Vesicoureteral Reflux Children Research Articles

Understanding and Managing Pediatric Urinary Tract Infections in Vesicoureteral Reflux: Insights Into Pathophysiology and Care.

Vesicoureteral reflux (VUR) is a pediatric condition identified by the backward flow of urine from the bladder to one or both ureters and kidneys, predisposing patients to recurrent urinary tract infections (UTIs) and kidney scarring. Continuous antibiotic prophylaxis has long been a mainstay of management aimed at preventing recurrent UTIs and resulting renal damage. This review critically discusses the evidence supporting the utilization of antibiotic prophylaxis in VUR, with a focus on its efficacy, safety, long-term outcomes, and future directions in management. The literature reveals that continuous antibiotic use as a prophylactic measure minimizes the possibility of having recurrent UTIs in VUR children, especially in high-grade reflux children. However, the overall benefit of continuous antibiotic prophylaxis in protecting against kidney scarring remains controversial. Furthermore, concerns about antibiotic resistance, adverse drug reactions, and the psychosocial burden on families have led to a reevaluation of this option's role in managing VUR. Emerging evidence supports the role of non-antibiotic interventions and the potential of surgical management in select cases. Future research should focus on identifying criteria of patients who would benefit most from continuous antibiotic prophylaxis and on developing novel therapeutic approaches to minimize the need for prolonged antibiotic use.

Is technetium-99m dimercaptosuccinic acid renal scintigraphy available for predicting vesicoureteral reflux in children with first febrile urinary tract infection under the age of 24 months?

Vesicoureteral reflux (VUR) is a common complication after urinary tract infection (UTI) and can lead to irreversible renal scar. Voiding cystourethrogram is the most reliable technology to detect VUR and its severity, but it is restricted in children's examinations for various shortcomings. This study aimed to evaluate and compare the efficiency of Tc-99m DMSA renal scintigraphy and conventional ultrasonography (USG) in predicting VUR with the gold standard of cystourethrogram results. This retrospective study consisted of 285 first febrile UTI children under the age of 24 months who completed inflammatory indicator examinations, USG, Tc-99m DMSA renal scintigraphy and underwent cystourethrography after controlling infection with prophylactic antibiotics. The efficiency of Tc-99m DMSA renal scintigraphy and USG in predicting VUR was calculated and compared. Abnormal USG (40.23% vs. 21.72%, P = 0.001) and Tc-99m DMSA renal scintigraphy results (87.36% vs. 71.72%, P = 0.004) were more common in VUR children. The sensitivity of USG in predicting VUR was only 40.23%, whereas the sensitivity and negative predictive value of Tc-99m DMSA renal scintigraphy reached 87.63 and 83.58%, respectively. Tc-99m DMSA renal scintigraphy had a higher efficacy than USG in predicting high-grade reflux kidneys (73.87% vs. 33.33%; P < 0.001), but there was no significant difference in predicting low-grade reflux kidneys ( P = 0.703). Tc-99m DMSA renal scintigraphy had a significant higher efficiency in predicting VUR (a common cause of renal scarring, detected on DMSA) in first febrile urinary tract infection children under the age of 24 months as compared with USG, especially in high-grade reflux.

Risk factors for breakthrough urinary tract infection in children with vesicoureteral reflux receiving continuous antibiotic prophylaxis.

BackgroundTo investigate the risk factors for breakthrough urinary tract infection (BT-UTI) in children with vesicoureteral reflux (VUR) receiving continuous antibiotic prophylaxis (CAP).MethodsThis was a single-centre cohort study (January 2016 to December 2019). The clinical data of 256 children with grade I–V VUR receiving CAP were analysed. In this study, exposure variables were sex, younger age at the initial diagnosis of UTI ≤12 months, high-grade VUR, bilateral VUR, aetiology, presence of renal scarring at the initial diagnosis, presence of renal function impairment at the initial diagnosis, ultrasound abnormalities, antibiotic used and bladder and bowel dysfunction (BBD). Outcome was BT-UTI.ResultsBT-UTI occurred in 81 out of 256 children with grade I–V VUR who received CAP, an incidence of 31.64%. Univariate analysis showed that younger age at the initial diagnosis of UTI (≤12 months), bilateral VUR, renal scarring on the dimercaptosuccinic acid (DMSA) scan at the initial diagnosis of UTI and BBD were correlated with the occurrence of BT-UTI. Multivariate analysis showed that younger age at the initial diagnosis of UTI (≤12 months) [hazard ratio (HR): 4.629; 95% confidence interval (CI): 1.302–16.462], bilateral VUR (HR: 2.078; 95% CI: 1.084–4.022) and BBD (HR: 3.194; 95% CI: 1.243–8.206) were independent risk factors for the occurrence of BT-UTI.ConclusionsFor VUR children receiving CAP, younger age at the initial diagnosis of UTI (≤12 months), bilateral VUR, and BBD were independent risk factors for the occurrence of BT-UTI.

Types of Parenchymal Changes Diagnosed on DMSA Scans of Kidneys Affected by Different Grades of Vesicoureteral Reflux.

BackgroundRenal parenchymal damage and scarring usually is associated with urinary tract infection (UTI), whereas the impact of vesicoureteral reflux (VUR) on the kidneys is unclear. We aimed to compare kidneys with all grades of VUR (grades Io-V) and those without VUR by using direct radionuclide cystography, voiding cystourethrography, and findings from 99mTc-DMSA scintigraphy (DMSA scan).Material/MethodsThe present analysis included 253 renal ureteral units (RUU) from 129 children with VUR and recurrent UTI and children with a single febrile UTI associated with abnormal ultrasonographic findings. The 6 grades of VUR (Io, I, II, III, IV, and V) and 35 RUUs without VUR were divided into 4 groups: 1. Non-dilated VUR (grades Io-II); 2. Mildly dilated VUR (grade III); 3. Dilated VUR (grades IV–V); and 4. The control group.ResultsDMSA scanning showed significant differences between the groups with non-dilated VUR, grade III VUR, grades IV–V VUR, and the control group in kidney width (χ2=30.5; P<0.001); position and shape (χ2=30.6; P<0.001); intensity of activity (χ2=38.1; P<0.001); distribution of activity (χ2=34.5; P<0.001); and existence of scars (χ2=16; P<0.001). The probability of abnormalities on DMSA scans increased with the VUR grade. However, inside the groups of dilated and non-dilated VUR we found no significant statistical differences between those characteristics.ConclusionsOur results indicate that kidneys without VUR or with non-dilated lateral VUR and dilated VUR on the contralateral side represent 2 different categories of parenchymal changes.

Association of Genetic Polymorphisms in GSTP1, GSTM1, and GSTT1 Genes with Vesicoureteral Reflux Susceptibility in the Children of Southeast Iran.

Background:Vesicoureteral reflux (VUR) disease is the most common type of urinary tract anomalies in children. Genetic risk factors may be associated with the etiology of VUR. The role of the Glutathione S-transferases (GSTs) as multifunctional enzymes is cellular oxidative stress handling. This is the first study aimed at evaluating the relative risk of GSTP1, GSTM1, and GSTT1 polymorphisms in VUR susceptibility in children and provides new important insights into the genetics of affected children.Methods:The study was done in 2013 in Sistan and Baluchestan University, eastern Iran. Genotyping of three GSTP1, GSTM1, and GSTT1 genes were determined using the multiplex polymerase chain reaction assay in 216 reactions for 72 VUR children and 312 reactions for 104 healthy controls.Results:The presence of GSTT1 deletion was associated with high risk of VUR in children, whereas GSTP1 and GSTM1 genotypes did not show the same effect. Furthermore, the combination of GSTT1/GSTM1 and GSTT1/ GSTP1 genotypes showed a significant influence on lower risk of VUR in children.Conclusion:Deletion of GSTT1 functional gene is a genetic risk factor causing VUR in children. Interestingly, the combination of GSTM1 and GSTP1 null genotypes with GSTT1 has shown a protective role against risk of GSTT1 deletion.

Urinary excretion of EGF and MCP-1 in children with vesicoureteral reflux.

ABSTRACTPurpose The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR).Materials and methods A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI.Results In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls.Conclusions Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

Impact of common functional polymorphisms in renin angiotensin system genes on the risk of renal parenchymal scarring following childhood urinary tract infection

Pathogenesis of renal parenchymal scarring (RPS) after acute pyelonephritis (APN) is unclear. The risk of RPS varies markedly among individuals, suggesting a genetic role. To investigate a possible role of common polymorphisms in renin angiotensin system genes in APN-associated RPS in children. This study included 104 APN children and 300 controls. APN was diagnosed by urine culture and typical findings on 99Tc-DMSA scans. Voiding cystourethrogram tested the presence of vesicoureteral reflux (VUR). Follow-up DMSA scans were performed 4-6 months later to identify new RPS. Angiotensin converting enzyme gene I/D, angiotensin II receptor type-1 A1166C and angiotensinogen M235T polymorphisms were genotyped. New RPS developed in 44.2% (46/104) of children with APN. VUR was diagnosed in 35.6% (37/104) of APN cases. RPS developed in 73% of cases of VUR. The D allele of ACE gene I/D polymorphism was significantly more common in APN cases with RPS (73.91%) than non-RPS (58.6%) and controls (54.5%) (p = 0.021, p = 0.002, respectively). The AGTR-1 A1166C A allele was significantly more common in VUR than the non-reflux children (91.9% versus 76.1%; p = 0.005). VUR, in contrast to the D allele (OR 6.1, 95% CI 0.878-19.7; p = 0.05), was an independent risk factor for RPS. ACE gene D allele is associated with a twofold increase in RPS risk, which could be a result of a functional effect to increase tissue levels and activity of ACE during APN. However, D allele failed to qualify as an independent risk and its RPS association could be dependent on other co-factors, such as TGFβ1 activation, or the D-allele might link with recently discovered functional polymorphisms at the 5' end of the ACE gene. Although VUR is an independent risk for RPS, it is not clear whether this is due to exposure of the kidneys to infected urine, or VUR-associated dysplasia. In contrast with published literature, we noted higher rates of RPS and high-grade VUR, suggesting a more aggressive VUR course or local unawareness of APN. Our study has its limitations; the small number of VUR children, and the clinical and ethical difficulties of testing VCUG and DMSA in controls. ACE gene D allele is associated with, but cannot independently predict, RPS in children. VUR is an independent risk for post-pyelonephritic scarring. AGTR-1 1166A/C polymorphism is associated with occurrence, but not progression, of VUR.

TGF-β1 gene polymorphisms and primary vesicoureteral reflux in childhood

The aim of this study was to assess the association between the transforming growth factor-beta1 (TGF-beta1) gene polymorphisms rs1800469 (commonly known as T-509C) and rs1982073 (commonly known as Leu (10)-->Pro) and primary vesicoureteral reflux (VUR) and renal scarring. Using a case-control approach, we examined 121 children with primary VUR and 169 controls. Genotyping of the TGF-beta1 gene polymorphisms was performed by restriction fragment length polymorphism (RFLP) analysis. The (99m)Tc-DMSA- or (99m)Tc-unitiol-single photon emission computed tomography method was used to evaluate renal scars in 84 of 121 VUR children. Statistical analysis revealed differences in rs1800469 genotype frequencies between VUR patients and controls (p = 0.0021). Our data demonstrate that individuals homozygous for the TT genotype are at risk of primary VUR [odds ratio (95% confidence interval) = 2.7 (1.46-5.08)]. Distribution of the rs1982073 polymorphism was similar in VUR children and controls. In terms of renal scarring, patients were stratified into non-scar and scar subgroups, and no differences in the genotype frequencies of either polymorphism was found. Previous reports have shown that the TT genotype of the rs1800469 polymorphism is a risk factor for renal scarring in primary VUR, and the results of our study suggest that this same polymorphism is associated with susceptibility to this congenital uropathy.

Serum and urine fibronectin levels in children with vesicoureteral reflux

The study objective was to assess serum and urine fibronectin (FN) levels in children with vesicoureteral reflux (VUR) depending on reflux grade and urine osmolality. The study group (1) consisted of 54 VUR children, median age 4.28 (range 0.6-15) years: subgroup A, 19 children with grade II; subgroup B, 19 with grade III; and subgroup C, 16 with grade IV or V VUR. The control group (2) included 27 healthy children. The immunoenzymatic method enzyme immunoassay (EIA) was used to determine serum soluble and urine FN levels, with an osmometer to measure urinary osmolality. The median urine FN in VUR children was 224.1 (15.4-3537) ng/mg creatinine (Cr), compared with the control group: 137.9 (20.3-670.6) ng/mg Cr (p<0.05), whereas median serum FN was 395.0 (13.0-779.9) ng/ml and 121.9 (25-345.1) ng/ml (p<0.05), respectively. A detailed analysis showed that only in subgroup C was the level of urinary FN significantly higher than in the control group (p<0.01). However, serum concentration was elevated in all VUR children (A-C) compared with controls (p<0.01). Reduced osmolality, below 800 mOsm/kg H2O, was observed in subgroup C. Negative correlation between urinary osmolality and urinary FN was found (r=-0.426, p < 0.01). In children with VUR, serum FN increased with reflux grade, whereas its urinary level was elevated only in grade IV and V reflux with impaired urine concentration.

Genetic Control of VEGF and TGF-β1 Gene Polymorphisms in Childhood Urinary Tract Infection and Vesicoureteral Reflux

We investigated whether genetic polymorphisms of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1), potential candidate genes in the pathogenesis of urinary tract infection (UTI) and vesicoureteral reflux (VUR), are associated with the susceptibility to UTI and VUR, and renal scarring. We recruited 89 controls and 86 UTI and 58 VUR children. The UTI group was subdivided into two groups according to renal scarring. Two polymorphisms of VEGF and three of TGF-beta1 genes were investigated by using PCR-restriction fragment length polymorphism analysis. In both UTI and VUR groups, there was an increase in frequency of the VEGF -460 CC (control, 4.3; UTI, 15.9; VUR, 17.8%; p < 0.05), TGF-beta1 -509 CC (control, 8.7; UTI, 34.6; VUR, 35.1%; p < 0.001), and TGF-beta1 -800 GG genotypes (control, 19.1; UTI, 40.5; VUR, 40.4%; p < 0.05). An increase in the TGF-beta1 +869 CC (scar-positive, 35.4; scar-negative, 10.3%; p < 0.05) and a decrease in the +869 TC genotype (scar-positive, 29.2; scar-negative, 55.2%; p < 0.05) were observed in the scar-positive subjects. There were no differences in +405 VEGF genotype frequencies. The VEGF T-460C and the TGF-beta1 C-509T, G-800A, and T869C polymorphisms could be genetic markers of the process of UTI and VUR.

Renin-angiotensin system polymorphisms in Taiwanese primary vesicoureteral reflux.

We studied the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms for association with susceptibility to primary vesicoureteral reflux (VUR) and disease progression in 74 Taiwanese children, including 16 with end-stage renal disease (ESRD), and 117 normal controls. Polymerase chain reaction-amplified products containing the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, Alu I/D, the AGT gene C-532T, G-217A, G-152A, A-20C, A-6G, T174M, T235M, and the AT1R gene A-1138T, T-810A, T-713G, C-521T, AG-214CC, A-153G, A1166C polymorphisms were analyzed by restriction enzyme digestion, gel electrophoresis, or single-strand conformation polymorphism analysis. All the polymorphisms examined were in Hardy-Weinberg equilibrium. The strong non-random association within the ACE, AGT, and AT1R genes suggests low levels of intragenic recombination. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of the six ACE polymorphisms among primary VUR patients with or without ESRD was statistically different. The linked ACE T-A-T-A-A-I allele was observed significantly more frequently in VUR children with ESRD (P<0.001). A significant increase of left ventricular mass index was also found in the linked ACE T-A-T-A-A-I allele group compared with the non-ACE T-A-T-A-A-I allele group of patients aged 18 years with renal progression. The AGT A-6G genotype frequencies were significantly different when the analysis was stratified by genotype of the ACE polymorphisms. The data showed that ACE gene polymorphisms were associated with progressive renal deterioration in Taiwanese children with VUR and might act synergistically with the -6 G allele of the AGT gene.