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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. [ABSTRACT FROM AUTHOR]

Our study aimed to investigate the association between the characteristics of patients/images and complete remission of renal scarring shown in the first chronic phase Technetium-99m dimercaptosuccinic acid (DMSA) renal scintigraphy images in children with urinary tract infection (UTI). Fifty children, who underwent the chronic phase of DMSA scintigraphy more than twice following UTI diagnosis and had renal scarring in the first chronic phase DMSA renal scintigraphy, were enrolled. They were classified into 2 groups: with and without complete remission of renal scarring on the second chronic phase DMSA renal scintigraphy. Renal scarring was classified into 3 grades based on severity per the image findings. Seven cases had complete remission from renal scarring. There were significant differences in age and severity. Renal scarring might be completely reversed in young children without severe findings on DMSA renal scintigraphy. Additional chronic phase examination may aid in follow-up completion and patients' peace of mind. [ABSTRACT FROM AUTHOR]

Background: Childhood urinary tract infection (UTI) can cause renal scarring, and possibly hypertension, chronic kidney disease (CKD), and end-stage renal failure (ESRF). Previous studies have focused on selected populations, with severe illness or underlying risk factors. The risk for most children with UTI is unclear. Aim: To examine the association between childhood UTI and outcomes in an unselected population of children. Design and setting: A retrospective population-based cohort study using linked GP, hospital, and microbiology records in Wales, UK. Method: Participants were all children born in 2005–2009, with follow-up until 31 December 2017. The exposure was microbiologically confirmed UTI before the age of 5 years. The key outcome measures were renal scarring, hypertension, CKD, and ESRF. Results: In total, 159 201 children were included; 77 524 (48.7%) were female and 7% (n = 11 099) had UTI before the age of 5 years. A total of 0.16% (n = 245) were diagnosed with renal scarring by the age of 7 years. Odds of renal scarring were higher in children by age 7 years with UTI (1.24%; adjusted odds ratio 4.60 [95% confidence interval [CI] = 3.33 to 6.35]). Mean follow-up was 9.53 years. Adjusted hazard ratios were: 1.44 (95% CI = 0.84 to 2.46) for hypertension; 1.67 (95% CI = 0.85 to 3.31) for CKD; and 1.16 (95% CI = 0.56 to 2.37) for ESRF. Conclusion: The prevalence of renal scarring in an unselected population of children with UTI is low. Without underlying risk factors, UTI is not associated with CKD, hypertension, or ESRF by the age of 10 years. Further research with systematic scanning of children's kidneys, including those with less severe UTI and without UTI, is needed to increase the certainty of these results, as most children are not scanned. Longer follow-up is needed to establish if UTI, without additional risk factors, is associated with hypertension, CKD, or ESRF later in life. [ABSTRACT FROM AUTHOR]

This update of the guidelines on vesicoureteral reflux (VUR) in children emphasises the importance of treating bladder and bowel dysfunction (BBD) if/when present. Although the current literature does not provide any reliable information regarding the duration of continuous antibiotic prophylaxis (CAP) in VUR patients, a practical approach might be to consider CAP until BBD resolution. 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. A structured literature review was performed for all relevant publications published from the last update up to March 2022. 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. This summary of the updated 2023 EAU/ESPU guidelines provides practical considerations for the management and diagnostic evaluation of VUR in children. 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. 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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the role of heavy ipsilateral scarring in the development of the contralateral reflux after unilateral reimplantation. Materials and Methods: The study included 43 patients (24 male, 19 female) who had undergone unilateral reimplantation. Heavy scarring was defined as the presence of multiple central scars on renal scan and differential function of less than 30% with diffuse paraenchymal damage. Postoperative voiding cystourethrography was performed to evaluate febrile urinary tract infection or hydronephrosis during follow-up. The development of the contralateral reflux was compared based on the type of reimplantation, age, preoperative renal scar status, and reflux grade. Results: Contralateral reflux developed in 6 children. No significant relationship was found between the pre-operative grade, type of reimplantation, and incidence of the contralateral reflux. However, de novo contralateral reflux was significantly higher in children with heavy scarring on the ipsilateral kidney. Among the five children with heavy kidney scarring and aged 4 years or younger, contralateral reflux was found in three children. Reflux was resolved within 24.6±12.2 months on average although one child recovered with Dx/HA implantation. Conclusion: We found that the presence of heavy scarring in the ipsilateral kidney may play a role in the prediction of contralateral reflux development.

Abstract Background The best way to assess renal cortical scarring is planar scintigraphy with 99mTc-dimercaptosuccinic acid (DMSA), while the value of single-photon emission computed tomography/computed tomography (SPECT/CT) is not well validated. The aim of the present study was to assess the value of planar, SPECT, and SPECT/CT scanning using 99mTc-DMSA in detecting renal cortical scarring. Methods Patients with clinically suspected renal cortical scar were included in this prospective cohort. 99mTc-DMSA Planar images were obtained approximately 3–4 h after intravenous injection (IV) of 185 MBq of the tracer. SPECT/CT scans were obtained immediately after the planar ones. An expert nuclear medicine doctor who was unaware of the patient's clinical history or any previous imaging results analyzed the images. Each kidney was given a score of 0 for no obvious defects, 1 for equivocal lesions, 2 for a single defect, 3 for several defects, and 4 for non-visualized/non-functioning kidney (in CT images). The results of each method were then compared to each other. Results One hundred eighty-six kidneys from ninety-three individuals were eligible for assessment. Planar scans detected 21 kidneys with equivocal lesions, 5 with single and 7 with multiple defects. SPECT scans detected 17 kidneys with single and 40 with multiple defects, while SPECT/CT scans revealed 5 with single and 11 with multiple defects. Only 5 of the 17 kidneys with single defects diagnosed by SPECT imaging had a scar in the SPECT/CT scans, whereas the remaining 12 had a solitary cortical cyst in the CT images. Only 11 of 40 kidneys with multiple defects on SPECT were shown to have a scar in the corresponding SPECT/CT images, whereas the rest matched to either hydro-nephrotic changes or multiple cortical cysts. Four kidneys with multiple defects on the SPECT/CT images were normal in the planar readings, were ascribed to an increase in renal background activity and a reduction in renal function. Conclusions In cases with suspected renal cortical scar, 99mTc-DMSA SPECT/CT scanning outperformed both planar and SPECT imaging by reducing the number of false-positive SPECT readings and false-negative planar readings.

Background: The best way to assess renal cortical scarring is planar scintigraphy with 99mTc-dimercaptosuccinic acid (DMSA), while the value of single-photon emission computed tomography/computed tomography (SPECT/CT) is not well validated. The aim of the present study was to assess the value of planar, SPECT, and SPECT/CT scanning using 99mTc-DMSA in detecting renal cortical scarring. Methods: Patients with clinically suspected renal cortical scar were included in this prospective cohort. 99mTc-DMSA Planar images were obtained approximately 3–4 h after intravenous injection (IV) of 185 MBq of the tracer. SPECT/CT scans were obtained immediately after the planar ones. An expert nuclear medicine doctor who was unaware of the patient's clinical history or any previous imaging results analyzed the images. Each kidney was given a score of 0 for no obvious defects, 1 for equivocal lesions, 2 for a single defect, 3 for several defects, and 4 for non-visualized/non-functioning kidney (in CT images). The results of each method were then compared to each other. Results: One hundred eighty-six kidneys from ninety-three individuals were eligible for assessment. Planar scans detected 21 kidneys with equivocal lesions, 5 with single and 7 with multiple defects. SPECT scans detected 17 kidneys with single and 40 with multiple defects, while SPECT/CT scans revealed 5 with single and 11 with multiple defects. Only 5 of the 17 kidneys with single defects diagnosed by SPECT imaging had a scar in the SPECT/CT scans, whereas the remaining 12 had a solitary cortical cyst in the CT images. Only 11 of 40 kidneys with multiple defects on SPECT were shown to have a scar in the corresponding SPECT/CT images, whereas the rest matched to either hydro-nephrotic changes or multiple cortical cysts. Four kidneys with multiple defects on the SPECT/CT images were normal in the planar readings, were ascribed to an increase in renal background activity and a reduction in renal function. Conclusions: In cases with suspected renal cortical scar, 99mTc-DMSA SPECT/CT scanning outperformed both planar and SPECT imaging by reducing the number of false-positive SPECT readings and false-negative planar readings. [ABSTRACT FROM AUTHOR]

To review the urological outcomes of proactive versus delayed management of children with a neurogenic bladder (NB). We performed a literature search on EMBASE, MEDLINE, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials between January 1, 2000 to August 21, 2023 for studies investigating the management of spina bifida-associated NB in pediatric patients (0–18 years of age). Proactive management was defined as use of clean intermittent catheterization, and/or anticholinergics at presentation, or based on initial high-risk urodynamic findings by 1 year of age. Delayed management was defined as beginning management after 1 year of age or no intervention. Outcomes included incidence or diagnosis of secondary vesicoureteral reflux (VUR), urinary tract infection (UTI), and renal deterioration, which included renal scarring, loss of differential renal function on a nuclear scan, or a decrease in renal function defined by glomerular filtration rate or serum creatinine estimation. Forest plots were synthesized using the Inverse Variance method with random-effect model. The Risk of Bias was assessed using the ROBINS-I tool. We included 8 observational studies on 652 pediatric patients with spina bifida-associated NB (mean follow-up - 7 years). Proactive management following initial assessment was associated with significantly lower risks of secondary VUR (OR 0.37 [0.19, 0.74], p = 0.004), non-febrile UTI (OR 0.35 [0.19, 0.62], p = 0.0004), and renal deterioration (OR 0.31 [0.20, 0.47], p < 0.00001). Delayed management of NB potentially has 3 times higher risks of secondary VUR, non-febrile UTI, and renal deterioration. However, the evidence is limited by the high risk of bias due to lack of randomization and standardized reporting in observational studies. While further well-defined prospective studies with long-term follow-up should be conducted to confirm this finding, this study supports the EAU/ESPU recommendations for early intervention in children with NB. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction : Renal scarring is prominently observed in children with vesicoureteral reflux (VUR) and can lead to complicated renal outcomes. Although biopsy is the gold standard to detect renal scarring, it is an invasive procedure. There are established renal biomarkers which can help detect renal scarring. Individual biomarkers have not shown to have extensively good discriminatory ability for this. Aim: This paper aims at combining the values of multiple biomarkers in models to detect renal scarring. Methodology: Secondary data with the values of renal biomarkers like kidney injury molecule-1, neutrophil gelatinase–associated lipocalin (NGAL), and urinary creatinine along with the renal scarring status was considered. Logistic regression, discriminant analysis, Bayesian logistic regression, Naïve Bayes, and decision tree models were developed with these markers. The discriminatory ability of individual biomarkers along with the models was assessed using the area under the curve from ROC curve. Sensitivity, specificity, and misclassification rates were estimated and compared. Results: NGAL was the most predominant renal biomarker in classifying the patients with renal scarring (AUC: 0.77 (0.67, 0.87); p value < 0.001). Each of the model performed better than individual biomarkers. Decision tree (AUC: 0.83 (0.74, 0.91); p value < 0.001) and Naïve Bayes model (misclassification rate = 20.2%) performed the best amongst the models. Conclusion: Combining the values of renal biomarkers through a statistical or machine learning model to detect renal scarring is a better approach as compared to considering individual renal biomarkers. [ABSTRACT FROM AUTHOR]

Long-term adult outcomes of children diagnosed with urinary tract dilatation (UTD) and vesicoureteral reflux (VUR) are not clearly documented in the literature. Likewise, follow-up protocols for these patients as they transition through adolescence and into adulthood vary with institution and cultures. Several studies have shown that individuals diagnosed with VUR in childhood are at higher risk of urinary tract infection (UTI) throughout their lives, even in the setting of prior VUR resolution or surgical correction. This is particularly relevant in patients with renal scarring, who are at higher risk of UTIs, hypertension and renal function deterioration in pregnancy. The risk of adverse maternal and fetal outcomes in pregnancy are higher for women with significant chronic kidney disease (CKD). Patients who underwent endoscopic injection or reimplantation should be counselled on the long-term particular risks associated with each intervention, including calcification of ureteric injection mounds, and the potential challenges of future endoscopic procedures following reimplantation. Although there is no evidence for the direct correlation between conservatively managed UTD in childhood, and symptomatic UTD diagnosed in adulthood, all patients should be aware of the long-term risks of persistent upper tract dilatation. Lastly, bladder-bowel dysfunction (BBD) management in adolescence can be more challenging and may contribute to symptomatic recurrence in this age group. [ABSTRACT FROM AUTHOR]

Background: Vesicoureteral reflux (VUR) is the most common congenital urinary tract abnormality in children. Renal parenchymal damage is the most devastating complication of severe undiagnosed VUR. Different diagnostic biomarkers have been introduced as alternatives for radiologic evaluation in these patients. This review article aimed to increase the knowledge about the role of urine neutrophil gelatinase-associated lipocalin (uNGAL) in children affected by primary VUR and renal parenchymal damage. Methods: A systematic review of PubMed, Scopus, Web of Science, ProQuest, and Ovid was conducted in September 2022 to retrieve studies that investigated the correlation between uNGAL or uNGAL/Cr excretion and primary VUR in male/female patients younger than 18 years of age. Patients with secondary VUR, age older than 18 years, infectious or inflammatory disorders, obstructive uropathies, and acute or chronic kidney diseases were excluded. Two reviewers independently screened the titles and abstracts of the search results and then assessed the full texts selected from the pertinent studies. Results: Eighteen research articles with a total sample of 699 patients were found to measure uNGAL in VUR or renal scarring. UNGAL or uNGAL/Cr had increased excretion in the majority of children with primary VUR or RPD, with a positive or no correlation to the severity of VUR. Conclusions: Several studies addressed uNGAL and uNGAL/Cr as putative biomarkers for the prediction of VUR or reflux-associated RPD.

Background. We aimed to detect complications and associated risk factors in patients with renal scarring (RS) secondary to recurrent urinary tract infections (UTI). Methods. Fifty patients with RS were compared with 25 patients without RS by means of, serum creatinine, 24-hour urinary creatinine clearance, and 24-hour urinary albumin levels. Office blood pressure (BP) examination and ambulatory BP monitoring (ABPM) were also performed. Results. Vesicoureteral reflux was detected in 50 patients. Glomerular filtration rate (GFR) <90 ml/min/1.73 m2 was observed in 5 patients with RS but in no patient without RS. Albuminuria was significantly higher in patients with bilateral RS and severe RS. Patients with albuminuria had a significantly lower GFR than those without. All patients with ambulatory hypertension (HT) were in the RS group, and 60% of those had isolated nocturnal HT. Compared to those without RS, patients with RS had significantly higher SDS values for all BP readings, 24-hour and nighttime systolic and diastolic BP loads with significantly lower systolic dipping. GFR was negatively correlated with diastolic BP SDS and diastolic BP load in patients with RS. Daytime diastolic BP load was significantly higher in those with severe RS than in those with mild RS. Conclusions. Isolated nocturnal HT could be an early sign of complications in RS of UTI. Albuminuria is related to increased BP and impaired renal function. Therefore, ABPM and assessing albuminuria should be a routine part of the follow-up. Diastolic BP elevations could be associated with worse outcomes in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Urinary Tract Infection (UTI) is a common problem in children. It is a very common cause of fever in children after gastrointestinal and respiratory diseases. Uropathogens causing community acquired UTI is increasing due to changing antibiotic sensitivity pattern over time. Appropriate choice of antibiotic is crucial to prevent complications related to UTI. Aim: To study the clinical profile, risk factors, associated pathogen spectrum and their antibiotic sensitivity pattern in community acquired UTI. Materials and Methods: A cross-sectional observational study with 150 sample size was conducted in the Department of Paediatrics, Gauhati Medical College and Hospital, Guwahati, Assam, India and was carried out among children (1 month to 12 years of age) with community acquired UTI, over a period of one year in the state of Assam. Fresh urine samples were collected by clean catch mid-stream method for toilet trained children and by transurethral catheterisation for infants and young children. It was followed by routine urine examination and culture and sensitivity testing to diagnose UTI. Descriptive statistics was used to describe the results. Proportion test was used for statistical evaluation. Results: Majority of UTI cases were in the age group 1 to 5 years (57.3%) and there was female preponderance (59.3%). Fever was the most common presentation (55.3% cases) in the present study. This was followed by poor feeding (12.6%), lower abdominal pain (10.6%), failure to gain weight (10.6%). In urinalysis, 87 cases (58%) showed pyuria, 6 cases (4%) showed significant haematuria. Most prevalent uropathogens in the present study was Escherichia coli (E.coli) (66%cases), followed by Enterococcus sp. (16.7%), Klebsiella sp. (14%). E.coli had maximum sensitivity for nitrofurantoin (90.9%). It was followed by amikacin (80%), co-trimoxazole in 64.6% and gentamycin in 62.6% cases. Conclusion: All fever cases in children should be screened to rule out UTI. All UTI cases should undergo culture and sensitivity testing to determine the sensitivity pattern. [ABSTRACT FROM AUTHOR]

Introduction: Urinary Tract Infection (UTI) is a common problem in children. It is a very common cause of fever in children after gastrointestinal and respiratory diseases. Uropathogens causing community acquired UTI is increasing due to changing antibiotic sensitivity pattern over time. Appropriate choice of antibiotic is crucial to prevent complications related to UTI. Aim: To study the clinical profile, risk factors, associated pathogen spectrum and their antibiotic sensitivity pattern in community acquired UTI. Materials and Methods: A cross-sectional observational study with 150 sample size was conducted in the Department of Paediatrics, Gauhati Medical College and Hospital, Guwahati, Assam, India and was carried out among children (1 month to 12 years of age) with community acquired UTI, over a period of one year in the state of Assam. Fresh urine samples were collected by clean catch mid-stream method for toilet trained children and by transurethral catheterisation for infants and young children. It was followed by routine urine examination and culture and sensitivity testing to diagnose UTI. Descriptive statistics was used to describe the results. Proportion test was used for statistical evaluation. Results: Majority of UTI cases were in the age group 1 to 5 years (57.3%) and there was female preponderance (59.3%). Fever was the most common presentation (55.3% cases) in the present study. This was followed by poor feeding (12.6%), lower abdominal pain (10.6%), failure to gain weight (10.6%). In urinalysis, 87 cases (58%) showed pyuria, 6 cases (4%) showed significant haematuria. Most prevalent uropathogens in the present study was Escherichia coli (E.coli) (66%cases), followed by Enterococcus sp. (16.7%), Klebsiella sp. (14%). E.coli had maximum sensitivity for nitrofurantoin (90.9%). It was followed by amikacin (80%), co-trimoxazole in 64.6% and gentamycin in 62.6% cases. Conclusion: All fever cases in children should be screened to rule out UTI. All UTI cases should undergo culture and sensitivity testing to determine the sensitivity pattern.

Objective  Ribonuclease 7 (RNase 7) is one of the members of the antimicrobial peptides playing a role in maintaining urinary tract sterility. We aimed to investigate the predictive value of the urine RNase 7 levels in children with pyuria and associations between RNase 7 and vesicoureteral reflux (VUR) and renal scarring. Methods  This study included 109 children with pyuria (46 febrile urinary tract infections [UTIs], 38 nonfebrile UTIs, and 25 sterile pyuria) whose RNase 7 levels were measured by enzyme-linked immunoassay. The results for urine RNase 7 concentrations were expressed as micrograms per milligrams creatinine. Results  RNase 7/Cr levels were higher in patients with both febrile and nonfebrile UTIs than the patients with sterile pyuria (p  = 0.001). RNase 7/Cr had predictive values of diagnosis of febrile and nonfebrile UTIs (cut-off value: 2.92 µg/mg, p  = 0.003; cut-off value: 3.67 µg/mg, p  < 0.001, respectively). RNase 7/Cr had higher levels in the patients with VUR than without VUR (cut-off value: 4.28 µg/mg, p  = 0.037). The patients with renal scarring had higher urine RNase 7/Cr than those without scarring (cut-off value: 4.54 µg/mg, p  = 0.041). Conclusion  The evaluation of RNase 7/Cr may help prevent unnecessary and/or inappropriate antibiotic use in children with pyuria. The higher RNase 7 levels in patients with VUR and renal scarring may reflect long-term inflammation or greater inflammatory response during acute infection. [ABSTRACT FROM AUTHOR]

Abstract Background Midregional-proadrenomedullin (MR-proADM) is a useful prognostic peptide in severe infectious pathologies in the adult population. However, there are no studies that analyze its utility in febrile urinary tract infection (fUTI) in children. An accurate biomarker would provide an early detection of patients with kidney damage, avoiding other invasive tests like renal scintigraphy scans. Our objective is to study the usefulness of MR-proADM as a biomarker of acute and chronic renal parenchymal damage in fUTI within the pediatric population. Methods A prospective cohort study was conducted in pediatric patients with fUTI between January 2015 and December 2018. Plasma and urine MR-proADM levels were measured at admission in addition to other laboratory parameters. After confirmation of fUTI, renal scintigraphy scans were performed during the acute and follow-up stages. A descriptive study has been carried out and sensitivity, specificity and ROC curves for MR-proADM, C-reactive protein, and procalcitonin were calculated. Results 62 pediatric patients (34 female) were enrolled. Scintigraphy showed acute pyelonephritis in 35 patients (56.5%). Of those patients, the median of plasmatic MR-proADM (P-MR-proADM) showed no differences compared to patients without pyelonephritis. 7 patients (11.3%) developed renal scars (RS). Their median P-MR-proADM levels were 1.07 nmol/L (IQR 0.66–1.59), while in patients without RS were 0.48 nmol/L (0.43–0.63) (p

PURPOSE. SOURCES OF INFORMATION. Urinary tract infection (UTI) is the second most common infection in children, the most important complication of which is renal scarring. The aim of present study was to evaluate the prevalence of renal scarring after UTI in children through systematic review and meta-analysis. METHODS. The international databases of Science Direct, PubMed, Scopus, and Web of Science and the Google Scholar search engine were searched using standard keywords. The sources found were from 2010 to 2020 and the search stage was updated until 2021.02.16. Data were analyzed using STATA-14 software and the significance level was considered at P<0.05. RESULTS. In 29 studies with a sample size of 9,986 children, the prevalence of renal scarring in children was estimated at 35% (95% CI: 29-41). Also, the prevalence of renal scarring was in girls 61% (95% CI: 40-81) and in boys 34% (95% CI: 11-57). The prevalence of unilateral renal scarring in children was 56% (95% CI: 48-65) and bilateral renal scarring was 31% (95% CI: 14-48). In addition, the prevalence of scar was 54% in children with reflux and 12% in children without vesicoureteral reflux. CONCLUSIONS. More than one third of people under the age of 18 after UTI have renal scarring. The prevalence of this complication in girls is about 2 times higher than that in boys and in people with reflux, it is about 4 times higher than people who do not have urinary reflux. Also, about half of people under the age of 18 suffer from unilateral renal scarring and about one third of them suffer from bilateral renal scarring. [ABSTRACT FROM AUTHOR]

Children with vesicoureteral reflux (VUR) are at an increased risk of recurrent urinary tract infections (UTIs) and renal scarring. Gut microbiota are associated with disease phenotypes, but there has been no study that associates urinary microbiota (uMB) and metabolic profiles with VUR pathology. To identify dominant uMB genera and metabolites associated with UTIs in VUR, urine samples collected under sterile conditions underwent 16S ribosomal RNA sequencing (n = 49) and metabolomic analysis by mass spectrometry (n = 96). Alterations in uMB and metabolomic profiles in VUR patients suggest remodeling of urinary bacterial communities after UTIs: Dorea - and Escherichia -dominant uMB profiles were more frequently identified in participants with VUR. Prevotella - and Lactobacillus -dominant uMB profiles were more prevalent in controls (p < 0.001). Microbial composition varied based on recurrent febrile UTI status (p = 0.001). A total of 243 urinary metabolites involved in energy, amino acid, nucleotide, and lipid metabolism were altered in VUR patients with UTIs (p < 0.05). Importantly, VUR specimens revealed changes in the bacteria-associated metabolic pathways such as glutamate degradation, methyl-citrate cycle, and bile acid metabolism. Differences in urinary commensal bacteria and metabolites exist between children with and without vesicoureteral reflux (VUR). These changes may be utilized to identify patients at risk of VUR-associated kidney damage. We identified differences in urinary microbiota and metabolic profiles of patients with vesicoureteral reflux (VUR) versus controls. These included alterations in amino acid, energy, lipid, and bile acid metabolism. Such changes persisted in VUR patients even after the resolution of urinary tract infections. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study is to evaluate the clinical utility of late 6-month dimercapto-succinic acid (DMSA) renal scan in predicting vesicoureteral reflux (VUR) and long-lasting renal scars in children with first acute pyelonephritis (APN). Methods A retrospective case study of children admitted with APN from January 2010 to July 2017 was performed. The study included patients with voiding cystourethrography (VCUG) and acute and late 6-month DMSA scan. We analyzed the clinical, laboratory and imaging findings of patients with and without late cortical defects at 6 months and those with or without VUR. Results Among 145 children with APN, 50 (34.5%) had cortical defects on the late DMSA renal scan and 60 (41.4%) showed VUR. Thirteen of 38 (34.2%) children undergoing 18-month DMSA renal scan showed a long-lasting renal scars. Compared with children without late cortical defects, patients with late 6-month cortical defects had a higher incidence of VUR and long-lasting renal scars, and relapse of UTI (all P

Abstract Background In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as “point of no return” leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. Methods Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. Results Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-β1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. Conclusions This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as “point of no return” leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.

Objectives: Vesicoureteral reflux (VUR) exacerbates the risk of renal scarring by establishing a ground for pyelonephritis. It is known that the inflammatory process is more influential than the direct damage caused by bacterial infection in the development of renal scars after pyelonephritis. Therefore, the present study aims to investigate the relationship between renal scarring and systemic inflammatory markers in patients with VUR. Material and methods: Hundred and ninety-two patients (116 females, 76 males) diagnosed with VUR were divided into two groups based on the presence or absence of renal scarring and into three groups according to the grade of VUR (low, moderate and high). Neutrophil count, lymphocyte count, mean platelet volume (MPV) and neutrophil-to-lymphocyte ratio (NLR) were compared among the groups. Results: Of the 192 patients, 102 had renal scarring. The age and gender distribution did not differ significantly between the groups with and without renal scarring (p > 0.05). However, the grade of reflux and lymphocyte count were significantly higher in the group with renal scarring (p < 0.05), and the NLR was significantly lower in the group with renal scarring (p < 0.05). The lymphocyte count was significantly higher (p < 0.05) and NLR was significantly lower in the high-grade VUR group (p < 0.05). However, MPV values did not differ significantly (p > 0.05) between the groups. Conclusions: NLR can be used to predict renal scarring in patients with VUR, especially in the period of 3-6 months after the first attack of infection, and may even serve as a candidate marker for treatment selection. However, larger series and prospective studies are needed.

Background: Midregional-proadrenomedullin (MR-proADM) is a useful prognostic peptide in severe infectious pathologies in the adult population. However, there are no studies that analyze its utility in febrile urinary tract infection (fUTI) in children. An accurate biomarker would provide an early detection of patients with kidney damage, avoiding other invasive tests like renal scintigraphy scans. Our objective is to study the usefulness of MR-proADM as a biomarker of acute and chronic renal parenchymal damage in fUTI within the pediatric population.Methods: A prospective cohort study was conducted in pediatric patients with fUTI between January 2015 and December 2018. Plasma and urine MR-proADM levels were measured at admission in addition to other laboratory parameters. After confirmation of fUTI, renal scintigraphy scans were performed during the acute and follow-up stages. A descriptive study has been carried out and sensitivity, specificity and ROC curves for MR-proADM, C-reactive protein, and procalcitonin were calculated.Results: 62 pediatric patients (34 female) were enrolled. Scintigraphy showed acute pyelonephritis in 35 patients (56.5%). Of those patients, the median of plasmatic MR-proADM (P-MR-proADM) showed no differences compared to patients without pyelonephritis. 7 patients (11.3%) developed renal scars (RS). Their median P-MR-proADM levels were 1.07 nmol/L (IQR 0.66-1.59), while in patients without RS were 0.48 nmol/L (0.43-0.63) (p < 0.01). The AUC in this case was 0.92 (95% CI 0.77-0.99). We established an optimal cut-off point at 0.66 nmol/L with sensitivity 83.3% and specificity 81.8%.Conclusion: MR-ProADM has demonstrated a poor ability to diagnose pyelonephritis in pediatric patients with fUTI. However, P-MR-proADM proved to be a very reliable biomarker for RS prediction. [ABSTRACT FROM AUTHOR]

Abstract. The vesicoureteral reflux (VUR) provokes development of nephrosclerosis in 48% of children with connective tissue dysplasia. Aim: Detection of clinical significance of biological markers of fibrogenesis (TGF-β1) and indices of collagen metabolism urine excretion in children with chronic pyelonephritis after conservative, endoscopic and operative correction of VUR for predicting the development of renal scarring was the aim of this trial. Material and Methods. 69 patients from 2 to 16 years with various variants of VUR (II-V grade) repair in a period of clinical-laboratory remission of pyelonephritis were examined. Results. We have found a significantly higher TGF-β1 (р

Background: Renal scarring is a serious complication in recurrent urinary tract infections (UTIs). Vitamin D deficiency has also been reported to be a risk factor for UTIs although, to date, no association between vitamin D deficiency and renal scarring has yet been identified. In the present study, it was investigated whether vitamin D deficiency may be a risk factor for renal scarring in patients with recurrent UTIs. Methods: The study included patients between the ages of 1 and 18 years who were admitted to the pediatric nephrology department of the center between November 1, 2018 and November 1, 2019 and who were diagnosed with recurrent UTIs. The medical records of the patients were reviewed for the collection of demographic data, vitamin D levels, ultrasonography results and scintigraphic investigations with 99m‐technetium dimercaptosuccinic acid (99mTc‐DMSA). The patients were divided into two groups: those with and without renal scarring, diagnosed via 99mTc‐DMSA. The vitamin D levels and other parameters of the two groups were compared. Results: Vitamin D deficiency (<20 ng/mL) was observed in 73.9% of the patients without renal scarring, and in 94.1% of those with renal scarring (P = 0.015). A logistic regression analysis revealed vitamin D deficiency to be an independent risk factor for renal scarring in patients with recurrent UTIs (OR = 0.796 [0.691–0.917]). Conclusions: Vitamin D deficiency is found to be a risk factor for renal scarring in patients with recurrent UTIs. Vitamin D treatment may contribute to the prevention of renal scarring in patients with recurrent UTI. [ABSTRACT FROM AUTHOR]

Objectives: Functional urinary incontinence is often associated with recurrent urinary tract infection (UTI), vesicoureteral reflux (VUR), and renal scarring. This study aims to evaluate the correlations between urodynamic findings and recurrence of UTI, VUR, and renal scarring in children with functional incontinence. Methods: In this retrospective observational study, data on the presence of VUR, urodynamics and 99Tc‐dimercaptosuccinic acid scintigraphy findings, and episodes of febrile UTI were obtained from patientsʼ records. The patients had at least 3 years of follow‐up. Results: There were significant associations between recurrence of UTI and decreased bladder capacity (hazard ratio: 1.321, P =.028). The receiver operator characteristic curve analysis showed a cutoff value for compliance of 13.25 mL/cmH2O for renal scarring (P =.000). There was a significant association between bladder wall thickening and VUR (odds ratio: 2.311, P =.008). The compliance had a cutoff value of 14.7 mL/cm H2O (P =.023) for severe VUR. The frequency of renal scarring was higher in patients with severe VUR and dysfunctional voiding (P =.001 and P =.041, respectively). The independent risk factors for renal scarring were low compliance, severe VUR, and dysfunctional voiding in children with functional incontinence, but recurrence of febrile UTI was not a risk factor for renal scarring. Decreased bladder capacity was a risk factor for recurrence of febrile UTI. Conclusions: The present study suggests that low compliance, severe VUR, and dysfunctional voiding, but not the recurrence of febrile UTI, are the independent risk factors for renal scarring in children with functional incontinence, and decreased bladder capacity is the risk factor for the recurrence of febrile UTI. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review will hopefully serve as a brief update on the current approaches to vesicoureteral reflux (VUR) within the context of historical approaches to this disorder and dispelling some of the myths surrounding its treatment. There is also greater focus on certain populations with VUR that may (or may not) be at particular risk. Recent Findings: Despite several large studies showing the benefit of antibiotic prophylaxis in preventing infections in VUR, there continues to be conflicting results in smaller scale studies or in regard to renal scarring that prevent its accepted use universally. Some of these conflicting results are a product of comparing a mixed population of individuals, as there are certain populations that seem to benefit from antibiotic prophylaxis and for which it should be considered. Similarly, surgical correction of VUR is not beneficial for many individuals even within certain higher risk populations, such as higher grade VUR, pre-pubertal females, and renal transplant recipients. Summary: Preceding febrile infections and the presence of renal scarring are two indicators of higher risk individuals. However, renal scarring in some individuals may not be secondary to infections. Therefore, an individualized approach to each patient with VUR is needed, with some needing treatment by surgery, some needing antibiotic prophylaxis, some needing optimal bladder care, and even others needing treatment of the sequelae of renal scarring. [ABSTRACT FROM AUTHOR]

Abstract Renal scarring after pyelonephritis is linked to long‐term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti‐androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post‐infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)‐like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non‐androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC‐like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.

Background. Vesicoureteral reflux (VUR) is observed in 1–2 % of children’s population, and its incidence among children with urinary infection achieves 70 %. The objective of this study was to assess the urine levels of transforming growth factor b1 (TGF-b1) and vascular endothelial growth factor (VEGF) as noninvasive markers of VUR and renal parenchymal scarring in children. Materials and methods. Fifty four patients aged 6 months to 16 years with III–V degrees of VUR after endoscopic treatment in a period of clinical and laboratory remission of pyelonephritis were examined. Urine TGF-b1 and VEGF concentrations were measured using commercially kit Platinum ELISA (Austria), according to the manufacturer’s instructions. Results. We have found a significantly higher urine TGF-b1 and VEGF level in children with VUR than in children of control groups (рc–1 = 0.000125 and рc–2 = 0.000081; рc–1 = 0.0000 and рc–2 = 0.000021, respectively). Median urinary TGF-b1 level in patients with VUR and renal scarring was significantly higher than in those with VUR without renal scarring (р1–2 = 0.0269). Median urinary VEGF level in patients with VUR and renal scarring was significantly lower than in individuals with VUR without renal scarring (р1–2 = 0.0163). When studying TGF-b1 and VEGF urine levels, it was found that the Kruskal-Wallis criterion was highly statistically significant, therefore, the statistical characteristics of the corresponding indices differed significantly in the various groups. Conclusions. Thus, levels of urinary excretion of biomarkers of fibrogenesis and angiogenesis can be used as markers for renal parenchymal scarring in children with VUR.

Renal scarring after pyelonephritis is linked to long‐term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti‐androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post‐infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)‐like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non‐androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC‐like cells and the Gli1 + activated myofibroblasts that are responsible for scarring. [ABSTRACT FROM AUTHOR]

Background: In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. Methods: Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. Results: Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-β1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. Conclusions: This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury. [ABSTRACT FROM AUTHOR]

We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis; a matching fraction of mice 1 month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5 months post-treatment; hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.

Current management of vesicoureteral reflux (VUR) in children is the result of a steady albeit controversial evolution of data and thinking related to the clinical impact of VUR and urinary tract infection (UTI) in children, the value of clinical screening, and the relative impact of testing and interventions for VUR. While controversy continues, there is consensus on the importance of bladder dysfunction on VUR outcomes, the likelihood of VUR resolution, and the fact that not all children with VUR require active treatment. Early efforts to define risk stratification hold the most promise to provide more patient-specific treatment of UTI and VUR in children.