Is Vitamin D the Missing Link in Recurrent Urinary Tract Infections in Children? A Prospective Study

Is Vitamin D the Missing Link in Recurrent Urinary Tract Infections in Children? 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A Prospective Study Burak Özçift, Aslı Kantar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8944759/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Purpose Vitamin D's key role in immunity may help prevent urinary tract infections (UTIs). This study aimed to explore the impact of vitamin D supplementation on preventing recurrent UTIs in children. Methods This prospective case-control study included 18 school-aged children with recurrent UTIs and 19 healthy children. Serum vitamin D levels were compared between the groups. Vitamin D supplementation was administered to children with recurrent UTIs. Vitamin D concentrations before and after supplementation, and recurrence frequency during the study period, were evaluated. Results The mean serum vitamin D levels in the patient group were lower than those in the healthy control group (15.89 ± 6.76 vs. 19.96 ± 10.08 ng/mL), but this difference was not statistically significant (p = 0.16). However, vitamin D deficiency was significantly more prevalent in the patient group (88.9% vs 36.8%, p = 0.002). Vitamin D serum levels increased significantly after supplementation (15.89 ± 6.76 vs 19.96 ± 8.77 ng/mL, p = 0.04) and the proportion of patients with vitamin D deficiency decreased significantly (%88.9 vs %38.9, p = 0.004). The median number of UTI episodes decreased significantly (2.0 vs. 1.5 episodes, p = 0.014). Conclusion Vitamin D deficiency is more common in children with recurrent UTIs. Vitamin D supplementation significantly increased vitamin D levels and is associated with a lower recurrence rate of UTIs. Correcting vitamin D deficiency and maintaining adequate levels may be a simple and effective method for preventing recurrent UTIs in school-aged children. Trial registration number and date of registration: 2021/605, 09.09.2021 Children immunity prevention supplementation urinary tract infection Vitamin D Figures Figure 1 Introduction UTI is considered one of the most common bacterial infections associated with morbidities such as hypertension, growth retardation, and renal dysfunction in children, and recurrent infections develop in 12–30% of children who experience UTI [ 1 , 2 ]. Therefore, UTI prevention strategies are particularly important in pediatric patients [ 3 ]. UTI treatment is considered a challenging topic due to factors such as antibiotic resistance, side effects, and recurrence [ 4 , 5 ]. The risk of recurrence is quite high in school-aged children (≥ 5 years) who have experienced their first urinary tract infection (UTI) [ 4 – 7 ]. In children older than 5 years, recurrence rates are greatly influenced by gender, with recurrence reported in 15–30% of girls and 3–10% of boys [ 1 , 2 ]. The risk increases significantly when predisposing conditions such as vesicoureteral reflux (especially ≥ grade III), bladder-bowel dysfunction, dysfunctional voiding, constipation, and structural urinary tract anomalies are present, with recurrence rates reaching 30–50% [ 2 , 8 ]. Various treatment approaches have been introduced for both the treatment and prevention of recurrent UTIs. While antibiotics can be used to prevent recurrent UTIs and related complications, they may also increase the risk of microbial resistance. Given the role of vitamins and minerals in the proper functioning of the immune system, certain supplements, such as cranberry, mannose, probiotics, and vitamin A, have also been suggested as alternatives [ 9 – 13 ]. Recent studies have highlighted the role of vitamin D in immune defense. Vitamin D is considered a crucial regulator of the immune system. Activation of vitamin D receptors inhibits uropathogenic Escherichia coli and induces the expression of antimicrobial peptides that have been shown to enhance urothelial defense, such as cathelicidin (LL-37) [ 14 , 15 ]. Vitamin D is also thought to play a protective role against infections by modulating inflammatory pathways and supporting epithelial barrier integrity [ 16 ]. Recent studies have shown that vitamin D deficiency is more common in children with UTIs compared to healthy controls [ 13 ]. The relationship between vitamin D receptor gene polymorphisms and UTIs has also been reported in one study [ 14 ]. Furthermore, a meta-analysis has identified vitamin D deficiency as a potential risk factor for the development of UTIs [ 17 ]. However, evidence regarding the effect of vitamin D supplementation on recurrence rates remains limited. The association between vitamin D, immune function, and infections in children suggests that vitamin D supplementation may play a potential role as an interventional or adjuvant therapeutic agent for the management and prevention of urinary tract infections (UTIs). Therefore, this study aims to evaluate the relationship between vitamin D levels and recurrent UTIs and to investigate the effect of vitamin D supplementation on recurrence rates in school-aged children. Material and Methods This prospective case-control study was conducted among children referred to the Pediatric Urology outpatient clinic of Dr. Behçet Uz Children's Diseases and Surgery between 2018 and 2024 due to recurrent UTIs despite prophylactic antibiotic treatment in the last 6 months. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital (Date. 09.09.2021 / No. 2021 − 605). All participants (or their parents or legal caregivers for children under 18) freely provided informed written and verbal consent to participate in the study. Children who were not in the active phase of UTI, were over 5 years of age, had completed toilet training, had no anatomical defects, kidney stones, neurogenic bladder, VUR, obstructive uropathy, or congenital or acquired immunodeficiency, and had documented recurrent UTIs were included in the study. Recurrent UTI was defined as two infections within 6 months or three infections within one year, following at least two weeks of remission [ 2 , 8 ]. Patients without regular follow-up or treatment were excluded from the study. Serum vitamin D levels in the patient group were compared with those in the healthy child group before the study. The number of UTIs experienced in the patient group in the last 6 months before vitamin D supplementation was noted. The patient group received appropriate vitamin D treatment according to their vitamin D levels for 6 months. Vitamin D deficiency (< 20 ng/ml) was treated with oral vitamin D3 drops: 2000 IU/day for those 10 years of age (8 weeks), followed by 4 months of maintenance therapy. For those with sufficient vitamin D (> 20 ng/ml), oral vitamin D3 drops were administered at 600–1000 IU/day (maintenance therapy) for 6 months. The demographic characteristics of each patient were recorded before the study. Patients were followed monthly for UTI recurrence and vitamin D treatment use. Urinalysis and culture were performed for patients showing UTI signs or symptoms. UTI diagnosis was defined as ≥ 10 5 colony-forming units/mL in a fresh urine sample obtained using the midstream method (7,8). Serum vitamin D levels before and after the study and the proportion of patients with vitamin D deficiency were compared. Serum 25-hydroxyvitamin D concentration was measured using a chemiluminescent immunoassay. The 6-month UTI incidence was recorded in the patient group during the study period and compared with the incidence before vitamin D supplementation. Statistical analysis was performed using SPSS version 22 (SPSS Inc., Chicago, IL, USA) software with dependent and independent sample t-tests, Wilcoxon Signed-Rank Test, and Fisher's Exact Test. P < 0.05 was considered statistically significant. Results This study included 18 children with recurrent UTI and 19 healthy children. In the patient group, there were 16 (88.9%) girls and 2 (11.1%) boys, while in the healthy child group, there were 13 (68.4%) girls and 6 (31.6%) boys (p = 0.11). The mean age of the patient group was 8.50 ± 2.77 years, while that of the control group was 8.57 ± 2.22 years (p = 0.93). There was no significant difference between the two groups in terms of age and gender. In addition, the mean serum vitamin D level was lower in the patient group than in the control group (15.89 ± 6.76 vs. 19.96 ± 10.08 ng/mL); however, this difference was not statistically significant (p = 0.16). In contrast, vitamin D deficiency was significantly more prevalent in the patient group than in the controls (88.9% vs. 36.8%, p = 0.002). (P > 0.05) (Table 1 ). Table 1 Comparison of Vitamin D Status Between Groups Variable Patient (n = 18) Control (n = 19) p value Vitamin D level (ng/mL) 15.89 ± 6.76 19.96 ± 10.08 0.16 a Vitamin D deficiency, n (%) 16 (88.9%) 7 (36.8%) 0.002 b a Continuous variables were compared using independent samples t-test (Welch). b Categorical variables were analyzed using Fisher’s exact test. Following vitamin D supplementation, serum vitamin D levels significantly increased in the patient group (p = 0.04). The distribution of change differences is shown in Fig. 1 , with the majority of patients experiencing a positive change. The number of patients with vitamin D deficiency decreased markedly (p = 0.004). More importantly, the frequency of recurrent UTIs decreased significantly after treatment (median 2 vs 1.5 episodes, p = 0.014) (Table 2 ). Table 2 Changes After Vitamin D Treatment Variable Before Treatment (n = 18) After Treatment (n = 18) p value Vitamin D level (ng/mL) 15.89 ± 6.76 19.96 ± 8.77 0.04 a Vitamin D deficiency, n (%) 16 (88.9%) 7 (38.9%) 0.004 b UTI frequency (median) 2 1.5 0.014 c UTI episodes = 0, n (%) 3 (16.7%) 4 (22.2%) UTI episodes = 1, n (%) 3 (16.7%) 5 (27.8%) UTI episodes = 2, n (%) 6 (33.3%) 4 (22.2%) UTI episodes = 3, n (%) 3 (16.7%) 3 (16.7%) UTI episodes = 4, n (%) 2 (11.1%) 1 (5.6%) UTI episodes = 5, n (%) 1 (5.6%) 1 (5.6%) a Continuous variables were compared using paired t-test. b Categorical variables were analyzed using Fisher’s exact test. c Categorical paired data were analyzed using Wilcoxon signed-rank / marginal homogeneity tests. The distribution of recurrent UTI frequency shifted toward lower frequencies following vitamin D supplementation. The proportion of children experiencing two or more UTIs decreased from 66.7% to 50%, while the proportion experiencing 0–1 UTIs increased from 33% to 50%. The median number of UTIs decreased by 25%. This decrease was statistically significant (Wilcoxon signed-rank test, p = 0.014) and had a moderate effect size (r ≈ 0.40) (Table 2 ). Discussion Vitamin D plays an important role in immunity and uroepithelial defense. Vitamin D receptors have been demonstrated in the bladder epithelium. Activation of these receptors stimulates the production of antimicrobial peptides such as cathelicidin (LL-37) and β-defensin, which inhibit uropathogenic bacteria and enhance mucosal barrier function [ 14 , 15 ]. Vitamin D also modulates inflammatory responses and improves epithelial integrity, suggesting that it plays a protective role against UTIs [ 3 , 18 , 19 ]. Nseir and colleagues were the first to report an association between recurrent UTI and vitamin D deficiency in premenopausal women [ 12 ]. In a recent study, van der Starre and colleagues reported that most adult patients with UTI had vitamin D insufficiency and that vitamin D levels were lower in patients than in the control group [ 13 ]. Some clinical studies have reported an association between vitamin D deficiency and an increased risk of recurrent UTIs in children [ 4 – 6 ]. Tekin et al. showed that vitamin D levels were significantly lower in children with UTIs compared to healthy children (11.7 vs. 27.6 ng/ml) and that children with vitamin D levels below 20 ng/ml had a 3.5-fold higher incidence of UTIs compared to children with normal vitamin D levels (3). Similarly, Mahyar et al. reported that vitamin D deficiency is more common in pediatric patients with recurrent infections [ 20 ]. Furthermore, a meta-analysis supported that vitamin D deficiency is a potential risk factor for pediatric UTI [ 17 ]. Considering the evidence showing low vitamin D levels associated with UTIs in both adults and children, we believe that vitamin D, with these effects, may have a protective effect in preventing recurrent UTIs in children when used as an alternative treatment or supplement to antibiotics. Studies have reported that vitamin D supplementation is effective in preventing recurrent acute otitis media and pneumonia.[ 19 , 20 ] There are lack of studies on vitamin D in preventing recurrent UTIs. El-Mazary and colleagues evaluated the effect of daily 400 IU vitamin D supplementation for 6 months on the risk of infections, including urinary UTIs, in infants up to 1 year of age. They found no difference in the incidence of UTIs between infants receiving vitamin D supplementation and those not receiving it. They attributed this to the upward spread of UTIs and the weakness of the local urinary tract immune system [ 21 ]. Another study compared control groups receiving vitamin D supplementation and placebo in children with recurrent UTIs. It was shown that vitamin D supplementation at a dose of 1000 IU had no significant effect on preventing recurrent UTIs in the patient group. The authors believe that the protective effect of vitamin D against recurrent UTIs in pediatric patients may be due to higher or normal vitamin D levels [ 22 ]. In our study, vitamin D supplementation was observed to cause a significant increase in serum vitamin D levels and a significant decrease in vitamin D deficiency. More importantly, we observed a significant decrease in the frequency of recurrent UTIs; there was a 25% decrease in the average number of infections, and patients experienced fewer UTIs. The proportion of children who experienced ≥ 2 UTIs decreased from 66.7% to 50%, while the percentage of children who experienced 0–1 infections increased from 33% to 50%. The moderate effect size indicates that the effect of vitamin D supplementation is not only statistically significant but also clinically meaningful. This study has some limitations. First, the sample size is relatively small, which may limit the generalizability of the findings. Although there were no restrictions on patient selection based on gender, after excluding patients with anatomical abnormalities (UTIs are more common in girls), most of the selected patients were girls, and the number of males in the sample was quite low. Increasing the sample size would help resolve this issue. Second, the study was conducted at a single center, and therefore, the results may not be representative of the general population. Third, the study lacked randomization and a placebo-controlled design. Although a significant reduction in recurrent UTIs was observed after vitamin D supplementation, causality cannot be definitively established. Potential confounding factors such as seasonal changes in vitamin D levels, sun exposure, and diet were not systematically evaluated. Finally, the follow-up period was relatively short, and the long-term effects of vitamin D supplementation on UTI recurrence remain uncertain. Despite these limitations, this study also has several strengths. To our knowledge, this study is one of the few that evaluates the effect of vitamin D supplementation on the recurrence rate of recurrent UTIs in school-aged children. The prospective pre-post study design reduced inter-individual variability by allowing for the assessment of treatment response in the same patient group. Furthermore, both biochemical outcomes (serum vitamin D levels) and clinically relevant outcomes (UTI recurrence rate) were assessed, enabling an evaluation of vitamin D's potential role in preventing recurrent UTIs. Conclusion Our findings support previous literature suggesting that correcting vitamin D deficiency may contribute to decreasing the recurrence rate of UTIs in children. Therefore, rather than a single standard dose for every patient, supplementation based on vitamin D levels could serve as a supportive preventive strategy, particularly in patients with recurrent infections and documented vitamin D deficiency. To arrive at a more meaningful conclusion, we recommend prospective studies with a larger patient cohort and a longer follow-up period, including a control group of patients with recurrent UTIs who did not receive vitamin D supplementation. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the he Ethics Committee of Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital (No. 2021 − 605). No funding was received to assist with the preparation of this manuscript. The authors declare they have no financial interests. The authors have no conflicts of interest to declare that are relevant to the content of this article Declarations Funding No funding was received to assist with the preparation of this manuscript. Financial interest The authors declare they have no financial interests. Conflict of interest The authors have no conflicts of interest to declare that are relevant to the content of this article References Shaikh N, Morone NE, Bost JE, Farrell MH (2008) Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 27:302–308. https://doi.org/10.1097/INF.0b013e31815e4122 Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R (2007) Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 11:298:179–186. https://doi.org/10.1001/jama.298.2.179 Tekin M, Konca C, Celik V et al (2015) The association between vitamin D levels and urinary tract infection in children. Hormone Res Paediatrics 83:198–203. https://doi.org/10.1159/000370046 Awais M, Rehman A, Baloch NU, Khan F, Khan N (2015) Evaluation and management of recurrent urinary tract infections in children: State of the art. Expert Rev Anti Infect Ther 13:209–231. https://doi.org/10.1586/14787210.2015.991717 Frankul FA, Tawaige ZH, AL-Janabi AA (2003) Urinary tract infections in febrile children. J Fac Med (Baghdad) 45:41–50 Montini G, Tullus K, Hewitt I (2011) Febrile urinary tract infections in children. N Engl J Med 13:239–250. https://doi.org/10.1056/NEJMra1007755 National Institute for Health and Care Excellence (2022) Urinary tract infection in under 16s: diagnosis and management. NICE guideline No 224, London European Association of Urology (EAU) (2023) European Society for Paediatric Urology (ESPU). EAU-ESPU Guidelines on Paediatric Urology. EAU Guidelines Office, Arnhem, The Netherlands Yang SS, Chiang IN, Lin CD, Chang SJ (2012) Advances in non-surgical treatments for urinary tract infections in children. World J Urol 30:69–75. https://doi.org/10.1007/s00345-011-0700-5 Gurley BJ (2011) Cranberries as antibiotics? Comment on Cranberries vs. antibiotics to prevent urinary tract infections: A randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med 171:1279–1280. https://doi.org/10.1001/archinternmed.2011.332 Head KA (2008) Natural approaches to prevention and treatment of infections of the lower urinary tract. Altern Med Rev 13:227–244 Nseir W, Taha M, Nemarny H, Mograbi J (2013) The association between serum levels of Vitamin D and recurrent urinary ract infections in premenopausal women. Int J Infect Dis 17:e1121–e1124. https://doi.org/10.1016/j.ijid.2013.06.007 van der Starre WE, van Nieuwkoop C, Thomson U et al (2015) Urinary proteins, Vitamin D and genetic polymorphisms as risk factors for febrile urinary tract infection and relation with bacteremia: A case control study. PLoS ONE 10:e0121302. https://doi.org/10.1371/journal.pone.0121302 Wang TT, Nestel FP, Bourdeau V et al (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912. https://doi.org/10.4049/jimmunol.173.5.2909 Hertting O, Holm Å, Lüthje P et al (2010) Vitamin D induction of the human antimicrobial peptide cathelicidin in the urinary bladder. PLoS ONE 5:e15580. https://doi.org/10.1371/journal.pone.0015580 Aranow C (2011) Vitamin D and the immune system. J Investig Med 59:881–886. https://doi.org/10.2310/JIM.0b013e31821b8755 Gan Y, You S, Ying J, Mu D (2023) The Association between Serum Vitamin D Levels and Urinary Tract Infection Risk in Children: A Systematic Review and Meta-Analysis. Nutrients 15:2690. https://doi.org/10.3390/nu15122690 Walker VP, Modlin RL (2009) The Vitamin D connection to pediatric infections and immune function. Pediatr Res 65. https://doi.org/10.1203/PDR.0b013e31819dba91 . :106 – 13 Wu S, Sun J, Vitamin D (2011) Vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med 11:325–335 Mahyar A, Ayazi P, Safari S, Dalirani R, Javadi A, Esmaeily S (2018) Association between vitamin D and urinary tract infection in children. Korean J Pediatr 61:90–94. https://doi.org/10.3345/kjp.2018.61.3.90 El-Mazary AM, Maaboud MA, Momen MM, Nasef KA, Egypt (2012) J Pediatr Allergy Immunol 10:87–94 Merrikhi A, Ziaei E, Shahsanai A, Kelishadi R, Maghami-Mehr A (2018) Is Vitamin D Supplementation Effective in Prevention of Recurrent Urinary Tract Infections in the Pediatrics? A Randomized Triple-Masked Controlled Trial. Adv Biomed Res 7:150. https://doi.org/10.4103/abr.abr_149_18 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8944759","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":599277672,"identity":"7b88afe7-81c0-4d85-81a0-5919089d9b32","order_by":0,"name":"Burak Özçift","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACAyBmbAASbMwHGB8AaR4+4rWwJTODODxsRGthYEtmkwDThLSYS+Q+/Dijok6ej43/WOXXHDsZNgbmh49u4NFiOSPdWHLDGTbDNjZmttuy25KBDmMzNs7B57AbaQySD9t4Etjkm9luS25jBmrhYZMmoIX558M2iQQ2oC3FktvqidLCJrmxzQCshfHjtsOEtVj2PGOznHEmAeQXY2nGbcd5gFrx+8WcPY35Zg8wxOTbGB9+/Lmt2p6fvfnhY3xaUAAzD5gkVjkIMP4gRfUoGAWjYBSMGAAAesY8gki5GbkAAAAASUVORK5CYII=","orcid":"","institution":"Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Burak","middleName":"","lastName":"Özçift","suffix":""},{"id":599277674,"identity":"0e2ae11a-7cc7-4426-81a1-f79a7f6a973e","order_by":1,"name":"Aslı Kantar","email":"","orcid":"","institution":"Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aslı","middleName":"","lastName":"Kantar","suffix":""}],"badges":[],"createdAt":"2026-02-23 08:39:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8944759/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8944759/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104177625,"identity":"478d0eee-7446-49ad-bbe3-6db6d1a0499e","added_by":"auto","created_at":"2026-03-08 16:49:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":161762,"visible":true,"origin":"","legend":"\u003cp\u003eVitamin D Change Difference Distribution\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8944759/v1/2762312004919b5bd60bf233.png"},{"id":104177629,"identity":"e37f591a-3baf-4f5e-b24c-e54a8e4f11f8","added_by":"auto","created_at":"2026-03-08 16:49:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":555509,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8944759/v1/ea73f0fd-d855-4c76-893b-fa945b281200.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Is Vitamin D the Missing Link in Recurrent Urinary Tract Infections in Children? A Prospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUTI is considered one of the most common bacterial infections associated with morbidities such as hypertension, growth retardation, and renal dysfunction in children, and recurrent infections develop in 12\u0026ndash;30% of children who experience UTI [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, UTI prevention strategies are particularly important in pediatric patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. UTI treatment is considered a challenging topic due to factors such as antibiotic resistance, side effects, and recurrence [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe risk of recurrence is quite high in school-aged children (\u0026ge;\u0026thinsp;5 years) who have experienced their first urinary tract infection (UTI) [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In children older than 5 years, recurrence rates are greatly influenced by gender, with recurrence reported in 15\u0026ndash;30% of girls and 3\u0026ndash;10% of boys [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The risk increases significantly when predisposing conditions such as vesicoureteral reflux (especially\u0026thinsp;\u0026ge;\u0026thinsp;grade III), bladder-bowel dysfunction, dysfunctional voiding, constipation, and structural urinary tract anomalies are present, with recurrence rates reaching 30\u0026ndash;50% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVarious treatment approaches have been introduced for both the treatment and prevention of recurrent UTIs. While antibiotics can be used to prevent recurrent UTIs and related complications, they may also increase the risk of microbial resistance. Given the role of vitamins and minerals in the proper functioning of the immune system, certain supplements, such as cranberry, mannose, probiotics, and vitamin A, have also been suggested as alternatives [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recent studies have highlighted the role of vitamin D in immune defense. Vitamin D is considered a crucial regulator of the immune system. Activation of vitamin D receptors inhibits uropathogenic Escherichia coli and induces the expression of antimicrobial peptides that have been shown to enhance urothelial defense, such as cathelicidin (LL-37) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Vitamin D is also thought to play a protective role against infections by modulating inflammatory pathways and supporting epithelial barrier integrity [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have shown that vitamin D deficiency is more common in children with UTIs compared to healthy controls [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The relationship between vitamin D receptor gene polymorphisms and UTIs has also been reported in one study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, a meta-analysis has identified vitamin D deficiency as a potential risk factor for the development of UTIs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, evidence regarding the effect of vitamin D supplementation on recurrence rates remains limited.\u003c/p\u003e \u003cp\u003eThe association between vitamin D, immune function, and infections in children suggests that vitamin D supplementation may play a potential role as an interventional or adjuvant therapeutic agent for the management and prevention of urinary tract infections (UTIs). Therefore, this study aims to evaluate the relationship between vitamin D levels and recurrent UTIs and to investigate the effect of vitamin D supplementation on recurrence rates in school-aged children.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eThis prospective case-control study was conducted among children referred to the Pediatric Urology outpatient clinic of Dr. Beh\u0026ccedil;et Uz Children's Diseases and Surgery between 2018 and 2024 due to recurrent UTIs despite prophylactic antibiotic treatment in the last 6 months. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital (Date. 09.09.2021 / No. 2021\u0026thinsp;\u0026minus;\u0026thinsp;605). All participants (or their parents or legal caregivers for children under 18) freely provided informed written and verbal consent to participate in the study.\u003c/p\u003e \u003cp\u003eChildren who were not in the active phase of UTI, were over 5 years of age, had completed toilet training, had no anatomical defects, kidney stones, neurogenic bladder, VUR, obstructive uropathy, or congenital or acquired immunodeficiency, and had documented recurrent UTIs were included in the study. Recurrent UTI was defined as two infections within 6 months or three infections within one year, following at least two weeks of remission [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Patients without regular follow-up or treatment were excluded from the study.\u003c/p\u003e \u003cp\u003eSerum vitamin D levels in the patient group were compared with those in the healthy child group before the study. The number of UTIs experienced in the patient group in the last 6 months before vitamin D supplementation was noted. The patient group received appropriate vitamin D treatment according to their vitamin D levels for 6 months.\u003c/p\u003e \u003cp\u003eVitamin D deficiency (\u0026lt;\u0026thinsp;20 ng/ml) was treated with oral vitamin D3 drops: 2000 IU/day for those\u0026thinsp;\u0026lt;\u0026thinsp;10 years of age, 4000 IU/day for those\u0026thinsp;\u0026gt;\u0026thinsp;10 years of age (8 weeks), followed by 4 months of maintenance therapy. For those with sufficient vitamin D (\u0026gt;\u0026thinsp;20 ng/ml), oral vitamin D3 drops were administered at 600\u0026ndash;1000 IU/day (maintenance therapy) for 6 months.\u003c/p\u003e \u003cp\u003eThe demographic characteristics of each patient were recorded before the study. Patients were followed monthly for UTI recurrence and vitamin D treatment use. Urinalysis and culture were performed for patients showing UTI signs or symptoms. UTI diagnosis was defined as \u0026ge;\u0026thinsp;10\u003csup\u003e5\u003c/sup\u003e colony-forming units/mL in a fresh urine sample obtained using the midstream method (7,8). Serum vitamin D levels before and after the study and the proportion of patients with vitamin D deficiency were compared. Serum 25-hydroxyvitamin D concentration was measured using a chemiluminescent immunoassay. The 6-month UTI incidence was recorded in the patient group during the study period and compared with the incidence before vitamin D supplementation.\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using SPSS version 22 (SPSS Inc., Chicago, IL, USA) software with dependent and independent sample t-tests, Wilcoxon Signed-Rank Test, and Fisher's Exact Test. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 18 children with recurrent UTI and 19 healthy children. In the patient group, there were 16 (88.9%) girls and 2 (11.1%) boys, while in the healthy child group, there were 13 (68.4%) girls and 6 (31.6%) boys (p\u0026thinsp;=\u0026thinsp;0.11). The mean age of the patient group was 8.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.77 years, while that of the control group was 8.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22 years (p\u0026thinsp;=\u0026thinsp;0.93). There was no significant difference between the two groups in terms of age and gender. In addition, the mean serum vitamin D level was lower in the patient group than in the control group (15.89\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76 vs. 19.96\u0026thinsp;\u0026plusmn;\u0026thinsp;10.08 ng/mL); however, this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.16). In contrast, vitamin D deficiency was significantly more prevalent in the patient group than in the controls (88.9% vs. 36.8%, p\u0026thinsp;=\u0026thinsp;0.002). (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Vitamin D Status Between Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D level (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.89\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.96\u0026thinsp;\u0026plusmn;\u0026thinsp;10.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D deficiency, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (88.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (36.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Continuous variables were compared using independent samples t-test (Welch).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Categorical variables were analyzed using Fisher\u0026rsquo;s exact test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFollowing vitamin D supplementation, serum vitamin D levels significantly increased in the patient group (p\u0026thinsp;=\u0026thinsp;0.04). The distribution of change differences is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, with the majority of patients experiencing a positive change. The number of patients with vitamin D deficiency decreased markedly (p\u0026thinsp;=\u0026thinsp;0.004). More importantly, the frequency of recurrent UTIs decreased significantly after treatment (median 2 vs 1.5 episodes, p\u0026thinsp;=\u0026thinsp;0.014) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges After Vitamin D Treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D level (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.89\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.96\u0026thinsp;\u0026plusmn;\u0026thinsp;8.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e \u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D deficiency, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (88.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (38.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI frequency (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;0, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;1, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (27.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;2, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;3, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;4, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTI episodes\u0026thinsp;=\u0026thinsp;5, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Continuous variables were compared using paired t-test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Categorical variables were analyzed using Fisher\u0026rsquo;s exact test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e Categorical paired data were analyzed using Wilcoxon signed-rank / marginal homogeneity tests.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe distribution of recurrent UTI frequency shifted toward lower frequencies following vitamin D supplementation. The proportion of children experiencing two or more UTIs decreased from 66.7% to 50%, while the proportion experiencing 0\u0026ndash;1 UTIs increased from 33% to 50%. The median number of UTIs decreased by 25%. This decrease was statistically significant (Wilcoxon signed-rank test, p\u0026thinsp;=\u0026thinsp;0.014) and had a moderate effect size (r\u0026thinsp;\u0026asymp;\u0026thinsp;0.40) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVitamin D plays an important role in immunity and uroepithelial defense. Vitamin D receptors have been demonstrated in the bladder epithelium. Activation of these receptors stimulates the production of antimicrobial peptides such as cathelicidin (LL-37) and β-defensin, which inhibit uropathogenic bacteria and enhance mucosal barrier function [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Vitamin D also modulates inflammatory responses and improves epithelial integrity, suggesting that it plays a protective role against UTIs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNseir and colleagues were the first to report an association between recurrent UTI and vitamin D deficiency in premenopausal women [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In a recent study, van der Starre and colleagues reported that most adult patients with UTI had vitamin D insufficiency and that vitamin D levels were lower in patients than in the control group [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome clinical studies have reported an association between vitamin D deficiency and an increased risk of recurrent UTIs in children [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Tekin et al. showed that vitamin D levels were significantly lower in children with UTIs compared to healthy children (11.7 vs. 27.6 ng/ml) and that children with vitamin D levels below 20 ng/ml had a 3.5-fold higher incidence of UTIs compared to children with normal vitamin D levels (3). Similarly, Mahyar et al. reported that vitamin D deficiency is more common in pediatric patients with recurrent infections [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Furthermore, a meta-analysis supported that vitamin D deficiency is a potential risk factor for pediatric UTI [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsidering the evidence showing low vitamin D levels associated with UTIs in both adults and children, we believe that vitamin D, with these effects, may have a protective effect in preventing recurrent UTIs in children when used as an alternative treatment or supplement to antibiotics.\u003c/p\u003e \u003cp\u003eStudies have reported that vitamin D supplementation is effective in preventing recurrent acute otitis media and pneumonia.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] There are lack of studies on vitamin D in preventing recurrent UTIs.\u003c/p\u003e \u003cp\u003eEl-Mazary and colleagues evaluated the effect of daily 400 IU vitamin D supplementation for 6 months on the risk of infections, including urinary UTIs, in infants up to 1 year of age. They found no difference in the incidence of UTIs between infants receiving vitamin D supplementation and those not receiving it. They attributed this to the upward spread of UTIs and the weakness of the local urinary tract immune system [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Another study compared control groups receiving vitamin D supplementation and placebo in children with recurrent UTIs. It was shown that vitamin D supplementation at a dose of 1000 IU had no significant effect on preventing recurrent UTIs in the patient group. The authors believe that the protective effect of vitamin D against recurrent UTIs in pediatric patients may be due to higher or normal vitamin D levels [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, vitamin D supplementation was observed to cause a significant increase in serum vitamin D levels and a significant decrease in vitamin D deficiency. More importantly, we observed a significant decrease in the frequency of recurrent UTIs; there was a 25% decrease in the average number of infections, and patients experienced fewer UTIs. The proportion of children who experienced\u0026thinsp;\u0026ge;\u0026thinsp;2 UTIs decreased from 66.7% to 50%, while the percentage of children who experienced 0\u0026ndash;1 infections increased from 33% to 50%. The moderate effect size indicates that the effect of vitamin D supplementation is not only statistically significant but also clinically meaningful.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, the sample size is relatively small, which may limit the generalizability of the findings. Although there were no restrictions on patient selection based on gender, after excluding patients with anatomical abnormalities (UTIs are more common in girls), most of the selected patients were girls, and the number of males in the sample was quite low. Increasing the sample size would help resolve this issue. Second, the study was conducted at a single center, and therefore, the results may not be representative of the general population. Third, the study lacked randomization and a placebo-controlled design. Although a significant reduction in recurrent UTIs was observed after vitamin D supplementation, causality cannot be definitively established. Potential confounding factors such as seasonal changes in vitamin D levels, sun exposure, and diet were not systematically evaluated. Finally, the follow-up period was relatively short, and the long-term effects of vitamin D supplementation on UTI recurrence remain uncertain.\u003c/p\u003e \u003cp\u003eDespite these limitations, this study also has several strengths. To our knowledge, this study is one of the few that evaluates the effect of vitamin D supplementation on the recurrence rate of recurrent UTIs in school-aged children. The prospective pre-post study design reduced inter-individual variability by allowing for the assessment of treatment response in the same patient group. Furthermore, both biochemical outcomes (serum vitamin D levels) and clinically relevant outcomes (UTI recurrence rate) were assessed, enabling an evaluation of vitamin D's potential role in preventing recurrent UTIs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings support previous literature suggesting that correcting vitamin D deficiency may contribute to decreasing the recurrence rate of UTIs in children. Therefore, rather than a single standard dose for every patient, supplementation based on vitamin D levels could serve as a supportive preventive strategy, particularly in patients with recurrent infections and documented vitamin D deficiency. To arrive at a more meaningful conclusion, we recommend prospective studies with a larger patient cohort and a longer follow-up period, including a control group of patients with recurrent UTIs who did not receive vitamin D supplementation.\u003c/p\u003e \u003cp\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the he Ethics Committee of Izmir Dr. Behcet Uz Child Diseases and Surgery Training and Research Hospital (No. 2021\u0026thinsp;\u0026minus;\u0026thinsp;605).\u003c/p\u003e \u003cp\u003eNo funding was received to assist with the preparation of this manuscript.\u003c/p\u003e \u003cp\u003eThe authors declare they have no financial interests.\u003c/p\u003e \u003cp\u003eThe authors have no conflicts of interest to declare that are relevant to the content of this article\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare they have no financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare that are relevant to the content of this article\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShaikh N, Morone NE, Bost JE, Farrell MH (2008) Prevalence of urinary tract infection in childhood: a meta-analysis. 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Korean J Pediatr 61:90\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3345/kjp.2018.61.3.90\u003c/span\u003e\u003cspan address=\"10.3345/kjp.2018.61.3.90\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Mazary AM, Maaboud MA, Momen MM, Nasef KA, Egypt (2012) J Pediatr Allergy Immunol 10:87\u0026ndash;94\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMerrikhi A, Ziaei E, Shahsanai A, Kelishadi R, Maghami-Mehr A (2018) Is Vitamin D Supplementation Effective in Prevention of Recurrent Urinary Tract Infections in the Pediatrics? A Randomized Triple-Masked Controlled Trial. Adv Biomed Res 7:150. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4103/abr.abr_149_18\u003c/span\u003e\u003cspan address=\"10.4103/abr.abr_149_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Children, immunity, prevention, supplementation, urinary tract infection, Vitamin D","lastPublishedDoi":"10.21203/rs.3.rs-8944759/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8944759/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVitamin D's key role in immunity may help prevent urinary tract infections (UTIs). This study aimed to explore the impact of vitamin D supplementation on preventing recurrent UTIs in children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective case-control study included 18 school-aged children with recurrent UTIs and 19 healthy children. Serum vitamin D levels were compared between the groups. Vitamin D supplementation was administered to children with recurrent UTIs. Vitamin D concentrations before and after supplementation, and recurrence frequency during the study period, were evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean serum vitamin D levels in the patient group were lower than those in the healthy control group (15.89 ± 6.76 vs. 19.96 ± 10.08 ng/mL), but this difference was not statistically significant (p = 0.16). However, vitamin D deficiency was significantly more prevalent in the patient group (88.9% vs 36.8%, p = 0.002). Vitamin D serum levels increased significantly after supplementation (15.89 ± 6.76 vs 19.96 ± 8.77 ng/mL, p = 0.04) and the proportion of patients with vitamin D deficiency decreased significantly (%88.9 vs %38.9, p = 0.004). The median number of UTI episodes decreased significantly (2.0 vs. 1.5 episodes, p = 0.014).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVitamin D deficiency is more common in children with recurrent UTIs. Vitamin D supplementation significantly increased vitamin D levels and is associated with a lower recurrence rate of UTIs. Correcting vitamin D deficiency and maintaining adequate levels may be a simple and effective method for preventing recurrent UTIs in school-aged children.\u003c/p\u003e\n\u003cp\u003eTrial registration number and date of registration: 2021/605, 09.09.2021\u003c/p\u003e","manuscriptTitle":"Is Vitamin D the Missing Link in Recurrent Urinary Tract Infections in Children? A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 16:48:56","doi":"10.21203/rs.3.rs-8944759/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-30T14:48:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-21T05:16:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T08:59:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-09T07:31:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"232688226337136367613233456049685367124","date":"2026-03-07T07:49:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102981890126372004459004794338089797741","date":"2026-03-02T11:47:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73365746273215921477617880932152066523","date":"2026-03-02T07:52:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-02T07:35:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-26T02:33:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-25T14:38:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Urology","date":"2026-02-23T08:27:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8d7de91b-e951-48f6-9100-be5c98b8d5b2","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T10:39:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 16:48:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8944759","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8944759","identity":"rs-8944759","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}