- Email: [email protected]
Metabolic Disorders in Turkish Children With Urolithiasis
Pediatric Urology Metabolic Disorders in Turkish Children With Urolithiasis Mehmet Halil Celiksoy, Alev Yilmaz, Gonul Aydogan, Aysel Kiyak, Erdem Topal, and Serdar Sander OBJECTIVE MATERIALS AND METHODS
RESULTS
CONCLUSION
To review metabolic disorders in Turkish children with urinary tract stone disease. The medical records of 308 pediatric patients with the diagnosis of urolithiasis between 1996 and 2008, whose disease progression was followed in a single tertiary-care center, were reviewed retrospectively. Two hundred forty-eight patients whose metabolic analyses were performed were included in the study. Of the 248 patients participating in the study, 142 (57%) were men and 106 (43%) were women. The median age of the patients was 48 months (minimum-maximum, 2-180 months). Seventy-six percent of the patients had metabolic disorders. Of all patients, 44% had 1, 23% had 2, and 7% had 3 metabolic disorders. Hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and cystinuria were detected in 41%, 39%, 22%, 9%, and 4% of the patients, respectively. The rate of multiple stone formation, infection, and recurrence was significantly higher in the 0-2 years age group (P ¼ .030, P ¼ .001, P ¼ .019, respectively). The median age of patients was greater (P ¼ .001) in patients with hyperoxaluria in comparison with other metabolic disorders. Compared with other metabolic disorders, multiple stones and recurrence were more frequent in patients with cystinuria (P ¼ .022 and P ¼ .008, respectively). The size of the stones was greater in patients with hyperuricosuria in comparison with other metabolic disorders (P ¼ .009). The majority of children with urinary tract stone disease exhibited 1 metabolic risk factors. Metabolic risk factors should be evaluated in all children with urinary stone disease to provide appropriate treatment. UROLOGY 85: 909e913, 2015. 2015 Elsevier Inc.
U
rolithiasis is a condition resulting in a crystallized mass mixed with protein and lipid found in the kidney and the urinary tract, resulting from metabolic, endocrinologic, and urologic causes.1 Pediatric urolithiasis is less common than in adults, and its characteristics, incidence, etiology, and localization vary greatly by geographic region.2 The actual incidence of urolithiasis in children is unknown with a prevalence of 1%-5% in the developed countries and 5%-15% in developing countries.3 The prevalence of urolithiasis in Turkey has been reported as 14.8%.4 Although there are insufficient data in children, an incidence of urolithiasis in Turkish school-age children as 0.8% was reported by Remzi et al.5 In the majority of pediatric patients with urolithiasis, a metabolic cause for stone formation can be identified and
Financial Disclosure: The authors declare that they have no relevant financial interests. _ From the Department of Pediatrics, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey; the Division of Pediatric _ Nephrology, Department of Pediatrics, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey; and the Department of _ Pediatric Surgery, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey Address correspondence to: Mehmet Halil Celiksoy, M.D., Department of Pediatric Allergy and Immunology, Ondokuz Mayıs University, Faculty of Medicine, 55139 Kurupelit, Samsun, Turkey. E-mail: [email protected] Submitted: October 14, 2014, accepted (with revisions): December 22, 2014
ª 2015 Elsevier Inc. All Rights Reserved
several metabolic disorders are well-defined (eg, cystinuria or primary hyperoxaluria type 1). There is a large subgroup of patients showing a subtle increase of urinary lithogenic factors (calcium, oxalate) or a reduction of stone inhibitory substances, like urinary citrate.6 In Turkey, the rate of metabolic disorders in the studies on childhood urinary tract stone disease was reported to be 33.0%-83.2%.7-9 The recurrence rate of stones due to metabolic abnormalities in children is high, and this rate can be up to 50%, if medical treatment protocol is not followed.10 Children exhibit more ambiguous signs and symptoms of urolithiasis than adults, leading to delayed diagnosis, resulting in chronic pyelonephritis and endstage renal failure.1 The aim of this research was to review metabolic risk factors in urolithiasis patients whose progress was investigated at our clinic.
MATERIALS AND METHODS In this study, the medical records of 308 patients, whose progress _ was investigated at the Istanbul Bakırk€ oy Maternity and Children’s Diseases Training and Research Hospital, Division of Pediatric Nephrology, with the diagnosis of urolithiasis, were evaluated retrospectively. The patients whose urinary metabolic screens showed anomaly were included in the study. The patients who did not have any metabolic screens were excluded. http://dx.doi.org/10.1016/j.urology.2014.12.032 0090-4295/15
909
Also, patients with renal anatomic anomalies and those who developed urinary stone disease owing to the use of high-dose vitamin D were excluded from the study. For the remaining 248 patients, data related to age, gender, family history, and consanguineous marriage were extracted from the medical records of the patients. Data for urea, creatinine, uric acid, sodium, potassium, chlorine, magnesium, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, the sodiumnitroprusside test, blood gases, the 3-day spot urinary calciumto-creatinine ratio, the 24-hour metabolic stone analysis, and, if available, biochemical analysis results of the stone were obtained from the medical records of the patients. Ultrasonographic findings were also collected from the medical records. Stones <3 mm in diameter were defined as microcalculi, and those >3 mm in diameter were defined as macrocalculi.11 Hypercalciuria was defined as urinary calcium excretion >4 mg/ kg/d; hyperoxaluria as urinary oxalate >40 mg/1.73 m2/d; hyperuricemia as urinary urate >815 mg/1.73 m2/d; hypocitraturia as urinary citrate <400 mg/g creatinine; and cystinuria as urinary cystine >75 mg/1.73 m2/d.12 Urinary calcium-tocreatinine ratio 95th percentile values from the same area by age were used for hypercalciuria; 0.76, 0.60, 0.69, and 0.24 values were used for the 0-7 months, 8-18 months, 19 months to 6 years, and 7-14 years age groups, respectively.13 The relationship between the each of the metabolic disorders (eg, hypercalciuria and hypocitraturia) and age, sex, consanguinity, recurrence, family history, bilaterality, multiplicity, stone localization, and stone size was compared. We performed statistical analysis using Statistical Package for Social Sciences 15.0 software (SPSS Inc., Chicago, IL). Descriptive statistics were expressed as frequency and percentage for categorical variables, whereas quantitative data were expressed as median for non-normally distributed data. We used the Mann-Whitney U test to compare quantitative data and used the chi-square test (Fisher exact test, when needed) to compare the categorical variables. We considered 2-sided P <.05 as statistically significant.
RESULTS Of the 248 patients participating in the study, 142 (57.3%) were men and 106 (42.7%) were women. The median age of the patients was 48 months (minimummaximum, 2-180 months). A familial history of urolithiasis was found in 131 of 240 patients (54.6%). This percentage was obtained by omitting the 8 cases for which the family history of urolithiasis was not specified in the medical records. This rate was found in 55 of 240 patients (22.9%) in the first-degree relatives and in 76 of 240 patients (31.7%) in the second-degree relatives. Consanguinity was found in 28 of 119 patients (23.5%). Information regarding consanguinity was absent for 129 patients. Macrocalculi and microcalculi were present in 186 (75.0%) and 62 (25.0%) of the cases, respectively. Multiplicity and bilaterality at initial presentation were identified in 119 (48.0%) and 61 (24.6%) of the cases, respectively. An analysis of the locations of the stones revealed that 229 patients (92.3%) had upper urinary tract stones and 19 patients (7.7%) had lower urinary tract stones. All patients had at least a partial metabolic study. Hypercalciuria, hypocitraturia, hyperoxaluria, 910
Table 1. Demographics of patients with urolithiasis Variables Age, median (min-max), mo Male Consanguinity Family history of urolithiasis First degree Second degree Infection Bilaterality Multiplicity Stone localization Upper urinary system (pelvis, calyces, ureter) Lower urinary system (bladder, urethra) Size of stone Microcalculi (3 mm) Macrocalculi (>3 mm) Metabolic disorders Hypercalciuria Hypocitraturia Hyperoxaluria Hyperuricosuria Cystinuria Total
N (%) 48 142 28/119 131/240 55/240 76/240 51 61 119
(2-180) (57.3) (23.5) (54.6) (22.9) (31.7) (20.6) (24.6) (48.0)
229 (92.3) 19 (7.7) 62 186 189 103 98 54 23 11 248
(25.0) (75.0) (76.2) (41.5) (39.5) (21.8) (9.3) (4.4) (100.0)
max, maximum; min, minimum.
hyperuricosuria, and cystinuria were detected in 41.5%, 39.5%, 21.8%, 9.3%, and 4.4% of the cases, respectively. Table 1 shows the demographics of patients with urolithiasis. Of the patients, 189 (76.2%) had metabolic disorders; 44.2% had 1, 23.1% had 2, and 7.6% had 3 metabolic disorders. One patient had 4 metabolic disorders (Fig. 1). In patients with metabolic disorders, combined hypercalciuria and hypocitraturia in 38 of 189 patients (20.1%) was the most common metabolic disorder with multiple components. One patient had chronic renal insufficiency at the time of the diagnosis. A stone composed of uric acid was detected in this patient. No relationship was observed between the metabolic disorders and the incidence of bilaterality, multiplicity, recurrence, sex, macrocalculi, microcalculi, stone localization, consanguinity, family history of urolithiasis, and infection (P ¼ .118, P ¼ .614, P ¼ .926, P ¼ .504, P ¼ .438, P ¼ .438, P ¼ .158, P ¼ .418, P ¼ .400, and P ¼ .431, respectively). The rate of multiple stone formation, infection, and recurrence was significantly higher in the 0-2 years age group (P ¼ .030, P ¼ .001, and P ¼ .019, respectively). History of stones in family was significantly higher in the >2 years group (P ¼ .034; Table 2). The median age of patients was higher (P ¼ .001) in patients with hyperoxaluria in comparison with other metabolic disorders. Relationship was observed between the history of stones in family and hypocitraturia (P ¼ .040). Compared with other metabolic disorders, multiple stones and recurrence were more frequent in patients with cystinuria (P ¼ .022 and P ¼ .008, respectively). Lower urinary tract stones were significantly higher in patients with cystinuria (P ¼ .012). The size of the stones was UROLOGY 85 (4), 2015
Figure 1. Distribution of multiple metabolic disorders in patients with urolithiasis.
Table 2. Distribution by age in patients with urolithiasis Variables Male Consanguinity History of stones in family Bilateralism Multiplicity Recurrence Infection Stone localization Upper urinary system Lower urinary system Size, median (min-max) Microcalculi (3 mm) Macrocalculi (>3 mm) Metabolic disorders Hypercalciuria Hypocitraturia Hyperoxaluria Hyperuricosuria Cystinuria
2 years, N (%)
>2 years, N (%)
P Value
53 (62.4) 10 (23.3) 37 (45.1)
89 (54.6) 18 (23.7) 94 (59.5)
.242 .958 .034
27 52 53 31
34 67 76 20
(20.9) (41.1) (46.6) (12.3)
.058 .030 .019 .001
77 (90.6) 8 (9.4)
152 (93.3) 11 (6.7)
.454 .454
18 67 59 34 28 10 7 6
44 119 130 69 70 44 16 5
.315 .315 .069 .724 .126 .006 .684 .147
(31.8) (61.2) (62.4) (36.5)
(21.2) (78.8) (69.4) (40.0) (32.9) (11.8) (8.2) (7.1)
(27.0) (73.0) (79.8) (42.3) (42.9) (27.0) (9.8) (3.1)
Abbreviations as in Table 1. The chi-square test was used. Bolded P-values indicate statistical significance.
greater in patients with hyperuricosuria in comparison with other metabolic disorders (P ¼ .009; Table 3). In 39 cases (12.6%), urolithiasis was accompanied by anatomic abnormalities. Of these, the most common anatomic abnormality was the vesicoureteral reflux in 20 of 39 patients (51.2%). Nineteen cases (6.1%) were secondary to high-dose vitamin D. Urinary tract infections (UTIs) were present in 51 patients (20.5%). The most common infecting organisms were Escherichia coli and Klebsiella. Biochemical analyses of the stones were performed in 75 of the cases. Chemically, the stones consisted of calcium oxalate (53.3%), cystine (14.6%), calcium-phosphatecarbonate (10.6%), uric acid (6.6%), struvite (10.6%), ammonium acid urate (2.6%), and xanthine (1.3%).
COMMENT Although more common in adults, urolithiasis may occur in childhood as well.7 Urolithiasis may result from UROLOGY 85 (4), 2015
metabolic disorders, anatomic abnormalities, infections, and environmental and nutritional factors. The incidence of urolithiasis in children and stone composition vary greatly by region and time. These differences are due to climate, dietary, socioeconomic, and genetic factors.14 Although the incidence and prevalence of pediatric urolithiasis is less than that of adult urolithiasis, it has high rates of recurrence and morbidity.15 Delayed diagnosis or inadequate treatment of urolithiasis may lead to renal parenchymal damage or obstructive renal failure.16 At the beginning of the last century, bladder calculi composed of ammonium urate were relatively common in Europe. However, over time—most probably due to protein-, refined carbohydratee, and sodium-rich diets with low potassium and citrate—reno-ureteral calculi composed of calcium oxalate and/or phosphate have become more frequent.17 The occurrence of bladder stones is endemic in developing regions, such as the Southeast Asia and India, where people are fed on carbohydrate rich but low-protein food. In contrast, upper urinary tract stones are more common in the developed countries.2 In a study conducted in Turkey in 1961, stones were localized in the bladder in nearly half of the patients.18 However, in recent studies conducted in Turkey, localization of the upper urinary tract was reported to be more common.7,8,19 In our investigation, most of the stones were localized in the upper urinary tract. Previous studies have reported that pediatric urolithiasis was associated with underlying metabolic risk factors.7,9,14,15,20-23 In a study conducted in India, Hari et al and Abhishek et al reported lower rates of metabolic disorders in comparison with other studies.22,23 € Recently, Ozokutan et al and Bak et al conducted studies in Turkey and reported lower rates of metabolic disorders in comparison with this research.7,8 In 2013, in a study conducted by Elmacı et al,9 the ratio of patients having metabolic disorders was similar to that in our study. These changes can be attributed to the ever-changing nutritional habits and increasing living standards. Age, gender, race, metabolic risk factors, inhibitors, and promoters play an important role in urinary tract stone disease.24 Comparison of the studies conducted in the same geographic area and with the same races and age groups has shown that changes in diet and lifestyle increase metabolic risk factors 911
912
.012 .012 .563 .593 .593 (72.7) (27.3) (1-20) (18.2) (81.8) 8 3 6 2 9 .530 .530 .009 .058 .058 (95.7) (4.3) (2-20) (8.7) (91.3) 22 1 7 2 21 .511 .511 .669 .051 .051 (94.4) (5.6) (1-20) (14.8) (85.2) 51 3 5 8 46 .224 .224 .808 .453 .453 (89.8) (10.2) (1-25) (24.5) (72.4) 88 10 6 27 71 (90.3) (9.7) (1-45) (25.2) (74.8) 93 10 5 26 77
Abbreviations as in Table 1. Bolded P-values indicate statistical significance. * The Mann-Whitney U test was used. y The chi-square test was used.
(2-168) (56.3) (26.5) (55.6) (29.1) (43.6) (50.4) 48 58 13 55 30 45 52
Age, median (min-max), mo* Maley Consanguinityy History of stones in familyy Bilateralismy Multiplicityy Recurrencey Stone localizationy Upper urinary systemy Lower urinary systemy Size, median (min-max), mm* Microcalculi (3 mm)y Macrocalculi (>3 mm)y
.307 .307 .337 .941 .941
.312 .418 .117 .317 .833 .022 .008
n (%)
.397 .799 .518 .800 .163 .254 .684
60 60 7 42 30 54 58
(4-168) (61.2) (16.3) (46.2) (30.6) (55.1) (59.2)
.595 .307 .161 .040 .075 .070 .068
72 29 9 30 15 26 28
(3-180) (53.7) (36.0) (57.7) (27.8) (48.1) (51.9)
.001 .551 .098 .611 .539 .978 .978
60 11 1 13 3 8 11
(4-168) (47.8) (12.5) (56.5) (13.0) (34.8) (47.8)
.296 .337 .446 .844 .177 .183 .673
18 5 3 7 3 9 10
(4-120) (45.5) (50.0) (70.0) (27.3) (81.8) (90.9)
P Value
Cystinuria (N ¼ 11)
n (%) P Value
Hyperuricosuria (N ¼ 23)
n (%) P Value n (%)
Hyperoxaluria (N ¼ 54)
P Value P Value
n (%)
Hypocitraturia (N ¼ 98) Hypercalciuria (N ¼ 103)
Variables
Table 3. Characteristics of patients with urolithiasis due to metabolic disorders
and affect stone localization significantly by the time.7-9,18 The difference may be attributed to the rapidly changing lifestyle and eating habits in our country. Observing hypercalciuria in our study is consistent with the results of recent studies.14,15 However, this rate was lower than that reported by Coward et al and higher than that reported by Edvardsson et al.20,21 The study by Edvardson et al21 involved only 23 patients. Hypocitraturia was the second most common metabolic disorder observed in our study. Comparison of urolithiasis in children with multiple metabolic disorders revealed that combined hypercalciuria and hypocitraturia constituted the most common metabolic disorder with multiple components. This result is similar to that reported by Spivacow et al.15 Recently, the calcium oxalate content in calculi showed a strong relationship with calciuria and a moderate association with oxaluria, magnesuria, and acidification of urine. The percent content of struvite presented reverse and lower correlations with regard to the aforementioned parameters. Calcium phosphate stone proportion had low associations with urinary risk factors.25 This suggests that dietary habits play an important role in stone formation. In the study, no significant relationship was observed between metabolic disorder and the type of stone. These results may be attributed to the limited number of biochemical analysis of urinary stones available in the study. In present study, no relationship was observed between the metabolic disorders and the incidence of bilaterality, multiplicity, recurrence, sex, macrocalculi, microcalculi, stone localization, consanguinity, family history of urolithiasis, and infection. Because cystinuria is an inherited autosomal recessive disease, having no association between cystine stones and consanguinity is a surprising result.26 However, patients’ files involve missing data about consanguineous marriages. It is known that urolithiasis is related with UTI. Urolithiasis can occur as a result of UTI (e.g., struvite and carbonate apatite stones). UTI is more frequent in young children. In contrast, acute renal colic is more common in older children.17 The absence of classical symptoms such as renal colic in this age group is probably cause late diagnosis. Therefore, infection, multiplicity, and recurrence were more common in young children in present study. In this study, the rate of recurrence risk was similar between the patients with metabolic disorder and the patients with nonmetabolic disorders. In contrast, the rate of recurrence was greater in patients with cystinuria. However, it should be noted that this is a retrospective cohort review study, and almost all the patients were receiving medical treatment (eg, thiazide diuretics and potassium citrate). Therefore, the similar rate of recurrence in patients with metabolic and nonmetabolic disorders was affected by these treatments. Compared with the literature, cystine stones were found to be more common in this study.7 Because of the widespread use of extracorporeal shock wave lithotripsy
UROLOGY 85 (4), 2015
(ESWL) in children with urolithiasis in recent years, the rate of open stone surgery for urolithiasis has become rare. However, ESWL does not successfully treat cystine kidney stones. Therefore, stones are surgically removed, and stone analysis can be performed. Conversely, calcium-containing stones are successfully treated with ESWL; therefore, the stones cannot be retrieved. For this reason, the presence of cysteine-type stones may seem to be more frequent.
CONCLUSION Urinary tract stone disease is an important health problem in childhood. Most patients have 1, or >1, metabolic risk factor. Metabolic risk factors should be evaluated in all children with urinary stone disease to provide appropriate treatment. References 1. Milliner DS. Urolithiasis. In: Avner ED, Harman WE, Niavdet P, eds. Pediatric Nephrology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:1091-1112. 2. Ece A, Ozdemir E, Gurkan F, et al. Characteristics of pediatric urolithiasis in south-east Anatolia. Int J Urol. 2000;7:330-334. 3. Rizvi SA, Naqvi SA, Hussain A, et al. Pediatric urolithiasis: developing nation perspectives. J Urol. 2002;168:1522-1525. 4. Akinci M, Esen T, Tellaloglu S. Urinary stone disease in Turkey: an updated epidemiological study. Eur Urol. 1991;20:200-203. 5. Remzi D, C ¸ akmak F, Erkan I. A study on the urolithiasis incidence in Turkish school-age children. J Urol. 1980;123:608. 6. Kok DJ, Papapoulos SE, Bijvoet OL. Excessive crystal agglomeration with low citrate excretion in recurrent stone formers. Lancet. 1986; 1:1056-1058. 7. Ozokutan BH, Kucukaydin M, Gunduz Z, et al. Urolithiasis in childhood. Pediatr Surg Int. 2000;16:60-63. 8. Bak M, Ural R, Agin H, et al. The metabolic etiology of urolithiasis in Turkish children. Int Urol Nephrol. 2009;41:453-460. 9. Elmacı AM, Ece A, Akın F. Clinical characteristics and metabolic abnormalities in preschool-age children with urolithiasis in southeast Anatolia. J Pediatr Urol. 2014;10:495-499. 10. Pietrow PK, Pope JC, Adams MC, et al. Clinical outcome of pediatric stone disease. J Urol. 2002;167:670-673.
UROLOGY 85 (4), 2015
11. Polito C, Cioce F, Manna AL, et al. Renal calyceal microlithiasis: clinical presentation may precede sonographic evidence. Clin Pediatr (Phila). 1999;38:521-524. 12. Cameron MA, Sakhae K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol. 2005;20:1587-1592. 13. Ceran O, Akin M, Akt€urk Z, Ozkozaci T. Normal urinary calcium/ creatinine ratios in Turkish children. Indian Pediatr. 2003;40: 884-887. 14. Ali SH, Rifat UN. Etiological and clinical patterns of childhood urolithiasis in Iraq. Pediatr Nephrol. 2005;20:1453-1457. 15. Spivacow FR, Negri AL, del Valle EE, et al. Metabolic risk factors in children with kidney stone disease. Pediatr Nephrol. 2008;23: 1129-1233. 16. Dursun I, Poyrazoglu HM, Dusunsel R, et al. Pediatric urolithiasis: an 8-year experience of single centre. Int Urol Nephrol. 2008;40: 3-9. 17. Alon US, Srivastava T. Urolithiasis. In: Kher KK, Schnaper HW, Makker SP, eds. Clinical Pediatric Nephrology Informa HealthCare. 2nd ed. 2007:539-551. 18. Eckstein HB. Endemic urinary lithiasis in Turkish children: a clinical study of 119 cases. Arch Dis Child. 1961;36:137-144. 19. Ertan P, Tekin G, Oger N, et al. Metabolic and demographic characteristics of children with urolithiasis in Western Turkey. Urol Res. 2011;39:105-110. 20. Coward RJM, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child. 2003;88:962-965. 21. Edvardsson V, Elidottir H, Indridason OS, Palsson R. High incidence of kidney stones in Icelandic children. Pediatr Nephrol. 2005; 20:940-944. 22. Hari P, Bagga A, Vasudev V, Singh M, Srivastava RN. Aetiology of nephrolithiasis in north Indian children. Pediatr Nephrol. 1995;9: 474-475. 23. Abhishek, Kumar J, Mandhani A, Srivastava A, et al. Pediatric urolithiasis: experience from a tertiary referral center. J Pediatr Urol. 2013;9:825-830. 24. Sas DJ. An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol. 2011;6:2062-2068. 25. Kirejczyk JK, Porowski T, Filonowicz R, et al. An association between kidney stone composition and urinary metabolic disturbances in children. J Pediatr Urol. 2014;10:130-135. 26. Segal S, Their SO. Cystinuria. In: Scriver CH, Beudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: Mc Graw-Hill; 1995:3581-3601.
913
RESULTS
CONCLUSION
To review metabolic disorders in Turkish children with urinary tract stone disease. The medical records of 308 pediatric patients with the diagnosis of urolithiasis between 1996 and 2008, whose disease progression was followed in a single tertiary-care center, were reviewed retrospectively. Two hundred forty-eight patients whose metabolic analyses were performed were included in the study. Of the 248 patients participating in the study, 142 (57%) were men and 106 (43%) were women. The median age of the patients was 48 months (minimum-maximum, 2-180 months). Seventy-six percent of the patients had metabolic disorders. Of all patients, 44% had 1, 23% had 2, and 7% had 3 metabolic disorders. Hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and cystinuria were detected in 41%, 39%, 22%, 9%, and 4% of the patients, respectively. The rate of multiple stone formation, infection, and recurrence was significantly higher in the 0-2 years age group (P ¼ .030, P ¼ .001, P ¼ .019, respectively). The median age of patients was greater (P ¼ .001) in patients with hyperoxaluria in comparison with other metabolic disorders. Compared with other metabolic disorders, multiple stones and recurrence were more frequent in patients with cystinuria (P ¼ .022 and P ¼ .008, respectively). The size of the stones was greater in patients with hyperuricosuria in comparison with other metabolic disorders (P ¼ .009). The majority of children with urinary tract stone disease exhibited 1 metabolic risk factors. Metabolic risk factors should be evaluated in all children with urinary stone disease to provide appropriate treatment. UROLOGY 85: 909e913, 2015. 2015 Elsevier Inc.
U
rolithiasis is a condition resulting in a crystallized mass mixed with protein and lipid found in the kidney and the urinary tract, resulting from metabolic, endocrinologic, and urologic causes.1 Pediatric urolithiasis is less common than in adults, and its characteristics, incidence, etiology, and localization vary greatly by geographic region.2 The actual incidence of urolithiasis in children is unknown with a prevalence of 1%-5% in the developed countries and 5%-15% in developing countries.3 The prevalence of urolithiasis in Turkey has been reported as 14.8%.4 Although there are insufficient data in children, an incidence of urolithiasis in Turkish school-age children as 0.8% was reported by Remzi et al.5 In the majority of pediatric patients with urolithiasis, a metabolic cause for stone formation can be identified and
Financial Disclosure: The authors declare that they have no relevant financial interests. _ From the Department of Pediatrics, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey; the Division of Pediatric _ Nephrology, Department of Pediatrics, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey; and the Department of _ Pediatric Surgery, Istanbul Bakırk€oy Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey Address correspondence to: Mehmet Halil Celiksoy, M.D., Department of Pediatric Allergy and Immunology, Ondokuz Mayıs University, Faculty of Medicine, 55139 Kurupelit, Samsun, Turkey. E-mail: [email protected] Submitted: October 14, 2014, accepted (with revisions): December 22, 2014
ª 2015 Elsevier Inc. All Rights Reserved
several metabolic disorders are well-defined (eg, cystinuria or primary hyperoxaluria type 1). There is a large subgroup of patients showing a subtle increase of urinary lithogenic factors (calcium, oxalate) or a reduction of stone inhibitory substances, like urinary citrate.6 In Turkey, the rate of metabolic disorders in the studies on childhood urinary tract stone disease was reported to be 33.0%-83.2%.7-9 The recurrence rate of stones due to metabolic abnormalities in children is high, and this rate can be up to 50%, if medical treatment protocol is not followed.10 Children exhibit more ambiguous signs and symptoms of urolithiasis than adults, leading to delayed diagnosis, resulting in chronic pyelonephritis and endstage renal failure.1 The aim of this research was to review metabolic risk factors in urolithiasis patients whose progress was investigated at our clinic.
MATERIALS AND METHODS In this study, the medical records of 308 patients, whose progress _ was investigated at the Istanbul Bakırk€ oy Maternity and Children’s Diseases Training and Research Hospital, Division of Pediatric Nephrology, with the diagnosis of urolithiasis, were evaluated retrospectively. The patients whose urinary metabolic screens showed anomaly were included in the study. The patients who did not have any metabolic screens were excluded. http://dx.doi.org/10.1016/j.urology.2014.12.032 0090-4295/15
909
Also, patients with renal anatomic anomalies and those who developed urinary stone disease owing to the use of high-dose vitamin D were excluded from the study. For the remaining 248 patients, data related to age, gender, family history, and consanguineous marriage were extracted from the medical records of the patients. Data for urea, creatinine, uric acid, sodium, potassium, chlorine, magnesium, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, the sodiumnitroprusside test, blood gases, the 3-day spot urinary calciumto-creatinine ratio, the 24-hour metabolic stone analysis, and, if available, biochemical analysis results of the stone were obtained from the medical records of the patients. Ultrasonographic findings were also collected from the medical records. Stones <3 mm in diameter were defined as microcalculi, and those >3 mm in diameter were defined as macrocalculi.11 Hypercalciuria was defined as urinary calcium excretion >4 mg/ kg/d; hyperoxaluria as urinary oxalate >40 mg/1.73 m2/d; hyperuricemia as urinary urate >815 mg/1.73 m2/d; hypocitraturia as urinary citrate <400 mg/g creatinine; and cystinuria as urinary cystine >75 mg/1.73 m2/d.12 Urinary calcium-tocreatinine ratio 95th percentile values from the same area by age were used for hypercalciuria; 0.76, 0.60, 0.69, and 0.24 values were used for the 0-7 months, 8-18 months, 19 months to 6 years, and 7-14 years age groups, respectively.13 The relationship between the each of the metabolic disorders (eg, hypercalciuria and hypocitraturia) and age, sex, consanguinity, recurrence, family history, bilaterality, multiplicity, stone localization, and stone size was compared. We performed statistical analysis using Statistical Package for Social Sciences 15.0 software (SPSS Inc., Chicago, IL). Descriptive statistics were expressed as frequency and percentage for categorical variables, whereas quantitative data were expressed as median for non-normally distributed data. We used the Mann-Whitney U test to compare quantitative data and used the chi-square test (Fisher exact test, when needed) to compare the categorical variables. We considered 2-sided P <.05 as statistically significant.
RESULTS Of the 248 patients participating in the study, 142 (57.3%) were men and 106 (42.7%) were women. The median age of the patients was 48 months (minimummaximum, 2-180 months). A familial history of urolithiasis was found in 131 of 240 patients (54.6%). This percentage was obtained by omitting the 8 cases for which the family history of urolithiasis was not specified in the medical records. This rate was found in 55 of 240 patients (22.9%) in the first-degree relatives and in 76 of 240 patients (31.7%) in the second-degree relatives. Consanguinity was found in 28 of 119 patients (23.5%). Information regarding consanguinity was absent for 129 patients. Macrocalculi and microcalculi were present in 186 (75.0%) and 62 (25.0%) of the cases, respectively. Multiplicity and bilaterality at initial presentation were identified in 119 (48.0%) and 61 (24.6%) of the cases, respectively. An analysis of the locations of the stones revealed that 229 patients (92.3%) had upper urinary tract stones and 19 patients (7.7%) had lower urinary tract stones. All patients had at least a partial metabolic study. Hypercalciuria, hypocitraturia, hyperoxaluria, 910
Table 1. Demographics of patients with urolithiasis Variables Age, median (min-max), mo Male Consanguinity Family history of urolithiasis First degree Second degree Infection Bilaterality Multiplicity Stone localization Upper urinary system (pelvis, calyces, ureter) Lower urinary system (bladder, urethra) Size of stone Microcalculi (3 mm) Macrocalculi (>3 mm) Metabolic disorders Hypercalciuria Hypocitraturia Hyperoxaluria Hyperuricosuria Cystinuria Total
N (%) 48 142 28/119 131/240 55/240 76/240 51 61 119
(2-180) (57.3) (23.5) (54.6) (22.9) (31.7) (20.6) (24.6) (48.0)
229 (92.3) 19 (7.7) 62 186 189 103 98 54 23 11 248
(25.0) (75.0) (76.2) (41.5) (39.5) (21.8) (9.3) (4.4) (100.0)
max, maximum; min, minimum.
hyperuricosuria, and cystinuria were detected in 41.5%, 39.5%, 21.8%, 9.3%, and 4.4% of the cases, respectively. Table 1 shows the demographics of patients with urolithiasis. Of the patients, 189 (76.2%) had metabolic disorders; 44.2% had 1, 23.1% had 2, and 7.6% had 3 metabolic disorders. One patient had 4 metabolic disorders (Fig. 1). In patients with metabolic disorders, combined hypercalciuria and hypocitraturia in 38 of 189 patients (20.1%) was the most common metabolic disorder with multiple components. One patient had chronic renal insufficiency at the time of the diagnosis. A stone composed of uric acid was detected in this patient. No relationship was observed between the metabolic disorders and the incidence of bilaterality, multiplicity, recurrence, sex, macrocalculi, microcalculi, stone localization, consanguinity, family history of urolithiasis, and infection (P ¼ .118, P ¼ .614, P ¼ .926, P ¼ .504, P ¼ .438, P ¼ .438, P ¼ .158, P ¼ .418, P ¼ .400, and P ¼ .431, respectively). The rate of multiple stone formation, infection, and recurrence was significantly higher in the 0-2 years age group (P ¼ .030, P ¼ .001, and P ¼ .019, respectively). History of stones in family was significantly higher in the >2 years group (P ¼ .034; Table 2). The median age of patients was higher (P ¼ .001) in patients with hyperoxaluria in comparison with other metabolic disorders. Relationship was observed between the history of stones in family and hypocitraturia (P ¼ .040). Compared with other metabolic disorders, multiple stones and recurrence were more frequent in patients with cystinuria (P ¼ .022 and P ¼ .008, respectively). Lower urinary tract stones were significantly higher in patients with cystinuria (P ¼ .012). The size of the stones was UROLOGY 85 (4), 2015
Figure 1. Distribution of multiple metabolic disorders in patients with urolithiasis.
Table 2. Distribution by age in patients with urolithiasis Variables Male Consanguinity History of stones in family Bilateralism Multiplicity Recurrence Infection Stone localization Upper urinary system Lower urinary system Size, median (min-max) Microcalculi (3 mm) Macrocalculi (>3 mm) Metabolic disorders Hypercalciuria Hypocitraturia Hyperoxaluria Hyperuricosuria Cystinuria
2 years, N (%)
>2 years, N (%)
P Value
53 (62.4) 10 (23.3) 37 (45.1)
89 (54.6) 18 (23.7) 94 (59.5)
.242 .958 .034
27 52 53 31
34 67 76 20
(20.9) (41.1) (46.6) (12.3)
.058 .030 .019 .001
77 (90.6) 8 (9.4)
152 (93.3) 11 (6.7)
.454 .454
18 67 59 34 28 10 7 6
44 119 130 69 70 44 16 5
.315 .315 .069 .724 .126 .006 .684 .147
(31.8) (61.2) (62.4) (36.5)
(21.2) (78.8) (69.4) (40.0) (32.9) (11.8) (8.2) (7.1)
(27.0) (73.0) (79.8) (42.3) (42.9) (27.0) (9.8) (3.1)
Abbreviations as in Table 1. The chi-square test was used. Bolded P-values indicate statistical significance.
greater in patients with hyperuricosuria in comparison with other metabolic disorders (P ¼ .009; Table 3). In 39 cases (12.6%), urolithiasis was accompanied by anatomic abnormalities. Of these, the most common anatomic abnormality was the vesicoureteral reflux in 20 of 39 patients (51.2%). Nineteen cases (6.1%) were secondary to high-dose vitamin D. Urinary tract infections (UTIs) were present in 51 patients (20.5%). The most common infecting organisms were Escherichia coli and Klebsiella. Biochemical analyses of the stones were performed in 75 of the cases. Chemically, the stones consisted of calcium oxalate (53.3%), cystine (14.6%), calcium-phosphatecarbonate (10.6%), uric acid (6.6%), struvite (10.6%), ammonium acid urate (2.6%), and xanthine (1.3%).
COMMENT Although more common in adults, urolithiasis may occur in childhood as well.7 Urolithiasis may result from UROLOGY 85 (4), 2015
metabolic disorders, anatomic abnormalities, infections, and environmental and nutritional factors. The incidence of urolithiasis in children and stone composition vary greatly by region and time. These differences are due to climate, dietary, socioeconomic, and genetic factors.14 Although the incidence and prevalence of pediatric urolithiasis is less than that of adult urolithiasis, it has high rates of recurrence and morbidity.15 Delayed diagnosis or inadequate treatment of urolithiasis may lead to renal parenchymal damage or obstructive renal failure.16 At the beginning of the last century, bladder calculi composed of ammonium urate were relatively common in Europe. However, over time—most probably due to protein-, refined carbohydratee, and sodium-rich diets with low potassium and citrate—reno-ureteral calculi composed of calcium oxalate and/or phosphate have become more frequent.17 The occurrence of bladder stones is endemic in developing regions, such as the Southeast Asia and India, where people are fed on carbohydrate rich but low-protein food. In contrast, upper urinary tract stones are more common in the developed countries.2 In a study conducted in Turkey in 1961, stones were localized in the bladder in nearly half of the patients.18 However, in recent studies conducted in Turkey, localization of the upper urinary tract was reported to be more common.7,8,19 In our investigation, most of the stones were localized in the upper urinary tract. Previous studies have reported that pediatric urolithiasis was associated with underlying metabolic risk factors.7,9,14,15,20-23 In a study conducted in India, Hari et al and Abhishek et al reported lower rates of metabolic disorders in comparison with other studies.22,23 € Recently, Ozokutan et al and Bak et al conducted studies in Turkey and reported lower rates of metabolic disorders in comparison with this research.7,8 In 2013, in a study conducted by Elmacı et al,9 the ratio of patients having metabolic disorders was similar to that in our study. These changes can be attributed to the ever-changing nutritional habits and increasing living standards. Age, gender, race, metabolic risk factors, inhibitors, and promoters play an important role in urinary tract stone disease.24 Comparison of the studies conducted in the same geographic area and with the same races and age groups has shown that changes in diet and lifestyle increase metabolic risk factors 911
912
.012 .012 .563 .593 .593 (72.7) (27.3) (1-20) (18.2) (81.8) 8 3 6 2 9 .530 .530 .009 .058 .058 (95.7) (4.3) (2-20) (8.7) (91.3) 22 1 7 2 21 .511 .511 .669 .051 .051 (94.4) (5.6) (1-20) (14.8) (85.2) 51 3 5 8 46 .224 .224 .808 .453 .453 (89.8) (10.2) (1-25) (24.5) (72.4) 88 10 6 27 71 (90.3) (9.7) (1-45) (25.2) (74.8) 93 10 5 26 77
Abbreviations as in Table 1. Bolded P-values indicate statistical significance. * The Mann-Whitney U test was used. y The chi-square test was used.
(2-168) (56.3) (26.5) (55.6) (29.1) (43.6) (50.4) 48 58 13 55 30 45 52
Age, median (min-max), mo* Maley Consanguinityy History of stones in familyy Bilateralismy Multiplicityy Recurrencey Stone localizationy Upper urinary systemy Lower urinary systemy Size, median (min-max), mm* Microcalculi (3 mm)y Macrocalculi (>3 mm)y
.307 .307 .337 .941 .941
.312 .418 .117 .317 .833 .022 .008
n (%)
.397 .799 .518 .800 .163 .254 .684
60 60 7 42 30 54 58
(4-168) (61.2) (16.3) (46.2) (30.6) (55.1) (59.2)
.595 .307 .161 .040 .075 .070 .068
72 29 9 30 15 26 28
(3-180) (53.7) (36.0) (57.7) (27.8) (48.1) (51.9)
.001 .551 .098 .611 .539 .978 .978
60 11 1 13 3 8 11
(4-168) (47.8) (12.5) (56.5) (13.0) (34.8) (47.8)
.296 .337 .446 .844 .177 .183 .673
18 5 3 7 3 9 10
(4-120) (45.5) (50.0) (70.0) (27.3) (81.8) (90.9)
P Value
Cystinuria (N ¼ 11)
n (%) P Value
Hyperuricosuria (N ¼ 23)
n (%) P Value n (%)
Hyperoxaluria (N ¼ 54)
P Value P Value
n (%)
Hypocitraturia (N ¼ 98) Hypercalciuria (N ¼ 103)
Variables
Table 3. Characteristics of patients with urolithiasis due to metabolic disorders
and affect stone localization significantly by the time.7-9,18 The difference may be attributed to the rapidly changing lifestyle and eating habits in our country. Observing hypercalciuria in our study is consistent with the results of recent studies.14,15 However, this rate was lower than that reported by Coward et al and higher than that reported by Edvardsson et al.20,21 The study by Edvardson et al21 involved only 23 patients. Hypocitraturia was the second most common metabolic disorder observed in our study. Comparison of urolithiasis in children with multiple metabolic disorders revealed that combined hypercalciuria and hypocitraturia constituted the most common metabolic disorder with multiple components. This result is similar to that reported by Spivacow et al.15 Recently, the calcium oxalate content in calculi showed a strong relationship with calciuria and a moderate association with oxaluria, magnesuria, and acidification of urine. The percent content of struvite presented reverse and lower correlations with regard to the aforementioned parameters. Calcium phosphate stone proportion had low associations with urinary risk factors.25 This suggests that dietary habits play an important role in stone formation. In the study, no significant relationship was observed between metabolic disorder and the type of stone. These results may be attributed to the limited number of biochemical analysis of urinary stones available in the study. In present study, no relationship was observed between the metabolic disorders and the incidence of bilaterality, multiplicity, recurrence, sex, macrocalculi, microcalculi, stone localization, consanguinity, family history of urolithiasis, and infection. Because cystinuria is an inherited autosomal recessive disease, having no association between cystine stones and consanguinity is a surprising result.26 However, patients’ files involve missing data about consanguineous marriages. It is known that urolithiasis is related with UTI. Urolithiasis can occur as a result of UTI (e.g., struvite and carbonate apatite stones). UTI is more frequent in young children. In contrast, acute renal colic is more common in older children.17 The absence of classical symptoms such as renal colic in this age group is probably cause late diagnosis. Therefore, infection, multiplicity, and recurrence were more common in young children in present study. In this study, the rate of recurrence risk was similar between the patients with metabolic disorder and the patients with nonmetabolic disorders. In contrast, the rate of recurrence was greater in patients with cystinuria. However, it should be noted that this is a retrospective cohort review study, and almost all the patients were receiving medical treatment (eg, thiazide diuretics and potassium citrate). Therefore, the similar rate of recurrence in patients with metabolic and nonmetabolic disorders was affected by these treatments. Compared with the literature, cystine stones were found to be more common in this study.7 Because of the widespread use of extracorporeal shock wave lithotripsy
UROLOGY 85 (4), 2015
(ESWL) in children with urolithiasis in recent years, the rate of open stone surgery for urolithiasis has become rare. However, ESWL does not successfully treat cystine kidney stones. Therefore, stones are surgically removed, and stone analysis can be performed. Conversely, calcium-containing stones are successfully treated with ESWL; therefore, the stones cannot be retrieved. For this reason, the presence of cysteine-type stones may seem to be more frequent.
CONCLUSION Urinary tract stone disease is an important health problem in childhood. Most patients have 1, or >1, metabolic risk factor. Metabolic risk factors should be evaluated in all children with urinary stone disease to provide appropriate treatment. References 1. Milliner DS. Urolithiasis. In: Avner ED, Harman WE, Niavdet P, eds. Pediatric Nephrology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:1091-1112. 2. Ece A, Ozdemir E, Gurkan F, et al. Characteristics of pediatric urolithiasis in south-east Anatolia. Int J Urol. 2000;7:330-334. 3. Rizvi SA, Naqvi SA, Hussain A, et al. Pediatric urolithiasis: developing nation perspectives. J Urol. 2002;168:1522-1525. 4. Akinci M, Esen T, Tellaloglu S. Urinary stone disease in Turkey: an updated epidemiological study. Eur Urol. 1991;20:200-203. 5. Remzi D, C ¸ akmak F, Erkan I. A study on the urolithiasis incidence in Turkish school-age children. J Urol. 1980;123:608. 6. Kok DJ, Papapoulos SE, Bijvoet OL. Excessive crystal agglomeration with low citrate excretion in recurrent stone formers. Lancet. 1986; 1:1056-1058. 7. Ozokutan BH, Kucukaydin M, Gunduz Z, et al. Urolithiasis in childhood. Pediatr Surg Int. 2000;16:60-63. 8. Bak M, Ural R, Agin H, et al. The metabolic etiology of urolithiasis in Turkish children. Int Urol Nephrol. 2009;41:453-460. 9. Elmacı AM, Ece A, Akın F. Clinical characteristics and metabolic abnormalities in preschool-age children with urolithiasis in southeast Anatolia. J Pediatr Urol. 2014;10:495-499. 10. Pietrow PK, Pope JC, Adams MC, et al. Clinical outcome of pediatric stone disease. J Urol. 2002;167:670-673.
UROLOGY 85 (4), 2015
11. Polito C, Cioce F, Manna AL, et al. Renal calyceal microlithiasis: clinical presentation may precede sonographic evidence. Clin Pediatr (Phila). 1999;38:521-524. 12. Cameron MA, Sakhae K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol. 2005;20:1587-1592. 13. Ceran O, Akin M, Akt€urk Z, Ozkozaci T. Normal urinary calcium/ creatinine ratios in Turkish children. Indian Pediatr. 2003;40: 884-887. 14. Ali SH, Rifat UN. Etiological and clinical patterns of childhood urolithiasis in Iraq. Pediatr Nephrol. 2005;20:1453-1457. 15. Spivacow FR, Negri AL, del Valle EE, et al. Metabolic risk factors in children with kidney stone disease. Pediatr Nephrol. 2008;23: 1129-1233. 16. Dursun I, Poyrazoglu HM, Dusunsel R, et al. Pediatric urolithiasis: an 8-year experience of single centre. Int Urol Nephrol. 2008;40: 3-9. 17. Alon US, Srivastava T. Urolithiasis. In: Kher KK, Schnaper HW, Makker SP, eds. Clinical Pediatric Nephrology Informa HealthCare. 2nd ed. 2007:539-551. 18. Eckstein HB. Endemic urinary lithiasis in Turkish children: a clinical study of 119 cases. Arch Dis Child. 1961;36:137-144. 19. Ertan P, Tekin G, Oger N, et al. Metabolic and demographic characteristics of children with urolithiasis in Western Turkey. Urol Res. 2011;39:105-110. 20. Coward RJM, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child. 2003;88:962-965. 21. Edvardsson V, Elidottir H, Indridason OS, Palsson R. High incidence of kidney stones in Icelandic children. Pediatr Nephrol. 2005; 20:940-944. 22. Hari P, Bagga A, Vasudev V, Singh M, Srivastava RN. Aetiology of nephrolithiasis in north Indian children. Pediatr Nephrol. 1995;9: 474-475. 23. Abhishek, Kumar J, Mandhani A, Srivastava A, et al. Pediatric urolithiasis: experience from a tertiary referral center. J Pediatr Urol. 2013;9:825-830. 24. Sas DJ. An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol. 2011;6:2062-2068. 25. Kirejczyk JK, Porowski T, Filonowicz R, et al. An association between kidney stone composition and urinary metabolic disturbances in children. J Pediatr Urol. 2014;10:130-135. 26. Segal S, Their SO. Cystinuria. In: Scriver CH, Beudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: Mc Graw-Hill; 1995:3581-3601.
913