Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 1 REVIEW 2021, with approximately 123,436 cases worldwide. In Indonesia, there were 1,829 reported cases, highlighting the growing concern for pediatric kidney stone disease (1). Urolithiasis in children warrants great attention, par- ticularly considering the potential long-term impacts on renal function and quality of life for affected children. Pediatric stone formers differ from adults. For instance, calcium oxalate (CaOx) stones, which are more prevalent in adults, are less commonly seen in children, who more frequently present with uric acid or ammonium acid stones, particularly in regions such as Southeast Asia and the Middle East (2). The proportion of calcium oxalate stones will increase with age as that of carbapatite stones will decrease. In contrast with adult urolithiasis forma- tion, which is more often idiopathic or diet-induced, pediatric urolithiasis necessitates a more nuanced under- standing of the factors that influence biomarker profiles in this population (3). The pathogenesis of urolithiasis in children is complex, involving both genetic and environmental factors. Over time, the primary causes of stone formation have shifted from being predominantly infectious to metabolic (4). In particular, kidney stone formation is closely associated with metabolic abnormalities, including calcium, oxalate, and urate dysregulation (5). Urine sampling is a widely used clinical tool for diagnos- ing diseases due to its non-invasive nature, cost-effective- ness, and reliability (6). Urinary risk factors such as calci- um, creatinine, and uric acid, detectable through urine sampling, have been implicated in the pathogenesis of kidney stones and offer potential diagnostic and prognos- tic value in clinical practice (7). The exploration of urinary biomarkers as predictors of urolithiasis in children demonstrates significant variability of research findings. A study identified increased urinary levels of Cystatin C and NGAL as potential indicators of early kidney tubular dysfunction in children with urolithi- asis, even when serum creatinine remained normal (8). In contrast, another study stated that these biomarkers were less reliable for assessing renal injury due to urinary stone in pediatric populations (9). The inconsistent results high- light the complexity of using urinary biomarkers in pedi- atric urolithiasis, indicating a critical need for larger, stan- dardized research to establish their clinical utility. Introduction: Urolithiasis in children has become a clinical concern because of its long- term impact on kidney function and quality of life. In previous studies, the role of urinary biomarkers in predicting the risk of urolithiasis in children was still unclear due to inconsistent find- ings. This meta-analysis aimed to evaluate the diagnostic poten- tial of various urinary risk factors in children with urolithiasis. Methods: A systematic review and meta-analysis was performed based on PRISMA 2020 guidelines, registered in PROSPERO (CRD42025644893). A total of six studies (1 cohort and 5 case- control) involving 2,060 pediatric patients (817 with urolithiasis; 1,243 controls) were analyzed. Urinary risk factors - including citrate/creatinine (Cit/Cr), oxalate/creatinine (Ox/Cr), calcium/creatinine (Ca/Cr), phosphorus/creatinine (P/Cr), mag- nesium/creatinine (Mg/Cr), and urea/creatinine (Ur/Cr) - were examined. Standard Mean Differences (SMD) were calculated, and heterogeneity was assessed using the I² statistic. Results: Significant differences were obtained in the Cit/Cr, Ca/Cr, Ox/Cr, and Mg/Cr ratios between children with urolithi- asis and controls. Hypocitraturia (Cit/Cr SMD: -0.60, 95% CI: -0.90 to -0.30, p = 0.0001), hyperoxaluria (Ox/Cr SMD: 0.76, 95% CI: 0.37-1.16, p = 0.0001), hypercalciuria (Ca/Cr SMD: 0.55, 95% CI: 0.10-1.01, p = 0.02), and hypomagnesuria (SMD -0.13 (95% CI: -0.24 to -0.01), p = 0.03) were significant- ly associated with the formation of stones in the urinary tract. On the contrary, there were no significant relationships for P/Cr and Ur/Cr ratios. Conclusions: This meta-analysis highlights Cit/Cr, Ox/Cr, and Ca/Cr ratios as potential urinary biomarkers to identify the risk of urolithiasis in pediatric patients. Hypocitraturia, hyperox- aluria, and hypercalciuria are the main metabolic abnormalities that contribute to urinary tract stone formation. Future studies with standardized methodology are essential to confirm these findings and guide clinical management strategies. KEY WORDS: Urolithiasis; Urinary risk factor; Pediatric kidney stones. Submitted 20 May 2025; Accepted 1 June 2025 INTRODUCTION Urolithiasis, the formation of calculi in the urinary tract, is a significant clinical condition that can affect children of all ages. The global prevalence of urolithiasis in chil- dren under 20 years of age was estimated at 0.01% in Urinary risk factors for urolithiasis in children: A systematic review and meta-analysis Derryl Rasad Texaga 1, Saskia Ratna Desita 1, Nadira Muthi Tsania 1, Junjungan Nismasratu Rahmatsani 1, Kevin Yuwono 1, I Gede Yogi Prema Ananda 2, Radika Naufal Hadi Surya 2, Dimas Panca Andhika 2, 3, 4 1 Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 2 Department of Urology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 3 Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 4 Universitas Airlangga Hospital, Surabaya, Indonesia. DOI: 10.4081/aiua.2025.13954 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 D. Rasad Texaga, S. Ratna Desita, N. Muthi Tsania, et al. 2 METHODS This meta-analysis was performed according to the 2020 Preferred Reporting Items for Systematic Review and meta- analysis (PRISMA) guideline and has been registered to PROSPERO database (https://www.crd.york.ac.uk/pros- pero/) with a registration number CRD42025644893. Eligibility criteria Inclusion criteria for this study were: (1) Patients under 18 years old with urolithiasis; (2) Study that examines urinary risk factor of stone formation; (3) Written full-text in English. The exclusion criteria were: (1) The type of studies being review, case-report, meeting report, comments and other unrelated studies; (2) Non-human studies; (3) Studies that focus only on healthy children. Selection of the study was demonstrated on the PRISMA diagram (Figure 1). Data selection, search strategy, and selection of studies A comprehensive literature research was conducted in sev- eral databases including MEDLINE, Science Direct, Springer, and PLOS One from the initial period of the study until January 2025. The following keywords were used as follows [(“Nephrolithiasis”) OR (“Urolithiasis”)] AND [(“Pediatric”) OR (“Infant”) OR (“Children”)] AND [(“Risk factor”) OR (“Dietary”)]. Studies retrieved were exported into Rayyan.ai–Intelligent Systematic review for article screening and duplication removal. Two authors (D.R.T and S.R.D) screened the literature and extracted the data independently. Disagreements between two authors were discussed until agreement was established. The following data were col- lected: (1) Information of the study: first author, publica- tion year, country; (2) Basic study characteristics: sample size, patient’s age of enrollment; (3) Study findings including key risk factors of urolithiasis, methods of diag- nosis, and biochemical measurement. Quality assessment Three authors (J.N.R., R.N.H.S, and I.Y.P.A) independ- ently assessed the Risks of Bias (RoB) from selected stud- ies using Newcastle Ottawa Scale (NOS) assessment tool for cohort and case-control studies. Statistical analysis The study was analyzed using Review Manager 5.4 (Cochrane Collaboration). The Standard Mean Differences (SMDs) were calculated as effect sizes using inverse variance methods for continuous outcomes. For dichotomous outcomes, pooled risk ratios (RRs) were computed using Mantel-Haenszel methods. Heterogeneity across the included studies was assessed using the I² sta- tistic. A random-effects model was applied if the I² value was greater than 50%, indicating moderate-to- high heterogeneity. Conversely, a fixed-effects model was used if the I² value was less than 50%. Statistical significance was determined with a p-value of less than 0.05. Begg’s fun- nel plots were employed to evaluate potential publication bias, and the trim-and-fill method was applied if any publication bias was detected. RESULTS Study selection From four databases, a total of 274 studies were retrieved. After the removal of duplicates and irrelevant studies, 191 studies remained for screening. Following the inclusion and exclusion criteria, 42 studies were assessed eligible. Upon full- text review, 6 studies were included in this study. The study selection process is summarized in the PRIS- MA flowchart. Figure 1. Flow of literature search and selection based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 3 Urinary risk factors for urolithiasis in children: A systematic review and meta-analysis The six studies included in this study included 5 case- control studies, and 1 cohort study. Quality assessment for case-control and cohort study using the NOS assess- ment tool revealed that 2 studies were classified as very good, while 4 were assessed as good quality. Study characteristics In our review, we analyzed a total cohort of 2,060 pedi- atric patients, consisting of 817 subjects with urolithiasis, and 1243 controls. Out of the six studies included, five were case-control studies and one is cohort studies. Two of the studies were conducted in Poland, one in Turkey, while the remaining three were done in Hungary, Germany, and Spain respectively. We examined multiple urinary biomarkers and their relationship to the inci- dence of urolithiasis. To diagnose urolithiasis, the studies used a range of methods, including standard ultrasound, intravenous urography, plain X-rays, infrared spec- troscopy, and surgical intervention. Detailed biochemical urinary measurements and additional study details are presented in Table 1. Urinary risk factors Cit/Cr Citrate/Creatinine ratios were evaluated using 24-hour uri- nary samples and urine spot samples. Four studies exam- ined a total of 1769 subjects (717 with urolithiasis, 1052 controls). The meta-analysis demonstrated there was a sig- Table 2. Quality assessment. Study Representativeness Sample size Non-respondents Ascertainment Comparability of subjects in Assessment Statistical Total Result of the sample of the exposure different outocome groups on of outcome test score (risk factor) the basis of design or analysis. Confounding factors controlled Tekin et al., 2001 1 0 0 2 2 2 1 8 Good Reustz et al., 1995 1 1 0 2 2 2 1 9 Very good Kuroczycka-Saniutycz et al., 2015 1 1 0 2 2 2 1 9 Very good Mir et al., 2020 1 1 0 1 1 1 1 6 Good Sikora et al., 2008 1 1 0 1 1 1 1 6 Good Porrowski et al., 2013 1 1 0 1 1 1 1 6 Good Table 1. Characteristics of the study. Study Study type Enrollment Participants Mean Age at enrollment Male (n) Key risks factor Outcomes Methods of diagnosis Biochemical measurement Tekin et al., 2001 Reustz et al., 1995 Kuroczycka-Saniutycz et al., 2015 Sikora et al, 2008 Mir et al, 2020 Porowski et al, 2013 Retrospective cohort Case-control study Case-control study Case-control study Case-control study Case-control study Turkey Hungary Poland Germany Spain Poland Intervention 90 children with normal anatomy and urolithiasis 27 with renal stones 478 children with urolithiasis 60 patients with idiopathic calcium oxalate urolithiasis 13 patients with primary hyperoxaluria 26 stone-forming children 123 Stone-formers with hypocitraturia Control 24 healthy children 156 healthy children 517 healthy children 35 healthy children 87 healthy children 424 healthy children Intervention 7.70 ± 10.45 years 6–16 years 14.19 ± 4.16 years 13.3 ± 4.1 years 12 ± 4 years 13.30 ± 8.06 years Control 7.8 ± 6.3 years 1–14.5 years 13.9 ± 4.43 years 11.1 ± 3.6 years 12 ± 3 years 12.3 ± 8.67 years Intervention NA NA 205 41 15 66 Control NA NA 219 23 50 212 Hypocitraturia Hyperoxaluria Hyperoxaluria Hypercalciuria Hyperuricemia Obesity Intestinal hyperabsorption of oxalate 12 hour daytime 12 hour overnight 24 hour Hypercalciuria Hypocitraturia Urinary Ph Ca2⁺/Citrate ratio Incidence of nephrolithiasis in children with upper tract anatomy anomalies Calcium, oxalate excretion, activity product (measurement of Ca/Cr and Ox/Cr in first-morning urine samples is suitable for screening for hypercalciuria and hyperoxaluria) Incidence of urolithiasis Incidence of idiopathic calcium oxalate urolithiasis Diagnosis of lithiasis Diagnosis of lithiasis Intravenous urography and ultrasonography Intravenous urography and sonography Ultrasonography X-ray Infrared spectroscopy NA Ultrasonography X-ray 24-hour-urine excretion Serum biochemistry Urine samples Blood sample Urine sample [13C2] oxalate absorption test 24-hour-urine excretion 12-hour-day-urine excretion 12-hour-overnight-urine excretion 24-hour-urine collection Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 D. Rasad Texaga, S. Ratna Desita, N. Muthi Tsania, et al. 4 nificant decrease of citrate in children with urolithiasis compared to controls (SMD -0.60 (95% CI: -0,90 to -0.30), p = 0.0001) with moderate effects. The heterogeneity test showed a statistically significant high heterogeneity (I2 = 81%, p = 0.0001) indicating the use of a random-effect model. Ox/Cr Six studies with a total of 2060 patients (817 with urolithiasis, 1243 controls) measured Oxalate/Creatinine ratios in 24-hour urinary and urine spot samples. This study found children with urolithiasis have significantly higher Ox/Cr ratios compared to controls (SMD 0.76 (95% CI: 0.37 to 1.16, p = 0.0001), with moderate to large effect. The heterogeneity test showed a statistically significant high heterogeneity (I2 = 91%, p = 0.0001) indicating the use of a random-effect model. Ca/Cr Calcium/Creatinine ratios were measured in 1952 sub- jects consisting in 744 patients with urolithiasis and 1208 controls using 24-hour urinary and urine spot samples. The meta-analysis revealed children with urolithiasis have a higher Ca/Cr ratios compared to controls (SMD 0.55 (95% CI: 0.10 to 1.01), p = 0.02, I2 = 93%), with a moderate effect. The I2 tests showed a high heterogeneity test, resulting in random-effect models methods. P/Cr Three studies with a total of 1232 patients examined Phosphorus/Creatinine ratios of 24 hour urinary and urine spotsamples, respectively. The meta-analysis demonstrated there was no significant difference in chil- dren with urolithiasis compared to controls (SMD -0.11 (95% CI: -0.23 to 0.01), p = 0.06, I2 = 0%), with low effect. A fixed-effect model was applied since the low het- erogeneity test. Mg/Cr Magnesium/Creatinine ratios were evaluated using 24 hour urinary and urine spot samples respectively. Three studies with a total of 1222 patients were examined. The studies Figure 2. Forest Plot of Cit/Cr biomarker in urolithiasis vs healthy children. Figure 3. Forest Plot of Ox/Cr biomarker in urolithiasis vs healthy children. Figure 4. Forest Plot of Ca/Cr biomarker in urolithiasis vs healthy children. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 5 Urinary risk factors for urolithiasis in children: A systematic review and meta-analysis have low heterogeneity (I2 = 0%) and a fixed-effect was applied. Meta-analysis demonstrated there was a statistical- ly significant difference in children with urolithiasis com- pared to controls (SMD -0.13 (95% CI: -0.24 to -0.01), p = 0.03). Ur/Cr Uric acid/Creatinine ratios were evaluated using 24-hour urinary excretions. Four studies with a total of 1222 patients examined 24-hour urinary excretions. The meta- analysis demonstrated there was no significant relation- ship in children with urolithiasis compared to controls (SMD 0.04 (95% CI: -0.07 to 0.16), p = 0.47, I2 = 0%). A fixed-effect was applied since the study had low het- erogeneity (I2 = 0%). DISCUSSION This study's findings demonstrate significant differences in urinary biomarkers - Cit/Cr, Ca/Cr, Ox/Cr, and Mg/Cr -between pediatric patients with urolithiasis and those without. Among children diagnosed with urolithiasis, the Ca/Cr ratio was markedly elevated in comparison to the controls (SMD 0.55, 95% CI: 0.10-1.01, p = 0.02). Of the five studies that reported Ca/Cr data, four studies identi- fied statistically significant different levels of Ca/Cr between stone-forming children and healthy children.10- 13 Hypercalciuria is one of the most prevalent metabolic disorders associated with pediatric urolithiasis, affecting approximately 30% to 50% of patients (2, 14). Idiopathic hypercalciuria is the most frequent etiology of calcium- stone (15). Several studies shown that hypercalciuria was found in nine of 74 children with recurrent unilateral stones (16). This study was similar to a prior study by Kamel et al. (17) that found 22% of children with urolithiasis had hyper- calciuria based on their laboratory findings. Similarly, another study by Kovacevic et al. (18) found that hyper- calciuria was the most common risk factor in pediatric urolithiasis. As most urinary stones are composed of cal- cium, hypercalciuria is the major risk factor for calcium stone. Kidney stones, particularly those composed of cal- cium oxalate, often originate from calcium deposits known as Randall's plaques. These plaques form in the renal papilla's interstitial tissue and can serve as a nidus for stone development. When the urothelium's integrity is compromised, regions of the plaque become exposed to urine and crystallization begin (19). Several factors contribute to hypercalciuria and the role of dietary sup- plementation of calcium or vitamin D had conflicting results towards the risk of urolithiasis. A meta-analysis revealed that patients undergoing long-term vitamin D Figure 6. Forest Plot of Mg/Cr biomarker in urolithiasis vs healthy children. Figure 7. Forest Plot of Ur/Cr biomarker in urolithiasis vs healthy children. Figure 5. Forest Plot of P/Cr biomarker in urolithiasis vs healthy children. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 D. Rasad Texaga, S. Ratna Desita, N. Muthi Tsania, et al. 6 supplementation experienced an increased risk of hyper- calciuria, though the risk of kidney stone disease remained unaffected (20). Other conditions that predis- pose individuals to hypercalciuria include hyperparathy- roidism, metabolic bone diseases, renal calcium leak, and diets that impose a high renal acid load (21). Hyperoxaluria plays a crucial role in the pathogenesis of crystallization and stone formation (15). Urinary oxalate excretion is an important determinant in the develop- ment of calcium oxalate (CaOx) urolithiasis, the most common type of kidney stone (22). This meta-analysis revealed that Ox/Cr levels were significantly elevated in stone-forming children compared to controls (SMD 0.76, 95% CI: 0.37-1.16, p = 0.0001). Among the six studies providing Ox/Cr data, five studies demonstrated a signifi- cant difference in Ox/Cr levels between the stone-forming and control groups (10-12, 22, 23). Prior studies found that hyperoxaluria was found in chil- dren with multiple and single kidney stones (24). This study align with a previous study by Issler et al. (25) that showed as 37 children with renal stone disease had hyperoxaluria as their metabolic abnormality. This study was similar with another study by Placzynska (26) that found hyperoxaluria in children with different composi- tion of renal stones, such as weddellite, whewellite, and non-calcium oxalate. Hyperoxaluria is also another major risk factor for stone formation, as calcium oxalate is the most common composition of urinary stones. An in vitro study demonstrated that elevated levels of oxalate boost the ability of renal epithelial cells to adhere to calcium oxalate monohydrate (COM) crystals. This increased bind- ing capability is facilitated by a rise in the surface expres- sion of α-enolase, a protein that binds to COM crystals.21 The concentration of urinary oxalate is primarily affected by the intake of dietary oxalate and its precursors, and the absorption rate from the gastrointestinal tract. Therefore, consumption of oxalate-rich foods and increased absorp- tion of oxalate from the intestine (eg. in bypass/bariatric surgery patients) is associated with hyperoxaluria and kidney stones formation (27, 28). The decrease of urinary stone inhibitors increases the risk of urolithiasis, with citrate being a key inhibitory factor (29). This meta-analysis found that Cit/Cr levels were sig- nificantly lower in the urolithiasis group compared to the control group (SMD -0.60, 95% CI: -0.90 to -0.30, p = 0.00001). Among the four studies providing Cit/Cr, three studies showed statistically significant results (10, 12, 23). Citrate mitigates stone formation by binding calcium ions in urine, thereby reducing calcium supersaturation and preventing crystallization (30). Another inhibitor, urinary magnesium (Mg), also showed a significant nega- tive association with stone formation in this study (SMD = -0.13; 95% CI: -0.24 to -0.01; p = 0.03). Interestingly, none of the three studies that separately analyzed Mg/Cr ratio demonstrated a significant association. Hypocitraturia was found frequently in pediatric kidney stones (31). Velasquez et al. (29) found that hypocitraturia was the main risk factors among children with urolithia- sis, which aligns with our meta-analysis. On the contrary, a study by Lee et al. (32) reported that hypocitraturia was the less frequent risk factor of urolithiasis in children. Hypocitraturia has long been linked to the development of kidney stones, especially to calcium stone formation. The mechanisms by which citrate inhibits crystal forma- tion are thought to be mediated by its ability to form sol- uble complexes with calcium, which significantly lowers urinary calcium supersaturation and helps prevent the nucleation of both calcium oxalate and calcium phos- phate crystals (33). Additionally, citrate can directly pre- vent the attachment of calcium oxalate crystals to renal epithelial cells by adsorbing onto the surfaces of the crys- tals (34). An in vivo study involving genetically hypercal- ciuric stone-forming rats demonstrated that administer- ing potassium citrate resulted in elevated urinary citrate levels and reduced urinary calcium concentrations in addition to urine alkalinization (35). In children, hypoc- itraturia has been commonly defined as 24-h citrate excretion of < 400 mg/g creatinine or < 180 mg/g creati- nine. However, other proposed definitions exist, and fac- tors such as age and gender also influence them, making interpretation rather difficult (33). Magnesium also acts as an inhibitor by preventing the crystallization of calcium oxalate and calcium phosphate. It binds to oxalate, which may reduce intestinal absorp- tion of oxalate and lower the supersaturation of calcium oxalate in urine. Some studies have shown that magne- sium supplementation may benefit children with second- ary hyperoxaluria (2). Urolithiasis in children is predom- inantly linked to metabolic abnormalities, which are identified in approximately 30% to 84% of cases. Among these, hypomagnesiuria is one of the contributing condi- tions, although idiopathic hypercalciuria remains the most commonly observed metabolic disorder (36). In identifying children at high risk of urolithiasis, these findings strengthen the potential use of urinary biomark- ers, particularly hypocitraturia and hyperoxaluria. Hypocitraturia in children with urolithiasis can be used as a benchmark for administering potassium citrate that can reduce stone size and recurrence rate (37). Hyperoxaluria can be managed by eating a diet low in oxalate precursors that can help prevent the formation of DECLARATIONS Ethical approval: Not Applicable, since this is a systematic review and meta-analysis. Availability of data: Available data are open for researchers and the corresponding author will provide it by request. Competing interests: The authors state no conflict of interest. Funding: Not Applicable. Authors' contributions: Concept, Design, and Methodology: D.R.T, S.R.D, D.P.A; Literature search: D.R.T., S.R.D., N.M.T., K.Y., J.N.R, I.Y.P.A, R.N.H.S; Data analysis: D.R.T, S.R.D, N.M.T, K.Y, D.P.A; Statistical analysis: D.R.T, S.R.D, D.P.A; Manuscript writing: D.R.T., S.R.D., N.M.T., K.Y., J.N.R, I.Y.P.A, R.N.H.S; Suprvision: D.P.A. Acknowledgments: These authors would like to thank to Department of Urology, Faculty of Medicine, Universitas Airlangga; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13954 7 Urinary risk factors for urolithiasis in children: A systematic review and meta-analysis kidney stones (38). A long-term normal intake of dietary calcium can decrease numbers of stone recurrences due to idiopathic hypercalciuria (39). CONCLUSIONS This meta-analysis highlights the important role of uri- nary biomarkers, especially Cit/Cr, Ox/Cr, and Ca/Cr ratios, in predicting the risk of urolithiasis in children. Hypocitraturia, hyperoxaluria, and hypercalciuria emerged as important risk factors, supporting their clin- ical relevance in assessing and managing urinary tract stone formation in children. These findings suggest that targeted interventions, such as administration of potassi- um citrate for hypocitraturia and dietary modification for hyperoxaluria and hypercalciuria, may be effective in preventing recurrence of urinary tract stones. However, the high heterogeneous and limited data on certain bio- markers indicate the need for further standardized and large-scale studies to establish definitive clinical guide- lines. REFERENCES 1. Murray CJL; GBD 2021 Collaborators. 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Correspondence Dimas Panca Andhika (Corresponding Author) dimaspanca26@gmail.com Department of Urology, Faculty of Medicine, Universitas Airlangga; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia Jl. Mayjend. Prof. Dr. Moestopo No. 6-8, Surabaya, East Java, Indonesia, 60286