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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. [ABSTRACT FROM AUTHOR]

Vesicoureteral reflux is a common congenital renal-urinary tract anomaly and causes f-UTI. In turn, f-UTI causes scarring of the renal parenchyma, which may affect future renal function. Reflux nephropathy is defined as vesicoureteral reflux accompanied by renal parenchymal damage. We review the current knowledge of reflux nephropathy and discuss how to reduce the number of pediatric patients with end-stage renal failure in the next 10 years. [ABSTRACT FROM AUTHOR]

Resumen: Objetivo: La nefropatía de reflujo es el término radiológico que se utilizó para expresar la existencia de lesiones morfológicas renales en pacientes con reflujo vesicoureteral (RVU). Este concepto morfológico se acuñó a partir de los datos de imagen recogidos, aunque sin realizar estudios complementarios básicos de función renal. Este estudio se diseñó para demostrar que las pruebas de función renal básicas muestran resultados distintos en presencia de RVU activo y una vez desaparecido. Pacientes y métodos: Estudio descriptivo retrospectivo longitudinal en el que se incluyeron 89 niños (46 V, 43 M) con RVU diagnosticado mediante cistouretrografía miccional seriada. Las pruebas básicas de función renal recogidas fueron la osmolalidad urinaria máxima (UOsm) y los cocientes urinarios albúmina/creatinina y NAG/creatinina. Los datos acopiados correspondían a dos momentos: al diagnosticarse el RVU y cuando ya se había curado. Resultados: Se comprobaron diferencias cuantitativas en los tres parámetros funcionales al comparar los correspondientes a ambos momentos del estudio. En el análisis cualitativo, en relación con la intensidad del RVU, se apreciaron diferencias en UOsm al diagnóstico y en el cociente albúmina/creatinina una vez desaparecido el RVU. En este último momento se observó un aumento significativo en el cociente albúmina/creatinina en los pacientes con pérdida de parénquima renal en relación con aquellos sin lesiones morfológicas residuales. Conclusiones: El defecto en la capacidad de concentración renal es el hallazgo más frecuente en niños con RVU activo (auténtica nefropatía de reflujo), mientras que una vez curado el RVU la alteración funcional más frecuente es el aumento de la excreción de albúmina, en relación con el daño residual existente en el parénquima renal. Puesto que la alteración funcional es diferente en los niños con RVU activo y cuando ya no está presente, no se debería utilizar el mismo término para ambas situaciones puesto que, aunque próximas, son entidades distintas. El término nefropatía displásico-cicatricial reflejaría mejor las características de estos pacientes una vez curado el RVU. Abstract: Objectives: Reflux nephropathy is a radiologic condition commonly used to express the existence of renal morphological lesions in patients who have or had vesicoureteral reflux (VUR). This morphological concept is used based on the image data collected, without conducting basic complementary renal function studies. The present study was designed to demonstrate that patients with active VUR present different functional renal alterations from those shown by patients with disappeared VUR. Patients and methods: Longitudinal descriptive retrospective analysis including 89 children (46 M, 43 F) with VUR diagnosis through a standard voiding cystourethrogram (VCUG). The basic renal function tests collected were the maximum urinary osmolality (UOsm) and the urinary albumin/creatinine and NAG/creatinine ratios. The data collected corresponded to two moments, when VUR was diagnosed and when it had already disappeared. Results: Quantitative differences were verified in the three functional parameters when comparing those corresponding to both moments of the study. In the qualitative analysis, in relation to the intensity of the VUR, differences were observed in UOsm at diagnosis and in the albumin/creatinine ratio once the VUR had cured. At this last moment, a significant increase in the albumin/creatinine ratio was observed in patients with loss of renal parenchyma in relation to those without residual morphological lesions. Conclusions: Concentrating ability defect is the most frequent finding in children with active reflux (true reflux nephropathy), whereas the most frequent functional disturbance found, once VUR has cured, is an increase in urinary albumin excretion, related to parenchymal damage. The term dysplastic-scarring nephropathy, could be more appropriate for patients with residual morphological lesions and impaired renal function, once VUR is cured.

Vesicoureteral reflux is the most common urinary tract abnormality among children, estimated to be present in approximately 1-2% of them. There are various possibilities of evolution, from asymptomatic forms with spontaneous remission to recurrent acute pyelonephritis, reflux nephropathy, or even end-stage chronic kidney disease. Therefore, the early diagnosis, with a correct staging, is essential, allowing the optimal therapeutic approach. The most common clinical situations requiring imaging investigation of vesicoureteral reflux are repeated urinary tract infections, fetal hydronephrosis, familial vesicoureteral reflux, bladder bowel dysfunction, and complex uropathies. The therapeutic management is decided according to the reflux severity, the clinical manifestations, and the patient’s age. The main objectives of the treatment are to prevent urinary tract infections, the development of renal scars, and the progression toward chronic kidney disease. The therapeutic approach may involve active follow-up, continuous antibiotic prophylaxis, or surgical intervention. Active follow-up applies to asymptomatic patients with an increased likelihood of spontaneous remission. Antibiotic prophylaxis is the most frequently adopted approach, used in patients with previous urinary tract infections and high-grade reflux. The surgical approach is reserved for cases with a low probability of spontaneous remission and for those with unfavorable evolution under conservative treatment. The surgical methods used are represented by endoscopic injection of an antireflux substance, classical or robotically assisted surgery, with similar success rates. Currently, there is no consensus regarding the therapeutic approach to these patients, the pediatrician being the one who must evaluate each case and propose and individualized therapeutic management adapted to the needs of each patient. [ABSTRACT FROM AUTHOR]

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.

Epidermolysis bullosa (EB) is a rare and genetically heterogeneous disorder characterized by skin fragility and blister formation occurring spontaneously or after minor trauma. EB is accompanied by congenital absence of skin (EB with CAS) in some patients. Pathogenic variants of COL7A1 are responsible for EB with CAS in the vast majority of cases. Type and subtype diagnosis of EB with CAS generally requires specific immunohistological examinations that are not widely available plus targeted gene analysis. The present study aimed to determine the clinical features of five patients affected by EB with CAS and to identify the underlying genetic defects using whole exome sequencing (WES) followed by focused analysis of the target genes. Four patients had generalized skin involvement and one had localized defects. Two patients exhibited extremely severe skin manifestations and congenital cloudy cornea along with pyloric atresia, and one had partial esophagogastric obstruction and anuria due to vesicoureteric obstruction. In the WES analysis, the average coverage of the target exons was 99.05% (726 of 733 exons), with a range of 96.4–100% for individual genes. We identified four novel and two known pathogenic/likely pathogenic variants of five distinct genes in the examined families: PLEC :c.2536G > T (p.Glu846Ter); LAMC2 :c.3385C > T (p.Arg1129Ter); KRT5 :c.429G > A (p.Glu477Lys); ITGB4: c.794dupC (p.Ala266SerfsTer5); COL7A1 :c.5440C > T (p.Arg1814Cys); and COL7A1 :c.6103delG. All alleles were inherited from the parents, except for the KRT5 variant as a de novo finding. The findings reveal extremely rare phenotypes found in EB with CAS, namely congenital cloudy cornea, esophagogastric obstruction, and anuria, and extend the genotypic spectrum of EB-related genes. The data confirm that WES provides very high coverage of coding exons/genes and support its use as a reasonable alternative method for diagnosis of EB. The present data from an underrepresented population in Southeast Asia could further broaden the knowledge and research on EB. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa (EB) is a rare and genetically heterogeneous disorder characterized by skin fragility and blister formation occurring spontaneously or after minor trauma. EB is accompanied by congenital absence of skin (EB with CAS) in some patients. Pathogenic variants of COL7A1 are responsible for EB with CAS in the vast majority of cases. Type and subtype diagnosis of EB with CAS generally requires specific immunohistological examinations that are not widely available plus targeted gene analysis. The present study aimed to determine the clinical features of five patients affected by EB with CAS and to identify the underlying genetic defects using whole exome sequencing (WES) followed by focused analysis of the target genes. Four patients had generalized skin involvement and one had localized defects. Two patients exhibited extremely severe skin manifestations and congenital cloudy cornea along with pyloric atresia, and one had partial esophagogastric obstruction and anuria due to vesicoureteric obstruction. In the WES analysis, the average coverage of the target exons was 99.05% (726 of 733 exons), with a range of 96.4–100% for individual genes. We identified four novel and two known pathogenic/likely pathogenic variants of five distinct genes in the examined families: PLEC:c.2536G > T (p.Glu846Ter); LAMC2:c.3385C > T (p.Arg1129Ter); KRT5:c.429G > A (p.Glu477Lys); ITGB4:c.794dupC (p.Ala266SerfsTer5); COL7A1:c.5440C > T (p.Arg1814Cys); and COL7A1:c.6103delG. All alleles were inherited from the parents, except for the KRT5 variant as a de novo finding. The findings reveal extremely rare phenotypes found in EB with CAS, namely congenital cloudy cornea, esophagogastric obstruction, and anuria, and extend the genotypic spectrum of EB-related genes. The data confirm that WES provides very high coverage of coding exons/genes and support its use as a reasonable alternative method for diagnosis of EB. The present data from an underrepresented population in Southeast Asia could further broaden the knowledge and research on EB.

Background: Infections in renal allograft recipients, especially urinary tract infections (UTI), are an essential factor leading to an increase in morbidity, graft failure, and degrading the health-related quality of life. Aims and Objectives: Our objective is to assess the causes, risk factors, microbiological profile, and antibiotic sensitivity pattern of UTI in renal transplant recipients. Material and Methods: It was a prospective observational study, conducted at the Department of Nephrology, Sir Gangaram Hospital, New Delhi, India. Three hundred ten renal transplant recipients were enrolled. Results: Out of 300 transplant recipients, 107 (35.6%) had UTI. The mean age of patients with UTI was 32 ± 10.5 years. Females have a higher incidence of UTI than males. 64.5% of all diabetic patients had UTI. Escherichia coli (41%) was the most common causative agent. Gram-negative bacilli attributed the majority (88.5%) of cases. Klebsiella pneumonia was found to be multidrug-resistant in most cases. 61% of patients with reflux kidney disease before transplant suffered from UTI. Conclusion: On multivariate analysis in our study, diabetes (P=0.01), prolonged urethral catheterization (p=0.002), and double J stent kept in situ (p=0.03) and reflux kidney disease before transplant (p < 0.02) were independently associated with UTI prolonged.

Reflux nephropathy is defined as 'renal scarring' associated with vesica-ureteral reflux (VUR) and consists of calyceal clubbing or deformity with overlying corticomedullary scarring. The older terms chronic pyelonephritis and chronic atrophic pyelonephritis should be strictly defined as a persistent or recurrent bacterial infection of the kidney involving the renal parenchyma and the pelvi-calyceal system with exudation of inflammatory cells.

Background: Infections in renal allograft recipients, especially urinary tract infections (UTI), are an essential factor leading to an increase in morbidity, graft failure, and degrading the health-related quality of life. Aims and Objectives: Our objective is to assess the causes, risk factors, microbiological profile, and antibiotic sensitivity pattern of UTI in renal transplant recipients. Material and Methods: It was a prospective observational study, conducted at the Department of Nephrology, Sir Gangaram Hospital, New Delhi, India. Three hundred ten renal transplant recipients were enrolled. Results: Out of 300 transplant recipients, 107 (35.6%) had UTI. The mean age of patients with UTI was 32 ± 10.5 years. Females have a higher incidence of UTI than males. 64.5% of all diabetic patients had UTI. Escherichia coli (41%) was the most common causative agent. Gram-negative bacilli attributed the majority (88.5%) of cases. Klebsiella pneumonia was found to be multidrug-resistant in most cases. 61% of patients with reflux kidney disease before transplant suffered from UTI. Conclusion: On multivariate analysis in our study, diabetes (P=0.01), prolonged urethral catheterization (p=0.002), and double J stent kept in situ (p=0.03) and reflux kidney disease before transplant (p < 0.02) were independently associated with UTI prolonged. [ABSTRACT FROM AUTHOR]

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of end-stage kidney failure in the young. However, there is limited information on long-term outcomes after kidney transplantation in this group. We explored the outcomes of kidney transplant in patients with the 3 most common severe forms of CAKUT: posterior urethral valves (PUV), reflux nephropathy and renal hypoplasia/dysplasia. Methods: Data were extracted from the Australian & New Zealand Dialysis & Transplant Registry on first kidney transplants performed between 1985 and 2015 in recipients with a primary diagnosis of PUV, renal hypoplasia/dysplasia or reflux nephropathy (under the age of 30 years). Using multivariate Cox regression, we compared death-censored graft survival between the three groups. Results: One hundred twenty-seven patients with PUV, 245 with hypoplasia/dysplasia and 727 with reflux nephropathy were included. A 10-year graft survival in PUV, hypoplasia/dysplasia and reflux nephropathy was 70%, 76% and 70%, respectively and a 20-year graft survival was 30%, 53% and 49%. After adjusting for age at transplant, graft source and HLA matching, there was evidence for poorer graft survival in PUV (HR, 1.65; 95% CI, 1.15 to 2.38). Conclusions: Graft survival of the first transplant in CAKUT is favourable at 10 years; however, recipients with PUV have increased risk of graft loss beyond a 10-year post-transplant, which may be related to bladder dysfunction. [ABSTRACT FROM AUTHOR]

Vesicoureteral reflux is a common disorder in children but can result in kidney scarring following acute pyelonephritis. The gold standard diagnostic to detect renal scars in children is 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. DMSA has a number of limitations including radiation exposure, need for sedation, and radiotracer supply shortages. Contrast-enhanced ultrasound (CEUS) is a technique whereby biocompatible microspheres of inert gas are administered i.v. that reflect ultrasonography sound waves and do not involve radiation. Because the contrast agent is rapidly cleared, contrast images must be obtained within minutes of administration. CEUS has been used in a variety of organ systems, but its use in pediatric kidney diseases is limited. Methods: In this study, we performed CEUS in 7 children with documented renal scars by radiographic imaging consistent with reflux nephropathy. Results: In all subjects, CEUS detected all previously known radiologic abnormalities as well as detecting new areas of hypoenhancing renal parenchyma. None of the patients experienced any serious adverse events. Discussion: This study represents the first report of using CEUS to characterize renal scars in children with reflux nephropathy. We conclude that CEUS is a highly sensitive, rapid, and cost-effective diagnostic imaging modality for detecting and monitoring renal scars in children with vesicoureteral reflux.

Vesicoureteral reflux (VUR) is the most common uropathy in childhood which leads to increased frequency of urinary tract infection (UTI) and renal scarring. Connective tissue growth factor (CTGF) plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. The aim of this study was to investigate the relation between urinary CTGF and renal damage resulted from VUR. This cross sectional study included 70 patients with VUR and 62 healthy sex and age matched children. Urinary creatinine and CTGF (uCTGF) concentrations were analysed in all cases and CTGF to creatinine ratio were calculated. The records of radiologic evaluations of the patients including ultrasound, voiding cystouretrography and 99m-technetium dimercaptosuccinic acid (DMSA) scintigraphy were obtained retrospectively. The patient group was further divided into two groups according to the existence of renal cortical scarring in the DMSA scan. The study consisted of three groups; Group 1 (control group) 62 children, Group 2 (VUR positive, scar negative) 24 patient, Group 3 (VUR positive, scar positive) 46 patient (VUR+scar). The medians of uCTGF and uCTGF to creatinine ratio of the three groups were significantly different (p <0.001). Pairwise group comparisons revealed that Group 1 had significantly lower uCTGF level and uCTGF/creatinine ratio, as compared to Groups 2 and 3 (p <0.001 and p=0.002, respectively). There was no statistically significant difference between Groups 2 and 3 (p=0.052). uCTGF is significantly increased in children with VUR, independent on the presence of renal scarring. Increased uCTGF, even in the absence of the renal scarring, could be interpreted as development and a progression of glomerular and tubulointerstitial fibrosis in vesicoureteral reflux. Further experimental and clinical investigations are required to fully elucidate the mechanism of CTGF in vesicoureteral reflux. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to assess renal outcomes of delayed diagnosis of dilating primary vesicoureteral reflux (VUR) following recurrent febrile urinary tract infections (fUTIs) and its diagnostic imaging procedures. Material and methods: The medical records of patients who underwent ultrasonography (US), non-acute dimercaptosuccinic acid (Tc-99mDMSA) scintigraphy and voiding cystourethrography (VCUG), and who were older than 2 years at the time of VUR diagnosis were retrospectively reviewed. Results: A total of 32 children (female, n=27: 84.4%) with a mean age of 7.67±3.34 years at the time of diagnosis of VUR were included in the study. Grade III, IV, V VUR were found in 22%, 69%, and 9% of the patients, respectively. At the time of VUR diagnosis, abnormal US findings were detected in 75% of the cases. Tc-99mDMSA detected abnormalities in 83.9% (7 with a single scar, 7 with multiple lesions, 12 with reduced kidney function) of the patients. Estimated glomerular filtration rate of 3 patients with bilateral grade IV VUR was <75 mL/min/1.73 m². In 5 patients (16%), VUR could not be predicted by US+DMSA scintigraphy (Grade IV VUR in 3 and Grade III in 2 cases ). The sensitivity in predicting VUR was 75.00% (95% CI: 56.60-88.54) and 83.87% (95% CI: 66.27-94.55), respectively, for US alone and combined US+DMSA. Conclusion: VCUG should be performed routinely in addition to US and non-acute DMSA in all children referred with recurrent fUTIs. Awareness of childhood UTI in public and healthcare personnels should be increased in order to refer these patients at a early stage to pediatric urology and nephrology units. [ABSTRACT FROM AUTHOR]

Congenital anomaly of kidney and urinary tract (CAKUT) are one of the most frequent causes for chronic kidney disease in children. However, the underlying molecular mechanisms of CAKUT are still largely unknown and are subjects of the investigations. Cytokines are master regulatory molecules of immune system with a key role in development of protective or harmful immune response. Today, it is known that progression of the parenchymal damages in reflux nephropathy and obstructive uropathies are tightly related to the immune processes, including chronic inflammatory response and fibrosis. The aim of the present review is to summarize the knowledge for the role of cytokines in pediatric CAKUT, focused on obstructive uropathies, VUR and reflux nephropathy, and to discuss their potential role in nephrogenesis. In addition we elucidate clinical use of cytokines as biomarkers with diagnostic value and development of a new therapeutic approach. Some our studies on the role of cytokines in CAKUT were also discussed. Bases on our knowledge we may suggested that cytokines, particularly TGF-b, IL-10 and probably IL-12, are involved into the molecular mechanisms of renal damage in CAKUT during embryonic and postembryonic development. [ABSTRACT FROM AUTHOR]

The primary goal in the management of a child with urinary tract infection (UTI) is to prevent recurrence of UTI and acquired renal damage. Approximately 15% of children develop renal scarring after a first episode of febrile UTI. Vesico-ureteric reflux (VUR) is diagnosed in 30-40% of children imaged after first febrile UTI. The 'top-down' approach involving ultrasound and dimercaptosuccinic acid scan (DMSA) first after an appropriate interval following UTI, can help in avoiding voiding cystourethrogram (VCUG), an invasive test with higher radiation exposure. The majority view remains that VCUG should be done after the second attack of UTI in girls and first attack of UTI in boys. Although the evidence in favour of antibiotic prophylaxis remains doubtful in preventing renal scars associated with VUR, it remains the first line treatment for high-grade reflux (grade 3-5) with an aim to prevent UTI and allow spontaneous resolution of VUR. Early identification and appropriate treatment of associated bowel bladder dysfunction is an essential part of successful medical management of VUR. Endoscopic treatment of VUR, using a bulking agent, is useful in grade 3 VUR. The main controversy regarding intervention (endoscopic/open surgical intervention) involves absence of strong evidence for these interventions in reducing renal scarring on randomized controlled trials. However, several recent trials have found the surgical interventions to be effective in reducing recurrent pyelonephritis and repeated hospital admissions. [ABSTRACT FROM AUTHOR]