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The posterior urethral valve (PUV) is one of the main causes of congenital obstruction of the lower urinary tract in pediatrics. Its occurrence, although rare, can cause chronic kidney disease (CKD), with frequent progression to end stage kidney disease. Therefore, the development of new diagnostic strategies, such as biomarkers, is crucial to better assess the prognosis of patients with PUV. We aimed to review the literature on traditional and new biomarkers in PUV. For that, searches were performed in PubMed/MEDLINE, Scopus and SciELO databases. To systematize the search, terms such as "Posterior Urethral Valve", "Prognosis", "Biomarkers" and variations described in the Medical Subject Headings (MeSH) database were used. The literature showed new biomarkers of disease prognosis, with emphasis on inflammatory cytokines, proteomics and genomics techniques, as well as classic biomarkers, focusing on serum creatinine and urine osmolality. As for biomarkers recently described in the literature, the 12PUV, a set of 12 fetal urinary peptides that accurately predicted postnatal kidney function in fetuses with PUV, stands out. Similarly, oxidative stress markers, inflammatory cytokines and components of the renin-angiotensin system (RAS), when increased, were indicative of severe kidney outcomes. Genetic alterations also correlated to worse prognosis among patients with PUV, with emphasis on RAS polymorphisms and, specifically, those affecting the angiotensin-converting enzyme (ACE) and the angiotensin II receptors types 1 and 2 (AGTR1 and AGTR2) genes. Considering the severity of the PUV condition, the identification of sensitive and cost-effective biomarkers, beyond improving diagnosis, may favor the investigation of new therapeutic strategies.

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INTRODUCTION: Posterior urethral valve (PUV) is a congenital malformation characterized by a membranous structure located in the prostatic portion of the male posterior urethra that obstructs the urinary flow. Efforts have been made to determine the degree of impairment of fetal kidney function in this condition. OBJECTIVE: This study aimed to measure the levels of urinary biomarkers of glomerular and tubular functions in fetuses with PUV and to compare with the levels of the same molecules in healthy male premature newborns. STUDY DESIGN: Urine samples from 43 fetuses with PUVs were collected and compared with urine samples from 40 healthy male newborns of the same gestational age (controls). Tubular and glomerular biomarkers levels were measured in urine samples by MILLIPLEX® assay kits. Levels of the molecules were related to creatinine (Cr) measurements at same urine samples and expressed as pg/mg Cr. Results were analysed with Graphpad Prism version 7.0 and SPSS version 20.0. RESULTS: Fetuses with PUV showed a significant reduction in urine levels of Epidermal Growth Factor (EGF), Calbindin, Osteoactivin, Molecule Renal Injury 1 (KIM-1 and Factor of trefoil 3 (TFF-3) when compared to controls. On the other hand, urine levels of cystatin C and renin were higher in PUV fetuses. The levels of molecules also differed according to urine osmolality and grade of hydronephrosis. DISCUSSION: Some urinary excreted molecules may indicate kidney damage in several segments along the nephron, while others may exert important functions. Mechanical and immunological mechanisms related to PUV might significantly modulate the synthesis of cytokines related to glomerular and tubular physiology, leading to alterations in urinary concentrations of those molecules. These biomarkers can be used as future diagnostic and prognostic markers in clinical practice. CONCLUSION: Early kidney structural and functional impairment influenced the synthesis of glomerular and tubular molecules related to kidney physiological processes in fetuses with PUV.

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Abstract Objective: Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end‐stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. Methods: Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme‐linked immunosorbent assay. Results: Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang‐(1‐7) and angiotensin‐converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. Conclusions: Increased urinary levels of angiotensin‐converting enzyme 2 and of Ang‐(1‐7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve.

Resumo Objetivo: A válvula de uretra posterior é a obstrução do trato urinário inferior mais comum em crianças do sexo masculino. Uma alta porcentagem de pacientes com válvula de uretra posterior evolui para doença renal em estágio final. Estudos anteriores mostraram que citocinas, quimiocinas e componentes do sistema renina-angiotensina contribuem para o dano renal em uropatias obstrutivas. Recentemente, descobrimos que amostras de urina de fetos com válvula de uretra posterior tinham níveis aumentados de moléculas inflamatórias. O objetivo deste estudo foi medir as moléculas de renina-angiotensina e investigar sua correlação com marcadores inflamatórios previamente detectados nas mesmas amostras de urina de fetos com válvula de uretra posterior. Métodos: Amostras de urina de 24 fetos com válvula de uretra posterior foram coletadas e comparadas com amostras de urina de 22 recém-nascidos saudáveis de mesma idade gestacional (controles). Os níveis dos componentes de SRA foram medidos por ensaio de imunoabsorção enzimática. Resultados: Os fetos com válvula de uretra posterior apresentaram níveis urinários aumentados de angiotensina (Ang) I, Ang-(1-7) e enzima conversora de angiotensina 2 em comparação com os controles. Os níveis de enzima conversora de angiotensina eram significativamente menores e os níveis de Ang II eram semelhantes nos fetos com válvula de uretra posterior em comparação com os controles. Conclusões: O aumento dos níveis urinários de enzima conversora de angiotensina 2 e de Ang-(1-7) em fetos com válvula de uretra posterior poderia representar uma resposta regulatória ao intenso processo inflamatório desencadeado pela válvula de uretra posterior.

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OBJECTIVE: Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end-stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. METHODS: Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme-linked immunosorbent assay. RESULTS: Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang-(1-7) and angiotensin-converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. CONCLUSIONS: Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-(1-7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve.

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BACKGROUND: The aim of this cross-sectional study was to investigate inflammatory biomarkers in urine samples of 24 fetuses with posterior urethral valve (PUV) collected at 22 ± 4 weeks of gestation and to compare the findings with measurements in urine samples of 22 male healthy preterm neonates at 23 ± 4 weeks (control group). METHODS: Inflammatory biomarkers in urine were measured using a cytometric bead array [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, soluable tumor necrosis factor receptor (TNFR) 1, sTNFR2, monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2), eotaxin/CCL11 and interferon gamma-induced protein/10/C-X-C motif chemokine 10 (IP-10/CXCL10)] and ELISA assays [TNF, IL-8/CXCL8 and transforming growth factor-beta (TGF-ß)]. The Mann-Whitney test was used to compare medians. Markers of glomerular (creatinine) and tubular [beta 2 (ß2)-microglobulin, uromodulin, osmolality] functions were correlated with inflammatory biomarkers (Spearman test). RESULTS: An intense inflammatory profile was identified, with significantly increased concentrations of urinary IL-2, IL-4, IL-6, TNF, sTNFRI, sTNFRII, IFN-γ, MCP-1/CCL2, eotaxin/CCL11 and IL-8/CXCL8 in the PUV group compared to the controls. The same was observed for the anti-inflammatory cytokine IL-10 and for the fibrogenic mediator TGF-ß. In the correlation analysis, ß2-microglobulin positively correlated with the presence of MCP-1/CCL2, sTNFRI and eotaxin/CCL11 and negatively correlated with the presence of creatinine. CONCLUSIONS: This study shows that inflammatory molecules are already increased in fetuses with PUV at the mean gestational age of 22 weeks, suggesting a physiopathological role for inflammation just after the embryological formation of the urethral membrane.

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A literatura relata somente alguns casos de recém-nascidos com ascite urinária, geralmente secundária a ruptura de bexiga urinária e não de um cálice renal. Este relato de caso descreve um caso raro de ascite urinária em recém-nascido com válvula de uretra posterior que teve ruptura de um cálice renal, neste caso diagnosticada, até onde sabemos, pela primeira vez por ultrassonografia.

The literature reports only rare cases of urinary ascites, usually secondary to rupture of the bladder and not to renal calyx rupture. The present report describes an uncommon case of posterior urethral valve in a newborn with ascites caused by the rupture of a renal calyx that, to our knowledge, was diagnosed for the first time by ultrasonography.

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A válvula de uretra posterior é a principal causa de obstrução do fluxo urinário na infância. Relatamos um caso de válvula de uretra posterior diagnosticada por uretrocistografia e ultra-sonografia, cuja função renal foi poupada devido a incomuns mecanismos redutores das pressões endovesicais.Seu diagnóstico e tratamento precoces foram decisivos no prognóstico do paciente.

The posterior urethral valve is the main cause of urinal flow obstructionin childhood. Here we report a case of a posterior urethral valve diagnosed by urethrocystography and ultrasonography,whose renal function was saved due to unusual reducing mechanisms of endovesical pressures. The diagnosis and early treatment were decisive in the prognosis of the patient.

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