| Abstract|| |
The clinical manifestations of hyperuricosuria (HU) are usually underestimated by the clinician. The aim of this study was to review the clinical spectrum of symptomatology of HU and to evaluate the presence of associated hypercalciuria (HC) and hyperoxaluria (HX). A retrospective review was done on 64 children with HU seen between January 2004 and December 2008. The patients were divided into HU 19, HU + HC 4, HU + HX 21 and HU + HC + HX 20. The mean age at diagnosis was 80 months (range six to 156 months). Duration of follow-up ranged was from six to 66 months. There were 228 symptomatic episodes for 64 patients (males 31, females 33). The relationship of symptomatology to age and gender were not significant. The most common symptoms were abdominal pain 67.2% (in 7/44 it was localized to the right lower quadrant, mimicking appendicitis), flank pain 59.4%, increased urinary frequency 43.4%, urgency 39%, enuresis 31.25%, oliguria 29.7%, dysuria 25%, red urine 20.35%, vaginal itching 15.21%, dribbling 14.06%, orange urine 12.5%, hesitancy 12.5% and penile pain 7.81%. To our knowledge, the vaginal itching and penile pain were not previously described. Family history was positive for stones and/or gout in 62.5%. The presence of a positive family history and red urine were significant (P-value <0.05) for the presence of an underlying HU. In the presence of recurrent abdominal/flank pain, hematuria without proteinuria or edema and urological symptomatology, especially in the presence of red urine, and a positive family history of gout or stones, a search for HU is in order. This will avoid unnecessary and invasive investigations.
|How to cite this article:|
Akl K, Ghawanmeh R. The clinical spectrum of idiopathic hyperuricosuria in children: Isolated and associated with hypercalciuria/hyperoxaluria. Saudi J Kidney Dis Transpl 2012;23:979-84
|How to cite this URL:|
Akl K, Ghawanmeh R. The clinical spectrum of idiopathic hyperuricosuria in children: Isolated and associated with hypercalciuria/hyperoxaluria. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jul 9];23:979-84. Available from: http://www.sjkdt.org/text.asp?2012/23/5/979/100879
| Introduction|| |
Interest in hyperuricosuria (HU) began to surface in the 1990s, after idiopathic hypercalciuria (HC) was recognized in the 1980s as an important cause of hematuria.  Later on, it became apparent that both HU and/ or HC may be responsible for abdominal pain, hematuria and other urological symptomatology.  The subject is rather new. There are no conflicting reports in the literature. In addition, in a recent cross-sectional study by Beiraghdar and associates, the importance of associated hyperoxaluria (HX) was emphasized.  The purpose of this study is to emphasize on the spectrum of symptomatology that occur in cases of HU in children and to determine whether associated HC or HX contributed to the findings. The topic is important because HU mimics several disease states, and timely diagnosis avoids unnecessary and invasive investigations.
| Materials and Methods|| |
This retrospective study was performed by reviewing the medical records of the pediatric renal service at the Jordan University Hospital from January 2004 to December 2008. Symptomatic patients who were found to have HU, whether alone or associated with hypercalciuria (HC), and HX were included in the study, whereas symptomatic patients who did not have HU were excluded even if they had HC and/or HX. Also excluded were patients with systemic disease like cystic fibrosis. Based on this, 64 children with the diagnosis of HU were included in the study.
The duration of follow-up ranged from six months to 66 months. Data collection included history, physical examination, laboratory data and imaging. History included age and month at presentation, sex, symptoms and the course. Family history covered consanguinity, gout (in adults) and stones. Dietary habits evaluation, which was documented by direct family questioning on 24 patients on >2 occasions, included intake of water (>20 mL/kg/day); purines [red meat: as hamburgers or pieces of cooked/ grilled meat, poultry, fish and humus (chickpeas)]; sweets, fruit juices (>2 cups/day), chocolate (>1 bar/day) and regular meal amount intake of tomatoes/sauce, mulukhiah (Middle Eastern vegetable), and spinach; and tea. Physical examination included height, weight and blood pressure. Laboratory data included serum creatinine, uric acid, venous blood gases and 24-h urine collections for volume, creatinine, uric acid, calcium and oxalate. Most patients had more than one 24-h urine collection. For children <2 years, urine collection was done via an indwelling urinary catheter. Adequacy of the urine collection was guided by urinary creatinine excretion. Because the study was retrospective, unfortunately, urinary sodium, magnesium and citrate were done only on a few patients. The urinary specific gravity was excluded from the study because it was not done on the same day of the symptoms and thus would be misleading. Imaging was done by ultrasonography for the detection of stones. Some patients had a non-enhanced computerized axial tomography as well. The patients were divided into four groups: isolated HU 19, HU + HC 4, HU + HX 21 and HU + HC + HX 20. There was no control group from the society.
Hyperuricosuria was defined as urinary uric acid excretion of >11 mg/kg/24 h for children <2 years and >520 ± 147 mg/1.73 m 2 /day for children older than two years,  HC as urinary calcium excretion >4 mg/kg/24 h  and hyperoxaluria as urinary oxalate excretion > 36.9 mg/ 1.73 m 2 /24 h for children older than three years and >0.5 mg/kg/day for children younger than three years.  Microscopic hematuria was defined as >3 red blood cells per high-power field  and recurrent urinary tract infections as more than three episodes per year.
Increased urinary frequency was defined as >8 voids/day for children >2 years of age and >8 wet diapers for children <2 years of age. Red urine was defined as reddish discoloration in the absence of red blood cells or a positive dipstick. Oliguria was defined as urine output less than 1 mL/kg/h in infants and less than 0.5 mL/kg/h in children.  Enuresis was defined as wetting the bed during sleep in children older than six years of age.
Body mass index (BMI) was calculated as weight/height  , and plotted against percentiles. 
| Statistical Method|| |
The statistical package for social studies (SPSS) for windows software package release 15 was used for statistical analysis. The Chi-square statistical method was employed. P-value < 0.05 was considered significant.
| Results|| |
There were 31 males and 33 females. Age at presentation ranged from six to 156 months (mean 80 months). The most frequent months at initial presentation were July and August. Most recurrences occurred during the hot summer months. There were 228 symptomatic episodes for 64 patients [Table 1].
The BMI was between the 90 th and 96 th percentile in five children (two males, three females) without associated stones, and above the 97 th percentile in seven children (five males, two females), with associated stones in two children.
Dietary habits were documented for 24 children: decreased water intake in 8/24 increased purine intake 8/24, excessive fruit juice (high fructose) drinking 9/24 and increased sweets intake in 12/24. Patients with high purine intake were meat lovers, who would usually eat meat for breakfast, lunch and dinner.
History of high oxalate dietary intake included spinach in 13/24, chocolate 12/24, tea 7/24 and tomatoes in 6/24 children. Those with high oxalate intake usually concentrated on one food item, usually tomatoes.
There was a positive family history of consanguinity in 16 /64 (25%) and stones and/or gout (in adult relatives) in 40/64 (62.5%). Seven patients had right lower quadrant (mimicking acute appendicitis in four).
Isolated HU, HU + HC, HU + HX and HU + HC + HX occurred in 19, 4, 21 and 20 children, respectively. The relationship of family history and red urine to the crystal type is shown in [Table 2], and it was significant for HU (P <0.05). Three patients with oliguria had transient elevation of the serum creatinine, which dropped back to normal for age after hydration.
|Table 2: Relationship of family history and red urine to types of crystalluria.|
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Relationship of crystal type to symptomatology is shown in [Table 3].
Ten patients had stones, with associated HC and HX in four and three, respectively. Two patients underwent extracorporeal lithotripsy, and both stones consisted of uric acid and calcium oxalate. Besides the calculi, other patients had the following ultrasonographic findings: pelvicalyceal dilatation in three, atrophic left kidney in two and horseshoe kidney in one. The rest of the patients had normal findings.
Treatment intially consisted of increasing fluid intake to >20 mL/kg m/day of fluids, mainly as water, or advised to drink as much water as needed to change the urine color to water color. If that failed, the next step was use potassium citrate (0.5-2 mEq/kg/day). As a crystal inhibitor, potassium citrate helped alleviate symptoms, but not decrease urinary uric acid levels.
If symptoms persisted, the xanthine oxidase inhibitor, allopurinol, was prescribed. Allopurinol decreased the level of urinary uric acid excretion. In a few patients, allopurinol was only used during the summer months.
| Discussion|| |
A variety of symptoms such as loin pain, dysuria, etc., are described in children with HU. We undertook this study to review the clinical spectrum of symptomatology that occurs in children with HU and to determine the associated HC and HX.
The familial prevalence of stones was emphasized by Polito and colleagues, who reported it in 75% of the cases of HU.  In our study, a positive family history of stones and/or gout, which was documented in 62.5%, served as an important clue to an underlying HU.
Recurrent abdominal/flank pain usually occurs in cases of HC,  HU and HU with HC.  The most frequently encountered symptoms in our patients were abdominal/flank pain, which occurred in the majority of the cases. Young children below the age of five years tend to complain of abdominal rather than flank pain.  Appendicitis like pain has been previously reported in association with HU and HC.  It occurred in 11% of our patients. Enuresis has been associated with HU.  It occurred in one-third of our patients.
It is known that children with disorders of purine metabolism may present with stones or oliguria secondary to crystal nephropathy. , The presence of hyperuricosuria in childhood may be an early manifestation of purine over-production. 
In our patients, oliguria occurred in 29.7%. Dysuria is known to occur with HU  and HC (manifesting as irritability in infants).  Hematuria was initially described to occur in association with HC,  and later on with HU, both in adults  and in children. ,,, It may be recurrent and/or familial. , Renal calyceal micro-lithiasis may present clinically earlier than sonographic evidence of stones. 
The presence of red urine color, vaginal itching and penile pain were not previously emphasized. Penile pain, was described in association with urolithiais,  but not with HU. It may be due to deposition of uric acid crystals on the surface of the urethral mucosa.
Besides purine intake, which contributes to a low urine pH, drinking fructose-rich fruit juices and indulgence in sweets may lead to future development of gout in men.  Both fructose and uric acid share a common transporter, the SLC2A9 gene. Ingestion of fructose leads to the generation of uric acid. ,,
The finding of HU or uric acid stones may be an early warning of a future metabolic syndrome. , With an inadequate fluid intake, the urine becomes supersaturated with uric acid, which, in the presence of an acid urine, enhances uric acid crystal formation.  Because uric acid crystals serve as a nidus for calcium oxalate crstalls, eating high oxalate foods contributed to symptomatology, especially in patients with associated HX.
Treatment of HU includes increasing fluid intake, use of alkalinizing agents such as potassium citrate (0.5-2 mEq/kg/day) to increase the urinary pH to 6.5-7.0 and, if the above measures fail and the patient remains symptomatic, employment of the xanthine oxidase inhibitor allopurinol (5-10 mg/kg/day).  Potassium citrate is superior to sodium citrate, as the latter increases the sodium load and predisposes to calcium oxalate stones by promoting the excretion of calcium. Potassium citrate decreases the risk of uric acid nephrolithiasis  and hyperuricosuric calcium oxalate stones.  A low purine diet is recommended, but is difficult to implement.
Our findings regarding the clinical findings of HU are in agreement with the literature. , While the importance of family history was mentioned before,  the occurrence of red urine has not been reported previously to the best of our knowledge. Limitations of this study are that it was retrospective and not a controlled study. In the presence of recurrent abdominal/flank pain, hematuria without proteinuria or edema, and urological symptomatology, especially in the presence of a positive family history of gout or stones, a search for crystalluria is in order. This will avoid unnecessary and invasive investigations.
| Acknowledgment|| |
The authors would like to thank the support provided by the University of Jordan in performing this study.
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Consultant Pediatric Nephrologist, Associate Professor of Pediatrics, Department of Pediatric Nephrology, Jordan University Hospital, College of Medicine, University of Jordan, P. O. Box 831373, Amman 11183
[Table 1], [Table 2], [Table 3]