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.

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.

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.

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.

Posterior Urethral Valves, Unilateral Vesicoureteral Reflux, and Renal Dysplasia (VURD) Syndrome: Long-Term Longitudinal Evaluation of the Kidney Function.

The presence of unilateral vesicoureteral reflux (VUR), and renal dysplasia associated with posterior urethral valves (PUV) (VURD syndrome) was believed to represent a pressure-released pop-off mechanism protecting kidney function. We aimed to investigate its role with respect to long-term kidney function in a cross-sectional and longitudinal analysis. We compared the iohexol glomerular filtration rate (GFR) measured at 5 (GFR5) and 10 (GFR10) years of age in children with (Group A) and without (Group B) VURD syndrome, who underwent PUV resection under 2 years of age. VURD syndrome was diagnosed in cases of unilateral loss of kidney function (<15% on nuclear medicine test) associated with ipsilateral grade IV-V VUR. VURD syndrome was diagnosed in 16 (12.8%) out of 125 patients who met the inclusion criteria. While the median GFR5 was similar in the 2 groups [Group A: 87.3 (74.7-101.2) mL/min/1.73 m2 vs. Group B: 99.6 (77-113) mL/min/1.73 m2, p-value: 0.181], the median GFR10 values were significantly lower in children with VURD syndrome [Group A: 75.7 (71.2-85.9) mL/min/1.73 m2 vs. Group B: 95.1 (81.2-114.2) mL/min/1.73 m2, p-value: 0.009]. Similar results were obtained in a longitudinal analysis of the children with GFR measurement available both at 5 and 10 years of age [GFR5 in Group A: 93.1 (76.9-103.5) mL/min/1.73 m2 vs. Group B: 97.5 (80-113) mL/min/1.73 m2, p-value: 0.460; GFR10: Group A: 71.9 (71.9-85.9) mL/min/1.73 m2 vs. Group B: 94.8 (81.5-110.6) mL/min/1.73 m2, p-value: 0.024]. In conclusion, VURD syndrome does not show a protective role in kidney function preservation. On the contrary, it seems to be associated with a deterioration of the kidney function on a long-term follow-up.

Vesicoureteral Reflux: Current Care Trends and Future Possibilities.

Although investigations over the past 2 decades have improved our understanding of the natural history of vesicoureteral reflux (VUR) and helped identify those at higher risk of both VUR itself as well as its potential severe sequelae, debate exists regarding key aspects of care, including when to perform diagnostic imaging and which patients benefit from continuous antibiotic prophylaxis. Artificial intelligence and machine learning have the potential to distill large volumes of granular data into practical tools that clinicians can use to guide diagnosis and management decisions. Surgical treatment, when indicated, remains highly effective and is associated with low morbidity.

Destroyed bladders: Characterization of progressive inflammatory cystitis.

PURPOSE: We identified a subset of patients with noninfectious cystitis who develop refractory symptoms marked by diffuse inflammatory changes, reduced bladder capacity, and vesicoureteral reflux (VUR), termed here as "progressive inflammatory cystitis" (PIC). Our objective was to describe the phenotype, disease outcomes, and pathologic findings of PIC. MATERIAL AND METHODS: A single institution retrospective cohort study of patients with PIC. Patients with a history of pelvic radiation, urologic malignancy, or neurogenic bladder were excluded. We describe cohort characteristics and use bivariate analyses to compare subgroups. Kaplan-Meier methods estimate time to urinary diversion. RESULTS: From 2008 to 2020, 46 patients with PIC were identified. The median age of symptom onset was 63 years old (interquartile range [IQR]: 56, 70) and the most common presenting symptoms were urinary urgency/frequency (54%) and incontinence (48%). Urodynamics showed a median maximum bladder capacity of 80 mL (IQR: 34, 152), commonly with VUR (68%) and hydronephrosis (59%). Ultimately 36 patients (78%) underwent urinary diversion at a median of 4.5 years (IQR: 2, 6.5) after symptom onset. Significant pathologic findings include presence of ulceration (52%), acute and chronic inflammation (68%), including eosinophils (80%), lymphoid follicles (56%), and mast cells in both lamina and muscularis propria (76%). CONCLUSIONS: PIC is a newly defined entity characterized by significantly diminished bladder capacity, upper tract changes, and relatively quick progression to urinary diversion. Larger prospective cohort studies are required to further characterize this severe phenotype of chronic noninfectious cystitis, aid earlier diagnosis, and guide management decisions.

The Role of Urinary NGAL in the Management of Primary Vesicoureteral Reflux in Children.

Vesicoureteral reflux (VUR) is the most frequent congenital urinary tract malformation and an important risk factor for urinary tract infections (UTIs). Up to 50% of children with VUR may develop reflux nephropathy (RN), and the diagnosis and monitoring of renal scars are invasive and costly procedures, so it is paramount to find a non-invasive and accurate method to predict the risk of renal damage. Neutrophil gelatinase-associated lipocalin (NGAL) has already proven to be a good predictive biomarker in acute kidney injuries, but there are few studies that have investigated the role of NGAL in primary VUR in children. Our aim is to review the predictive value of urine NGAL (uNGAL) as a non-invasive biomarker of RN in children with primary VUR, as well as its ability to predict the evolution of chronic kidney disease (CKD). Based on our analysis of the available original studies, uNGAL can be an accurate and reliable biomarker of RN and its progression to CKD. Some studies suggested a good correlation between VUR severity and uNGAL levels, but other studies found no significant correlation. The relationship between VUR severity and uNGAL levels is likely complex and influenced by factors such as UTIs, the timing of the urine sample collection, and the age and overall health of the patient.

Spontaneous vesicoureteral reflux resolution curves based on ureteral diameter ratio.

INTRODUCTION: Various factors influence the clinical course of vesicoureteral reflux (VUR) in the pediatric population. Distal ureteral diameter ratio (UDR) is an objective measure reflective of ureterovesical junction anatomy that has been shown to independently predict both spontaneous resolution and breakthrough febrile urinary tract infection (UTI) in children with primary reflux. UDR resolution curves were created, hypothesizing that a UDR value existed at which spontaneous resolution was unlikely to occur. MATERIALS AND METHODS: UDR was computed by measuring largest ureteral diameter within the pelvis and dividing by the distance between L1-L3 vertebral bodies. Recursive partitioning with 10-fold cross validation methodology for time to event data, utilizing martingale residuals was used to create high and low risk groups based on UDR, and stratified by age at diagnosis and laterality. RESULTS: Three hundred and four patients (226 female, 78 male) were analyzed with a mean age at diagnosis of 1.55 ± 1.98 years. Unilateral reflux (p = 0.02), VUR grades 1-3 (p < 0.001), and lower UDR (p < 0.001) were associated with spontaneous resolution on univariate analysis. UDR values were categorized into risk groups based on recursive partitioning. Low risk patients (those with UDR <0.30) achieved VUR resolution faster and with a continuing rate compared to the high-risk group (≥0.30), which had persistent reflux after 3 years [Summary Figure]. When the 0.30 cutoff was applied randomly to patients in test group, the cutoff significantly discriminated between low and high-risk patients (log rank test p = 0.02). DISCUSSION: Primary VUR is often a self-limiting diagnosis, with conservative management favored in low-risk children, UDR may be used to help distinguish those children who may benefit from intervention. Unlike traditional VUR grading where children with any grade of reflux may spontaneously resolve, there appears to be a consistent UDR cutoff whereby patients are very unlikely to spontaneously resolve, regardless of length of follow-up. Therefore, parents of children with a UDR above the 0.3 cutoff, regardless of VUR grade, may be counselled that VUR is very unlikely to resolve over time - thereby reducing the number of VCUGs and length of time these patients are on prophylactic antibiotic prior to surgical intervention. CONCLUSIONS: Children with primary VUR and a UDR of greater than 0.30 are significantly less likely to spontaneously resolve regardless of length of follow-up, and resolution after 3 years was rare. UDR provides objective prognostic information facilitating individualized patient management.

The role of height and weight growth in spontaneous resolution of vesicoureteral reflux.

BACKGROUND: The aim of this study was to investigate the role of height and weight growth in the resolution of primary vesicoureteral reflux (VUR). METHODS: We retrospectively evaluated the data of 74 males and 135 females who were diagnosed with primary VUR. According to the vesicoureteral reflux resolution, patients were divided into two groups. Patients with complete or partial resolution of VUR were included in Group 1 and patients with no resolution of VUR were included in Group 2. Patients were evaluated for weight Z-score, height Z-score and body mass index at the diagnosis and in the follow-up. In addition, age, sex, grade of reflux and laterality were recorded. RESULTS: There were no significant differences between the two groups, according to height Z-score, weight Z-score and body mass index at the diagnosis, in the follow-up and also annual changes of these parameters. In addition, the same parameters did not significantly differ in Groups 1 and 2, between the initial and final evaluations. However, when we evaluate the patients older than 12 months old, weight Z-scores were significantly higher at the final evaluation than at the diagnosis, in Group 1. This significant difference was not detected in Group 2 at the same age. CONCLUSIONS: Although we could not detect the hectic pace of height growth as being important in the prediction of long-term outcomes of VUR, weight growth should be considered to predict the resolution of VUR.

Vesicoureteral Reflux Causes Interstitial Inflammation in Pediatric Kidney Allograft: A Clinicopathological Analysis of 1-Year Protocol Biopsies.

INTRODUCTION: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. METHODS: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. RESULTS: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. CONCLUSION: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

Utility of preoperative urine cultures and cystoscopies before ureteral reimplantation in pediatrics.

BACKGROUND: Ureteral reimplantation remains the primary surgical method used for patients with vesicoureteral reflux (VUR). Cystoscopy is commonly performed first to visualize anatomy and rule out possible abnormalities. Urine cultures may also be obtained. The objective of this study is to evaluate the prudency of preoperative urine cultures and cystoscopies in pediatric patients undergoing ureteral reimplantation. METHODS: Pediatric urologists were surveyed regarding collecting urine cultures in asymptomatic patients and cystoscopies before reimplantation. A retrospective review was also conducted of patients who underwent ureteral reimplantation for VUR between March 2018 and April 2021 at Cook Children's Medical Center. RESULTS: When physicians were asked the frequency they obtain urine cultures before reimplantation on asymptomatic patients, 36% said "never" and 38% said "always." Regarding cystoscopy, 53% said "never" and 32% said "always." Inclusion criteria were met by 101 patients. Cystoscopies were performed in 46 patients and never altered the reimplantation. There were 20 preoperative, 90 intraoperative, and 61 postoperative urine cultures. Complications were associated with positive cultures of urine collected intraoperatively and postoperatively only. CONCLUSION: Cystoscopies and asymptomatic urine cultures obtained before ureteral reimplantation provide no additional benefit while increasing cost for patients' families. Further research is needed to thoroughly identify the prudency of such practices in ureteral reimplantation for VUR.

The ureteral diameter ratio as a predictive factor in renal scarring associated with primary vesicoureteral reflux.

INTRODUCTION: The ureteral diameter ratio (UDR) is reported to be effective in predicting the outcomes of vesicoureteral reflux (VUR) in several studies. OBJECTIVE: The objective of the current study was to compare the risk of scarring in patients with VUR relative to UDR and the VUR grade. We also aimed to demonstrate other associated risk factors in scarring and investigate the long-term complications of VUR and their relationship with UDR. STUDY DESIGN: Patients diagnosed with primary VUR were retrospectively enrolled in the study. UDR was calculated by dividing the largest ureteral diameter (UD) by the distance between L1-L3 vertebral bodies. Demographic and clinical data, laterality, VUR grade, UDR, delayed upper tract drainage on voiding cystourethrogram, recurrent urinary tract infections (UTI), and long-term complications of VUR were compared between the patients with and without renal scars. RESULTS: A total of 127 patients and 177 renal units were included in the study. There was a significant difference between the patients with and without renal scars according to age at diagnosis, bilaterality, reflux grade, UDR, recurrent UTI, bladder bowel dysfunction, hypertension, decreased estimated glomerular filtration rate, and proteinuria. The logistic regression analysis revealed that UDR had the highest odds ratio among the factors affecting scarring in VUR. DISCUSSION: VUR grading based on the evaluation of the upper urinary tract is one of the most important predictors for treatment options and prognosis. However, it is more likely to reflect ureterovesical junctional anatomy and function, which play a crucial role in the pathogenesis of VUR. CONCLUSION: UDR measurement seems to be an objective method that can help clinicians predict renal scarring in patients with primary VUR.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.