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Uric acid excretion in children with urolithiasis
Uric acid excretion in children with urolithiasis Leslie A. Miller, BS, MLT, H. N o r m a n N o e , MD, a n d F. Bruder S t a p l e t o n , MD From the Departments of Pediatrics and Pediatric Urology, Clinical Research Center and Le Bonheur Children's Medical Center, and the University of Tennessee, Memphis
Urinary uric acid excretion was assessed in 38 children to determine whether hyperuricuria was a risk factor in children with urolithiasis. Uric a c i d excretion (measured per deciliter glomerular filtration rate)i and fractional e x c r e t i o n of uric acid were similar in 27 children with hypercalciuria and c a l c i u m o x a l a t e urinary stones, in six children with idiopathic calcium o x a l a t e urolithiasis, and in five with uric acid urolithiasis, of w h o m four were white boys and o n e was an Asian girl. One b o y with a urate stone had cystinosis. Serum uric a c i d c o n c e n trations e x c e e d e d 6.0 m g / d l (360 ~mo!/L) in two children with hypercalciuria and in two patients with idiopathic calcium o x a l a t e urolithiasis. None of the children with calcium urolithiasis had excessive urinary excretion of uric acid. In children with hypercalciuria, uric a c i d excretion did not c h a n g e significantly when dietary sodium was increased from 4.0 to 5.0 gm/4.73 m 2. We c o n c l u d e that excessive urinary uric a c i d excretion is seldom an additional riskfactor in chi!dren with calcium urolithiasis and that dietary sod!um chloride does not have a strong influence on urinary e x c r e t i o n of uric a c i d in children with hypercalci-
uria. (J PEDIATR1989;145:923-6)
Uric acid promotes urinary crystal formation and is a major constituent of urinary calculi. 1 Uric acid stones are endemic to certain geographic locations2 and occur in patients with gout. 3 In addition, increased urinary excretion of uric acid is found in 14.6% of adult patients with calcium oxalate urolithiasis.4 Uric acid increases calcium oxalate crystal formation by various mechanisms. Several investigators have demonstrated calcium oxalate crystal growth on a uric acid "nidus" in vitro.5-7; furthermore, uric acid may reduce the activity of urine inhibitors of crystal formation. 8 Whether uric acid is an important promoter of urolithiasis in children is unknown. In this study, we examined urinary uric acid excretion in children with calcium oxalate
Supported by grants from the General Clinical Research Center (2MO1 RR00211-23) and the National Institutes of Health (1ROI AM HD31370). Submitted for publication March 16, 1989;accepted June 13, 1989. Reprint requests: F. Bruder Stapleton, MD, Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222. 9/20/14613
and uric acid urolithiasis. In addition, we also assessed the relationship of dietary sodium chloride and urinary uric acid excretion in children with hypercalciuria because a relationship has been shown between extracellular fluid volume and uric acid excretion. 9, 1o METHODS During an 8-year period, urinary uric acid, calcium, and creatinine excretion was measured in all children referred to LeBonheur Children's Medical Center for the evaluation of calcium oxalate and uric acid urolithiasis. Urine collections were obtained at home while the patients were ingesting their routine diets and were not receiving any medications. The children were categorized into three groups: group 1 consisted of 27 children (14 boys) having calcium oxalate urolithiasis and hyperca!ciuria (urinary calcium excretion >4 mg/kg/day during an unrestricted diet); group 2 consisted of six children (3 boys) with idiopathic calcium oxalate stones (patients were considered to have idiopathic urolithiasis if urinary calcium excretion was <4.0 mg/kg/day, 11 urinary uric acid per deciliter glomerular filtration rate 12 was <0.57, urinary citrate was >300 rag/
923
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The Journal of Pediatrics December 1989
Table. U r i n a r y c a l c i u m and uric acid excretion in children with urolithiasis
Age (yr) Urinary calcium (mg/kg/day)* Urinary uric acid (mg/dl GFR)~ FE uric acid (%) Urinary volume (ml/kg/day)
Hypercalciuria with CaOx Stones (n = 2 7 )
Idiopathic CaOx stones
9.3 +_ 0.8 5.3 +_ 0.4 0.30 +_ 0.02 6.29 _+ 0.45 26.4 +_ 2.8
14.8 +_ 0.9 1.9 +_ 0.3:~ 0.35 _+ 0.04 7.00 +_ 1.28 10.4 _+ 2.2~
(n = 6)
Uric acid urolithiasis (n = 5) 8.8 4.0 0.38 6.80 20.8
+_ 2.0 +_ 2.8 +__0.08 +_ 1.74 +_ 5.6
Data are expressedas mean +_SEM. CaOx, Calciumoxalate;GFR, gl0merularfiltrationrate; F'E,fractionalexcretion. *1 mg ca!cium= 0.025 mmol. "~1gm uric acid = 5.95 mmol. :~p'<0.001 fromchildrenwith hypercalciuriaand calciumoxalate stones.
gm creatinine.13 urinary oxalate was <50 mg/1.73 m 2 body surface area, 14 and urinary cystine screen was negative); group 3 consisted of five children (four boys) with uric acid urolithiasis defined as having a urinary stone composed primarily of uric acid. This patient population represents 56% of 67 children with all types of urolithiasis in whom a 24hour urinary uric acid excretion was determined during the same period. The effect of dietary sodium chloride intake on urinary acid excretion was determined in 15 children with hypercalciuria. Patients were first studied after ingestion of a study diet containing 300 mg calcium and 1.0 gm sodium t.73 m2 for 5 days. After at least 2 weeks of ingesting an unrestricted diet, a study diet containing 300 mg calcium and 5.0 gm sodium per 1.73 m 2 (given as sodium chloride supplements) was ingested. On the fifth day of each dietary regulation, a 24-hour urine collection was obtained and urinary sodium, calcium, uric acid, and creatinine levels were measured. Dietary records were maintained to ensure compliance with the study diets. Urinary calcium excretion was assayed by atomic absorption (Varian Instruments, Melbourne, Australia), and creatinine concentration was determined with a Beckman Creatinine Analyzer II chemistry analyzer (Beckman Instruments Inc., Fullerton, Calif.). Urinary uric acid was measured by means of a uricase technique (Raichem, Reagents Applications Inc.. San Diego, Calif.), and sodium was determined with an ion-selective electrode (model E2A analvzer. Beckman). Studies were performed in our clinical research center. Informed consent was obtained before each study. Statistical analyses were performed by mea~ts of the Student t test for both paired and unpaired data. RESULTS Children with hypercalciuria and urolithiasis and those with uric acid stones were similar in age. Children with idiopathic calcium oxalate stones were older (14.8 _~ 0.9
years) than patients with hypercalciuria (p <0.005) and the children with uric acid urolithiasis (p <0.02) (Table). Urinary calcium excretion in patients with hypercalciuric urolithiasis and in children with uric acid stones was similar; only one patient (with multiple renal tubular defects ) with urate Stones had urinary calcium excretion >4 mg/kg/day. Urinary calcium excretion in children with idiopathic urolithiasis, on the other hand, wa s significantly lower than in the patients with hypercalciuria (p <0.001) (Table). Urinary uric acid excretion corrected for creatinine clearance was similar in each of the three groups studied. Urate excretion in all three groups was similar to our previously published data in normal children (mean + SD: 0.34 _+ 0.t 1 mg/dl glomerular filtration rate] 2 Urinary volume was greater in children with hypercalciuria and with urate stones than in children with idiopathic urolithlasis. Four of the patients with uric acid urolithiasis were white boys, one of whom had cystinosis diagnosed at 1 year of age and had numerous radiolucent stones associated with a ureteropelvic obstruction. 15 Each of the three remaining boys was obese (weight greater than 20% above ideal weight for height). The o~.e girl in this grou p was Asian and had no family historybf stones. Uric acid urolithiasis was diagnosed wtien she was 10 years of age; serum uric acid concentration was 4.8 mg/dl (290 #mol/L). Urinary uric acid excretion data were not quantitated in this patient at the time of passing the stone, and she was subsequently lost to follow-up. In the group of patients with hypercalciuria and calcium oxalate stones, all had normal urate excretion. All patients were~white, and 13 of 27 were female. Fourteen of the children had a family history of stones. One boy and one girl with hypercaMuria had mildly elevated serum uric acid levels (6.5 and 6.0 mg/dl [390 and 360 ~mol/L], respectively). In the idiopathic calcium oxalate group, all patients were white and half were female. Only one child had a family history of ur01ithiasis. Two of these patients (both male) had hyperuricemia (serum uric acid concentration
Volume 115 Number 6
8.6 and 6.2 mg/dl [510 and 360 gmol/L], respectively). Of the four children with hyperuricemia associated with calcium oxalate urolithiasis, none had a family history of gout aad none had increased urinary urate excretion. One of these patients was markedly obese (body weight >36% above ideal weight for height). Urinary sodium and uric acid excretion with hypercalciuria was examined while the children were ingesting two diets differing only in sodium chloride content. As expected, fractional excretion of sodium was significantly lower during the low-sodium diet (0.19 z 0.02 vs 0.58 ~- 0.06, p <0.0005). Urinary uric acid excretion was similar during the two diets (0.29 _~ 0.02 vs 0.26 + 0.02 glomerular filtration rate), as was the fractional excretion of uric acid (6.91 z 1.12~ vs 5.61 + 0.64%). Uric acid excretion, expressed as mg/kg/day, also did not differ statistically during the low- and high-sodium diets (11.4 _+ 1.4 vs 9.6 + 1.0 mg/kg/day). Urinary calcium excretion did not differ statistically during the two dietary periods ( 3 . 6 _ 0.4 vs 4.2 -~ 0.4 mg/kg/day, p <0.08). DISCUSSION The prevalence of uric acid calculi among persons With urolithiasis in the United States has varied from 1.8% to 10%. depending on the geographic region and Study population. 1618 In regions outside the United States, the prevalence may be far greater. In Israel. for example, uric acid may account for as many as 75% of all urinary stones. 19 As we reported previously, children with uric acid stones represent 4% (5/120) of our total population of children with all types of urolithiasis.2~ Risk factors for uric acid urolithiasis include increased urinary excretion of uric acid resulting from idiopathic hyperuricemia, hyperuricemic states with rapid cell proliferation and destruction, disorders of purine metabolism, uricosuric drugs, and renal tubular dysfunction associated with renal uric acid wasting. Other factors known to predispose persons to uric acid calculi are ileostomy or colostomy with inflammatory bowel disease and persistently acid urine. 21 None of these conditions that result in a predisposition to excessive uric acid excretion were present in our patients with uric acid stones. In adult patients with idiopathic hyperuricemia in the United States, the prevalence of uric acid stones ranges from 1.8% to 9.4%. 17 In a review of 1258 patients with gout, Gutman and Yu 22reported urolithiasis in 22%. In adult men the prevalence of uric acid stones increases from 12.7% when the serum concentration of uric acid is 7 to 8 mg/dl (420 to 480 ~mol/L) to 40% when the serum uric acid concentration exceeds 9 mg (540 #tool/L). 23 More than 50% of the patients have urolithiasis when the serum uric acid level exceeds 13 mg/dl (770 #mol/L). 23 Idiopathic hyperuricemia is uncommon in children, and serum concentrations of uric acid are lower than adult val-
Uric acid excretion and urolithiasis
925
ues until adolescence. 23 In the five patients found to have uric acid stones in this study, the only risk factor was unexplained mild hyperuricemia in two of the patients. One patient had relatively high uric acid excretion because of a renal tubular disorder aSsociated with cystinosis. One girl had recentlY emigrated from Southeast Asia, a geographic region known to have a relatively high incidence of endemic urate stones. The three remaining boys were obese, which is known to increase serum uric acid concentrationY Other factors that may influence the risk of uric acid urolithiasis include persistently acidic urine,21 uricosuric drugs, and extracellular fluid volume contraction. We did not assess urinary acidification; however, none of the children had evidence of metabolic acidosis in the routine monitoring of serum electrolytes , and none was taking uricosuric agents. Radiocontrast media are known to increase uric acid excretion,25, 26 but none of the children underwent intravenous urography before the discovery of a uric acid stone. Finally, there was no evidence of a decrease in urinary volume in children with uric acid stones. The importance o f increased uric acid excretion in the genesis of urolithiasis in adults with idiopathic hypercalciuria has been emphasized by Coe and Kavalach. 27 Hyperuricuria occurred in 14.6% of all adults with calcium oxalate urolithiasis; 11.7% of such patients had both increased urinary calcium and uric acid excretion.4 The peak age range for stone formation in adults with increased uric acid excretion was 40 to 50 years of age. 27 This is later than the age range for peak stone formation in individuals with idiopathic hypercalciuria. Hyperuricuria in adults with urolithiasis has been attributed to excessive dietary Purine intake. The excessive intake of meat, fish, and poultry not only increases uric acid excretion, but also imposes a large acid load, thereby increasing urinary acidification. The findings of our studies suggest that increased urinary uric acid excretion is not a major complicating risk factor in children with idiopathic hypercalciuria. The importance of the modest hyperuricemia that we found in four children with idiopathic calcium oxalate stones is unknown. Dietary management of urinary urolithiasis has often included a recommendation of dietary sodium restriction. Urinary calcium excretion is known to be closely related to dietary sodium intake. 28 Changes in extracellular fluid volume also influence urinary excretion of uric acid. l~ 29 Previous studies have suggested that modifying dietary sodium chloride intake does not have a major influence on urinary excretion of uric acid in healthy adults. 11 Because dietary sodium restriction is frequently advised for individuals with idiopathic hypercalciuria, we examined the effect of such dietary manipulations on urinary acid excretion in children with idiopathic hypercalciuria. Under the dietary conditions of our study, uric acid excretion was not modified by significant changes in dietary sodium intake.
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Miller, Noe, and Stapleton
A l t h o u g h increased urinary uric acid excretion does not appear to be a m a j o r risk factor in children with urolithiasis, we contintm to believe t h a t urinary uric acid excretion Should be included in the initial examination of children with urinary stones. Often, recommendations for the medical m a n a g e m e n t of urolithiasis include empiric maneuvers to reduce the u r i n a r y excretion of all lithogenic factors. Such efforts to reduce urinary acid excretion b y dietary restrictions or with allopurinol t h e r a p y do not appear to be justified in most children with calcium oxalate urolithiasis, and should be reserved for selected patients with hyperuricuria.
REFERENCES 1. Lonsdale K, Mason P. Uric acid, uric acid dihydrate, and tirates in urinary calculi, ancient and modern. Science 1966;152:1511-2. 2. Sutor DJ,Wooley SE, lllingworth JJ. A geographical and historical survey of the composition of urinary stones. Br J Urol 1974;46:393-407. 3. Yu TF, Gutmann AB. Uric acid nepbrolithiasis in gout: predisposing factoJ~s. Ann Intern Med 19~57;67:1133-48. 4. Coe FL. Treated and untreated recurrent calcium nephrolitl~iasis in patients with idiiopathic hypercalciuria, hyperuricosuria or no metabolic disorder. Ann Intern Med 1977;89:40410. 5. Pak CYC, Waters O, Arnold L, et al. Mechanism for calcium urolithiasis among patients with hyperuficosuria. Supersaturation of urine with respect to monosodium urate. J Clin Invest 1977;59:426-31. 6. Coe FL, Lawton RB, Goldstein RB, Tembe V. Sodium urate accelerates precipitation of calcium oxalate in vitro. Proc Soc Exp Biol Med 1975;149:926-9. 7. Koutsoukos PG, Lam-Ervin CY, Nancollas GH. Epitaxial considerations in urinary stone formation. I. The urateoxalate-phosphate system. Invest Urol 1980;18:178-84. 8. Robertson WG. Physical chemical aspects of stone formation in the urinary tract. In: Fleisch H, Robertson WG, Smith LH, Vahlensieck W, eds. Urolithiasis research. New York: Plenum, 1976;331-6. 9. Weinman E J, Eknoyan G, Suki WN. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J Clin Invest 1975;55:283-91. I0. Steele TH. Evidence for altered renal urate reabsorption during changes in volume of the extracellular fluid. J Lab Clin Med 1969;74:288-99.
The Journal of Pediatrics December 1989
11. Stapleton FB, Roy S III, Noe HN, Jerkins G. Hypercalciuria in children with hematuria. N Engl J Med 1984;310:1345-8. 12. Stapleton FB, Nash D. A screening test for hyperuricosuria. J PEDIATR 1983;102:88-90. 13. Miller LA, Stapleton F B. Urinary citrate excretion in children with hypercalciuria. J PEmATR 1985;107:263-6. 14. Jones DP, Stapleton FB, Whitington G, Noe HN. Urolithiasis and enteric hyperoxaluria in a child with steatorrhea. Clin Pediatr 1987;26:304-6. 15. Black J, Stapleton FB, Roy S, et al. Varied types of urinary calculi in a patient with cysfinosis without renal tubular acidosis. Pediatrics 1986;78:295-7. 16. Holmes EW Jr. Uric acid nepbrolithiasis. In: Coe FL, ed. Nephrolithiasis: vol 5. New York: Churchill Livingstone, 1980:188-207 (Brenner BM, Stein VH, eds. Contemporary issues in nephrology). 17. Herring LC. Observations on the analysis of 10,000 urinary calculi. J Urol 1962;88:545-55. 18. Prien EL. Crystallographic analysis of urinary calculi: a 25-year study. J Urol 1963;89:917-28. 19. Neel JV, Rakie MT, Davidson RT, et al. Studies on hyperuricemia. Ii. A reconsideration of the distribution of serum uric acid values in the families of Smyth, Cotterman and Freyberg. Am J Hum Genet 1954;17:14-22. 20. Stapleton FB, McKay CP, Noe HN. Urolithiasis in children: the role of hypercalciuria. Pediatr Ann 1987;16:980-92. 21. Falls WF Jr. Comparison of urinary acidification and ammonium excretion in normal and gouty subjects. Metabolism t972;21:433-9. 22. Gutman AB, Yu T-F. Uric acid nephrolithiasis. Am J Med 1968;45:756-63. 23. Hall AP, Barry PE, Dauber TR, McNamara M. Epidemiology of gout and hyperuricemia: a long-term population study. Am J Med 1967;42:27-37. 24. Stapleton FB, Linshaw MA. Hassenein K, Gruskin AB. Uric acid excretion in healthy children. J PEDXATR 1978;92:912-4. 25. Postlethwaite AE, Kelly WN. Uricosuric effect of effects of radiocontrast agents. Ann Intern Med 1971;74:1845-52. 26. Sleasman JW, Stapleton FB, Tonkin IL. Effect of contrast media upon renal function in children undergoing cardiac catheterization [Abstract]. Clin Res 1982;30:885A. 27. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Engl J Med 1974; 291:1344-8. 28. Phillips M J, C o ~ e JNC. Relation between urinary calcium and sodium in patients with idiopathic hypercalciuria. Lancet 1967;1:1354-7. 29. Breslau NA, Pak CYC. Lack of effect of salt intake on urinary uric acid excretion. J Urol 1983;129:531-2.
Urinary uric acid excretion was assessed in 38 children to determine whether hyperuricuria was a risk factor in children with urolithiasis. Uric a c i d excretion (measured per deciliter glomerular filtration rate)i and fractional e x c r e t i o n of uric acid were similar in 27 children with hypercalciuria and c a l c i u m o x a l a t e urinary stones, in six children with idiopathic calcium o x a l a t e urolithiasis, and in five with uric acid urolithiasis, of w h o m four were white boys and o n e was an Asian girl. One b o y with a urate stone had cystinosis. Serum uric a c i d c o n c e n trations e x c e e d e d 6.0 m g / d l (360 ~mo!/L) in two children with hypercalciuria and in two patients with idiopathic calcium o x a l a t e urolithiasis. None of the children with calcium urolithiasis had excessive urinary excretion of uric acid. In children with hypercalciuria, uric a c i d excretion did not c h a n g e significantly when dietary sodium was increased from 4.0 to 5.0 gm/4.73 m 2. We c o n c l u d e that excessive urinary uric a c i d excretion is seldom an additional riskfactor in chi!dren with calcium urolithiasis and that dietary sod!um chloride does not have a strong influence on urinary e x c r e t i o n of uric a c i d in children with hypercalci-
uria. (J PEDIATR1989;145:923-6)
Uric acid promotes urinary crystal formation and is a major constituent of urinary calculi. 1 Uric acid stones are endemic to certain geographic locations2 and occur in patients with gout. 3 In addition, increased urinary excretion of uric acid is found in 14.6% of adult patients with calcium oxalate urolithiasis.4 Uric acid increases calcium oxalate crystal formation by various mechanisms. Several investigators have demonstrated calcium oxalate crystal growth on a uric acid "nidus" in vitro.5-7; furthermore, uric acid may reduce the activity of urine inhibitors of crystal formation. 8 Whether uric acid is an important promoter of urolithiasis in children is unknown. In this study, we examined urinary uric acid excretion in children with calcium oxalate
Supported by grants from the General Clinical Research Center (2MO1 RR00211-23) and the National Institutes of Health (1ROI AM HD31370). Submitted for publication March 16, 1989;accepted June 13, 1989. Reprint requests: F. Bruder Stapleton, MD, Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222. 9/20/14613
and uric acid urolithiasis. In addition, we also assessed the relationship of dietary sodium chloride and urinary uric acid excretion in children with hypercalciuria because a relationship has been shown between extracellular fluid volume and uric acid excretion. 9, 1o METHODS During an 8-year period, urinary uric acid, calcium, and creatinine excretion was measured in all children referred to LeBonheur Children's Medical Center for the evaluation of calcium oxalate and uric acid urolithiasis. Urine collections were obtained at home while the patients were ingesting their routine diets and were not receiving any medications. The children were categorized into three groups: group 1 consisted of 27 children (14 boys) having calcium oxalate urolithiasis and hyperca!ciuria (urinary calcium excretion >4 mg/kg/day during an unrestricted diet); group 2 consisted of six children (3 boys) with idiopathic calcium oxalate stones (patients were considered to have idiopathic urolithiasis if urinary calcium excretion was <4.0 mg/kg/day, 11 urinary uric acid per deciliter glomerular filtration rate 12 was <0.57, urinary citrate was >300 rag/
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The Journal of Pediatrics December 1989
Table. U r i n a r y c a l c i u m and uric acid excretion in children with urolithiasis
Age (yr) Urinary calcium (mg/kg/day)* Urinary uric acid (mg/dl GFR)~ FE uric acid (%) Urinary volume (ml/kg/day)
Hypercalciuria with CaOx Stones (n = 2 7 )
Idiopathic CaOx stones
9.3 +_ 0.8 5.3 +_ 0.4 0.30 +_ 0.02 6.29 _+ 0.45 26.4 +_ 2.8
14.8 +_ 0.9 1.9 +_ 0.3:~ 0.35 _+ 0.04 7.00 +_ 1.28 10.4 _+ 2.2~
(n = 6)
Uric acid urolithiasis (n = 5) 8.8 4.0 0.38 6.80 20.8
+_ 2.0 +_ 2.8 +__0.08 +_ 1.74 +_ 5.6
Data are expressedas mean +_SEM. CaOx, Calciumoxalate;GFR, gl0merularfiltrationrate; F'E,fractionalexcretion. *1 mg ca!cium= 0.025 mmol. "~1gm uric acid = 5.95 mmol. :~p'<0.001 fromchildrenwith hypercalciuriaand calciumoxalate stones.
gm creatinine.13 urinary oxalate was <50 mg/1.73 m 2 body surface area, 14 and urinary cystine screen was negative); group 3 consisted of five children (four boys) with uric acid urolithiasis defined as having a urinary stone composed primarily of uric acid. This patient population represents 56% of 67 children with all types of urolithiasis in whom a 24hour urinary uric acid excretion was determined during the same period. The effect of dietary sodium chloride intake on urinary acid excretion was determined in 15 children with hypercalciuria. Patients were first studied after ingestion of a study diet containing 300 mg calcium and 1.0 gm sodium t.73 m2 for 5 days. After at least 2 weeks of ingesting an unrestricted diet, a study diet containing 300 mg calcium and 5.0 gm sodium per 1.73 m 2 (given as sodium chloride supplements) was ingested. On the fifth day of each dietary regulation, a 24-hour urine collection was obtained and urinary sodium, calcium, uric acid, and creatinine levels were measured. Dietary records were maintained to ensure compliance with the study diets. Urinary calcium excretion was assayed by atomic absorption (Varian Instruments, Melbourne, Australia), and creatinine concentration was determined with a Beckman Creatinine Analyzer II chemistry analyzer (Beckman Instruments Inc., Fullerton, Calif.). Urinary uric acid was measured by means of a uricase technique (Raichem, Reagents Applications Inc.. San Diego, Calif.), and sodium was determined with an ion-selective electrode (model E2A analvzer. Beckman). Studies were performed in our clinical research center. Informed consent was obtained before each study. Statistical analyses were performed by mea~ts of the Student t test for both paired and unpaired data. RESULTS Children with hypercalciuria and urolithiasis and those with uric acid stones were similar in age. Children with idiopathic calcium oxalate stones were older (14.8 _~ 0.9
years) than patients with hypercalciuria (p <0.005) and the children with uric acid urolithiasis (p <0.02) (Table). Urinary calcium excretion in patients with hypercalciuric urolithiasis and in children with uric acid stones was similar; only one patient (with multiple renal tubular defects ) with urate Stones had urinary calcium excretion >4 mg/kg/day. Urinary calcium excretion in children with idiopathic urolithiasis, on the other hand, wa s significantly lower than in the patients with hypercalciuria (p <0.001) (Table). Urinary uric acid excretion corrected for creatinine clearance was similar in each of the three groups studied. Urate excretion in all three groups was similar to our previously published data in normal children (mean + SD: 0.34 _+ 0.t 1 mg/dl glomerular filtration rate] 2 Urinary volume was greater in children with hypercalciuria and with urate stones than in children with idiopathic urolithlasis. Four of the patients with uric acid urolithiasis were white boys, one of whom had cystinosis diagnosed at 1 year of age and had numerous radiolucent stones associated with a ureteropelvic obstruction. 15 Each of the three remaining boys was obese (weight greater than 20% above ideal weight for height). The o~.e girl in this grou p was Asian and had no family historybf stones. Uric acid urolithiasis was diagnosed wtien she was 10 years of age; serum uric acid concentration was 4.8 mg/dl (290 #mol/L). Urinary uric acid excretion data were not quantitated in this patient at the time of passing the stone, and she was subsequently lost to follow-up. In the group of patients with hypercalciuria and calcium oxalate stones, all had normal urate excretion. All patients were~white, and 13 of 27 were female. Fourteen of the children had a family history of stones. One boy and one girl with hypercaMuria had mildly elevated serum uric acid levels (6.5 and 6.0 mg/dl [390 and 360 ~mol/L], respectively). In the idiopathic calcium oxalate group, all patients were white and half were female. Only one child had a family history of ur01ithiasis. Two of these patients (both male) had hyperuricemia (serum uric acid concentration
Volume 115 Number 6
8.6 and 6.2 mg/dl [510 and 360 gmol/L], respectively). Of the four children with hyperuricemia associated with calcium oxalate urolithiasis, none had a family history of gout aad none had increased urinary urate excretion. One of these patients was markedly obese (body weight >36% above ideal weight for height). Urinary sodium and uric acid excretion with hypercalciuria was examined while the children were ingesting two diets differing only in sodium chloride content. As expected, fractional excretion of sodium was significantly lower during the low-sodium diet (0.19 z 0.02 vs 0.58 ~- 0.06, p <0.0005). Urinary uric acid excretion was similar during the two diets (0.29 _~ 0.02 vs 0.26 + 0.02 glomerular filtration rate), as was the fractional excretion of uric acid (6.91 z 1.12~ vs 5.61 + 0.64%). Uric acid excretion, expressed as mg/kg/day, also did not differ statistically during the low- and high-sodium diets (11.4 _+ 1.4 vs 9.6 + 1.0 mg/kg/day). Urinary calcium excretion did not differ statistically during the two dietary periods ( 3 . 6 _ 0.4 vs 4.2 -~ 0.4 mg/kg/day, p <0.08). DISCUSSION The prevalence of uric acid calculi among persons With urolithiasis in the United States has varied from 1.8% to 10%. depending on the geographic region and Study population. 1618 In regions outside the United States, the prevalence may be far greater. In Israel. for example, uric acid may account for as many as 75% of all urinary stones. 19 As we reported previously, children with uric acid stones represent 4% (5/120) of our total population of children with all types of urolithiasis.2~ Risk factors for uric acid urolithiasis include increased urinary excretion of uric acid resulting from idiopathic hyperuricemia, hyperuricemic states with rapid cell proliferation and destruction, disorders of purine metabolism, uricosuric drugs, and renal tubular dysfunction associated with renal uric acid wasting. Other factors known to predispose persons to uric acid calculi are ileostomy or colostomy with inflammatory bowel disease and persistently acid urine. 21 None of these conditions that result in a predisposition to excessive uric acid excretion were present in our patients with uric acid stones. In adult patients with idiopathic hyperuricemia in the United States, the prevalence of uric acid stones ranges from 1.8% to 9.4%. 17 In a review of 1258 patients with gout, Gutman and Yu 22reported urolithiasis in 22%. In adult men the prevalence of uric acid stones increases from 12.7% when the serum concentration of uric acid is 7 to 8 mg/dl (420 to 480 ~mol/L) to 40% when the serum uric acid concentration exceeds 9 mg (540 #tool/L). 23 More than 50% of the patients have urolithiasis when the serum uric acid level exceeds 13 mg/dl (770 #mol/L). 23 Idiopathic hyperuricemia is uncommon in children, and serum concentrations of uric acid are lower than adult val-
Uric acid excretion and urolithiasis
925
ues until adolescence. 23 In the five patients found to have uric acid stones in this study, the only risk factor was unexplained mild hyperuricemia in two of the patients. One patient had relatively high uric acid excretion because of a renal tubular disorder aSsociated with cystinosis. One girl had recentlY emigrated from Southeast Asia, a geographic region known to have a relatively high incidence of endemic urate stones. The three remaining boys were obese, which is known to increase serum uric acid concentrationY Other factors that may influence the risk of uric acid urolithiasis include persistently acidic urine,21 uricosuric drugs, and extracellular fluid volume contraction. We did not assess urinary acidification; however, none of the children had evidence of metabolic acidosis in the routine monitoring of serum electrolytes , and none was taking uricosuric agents. Radiocontrast media are known to increase uric acid excretion,25, 26 but none of the children underwent intravenous urography before the discovery of a uric acid stone. Finally, there was no evidence of a decrease in urinary volume in children with uric acid stones. The importance o f increased uric acid excretion in the genesis of urolithiasis in adults with idiopathic hypercalciuria has been emphasized by Coe and Kavalach. 27 Hyperuricuria occurred in 14.6% of all adults with calcium oxalate urolithiasis; 11.7% of such patients had both increased urinary calcium and uric acid excretion.4 The peak age range for stone formation in adults with increased uric acid excretion was 40 to 50 years of age. 27 This is later than the age range for peak stone formation in individuals with idiopathic hypercalciuria. Hyperuricuria in adults with urolithiasis has been attributed to excessive dietary Purine intake. The excessive intake of meat, fish, and poultry not only increases uric acid excretion, but also imposes a large acid load, thereby increasing urinary acidification. The findings of our studies suggest that increased urinary uric acid excretion is not a major complicating risk factor in children with idiopathic hypercalciuria. The importance of the modest hyperuricemia that we found in four children with idiopathic calcium oxalate stones is unknown. Dietary management of urinary urolithiasis has often included a recommendation of dietary sodium restriction. Urinary calcium excretion is known to be closely related to dietary sodium intake. 28 Changes in extracellular fluid volume also influence urinary excretion of uric acid. l~ 29 Previous studies have suggested that modifying dietary sodium chloride intake does not have a major influence on urinary excretion of uric acid in healthy adults. 11 Because dietary sodium restriction is frequently advised for individuals with idiopathic hypercalciuria, we examined the effect of such dietary manipulations on urinary acid excretion in children with idiopathic hypercalciuria. Under the dietary conditions of our study, uric acid excretion was not modified by significant changes in dietary sodium intake.
926
Miller, Noe, and Stapleton
A l t h o u g h increased urinary uric acid excretion does not appear to be a m a j o r risk factor in children with urolithiasis, we contintm to believe t h a t urinary uric acid excretion Should be included in the initial examination of children with urinary stones. Often, recommendations for the medical m a n a g e m e n t of urolithiasis include empiric maneuvers to reduce the u r i n a r y excretion of all lithogenic factors. Such efforts to reduce urinary acid excretion b y dietary restrictions or with allopurinol t h e r a p y do not appear to be justified in most children with calcium oxalate urolithiasis, and should be reserved for selected patients with hyperuricuria.
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The Journal of Pediatrics December 1989
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