ 156
526 ⫾ 217
0.03
6.45 ⫾ 0.3
6.20 ⫾ 0.4
0.003
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN
1795
FIG. 1. Linear regression of calcium oxalate supersaturation (SS) vs patient age
in the evaluation of pediatric urolithiasis has been confirmed by other investigators.13 However, in 1 series it was not believed to add appreciable information to the standard evaluation.14 A limitation of the current study is the relatively small number of normal samples in this pilot study compared to the stone forming cohort. Furthermore, mean age in the 2 groups was not quite matched since the stone forming group contained more adolescents. This was a concern because it is known that some indexes change with age. Further enrollment of normal subjects is planned in an upcoming National Institutes of Health trial of pediatric urolithiasis with emphasis on enrolling more adolescents in the control group. Moreover, due to the difficulty in obtaining a 24-hour urine collection in nontoilet trained children the groups did not include infants or children younger than 5 years. In addition, since this was not a clinical trial, there was no control of treatment effects in the stone forming population. In the period between presenting and being treated for the stone episode, and metabolic evaluation certain empirical treatments are generally recommended to patients. They generally include increasing oral fluid intake and decreasing added table salt but not empirical use of thiazides or potassium citrate until the metabolic evaluation is performed. However, these nonspecific therapies would only have biased the stone forming group toward the null hypothesis,
which is that there was no metabolic difference between the 2 groups. In our previous study we found significant differences in the urinary metabolic indexes between children and adults.9 This leads to the assumption that these indexes can change with increasing age. In the current study we were not able to determine a trend of changes toward adult values in the pediatric age ranges that were studied but this analysis may have been limited by the small number of subjects. Further investigation of metabolic changes with age may be helpful for counseling patients and their families regarding the findings of the evaluation.
CONCLUSIONS Despite the small numbers of patients in this pilot study there are significant differences in the urinary metabolic evaluations between normal and stone forming children. This may allow more precise treatment to prevent recurrent stone episodes. We continue to perform metabolic evaluations in all children with documented urolithiasis. Continued enrollment of normal children will be performed to develop pediatric reference ranges for supersaturation indexes as well as assess age related trends toward adult values.
FIG. 2. Stratification of calcium oxalate supersaturation (SS) by patient age
1796
URINARY METABOLIC EVALUATIONS IN NORMAL AND STONE FORMING CHILDREN
ACKNOWLEDGMENTS
7.
Evaluation of 24-hour urine collections was done at Litholink®.
8.
REFERENCES
9.
1. 2.
3.
4. 5.
6.
Kroovand, R. L.: Pediatric urolithiasis. Urol Clin North Am, 24: 173, 1997 Pietrow, P. K., Pope, J. C. T., Adams, M. C., Shyr, Y. and Brock, J. W., 3rd: Clinical outcome of pediatric stone disease. J Urol, 167: 670, 2002 Perrone, H. C., dos Santos, D. R., Santos, M. V., Pinheiro, M. E., Toporovski, J., Ramos, O. L. et al: Urolithiasis in childhood: metabolic evaluation. Pediatr Nephrol, 6: 54, 1992 Drach, G. W.: Metabolic evaluation of pediatric patients with stones. Urol Clin North Am, 22: 95, 1995 Tekin, A., Tekgul, S., Atsu, N., Sahin, A., Ozen, H. and Bakkaloglu, M.: A study of the etiology of idiopathic calcium urolithiasis in children: hypocitruria is the most important risk factor. J Urol, 164: 162, 2000 Asplin, J., Parks, J., Lingeman, J., Kahnoski, R., Mardis, H., Lacey, S. et al: Supersaturation and stone composition in a network of dispersed treatment sites. J Urol, 159: 1821, 1998
10.
11.
12. 13.
14.
Parks, J. H., Coward, M. and Coe, F. L.: Correspondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Int, 51: 894, 1997 Battino, B. S., DeFoor, W., Coe, F., Tackett, L., Erhard, M., Wacksman, J. et al: Metabolic evaluation of children with urolithiasis: are adult references for supersaturation appropriate? J Urol, 168: 2568, 2002 Defoor, W., Asplin, J., Jackson, E., Jackson, C., Reddy, P., Sheldon, C. et al: Results of a prospective trial to compare normal urine supersaturation in children and adults. J Urol, 174: 1708, 2005 Tefekli, A., Esen, T., Ziylan, O., Erol, B., Armagan, A., Ander, H. et al: Metabolic risk factors in pediatric and adult calcium oxalate urinary stone formers: is there any difference? Urol Int, 70: 273, 2003 Erbagci, A., Erbagci, A. B., Yilmaz, M., Yagci, F., Tarakcioglu, M., Yurtseven, C. et al: Pediatric urolithiasis— evaluation of risk factors in 95 children. Scand J Urol Nephrol, 37: 129, 2003 Bartosh, S. M.: Medical management of pediatric stone disease. Urol Clin North Am, 31: 575, 2004 Hoppe, B., Jahnen, A., Bach, D. and Hesse, A.: Urinary calcium oxalate saturation in healthy infants and children. J Urol, 158: 557, 1997 Lande, M. B., Varade, W., Erkan, E., Niederbracht, Y. and Schwartz, G. J.: Role of urinary supersaturation in the evaluation of children with urolithiasis. Pediatr Nephrol, 20: 491, 2005