Infant urinary tract infection in Sweden - A national study of current diagnostic procedures, imaging and treatment.

BACKGROUND: Urinary tract infection (UTI) in infants is a common, potentially life-threatening bacterial infection, and must be managed carefully through the entire chain of care from diagnosis, choice of treatment, follow-up and risk stratification of future complications. This Swedish nationwide study of infant UTI was conducted to evaluate the current management of infant UTI, yield of investigations and the Swedish UTI guidelines' ability to detect abnormalities of importance in the urinary tract. METHODS: Infants < 1 year with a first episode of UTI were included in a prospective multicenter study. Treatment and follow-up were provided by local pediatricians. Clinical and laboratory findings and imaging results were reported to the coordinating center. The current management and results were compared with a previous Swedish study. RESULTS: One thousand three hundred six infants were included. Urine sampling was performed with clean catch technique in 93% of patients. Initial oral antibiotic treatment was used in 63%, predominantly third generation cephalosporines. Permanent kidney abnormalities were found in 10% and dilating vesicoureteral reflux (VUR) in 8%. Higher rates of male gender, non-E. coli infection and ultrasound dilatation were seen in infants < 1 month. UTI recurrences were reported in 18%. CONCLUSIONS: Infant UTI is still generating a considerable amount of follow-up examinations. There is a significant shift towards clean catch as the main urine sampling method. Voiding cystourethrography is performed less frequently reducing the findings of low grade VUR. The incidence of renal scarring is comparable with earlier studies which suggests that the Swedish guidelines are able to identify individuals with risk for long-term complications.

The impact of the distal ureteral diameter ratio, bladder volume at onset of vesicoureteral reflux, and/or grade in predictive models of clinical outcomes in children with vesicoureteral reflux.

PURPOSE: Vesicoureteral reflux (VUR) grade has been used as a primary factor in assessing a child's risk of clinical outcomes. Unfortunately, grade has poor inter-observer reliability. We hypothesized that more objective and reliable VCUG parameters including the distal ureteral diameter ratio (UDR) and volume at onset of VUR (Vol) may either augment or replace the current grading system to provide more reliable prediction of clinical outcomes. MATERIALS AND METHODS: Multivariate clinical outcome models were analyzed to assess the impact on predictive accuracy by the addition of voiding cystourethrogram (VCUG) data including grade, UDR, and Vol, alone or in combinations. Clinical variables from retrospective review of 841 children's records included age, gender, presentation, VUR laterality, bowel and bladder dysfunction, history of febrile urinary tract infection (UTI), and number of UTIs. The primary outcomes assessed included VUR resolution or persistence and need for operative intervention. RESULTS: Grade, UDR, and Vol were independent predictors of resolution and operative intervention. Vol increased predictive accuracy in resolution models with grade or UDR alone; however, no significant difference occurred in models with the substitution of grade with UDR. CONCLUSIONS: A more reliable classification system for VUR, with improved predictive accuracy regarding clinical outcomes, may be developed incorporating UDR and Vol. Whether VUR grade can be completely replaced by Vol and UDR measurements requires further evaluation with larger number of patients.

Genetic determinants of renal scarring in children with febrile UTI.

BACKGROUND: Febrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring (RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs. METHODS: To assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy. RESULTS: In this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes. CONCLUSIONS: In this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.

Renal coloboma syndrome/dominant optic atrophy with severe retinal atrophy and de novo digenic mutations in PAX2 and OPA1.

Renal coloboma syndrome (RCS) and dominant optic atrophy are mainly caused by heterozygous mutations in PAX2 and OPA1, respectively. We describe a patient with digenic mutations in PAX2 and OPA1. A female infant was born without perinatal abnormalities. Magnetic resonance imaging at 4 months of age showed bilateral microphthalmia and optic nerve hypoplasia. Appropriate body size was present at 2 years of age, and mental development was favorable. Color fundus photography revealed severe retinal atrophy in both eyes. Electroretinography showed slight responses in the right eye, but no responses in the left eye, suggesting a high risk of blindness. Urinalysis results were normal, creatinine-based estimated glomerular filtration rate was 63.5 mL/min/1.73 m2, and ultrasonography showed bilateral hypoplastic kidneys. Whole exome sequencing revealed de novo frameshift mutations in PAX2 and OPA1. Both variants were classified as pathogenic (PVS1, PS2, PM2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Genetic testing for ocular diseases should be considered for patients with suspected RCS and a high risk of total blindness.

Urology Mythbusters: Does prevalence of vesicoureteral reflux in children vary by race?

In this edition of Mythbusters, we examine the premise that prevalence of vesicoureteral reflux (VUR) in children varies by race. Specifically, we consider whether there is evidence supporting the contention that VUR is more common in White children and less common in Black children. Statements regarding the lower prevalence of VUR in Black children are ubiquitous in both research papers and reviews. Many of the references cited in support of these statements do not actually support the existence of racial variation in VUR, due to uncontrolled single-arm study designs, highly selected samples at risk for bias, or simply not addressing VUR prevalence at all. There is a small group of studies which directly compared VUR prevalence among children undergoing cystography, and these studies have found VUR to be less common among Black children compared to White children. However, the results of such papers can only be considered in the context of a system in which systemic bias and racism may impact access and care delivery in profound ways. Given that race is a social construct that bears little relationship to shared genetic ancestry or underlying biological characteristics, these findings must be approached with extreme caution. The goals of pediatric urological care should be to confer equitable care to all young children regardless of race.

High-grade Vesicoureteral Reflux in Patients With Anorectal Malformation From the ARM-Net Registry: Is Our Screening Sufficient?

BACKGROUND: Vesico-ureteral reflux (VUR) is a common associated urological anomaly in anorectal malformation (ARM)-patients. High-grade VUR requires antibiotic prophylaxis to prevent urinary tract infections (UTI's), renal scarring and -failure. The exact prevalence of high-grade VUR in ARM patients is unknown. Hence, the aim of this study was determining the incidence of high-grade VUR in ARM-patients, and its associated risk factors. METHODS: A multicenter retrospective cohort study was performed using the ARM-Net registry, including data from 34 centers. Patient characteristics, screening for and presence of renal anomalies and VUR, sacral and spinal anomalies, and sacral ratio were registered. Phenotypes of ARM were grouped according to their complexity in complex and less complex. Multivariable analyses were performed to detect independent risk factors for high-grade (grade III-V) VUR. RESULTS: This study included 2502 patients (50 % female). Renal screening was performed in 2250 patients (90 %), of whom 648 (29 %) had a renal anomaly documented. VUR-screening was performed in 789 patients (32 %), establishing high-grade VUR in 150 (19 %). In patients with a normal renal screening, high-grade VUR was still present in 10 % of patients. Independent risk factors for presence of high-grade VUR were a complex ARM (OR 2.6, 95 %CI 1.6-4.3), and any renal anomaly (OR 3.3, 95 %CI 2.1-5.3). CONCLUSIONS: Although renal screening is performed in the vast majority of patients, only 32 % underwent VUR-screening. Complex ARM and any renal anomaly were independent risk factors for high-grade VUR. Remarkably, 10 % had high-grade VUR despite normal renal screening. Therefore, VUR-screening seems indicated in all ARM patients regardless of renal screening results, to prevent sequelae such as UTI's, renal scarring and ultimately renal failure. TYPE OF STUDY: Observational Cohort-Study. LEVEL OF EVIDENCE: III.

Case report: A novel compound heterozygous variant in the TNXB gene causes single kidney agenesis and vesicoureteral reflux.

Primary vesicoureteral reflux (VUR) is the prevailing congenital anomaly of the kidneys and urinary tract, posing a significant risk for pyelonephritis scarring and chronic renal insufficiency in pediatric patients. Nevertheless, the precise genetic etiology of VUR remains enigmatic. In this current investigation, we conducted whole-exome sequencing on a child exhibiting single kidney, devoid of any familial VUR background, along with both biological parents. Two missense variants (NM_019105.8: exon11: c.4111G>A and NM_019105.8: exon2: c.31A>T) in the TNXB gene were identified through whole-exome sequencing of the child. These variants were found to be inherited from the child's parents, with each parent carrying one of the variants. Molecular dynamics simulations were conducted to assess the impact of these variants on the tenascin XB proteins encoded by them, revealing varying degrees of impairment. Based on our findings, it is suggested that the TNXB compound heterozygous variant, consisting of c.4111G>A and c.31A>T, may be the underlying cause of right renal agenesis and left hydronephrosis in afflicted child. This discovery broadens the genetic range of the TNXB gene and establishes a genetic foundation for disease-specific preimplantation genetic diagnosis (PGD) in prospective pregnancies involving the parents of this afflicted child.

Management of Urinary Tract Infections and Vesicoureteric Reflux: Key Updates From Revised Indian Society of Pediatric Nephrology Guidelines 2023.

Non-specific symptoms and difficulty in collecting urine specimens make the diagnosis of urinary tract infection (UTI) challenging in children. However, timely diagnosis and initiation of therapy are essential to prevent complications. Children with recurrent UTIs require detailed evaluation and follow-up for optimal management. We report key updates from the revised evidence-based practice guidelines of the Indian Society of Pediatric Nephrology for UTIs and primary vesicoureteric reflux.

Update and Summary of the European Association of Urology/European Society of Paediatric Urology Paediatric Guidelines on Vesicoureteral Reflux in Children.

BACKGROUND AND OBJECTIVE: The prescriptive literature on vesicoureteral reflux (VUR) is still limited and thus the level of evidence is generally low. The aim of these guidelines is to provide a practical approach to the treatment of VUR that is based on risk analysis and selective indications for both diagnostic tests and interventions. We provide a 2023 update on the chapter on VUR in children from the European Association of Urology (EAU) and European Society for Paediatric Urology (ESPU) guidelines. METHODS: A structured literature review was performed for all relevant publications published from the last update up to March 2022. KEY FINDINGS AND LIMITATIONS: The most important updates are as follows. Bladder and bowel dysfunction (BBD) is common in toilet-trained children presenting with urinary tract infection (UTI) with or without primary VUR and increases the risk of febrile UTI and focal uptake defects on a radionuclide scan. Continuous antibiotic prophylaxis (CAP) may not be required in every VUR patient. Although the literature does not provide any reliable information on CAP duration in VUR patients, a practical approach would be to consider CAP until there is no further BBD. Recommendations for children with febrile UTI and high-grade VUR include initial medical treatment, with surgical care reserved for CAP noncompliance, breakthrough febrile UTIs despite CAP, and symptomatic VUR that persists during long-term follow-up. Comparison of laparoscopic extravesical versus transvesicoscopic ureteral reimplantation demonstrated that both are good option in terms of resolution and complication rates. Extravesical surgery is the most common approach used for robotic reimplantation, with a wide range of variations and success rates. CONCLUSIONS AND CLINICAL IMPLICATIONS: This summary of the updated 2023 EAU/ESPU guidelines provides practical considerations for the management and diagnostic evaluation of VUR in children. ADVANCING PRACTICE: For children with VUR, it is important to treat BBD if present. A practical approach regarding the duration of CAP is to consider administration until BBD resolution. PATIENT SUMMARY: We provide a summary and update of guidelines on the diagnosis and management of urinary reflux (where urine flows back up through the urinary tract) in children. Treatment of bladder and bowel dysfunction is critical, as this is common in toilet-trained children presenting with urinary tract infection.

Longitudinal follow-up of bladder function in children who participated in the Swedish Reflux Trial.

BACKGROUND: Several publications have reported the coexistence of vesicoureteral reflux (VUR) and bladder dysfunction in children. Whether this dysfunction remains in the longer term is not yet known. OBJECTIVE: This study revisited children who participated in the Swedish Reflux Trial (SRT) with the primary aim of evaluating whether bladder and bowel dysfunction (BBD) in these patients persisted until adolescence. The secondary aim was to evaluate two BBD subgroups, and relations to recurrent urinary tract infections (UTI). STUDY DESIGN: Of the 161 eligible children at SRT study-end, 73 children participated. Their bladder function was evaluated longitudinally using a validated BBD questionnaire with symptom score (cut-off ≥7) and uroflowmetry, at five (T2) and ten years (T3) after study-end. T1 was the SRT study-end. Besides BBD, the sub-diagnoses overactive bladder (OAB) and dysfunctional voiding symptoms (DVS) were calculated from symptom scores. RESULTS: BBD was diagnosed in 37% of children at mean age 3.7 years, which decreased with age to 23% of adolescents (mean age 15.7). DVS and OAB subgroups were equally common at T1, but only DVS was identified at the last follow-up (T3) (p = 0.0008). Recurrent UTIs were seen in 17% at T3 and were more common in patients with BBD (p = 0.038). The gender distribution of BBD also changed, from being equally common at the end of the SRT to affecting mainly adolescent girls at the last follow-up (p = 0.022). Information was available regarding VUR status after repeat VCUGs during follow-up in 22 patients, 12 of them after endoscopic treatment. An improvement in VUR grade was found in the 22, but during follow-up numbers with BBD or UTI did not differ between treated and non-treated groups. DISCUSSION: The prevalence of BBD decreased from 37% at 3-4 years of age to 23% in adolescence, when it was almost exclusively seen in girls. BBD and the subgroup DVS were associated with UTI. Even if epidemiological studies have established a predisposition to bladder symptoms and UTI in girls, little is known about bladder function in adolescents with a history of VUR during the first years of life. One limitation of the study was the number of patients participating. Also, the number of patients with kidney damage was more common in the cohort. CONCLUSION: In this longitudinal follow-up of BBD in children with VUR, the number of children with BBD decreased with age. In adolescence, both BBD and recurrent UTIs mainly affected girls.

Ocular manifestations of congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common birth defects worldwide and a major cause of kidney failure in children. Extra-renal manifestations are also common. This study reviewed diseases associated with the Genomics England CAKUT-associated gene panel for ocular anomalies. In addition, each gene was examined for expression in the human retina and an ocular phenotype in mouse models using the Human Protein Atlas and Mouse Genome Informatics databases, respectively. Thirty-four (54%) of the 63 CAKUT-associated genes (55 'green' and 8 'amber') had a reported ocular phenotype. Five of the 6 most common CAKUT-associated genes (PAX2, EYA1, SALL1, GATA3, PBX1) that represent 30% of all diagnoses had ocular features. The ocular abnormalities found with most CAKUT-associated genes and with five of the six commonest were coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataract. Seven of the CAKUT-associated genes studied (11%) had no reported ocular features but were expressed in the human retina or had an ocular phenotype in a mouse model, which suggested further possibly-unrecognised abnormalities. About one third of CAKUT-associated genes (18, 29%) had no ocular associations and were not expressed in the retina, and the corresponding mouse models had no ocular phenotype. Ocular abnormalities in individuals with CAKUT suggest a genetic basis for the disease and sometimes indicate the affected gene. Individuals with CAKUT often have ocular abnormalities and may require an ophthalmic review, monitoring, and treatment to preserve vision.

Evaluation of the results of urodynamic studies in patients with vesicoureteral reflux.

BACKGROUND: To investigate urodynamic abnormalities associated with vesicoureteral reflux (VUR) in toilet-trained children. METHODS: The data of 157 children who were diagnosed with vesicoureteral reflux and referred to our hospital between 2013 and 2022 were retrospectively examined. The urodynamic parameters were analyzed and correlated with age, gender, lower urinary tract symptoms (LUTS), reflux severity, and laterality. RESULTS: Overall, 131 (83.4%) patients had abnormal urodynamic findings with a male-to-female ratio of 1:1.4. The most common pathological finding was detrusor overactivity (DO), identified in 101 (64.3%) patients, followed by dysfunctional voiding (DV) in 74 (50.3%) patients. Children with VUR grades II and III exhibited a greater percentage of abnormal urodynamic findings than children with grades IV and V. The prevalence of DO was higher in children younger than 10 years old with unilateral and lower-grade VURs. DV was more frequent in children older than 10 years, with bilateral VUR, and higher grade VUR. The prevalence of LUTS, bowel and bladder dysfunction (BBD), and urinary tract infection (UTI) was higher among children with abnormal urodynamic findings. CONCLUSIONS: Children with VUR have a high incidence of urodynamic disorders. Urodynamic dysfunction may contribute to the pathogenesis of VUR, especially in mild cases.

Evidence-based clinical practice guideline for management of urinary tract infection and primary vesicoureteric reflux.

We present updated, evidence-based clinical practice guidelines from the Indian Society of Pediatric Nephrology (ISPN) for the management of urinary tract infection (UTI) and primary vesicoureteric reflux (VUR) in children. These guidelines conform to international standards; Institute of Medicine and AGREE checklists were used to ensure transparency, rigor, and thoroughness in the guideline development. In view of the robust methodology, these guidelines are applicable globally for the management of UTI and VUR. Seventeen recommendations and 18 clinical practice points have been formulated. Some of the key recommendations and practice points are as follows. Urine culture with > 104 colony forming units/mL is considered significant for the diagnosis of UTI in an infant if the clinical suspicion is strong. Urine leukocyte esterase and nitrite can be used as an alternative screening test to urine microscopy in a child with suspected UTI. Acute pyelonephritis can be treated with oral antibiotics in a non-toxic infant for 7-10 days. An acute-phase DMSA scan is not recommended in the evaluation of UTI. Micturating cystourethrography (MCU) is indicated in children with recurrent UTI, abnormal kidney ultrasound, and in patients below 2 years of age with non-E. coli UTI. Dimercaptosuccinic acid scan (DMSA scan) is indicated only in children with recurrent UTI and high-grade (3-5) VUR. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after UTI. Prophylaxis is recommended to prevent UTI in children with bladder bowel dysfunction (BBD) and those with high-grade VUR. In children with VUR, prophylaxis should be stopped if the child is toilet trained, free of BBD, and has not had a UTI in the last 1 year. Surgical intervention in high-grade VUR can be considered for parental preference over antibiotic prophylaxis or in children developing recurrent breakthrough febrile UTIs on antibiotic prophylaxis.

The Utility of Noninvasive Urinary Biomarkers for the Evaluation of Vesicoureteral Reflux in Children.

Vesicoureteral reflux (VUR) is one of the most important disorders encountered in pediatric nephrology due to its frequency and potential evolution to chronic kidney disease (CKD). The aim of our study was to identify noninvasive and easy-to-determine urinary markers to facilitate the diagnosis and staging of VUR. We performed a cross-section study including 39 patients with VUR followed over three years (August 2021-September 2023) and 39 children without urinary disorder (the control group). We measured the urinary concentration of interleukin-6 (IL-6), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in VUR and healthy controls. Moreover, we analyzed the correlation between these biomarkers and the presence of renal scars (RS), reflux nephropathy (RN), and CKD. The NGAL concentrations were significantly higher in patients with VUR than in the controls (p = 0.02). Regarding the severity of the reflux, NGAL/creatinine and LL-37/creatinine were positively correlated with severe reflux (p = 0.04, respectively, p = 0.02). In patients with VUR and RS, LL-37/creatinine was significantly lower (p = 0.01). LL-37/creatinine with an AUC of 0.71 and NGAL/creatinine with an AUC of 0.72 could be acceptable diagnostic tests for severe VUR. In conclusion, urinary IL-6, NGAL, and LL-37 could serve as valuable markers for diagnosing and predicting outcomes in patients with VUR and RN.

Pathogenesis and prognosis of intrarenal reflux.

Scar development in the children's renal cortex with vesicoureteral reflux (VUR) is one of the most important parameters of prognosis. It can develop regardless of the chosen treatment, even after the regression of VUR. The shape of the renal papillae, the ascending urinary tract infection, the greater than third-degree VUR, and finally the increased intra-calyceal pressure, induce the formation of renal scarring in the renal parenchyma. Renal scarring may complicate VUR independently of the therapeutic strategy (conservative or operative) and its regression. For restitution of this entity, many scientific terms have been used and the most common of them is intrarenal reflux (IRR). The effects of VUR on future renal function result from the limited ability of the affected kidney to grow (failure of renal growth) due to the existence of scars in the renal cortex, the worsening of these scars, or finally the creation of new scars. With the present study, we intend to clarify the etiology and the pathophysiology of IRR and the relation of VUR prognosis to newer biomarkers such as N-acetyl-beta-glycosaminidase, beta-2 microglobulin, Pen- traxin- 3 and Liver-type fatty-acid-binding protein.

Does previous endoscopic subureteric injection (STING) effect the outcomes of robot-assisted laparoscopic ureteral reimplantation surgery (RALUR) in children?

BACKGROUND: There is lack of evidence on the success of robot-assisted laparoscopic ureteral reimplantation (RALUR) for the treatment of vesicoureteral reflux (VUR) who had prior intervention. OBJECTIVE: This study aimed to evaluate the effect of previous unsuccessful STING on the outcomes of RALUR in children. STUDY DESIGN: A total of 67 children treated with RALUR by a single surgeon for the treatment of VUR were scanned between February 2018 and April 2022. Two patients were excluded from the final data analysis due to the presence of a megaureter. Patients were divided into two groups: those with a history of STING (Group A - n:14) and those without STING (Group B - n:51). Patient characteristics, previous numbers of injections, console time, total operative time, perioperative and postoperative complications and clinical success data were collected. Clavien Dindo and Satava complication scales were used as the standard record of peri and postoperative complications. Radiographic success was defined as absence of reflux detected on postoperative voiding cystourethrography, whereas clinical success was defined as the absence of a febrile urinary tract infection during the follow-up. Mann-Whitney U and Chi-square tests and Fisher exact test were used where appropriate. RESULTS: A total of 36 (55.3%) female versus 29 (44.6%) male patients were operated for 96 refluxive ureters. Nearly half of the patients were with bilateral VUR (n = 31). The mean follow-up was 20.2 ± 15.4 months. The median age of patients was 59 ± 31 (range: 28-132 months) versus 46 ± 33.1 (range: 7-206 months) for groups A and B respectively (p = 0.22). Gender, age, peri- and postoperative complication rates, and clinical success were comparable between the two groups. The median operative time and the console time was significantly higher in children with history of STING (op time: 142.5 ± 27.4 versus 120 ± 24.9 min (p = 0.008), console time: 117.5 ± 28.2 versus 100 ± 24.5 min (p = 0.011) for groups A and B, respectively. A total of six complications (9.2%) occurred with none of them were greater than Clavien grade 3b. The overall clinical success rate was 97%, with 2 cases of clinical failure. In both cases, VCUG demonstrated absence of VUR. DISCUSSION: The outcomes of our study provided that RALUR is effective with more than 95% success rates despite failed endoscopic injection procedures. CONCLUSION: The previous history of STING neither changes the success nor the complication rates of RALUR. However, this can lead to more challenging surgery by increasing the total operative times.