The protective arm of the renin–angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves

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Os fetos com VUP apresentaram níveis urinários diminuídos da enzima conversora da angiotensina (ACE), sem alteração nos níveis de angiotensina (Ang) II em comparação com os controles. Por outro lado, os níveis de ACE2, Ang I e, especialmente, de Ang‐ (1‐7) foram maiores na urina de fetos com VUP do que nos controles. Esses resultados mostram uma ativação do braço contrarregulatório do SRA em VUP. Cada figura mostra a média e o erro padrão da média (EPM). *p < 0,05, teste de Mann‐Whitney." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Natalia P. Rocha, Fernando M. Bastos, Érica L.M. Vieira, Thiago R.R. Prestes, Katia D. da Silveira, Mauro M. Teixeira, Ana Cristina Simões e Silva" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Natalia P." "apellidos" => "Rocha" ] 1 => array:2 [ "nombre" => "Fernando M." "apellidos" => "Bastos" ] 2 => array:2 [ "nombre" => "Érica L.M." "apellidos" => "Vieira" ] 3 => array:2 [ "nombre" => "Thiago R.R." 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Rocha, Fernando M. Bastos, Érica L.M. Vieira, Thiago R.R. Prestes, Katia D. da Silveira, Mauro M. Teixeira, Ana Cristina Simões e Silva" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Natalia P." "apellidos" => "Rocha" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Fernando M." "apellidos" => "Bastos" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Érica L.M." "apellidos" => "Vieira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Thiago R.R." "apellidos" => "Prestes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Katia D. da" "apellidos" => "Silveira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Mauro M." "apellidos" => "Teixeira" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 6 => array:4 [ "nombre" => "Ana Cristina" "apellidos" => "Simões e Silva" "email" => array:1 [ 0 => "acssilva@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica (LIIM), Belo Horizonte, MG, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Serviço de Medicina Fetal, Belo Horizonte, MG, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Instituto de Ciências Biológicas, Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, Belo Horizonte, MG, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "O braço protetor do sistema renina-angiotensina pode contrapor-se ao intenso processo inflamatório em fetos com válvula de uretra posterior" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2847 "Ancho" => 2179 "Tamanyo" => 164640 ] ] "descripcion" => array:1 [ "en" => "Levels of renin–angiotensin system (RAS) components in urine samples from fetuses with posterior urethral valve (PUV) and in a control group comprised of healthy male newborns. Fetuses with PUV presented decreased urinary levels of angiotensin-converting enzyme (ACE) with no change in angiotensin (Ang) II levels in comparison with controls. In turn, ACE2, Ang I and, notably, Ang-(1-7) levels were higher in the urine of fetuses with PUV than controls. These results show an activation of the counter-regulatory arm of the RAS in PUV. Each figure shows the mean and the standard error of the mean (SEM). *p<0.05, Mann–Whitney test." ] ] ] "textoCompleto" => "IntroductionPosterior urethral valve (PUV) is a membranous structure in posterior urethra that obstructs the urinary outflow from the bladder<a class="elsevierStyleCrossRef" href="#bib0155">1</a> and can lead to chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> PUV can be diagnosed in utero; antenatal ultrasound findings of PUV include bilateral hydronephrosis, megacystis, and dilated posterior urethra in male fetuses.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> The obstruction of urinary outflow can result in oligohydramnios, which cause pulmonary hypoplasia, leading to early death.<a class="elsevierStyleCrossRefs" href="#bib0170">4,5</a>Advances in diagnosis and management of PUV resulted in a dramatic decrease in mortality.<a class="elsevierStyleCrossRef" href="#bib0180">6</a> A retrospective cohort of fetuses with severe lower urinary tract obstruction (LUTO) attending two centers between January 1990 and August 2013 showed that the antenatal diagnosis and interventions in PUV were effective in improving the survival rate and renal function.<a class="elsevierStyleCrossRef" href="#bib0185">7</a> These findings were further corroborated by another study showing that antenatal interventions resulted in a 13-fold increase in the six-month chance of survival.<a class="elsevierStyleCrossRef" href="#bib0180">6</a>PUV is frequently associated with lesions in renal parenchyma, including dysplasia or hypoplasia.<a class="elsevierStyleCrossRef" href="#bib0190">8</a> As a result, PUV patients may evolve to end-stage renal disease (ESRD).<a class="elsevierStyleCrossRef" href="#bib0195">9</a> The outcomes appear to be dependent on the kind and extent of prenatal kidney damage. The functional outcome of patients with prenatally detected PUV was described as considerably better than clinically presenting, i.e., the long-term prognosis of intermediate severity PUV might be improved by prenatal diagnosis.<a class="elsevierStyleCrossRef" href="#bib0200">10</a> It is worth mentioning that a significant proportion of PUV cases are not yet detected antenatally, presenting outside the neonatal period.<a class="elsevierStyleCrossRef" href="#bib0205">11</a> Altogether, these facts highlight the relevance of finding antenatal PUV diagnosis biomarkers.The precise pathophysiology of ESRD due to PUV is not completely understood. This research team is investigating the mechanisms of renal damage in obstructive uropathies. First, inflammatory molecules in urine samples from fetuses with PUV were measured; it was observed that fetuses with PUV present higher urinary levels of inflammatory molecules than controls.<a class="elsevierStyleCrossRef" href="#bib0210">12</a> The present study is the continuation of the abovementioned investigation. Herein, the authors measured renin–angiotensin system (RAS) components in the same urine samples. Experimental studies showed that RAS components may interact with inflammatory molecules in obstructive nephropathies.<a class="elsevierStyleCrossRefs" href="#bib0215">13,14</a> Obstructed kidneys also exhibited an elevation in angiotensin (Ang) II activity, which, in turn, decreases renal blood flow and causes ischemia and kidney growth arrest.<a class="elsevierStyleCrossRef" href="#bib0225">15</a> Therefore, the current study was designed to measure RAS molecules and to investigate its correlation with previously detected inflammatory markers<a class="elsevierStyleCrossRef" href="#bib0210">12</a> in the same urine samples of fetuses with PUV.MethodsThis study included 24 pregnant women whose fetuses were diagnosed with LUTO by antenatal ultrasonography. All fetuses underwent a detailed ultrasound scan aimed at detecting renal abnormalities, other malformations, and markers of aneuploidy, as detailed elsewhere.<a class="elsevierStyleCrossRef" href="#bib0175">5</a> The exclusion criteria were: (i) pregnant women with formal contraindication for invasive procedures; (ii) fetuses with chromosomal abnormalities; and (iii) fetuses presenting other malformation findings at ultrasonography. The study also included a control group of 22 healthy male preterm newborns matched by gestational age and by race/ethnicity with the fetuses with PUV at the time of urine collection. Preterm newborns with congenital malformations, infections and/or any acute illness at the time of urine sampling were excluded. The institutional Ethics Committee approved the study and all subjects (i.e., pregnant women or mothers of newborns) provided written informed consent.Following the protocol, all fetuses with LUTO were submitted to bladder puncture in order to measure renal function parameters, including urinary osmolality, creatinine and β2-microglobulin. Fetal urine samples were collected using a long length spinal needle (BD Biosciences – San Jose, United States). Renal function markers helped clinical decisions regarding pregnancy and the need of fetal interventions as previously described.<a class="elsevierStyleCrossRef" href="#bib0210">12</a> Briefly, fetal intervention was considered when there was severe LUTO at gestational ages between 16 and 34 weeks, in the presence of oligohydramnios (after 18 weeks) and normal renal function parameters (18–30 weeks of gestation), including the absence of bilateral renal dysplasia or renal cysts on ultrasonography and/or acceptable values in urinary biochemistry analysis.<a class="elsevierStyleCrossRefs" href="#bib0230">16–18</a>Urine samples from healthy male newborns were collected at the fifth day of life (control group) using a newborn urinary bag collector. All urine samples were centrifuged (1800g, 10min, 4°C) immediately after collection, and the supernatant was aliquoted and stored at −80°C until assayed.Samples were then thawed and urine levels of Ang I, Ang II, Ang-(1-7), angiotensin-converting enzyme (ACE), and ACE2 were measured by enzyme-linked immunosorbent assay (ELISA), according to the procedures supplied by the manufacturer (MyBioSource, San Diego, CA, United States). All kits applied sandwich ELISA technique, except for ACE measurement whose kit applied competitive ELISA method. The sensitivity of the assays was 1.0pg/mL for ACE and ACE2; 3.9pg/mL for Ang I; 2.0pg/mL for Ang-(1-7); and 18.75pg/mL for Ang II. The biochemical assessments were performed blindly regarding the clinical diagnosis.The software SPSS version 22.0 (SPSS Inc., Chicago, IL, United states) was used for statistical analysis. Gaussian distribution was assessed using the Shapiro–Wilk test. Patients and controls were compared with Mann–Whitney or Student's t-tests, when appropriate. Spearman's correlation analyses assessed the relationship between urinary levels of RAS components and previous measurements of inflammatory molecules in the same samples.<a class="elsevierStyleCrossRef" href="#bib0210">12</a> All statistical tests were two-tailed with significance level set at p<0.05.ResultsAt the time of urine collection, PUV fetuses (n=24) had a mean gestational time of 22±5 weeks, and male preterm newborns (n=22) were matched for gestational age (23±4 weeks). Regarding ethnicity, 14 PUV fetuses were white (58.3%), nine were mixed-race (37.5%), and one was black (4.2%). Among controls, 13 were white (59.1%), eight were mixed-race (36.4%) and one was black (4.5%). No statistical difference between cases and controls were found regarding gestational age (p=0.76) and ethnicity (p=0.85). As previously reported,<a class="elsevierStyleCrossRef" href="#bib0210">12</a> most of the patients with PUV had bilateral kidney hyperechogenicity (78%), oligohidramnio or anihidramnio (83%) in antenatal ultrasonography; 17 (71%) died at the neonatal period due to pulmonary hypoplasia. Patients with PUV who survived (n=7) underwent vesicostomy (n=5) or endoscopic valve ablation (n=2) within the first weeks after birth. All patients presented higher urinary levels of creatinine, β2-microglobulin and osmolality than controls.<a class="elsevierStyleCrossRef" href="#bib0210">12</a>Fetuses with PUV presented decreased urinary levels of angiotensin-converting enzyme (ACE) with no difference in Ang II levels in comparison with controls. In turn, ACE2, Ang I and, notably, Ang-(1-7) levels were higher in the urine of fetuses with PUV than controls (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Correlations were found between RAS components and inflammatory mediators. Among controls, urinary levels of ACE were positively correlated with interleukin (IL)-2 levels (rho=0.790, p=0.020). ACE2 levels were significantly associated with eotaxin/CCL11 (rho=0.807, p=0.015) and interferon gamma-inducible protein (IP-10)/CXCL10 (rho=0.707, p=0.050) levels. In addition, Ang-(1-7) levels were negatively correlated with ACE levels (rho=−0.810, p=0.015) and positively correlated with ACE2 levels (rho=0.946, p=0.000).Regarding patients with PUV, urinary levels of ACE correlated negatively with β2-microglobulin (rho=−0.491, p=0.033) and soluble tumor necrosis factor receptor (sTNFR)1 (rho=−0.466, p=0.038) levels. ACE2 levels were positively correlated with IL-4 levels (rho=0.512, p=0.025). In addition, Ang I levels were significantly associated with IL-1β (rho=−0.455, p=0.044) and tumor necrosis factor (TNF) (rho=−0.546, p=0.013) levels.DiscussionFetal urine has been regarded as an important pool of peptides that can predict postnatal renal function.<a class="elsevierStyleCrossRef" href="#bib0245">19</a> Klein et al. identified and validated 12 fetal urinary peptides (called 12PUV) as predictors of postnatal renal function with high sensitivity and specificity, outperforming routine methods.<a class="elsevierStyleCrossRef" href="#bib0245">19</a> The present study aimed not only at searching for biomarkers but also to investigate potential involvement of RAS molecules in PUV. It was observed that the profile of RAS components significantly differed in PUV fetuses when compared with healthy neonates. PUV fetuses had higher urinary concentrations of ACE2 and of Ang-(1-7) than healthy neonates, whereas ACE levels were lower in the urine of PUV fetuses than in the urine of healthy neonates.Currently, it has been proposed that RAS has two major arms: (i) the classical arm formed by ACE, Ang II, and AT1 receptor, and (ii) the counter-regulatory arm composed by ACE2, Ang-(1-7), and Mas receptor.<a class="elsevierStyleCrossRef" href="#bib0250">20</a> While the classical arm mainly activates pathways related to tissue injury and inflammation; in sharp contrast, the counter-regulatory RAS axis has anti-inflammatory effects.<a class="elsevierStyleCrossRef" href="#bib0255">21</a> Therefore, the observed increase of components of the protective RAS arm may represent a regulatory response to the intense inflammatory process triggered by PUV.<a class="elsevierStyleCrossRef" href="#bib0210">12</a> The present study not only demonstrated that patients with PUV present increased levels of ACE2 and Ang-(1-7) in tandem with decreased levels of ACE, but also observed significant correlations between the urinary levels of RAS components and inflammatory mediators. Noteworthy, ACE2 levels were associated with IL-4 levels and ACE levels significant correlated with sTNFR1 levels in urine samples of fetuses with PUV.Altogether, the present data reinforces the hypothesis that changes in the RAS occur in parallel with the inflammatory process triggered by PUV. Indeed, some evidence linked RAS to the pathophysiology of PUV. Chowdhury et al.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> showed that serum pro-renin was higher in PUV cases than in controls and declined after corrective surgery. There is experimental evidence that the classical RAS arm contributed to tubulointerstitial scarring in obstructive uropathies.<a class="elsevierStyleCrossRef" href="#bib0265">23</a>Mice with genetic deletion of AT1a receptors presented less severe tubulointerstitial fibrosis induced by unilateral ureteral obstruction, suggesting a role for the classical RAS axis in renal injury.<a class="elsevierStyleCrossRef" href="#bib0270">24</a> More recently, two experimental studies supported a protective role for Ang-(1-7).<a class="elsevierStyleCrossRefs" href="#bib0275">25,26</a> The first showed that, in obstructed kidneys from mice with genetic deletion of Mas receptor, apoptosis and macrophage infiltration were increased when compared with wild-type mice.<a class="elsevierStyleCrossRef" href="#bib0275">25</a> In the second, Kim et al.<a class="elsevierStyleCrossRef" href="#bib0280">26</a> reported that the infusion of Ang-(1-7) in rats who underwent unilateral ureteral obstruction decreased pro-apoptotic and pro-fibrotic protein expression. Taken together, previous and the present findings suggest that inflammatory and fibrotic pathways triggered by obstructive uropathies might stimulate local production of Ang-(1-7) as a compensatory mechanism in fetuses with PUV.A possible mechanism by which Ang-(1-7) may protect against kidney injury due to obstruction could be the reduction of AT1 receptors expression through Mas receptor activation. In this regard, it was reported that mRNA expression for AT1 receptor was higher in Mas knockout mice.<a class="elsevierStyleCrossRef" href="#bib0285">27</a> Indeed, Mas receptor acts as an AT1 receptor antagonist through the constitutive formation of hetero-oligomeric complexes.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> Another possible explanation for the elevation of ACE2 and Ang-(1-7) in the urine of fetuses with PUV could be a dysfunction or reduced expression of the Mas receptor at kidney tissue in PUV fetuses. In this regard, Ng et al. reported that Mas receptor expression is reduced in the kidneys of CKD rats and the administration of the uremic toxin indoxyl sulfate induced down-regulation of Mas receptor probably via up-regulation of TGF-β1 in proximal tubules.<a class="elsevierStyleCrossRef" href="#bib0295">29</a> Therefore, it can be hypothesized that an alteration in Mas receptor expression and/or signaling may contribute to renal injury in PUV fetuses.The present study has limitations, including its relatively small sample size, cross-sectional design, and the use of urine samples from preterm newborns as control. Since urine collection from fetuses is an invasive procedure, it was impossible to collect urine from healthy fetuses due to ethical reasons. One study has found increased urinary angiotensinogen-to-creatinine ratio in preterm neonates when compared with that in full-term neonates. The urinary angiotensinogen-to-creatinine ratio decreased significantly with increasing gestational age.<a class="elsevierStyleCrossRef" href="#bib0300">30</a> It is important to emphasize that, in order to rule out the effects of gestational age in RAS components concentrations, in the present study the control group was composed of preterm newborns matched by gestational age with fetuses with PUV at the time of urine collection.In conclusion, urinary tract obstruction leads to complex molecular interactions in an early timing; in utero interventions are sometimes performed when renal lesions were already irreversible. Many studies evidenced the role of RAS in obstructive uropathies. However, up to now, the protective RAS arm has never been investigated in fetuses with PUV. The present findings support a role for ACE2-Ang-(1-7)-Mas receptor in PUV that deserve further investigation.FundingThis study was supported by FAPEMIG (Grant # PPM-00555-15), CAPES and CNPq (Grant # 470472/2014-6 and Grant # 460334/2014-0), Brazil.Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1197728" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1116446" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1197727" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusões" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1116445" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack409660" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-12-06" "fechaAceptado" => "2018-02-06" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1116446" "palabras" => array:6 [ 0 => "Posterior urethral valve" 1 => "Renin–angiotensin system" 2 => "Angiotensin II" 3 => "Angiotensin-(1-7)" 4 => "ACE2" 5 => "Inflammation" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec1116445" "palabras" => array:6 [ 0 => "Válvula de uretra posterior" 1 => "Sistema renina-angiotensina" 2 => "Angiotensina II" 3 => "Angiotensina-(1-7)" 4 => "ACE2" 5 => "Inflamação" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivePosterior 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. MethodsUrine 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. ResultsFetuses 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. ConclusionsIncreased 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." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "ObjetivoA 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. MétodosAmostras 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. ResultadosOs 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. ConclusõesO 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." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusões" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Rocha NP, Bastos FM, Vieira ÉL, Prestes TR, Silveira KD, Teixeira MM, et al. The protective arm of the renin–angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves. J Pediatr (Rio J). 2019;95:328–33." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2847 "Ancho" => 2179 "Tamanyo" => 164640 ] ] "descripcion" => array:1 [ "en" => "Levels of renin–angiotensin system (RAS) components in urine samples from fetuses with posterior urethral valve (PUV) and in a control group comprised of healthy male newborns. Fetuses with PUV presented decreased urinary levels of angiotensin-converting enzyme (ACE) with no change in angiotensin (Ang) II levels in comparison with controls. In turn, ACE2, Ang I and, notably, Ang-(1-7) levels were higher in the urine of fetuses with PUV than controls. These results show an activation of the counter-regulatory arm of the RAS in PUV. 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/00217557/0000009500000003/v1_201905310725/S0021755717311646/v1_201905310725/en/main.assets" "Apartado" => array:4 [ "identificador" => "10179" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/00217557/0000009500000003/v1_201905310725/S0021755717311646/v1_201905310725/en/main.pdf?idApp=UINPBA000049&text.app=https://jped.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755717311646?idApp=UINPBA000049"]

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O braço protetor do sistema renina-angiotensina pode contrapor-se ao intenso processo inflamatório em fetos com válvula de uretra posterior

Natalia P. Rochaa, Fernando M. Bastosa,b, Érica L.M. Vieiraa, Thiago R.R. Prestesa, Katia D. da Silveiraa, Mauro M. Teixeiraa,c, Ana Cristina Simões e Silvaa,

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acssilva@hotmail.com

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a Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica (LIIM), Belo Horizonte, MG, Brazil

b Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Serviço de Medicina Fetal, Belo Horizonte, MG, Brazil

c Universidade Federal de Minas Gerais (UFMG), Instituto de Ciências Biológicas, Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, Belo Horizonte, MG, Brazil

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which cause pulmonary hypoplasia&#44; leading to early death&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Advances in diagnosis and management of PUV resulted in a dramatic decrease in mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> A retrospective cohort of fetuses with severe lower urinary tract obstruction &#40;LUTO&#41; attending two centers between January 1990 and August 2013 showed that the antenatal diagnosis and interventions in PUV were effective in improving the survival rate and renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> These findings were further corroborated by another study showing that antenatal interventions resulted in a 13-fold increase in the six-month chance of survival&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">PUV is frequently associated with lesions in renal parenchyma&#44; including dysplasia or hypoplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> As a result&#44; PUV patients may evolve to end-stage renal disease &#40;ESRD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> The outcomes appear to be dependent on the kind and extent of prenatal kidney damage&#46; The functional outcome of patients with prenatally detected PUV was described as considerably better than clinically presenting&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; the long-term prognosis of intermediate severity PUV might be improved by prenatal diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> It is worth mentioning that a significant proportion of PUV cases are not yet detected antenatally&#44; presenting outside the neonatal period&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Altogether&#44; these facts highlight the relevance of finding antenatal PUV diagnosis biomarkers&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The precise pathophysiology of ESRD due to PUV is not completely understood&#46; This research team is investigating the mechanisms of renal damage in obstructive uropathies&#46; First&#44; inflammatory molecules in urine samples from fetuses with PUV were measured&#59; it was observed that fetuses with PUV present higher urinary levels of inflammatory molecules than controls&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> The present study is the continuation of the abovementioned investigation&#46; Herein&#44; the authors measured renin&#8211;angiotensin system &#40;RAS&#41; components in the same urine samples&#46; Experimental studies showed that RAS components may interact with inflammatory molecules in obstructive nephropathies&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">13&#44;14</span></a> Obstructed kidneys also exhibited an elevation in angiotensin &#40;Ang&#41; II activity&#44; which&#44; in turn&#44; decreases renal blood flow and causes ischemia and kidney growth arrest&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> Therefore&#44; the current study was designed to measure RAS molecules and to investigate its correlation with previously detected inflammatory markers<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> in the same urine samples of fetuses with PUV&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This study included 24 pregnant women whose fetuses were diagnosed with LUTO by antenatal ultrasonography&#46; All fetuses underwent a detailed ultrasound scan aimed at detecting renal abnormalities&#44; other malformations&#44; and markers of aneuploidy&#44; as detailed elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> The exclusion criteria were&#58; &#40;i&#41; pregnant women with formal contraindication for invasive procedures&#59; &#40;ii&#41; fetuses with chromosomal abnormalities&#59; and &#40;iii&#41; fetuses presenting other malformation findings at ultrasonography&#46; The study also included a control group of 22 healthy male preterm newborns matched by gestational age and by race&#47;ethnicity with the fetuses with PUV at the time of urine collection&#46; Preterm newborns with congenital malformations&#44; infections and&#47;or any acute illness at the time of urine sampling were excluded&#46; The institutional Ethics Committee approved the study and all subjects &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; pregnant women or mothers of newborns&#41; provided written informed consent&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Following the protocol&#44; all fetuses with LUTO were submitted to bladder puncture in order to measure renal function parameters&#44; including urinary osmolality&#44; creatinine and &#946;<span class="elsevierStyleInf">2</span>-microglobulin&#46; Fetal urine samples were collected using a long length spinal needle &#40;BD Biosciences &#8211; San Jose&#44; United States&#41;&#46; Renal function markers helped clinical decisions regarding pregnancy and the need of fetal interventions as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> Briefly&#44; fetal intervention was considered when there was severe LUTO at gestational ages between 16 and 34 weeks&#44; in the presence of oligohydramnios &#40;after 18 weeks&#41; and normal renal function parameters &#40;18&#8211;30 weeks of gestation&#41;&#44; including the absence of bilateral renal dysplasia or renal cysts on ultrasonography and&#47;or acceptable values in urinary biochemistry analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Urine samples from healthy male newborns were collected at the fifth day of life &#40;control group&#41; using a newborn urinary bag collector&#46; All urine samples were centrifuged &#40;1800<span class="elsevierStyleHsp" style=""></span>g&#44; 10<span class="elsevierStyleHsp" style=""></span>min&#44; 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#41; immediately after collection&#44; and the supernatant was aliquoted and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until assayed&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Samples were then thawed and urine levels of Ang I&#44; Ang II&#44; Ang-&#40;1-7&#41;&#44; angiotensin-converting enzyme &#40;ACE&#41;&#44; and ACE2 were measured by enzyme-linked immunosorbent assay &#40;ELISA&#41;&#44; according to the procedures supplied by the manufacturer &#40;MyBioSource&#44; San Diego&#44; CA&#44; United States&#41;&#46; All kits applied sandwich ELISA technique&#44; except for ACE measurement whose kit applied competitive ELISA method&#46; The sensitivity of the assays was 1&#46;0<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for ACE and ACE2&#59; 3&#46;9<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for Ang I&#59; 2&#46;0<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for Ang-&#40;1-7&#41;&#59; and 18&#46;75<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for Ang II&#46; The biochemical assessments were performed blindly regarding the clinical diagnosis&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The software SPSS version 22&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; United states&#41; was used for statistical analysis&#46; Gaussian distribution was assessed using the Shapiro&#8211;Wilk test&#46; Patients and controls were compared with Mann&#8211;Whitney or Student&#39;s <span class="elsevierStyleItalic">t</span>-tests&#44; when appropriate&#46; Spearman&#39;s correlation analyses assessed the relationship between urinary levels of RAS components and previous measurements of inflammatory molecules in the same samples&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> All statistical tests were two-tailed with significance level set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">At the time of urine collection&#44; PUV fetuses &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; had a mean gestational time of 22<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5 weeks&#44; and male preterm newborns &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41; were matched for gestational age &#40;23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 weeks&#41;&#46; Regarding ethnicity&#44; 14 PUV fetuses were white &#40;58&#46;3&#37;&#41;&#44; nine were mixed-race &#40;37&#46;5&#37;&#41;&#44; and one was black &#40;4&#46;2&#37;&#41;&#46; Among controls&#44; 13 were white &#40;59&#46;1&#37;&#41;&#44; eight were mixed-race &#40;36&#46;4&#37;&#41; and one was black &#40;4&#46;5&#37;&#41;&#46; No statistical difference between cases and controls were found regarding gestational age &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;76&#41; and ethnicity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;85&#41;&#46; As previously reported&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> most of the patients with PUV had bilateral kidney hyperechogenicity &#40;78&#37;&#41;&#44; oligohidramnio or anihidramnio &#40;83&#37;&#41; in antenatal ultrasonography&#59; 17 &#40;71&#37;&#41; died at the neonatal period due to pulmonary hypoplasia&#46; Patients with PUV who survived &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; underwent vesicostomy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; or endoscopic valve ablation &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41; within the first weeks after birth&#46; All patients presented higher urinary levels of creatinine&#44; &#946;2-microglobulin and osmolality than controls&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Fetuses with PUV presented decreased urinary levels of angiotensin-converting enzyme &#40;ACE&#41; with no difference in Ang II levels in comparison with controls&#46; In turn&#44; ACE2&#44; Ang I and&#44; notably&#44; Ang-&#40;1-7&#41; levels were higher in the urine of fetuses with PUV than controls &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Correlations were found between RAS components and inflammatory mediators&#46; Among controls&#44; urinary levels of ACE were positively correlated with interleukin &#40;IL&#41;-2 levels &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;790&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#41;&#46; ACE2 levels were significantly associated with eotaxin&#47;CCL11 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;807&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41; and interferon gamma-inducible protein &#40;IP-10&#41;&#47;CXCL10 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;707&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41; levels&#46; In addition&#44; Ang-&#40;1-7&#41; levels were negatively correlated with ACE levels &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;810&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41; and positively correlated with ACE2 levels &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;946&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Regarding patients with PUV&#44; urinary levels of ACE correlated negatively with &#946;2-microglobulin &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;491&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41; and soluble tumor necrosis factor receptor &#40;sTNFR&#41;1 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;466&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#41; levels&#46; ACE2 levels were positively correlated with IL-4 levels &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;512&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;025&#41;&#46; In addition&#44; Ang I levels were significantly associated with IL-1&#946; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;455&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;044&#41; and tumor necrosis factor &#40;TNF&#41; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;546&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#41; levels&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">Fetal urine has been regarded as an important pool of peptides that can predict postnatal renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> Klein et al&#46; identified and validated 12 fetal urinary peptides &#40;called 12PUV&#41; as predictors of postnatal renal function with high sensitivity and specificity&#44; outperforming routine methods&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> The present study aimed not only at searching for biomarkers but also to investigate potential involvement of RAS molecules in PUV&#46; It was observed that the profile of RAS components significantly differed in PUV fetuses when compared with healthy neonates&#46; PUV fetuses had higher urinary concentrations of ACE2 and of Ang-&#40;1-7&#41; than healthy neonates&#44; whereas ACE levels were lower in the urine of PUV fetuses than in the urine of healthy neonates&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Currently&#44; it has been proposed that RAS has two major arms&#58; &#40;i&#41; the classical arm formed by ACE&#44; Ang II&#44; and AT<span class="elsevierStyleInf">1</span> receptor&#44; and &#40;ii&#41; the counter-regulatory arm composed by ACE2&#44; Ang-&#40;1-7&#41;&#44; and Mas receptor&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> While the classical arm mainly activates pathways related to tissue injury and inflammation&#59; in sharp contrast&#44; the counter-regulatory RAS axis has anti-inflammatory effects&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> Therefore&#44; the observed increase of components of the protective RAS arm may represent a regulatory response to the intense inflammatory process triggered by PUV&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> The present study not only demonstrated that patients with PUV present increased levels of ACE2 and Ang-&#40;1-7&#41; in tandem with decreased levels of ACE&#44; but also observed significant correlations between the urinary levels of RAS components and inflammatory mediators&#46; Noteworthy&#44; ACE2 levels were associated with IL-4 levels and ACE levels significant correlated with sTNFR1 levels in urine samples of fetuses with PUV&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Altogether&#44; the present data reinforces the hypothesis that changes in the RAS occur in parallel with the inflammatory process triggered by PUV&#46; Indeed&#44; some evidence linked RAS to the pathophysiology of PUV&#46; Chowdhury et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> showed that serum pro-renin was higher in PUV cases than in controls and declined after corrective surgery&#46; There is experimental evidence that the classical RAS arm contributed to tubulointerstitial scarring in obstructive uropathies&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Mice with genetic deletion of AT<span class="elsevierStyleInf">1a</span> receptors presented less severe tubulointerstitial fibrosis induced by unilateral ureteral obstruction&#44; suggesting a role for the classical RAS axis in renal injury&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> More recently&#44; two experimental studies supported a protective role for Ang-&#40;1-7&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">25&#44;26</span></a> The first showed that&#44; in obstructed kidneys from mice with genetic deletion of Mas receptor&#44; apoptosis and macrophage infiltration were increased when compared with wild-type mice&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> In the second&#44; Kim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> reported that the infusion of Ang-&#40;1-7&#41; in rats who underwent unilateral ureteral obstruction decreased pro-apoptotic and pro-fibrotic protein expression&#46; Taken together&#44; previous and the present findings suggest that inflammatory and fibrotic pathways triggered by obstructive uropathies might stimulate local production of Ang-&#40;1-7&#41; as a compensatory mechanism in fetuses with PUV&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A possible mechanism by which Ang-&#40;1-7&#41; may protect against kidney injury due to obstruction could be the reduction of AT<span class="elsevierStyleInf">1</span> receptors expression through Mas receptor activation&#46; In this regard&#44; it was reported that mRNA expression for AT<span class="elsevierStyleInf">1</span> receptor was higher in Mas knockout mice&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> Indeed&#44; Mas receptor acts as an AT<span class="elsevierStyleInf">1</span> receptor antagonist through the constitutive formation of hetero-oligomeric complexes&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Another possible explanation for the elevation of ACE2 and Ang-&#40;1-7&#41; in the urine of fetuses with PUV could be a dysfunction or reduced expression of the Mas receptor at kidney tissue in PUV fetuses&#46; In this regard&#44; Ng et al&#46; reported that Mas receptor expression is reduced in the kidneys of CKD rats and the administration of the uremic toxin indoxyl sulfate induced down-regulation of Mas receptor probably <span class="elsevierStyleItalic">via</span> up-regulation of TGF-&#946;1 in proximal tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Therefore&#44; it can be hypothesized that an alteration in Mas receptor expression and&#47;or signaling may contribute to renal injury in PUV fetuses&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The present study has limitations&#44; including its relatively small sample size&#44; cross-sectional design&#44; and the use of urine samples from preterm newborns as control&#46; Since urine collection from fetuses is an invasive procedure&#44; it was impossible to collect urine from healthy fetuses due to ethical reasons&#46; One study has found increased urinary angiotensinogen-to-creatinine ratio in preterm neonates when compared with that in full-term neonates&#46; The urinary angiotensinogen-to-creatinine ratio decreased significantly with increasing gestational age&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> It is important to emphasize that&#44; in order to rule out the effects of gestational age in RAS components concentrations&#44; in the present study the control group was composed of preterm newborns matched by gestational age with fetuses with PUV at the time of urine collection&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion&#44; urinary tract obstruction leads to complex molecular interactions in an early timing&#59; <span class="elsevierStyleItalic">in utero</span> interventions are sometimes performed when renal lesions were already irreversible&#46; Many studies evidenced the role of RAS in obstructive uropathies&#46; However&#44; up to now&#44; the protective RAS arm has never been investigated in fetuses with PUV&#46; The present findings support a role for ACE2-Ang-&#40;1-7&#41;-Mas receptor in PUV that deserve further investigation&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0105" class="elsevierStylePara elsevierViewall">This study was supported by <span class="elsevierStyleGrantSponsor" id="gs1">FAPEMIG</span> &#40;Grant &#35; <span class="elsevierStyleGrantNumber" refid="gs1">PPM-00555-15</span>&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs2">CAPES</span> and <span class="elsevierStyleGrantSponsor" id="gs3">CNPq</span> &#40;Grant &#35; <span class="elsevierStyleGrantNumber" refid="gs2">470472&#47;2014-6</span> and Grant &#35; <span class="elsevierStyleGrantNumber" refid="gs3">460334&#47;2014-0</span>&#41;&#44; Brazil&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Posterior urethral valve is the most common lower urinary tract obstruction in male children&#46; A high percentage of patients with posterior urethral valve evolve to end-stage renal disease&#46; Previous studies showed that cytokines&#44; chemokines&#44; and components of the renin&#8211;angiotensin system contribute to the renal damage in obstructive uropathies&#46; The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules&#46; The aim of this study was to measure renin&#8211;angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">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 &#40;controls&#41;&#46; Renin&#8211;angiotensin system components levels were measured by enzyme-linked immunosorbent assay&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Fetuses with posterior urethral valve presented increased urinary levels of angiotensin &#40;Ang&#41; I&#44; Ang-&#40;1-7&#41; and angiotensin-converting enzyme 2 in comparison with controls&#46; ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-&#40;1-7&#41; in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A v&#225;lvula de uretra posterior &#233; a obstru&#231;&#227;o do trato urin&#225;rio inferior mais comum em crian&#231;as do sexo masculino&#46; Uma alta porcentagem de pacientes com v&#225;lvula de uretra posterior evolui para doen&#231;a renal em est&#225;gio final&#46; Estudos anteriores mostraram que citocinas&#44; quimiocinas e componentes do sistema renina-angiotensina contribuem para o dano renal em uropatias obstrutivas&#46; Recentemente&#44; descobrimos que amostras de urina de fetos com v&#225;lvula de uretra posterior tinham n&#237;veis aumentados de mol&#233;culas inflamat&#243;rias&#46; O objetivo deste estudo foi medir as mol&#233;culas de renina-angiotensina e investigar sua correla&#231;&#227;o com marcadores inflamat&#243;rios previamente detectados nas mesmas amostras de urina de fetos com v&#225;lvula de uretra posterior&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Amostras de urina de 24 fetos com v&#225;lvula de uretra posterior foram coletadas e comparadas com amostras de urina de 22 rec&#233;m-nascidos saud&#225;veis de mesma idade gestacional &#40;controles&#41;&#46; Os n&#237;veis dos componentes de SRA foram medidos por ensaio de imunoabsor&#231;&#227;o enzim&#225;tica&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Os fetos com v&#225;lvula de uretra posterior apresentaram n&#237;veis urin&#225;rios aumentados de angiotensina &#40;Ang&#41; I&#44; Ang-&#40;1-7&#41; e enzima conversora de angiotensina 2 em compara&#231;&#227;o com os controles&#46; Os n&#237;veis de enzima conversora de angiotensina eram significativamente menores e os n&#237;veis de Ang II eram semelhantes nos fetos com v&#225;lvula de uretra posterior em compara&#231;&#227;o com os controles&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O aumento dos n&#237;veis urin&#225;rios de enzima conversora de angiotensina 2 e de Ang-&#40;1-7&#41; em fetos com v&#225;lvula de uretra posterior poderia representar uma resposta regulat&#243;ria ao intenso processo inflamat&#243;rio desencadeado pela v&#225;lvula de uretra posterior&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Objetivo"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclus&#245;es"
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rocha NP&#44; Bastos FM&#44; Vieira &#201;L&#44; Prestes TR&#44; Silveira KD&#44; Teixeira MM&#44; et al&#46; The protective arm of the renin&#8211;angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves&#46; J Pediatr &#40;Rio J&#41;&#46; 2019&#59;95&#58;328&#8211;33&#46;</p>"
      ]
    ]
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        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Levels of renin&#8211;angiotensin system &#40;RAS&#41; components in urine samples from fetuses with posterior urethral valve &#40;PUV&#41; and in a control group comprised of healthy male newborns&#46; Fetuses with PUV presented decreased urinary levels of angiotensin-converting enzyme &#40;ACE&#41; with no change in angiotensin &#40;Ang&#41; II levels in comparison with controls&#46; In turn&#44; ACE2&#44; Ang I and&#44; notably&#44; Ang-&#40;1-7&#41; levels were higher in the urine of fetuses with PUV than controls&#46; These results show an activation of the counter-regulatory arm of the RAS in PUV&#46; Each figure shows the mean and the standard error of the mean &#40;SEM&#41;&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; Mann&#8211;Whitney test&#46;</p>"
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      "titulo" => "References"
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                          "etal" => false
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                            0 => "K&#46; Mehler"
                            1 => "B&#46;B&#46; Beck"
                            2 => "I&#46; Kaul"
                            3 => "G&#46; Rahimi"
                            4 => "B&#46; Hoppe"
                            5 => "A&#46; Kribs"
                          ]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfr046"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephrol Dial Transplant"
                        "fecha" => "2011"
                        "volumen" => "26"
                        "paginaInicial" => "3514"
                        "paginaFinal" => "3522"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21389070"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early risk factors for neonatal mortality in CAKUT&#58; analysis of 524 affected newborns"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;F&#46; Melo"
                            1 => "M&#46;B&#46; Aguiar"
                            2 => "M&#46;C&#46; Bouzada"
                            3 => "R&#46;L&#46; Aguiar"
                            4 => "A&#46;K&#46; Pereira"
                            5 => "G&#46;M&#46; Paixao"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1007/s00467-012-2107-y"
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                        "tituloSerie" => "Pediatr Nephrol"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fetal lower urinary tract obstruction&#58; proposal for standardized multidisciplinary prenatal management based on disease severity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Ruano"
                            1 => "N&#46; Sananes"
                            2 => "C&#46; Wilson"
                            3 => "J&#46; Au"
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                    0 => array:2 [
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                        "fecha" => "2016"
                        "volumen" => "48"
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              "etiqueta" => "7"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fetal intervention for severe lower urinary tract obstruction&#58; a multicenter case-control study comparing fetal cystoscopy with vesicoamniotic shunting"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Ruano"
                            1 => "N&#46; Sananes"
                            2 => "H&#46; Sangi-Haghpeykar"
                            3 => "S&#46; Hernandez-Ruano"
                            4 => "R&#46; Moog"
                            5 => "F&#46; Becmeur"
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                        "fecha" => "2015"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25157756"
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              "etiqueta" => "8"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Posterior urethral valves&#58; long-term outcome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Caione"
                            1 => "S&#46;G&#46; Nappo"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00383-011-2946-9"
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                        "tituloSerie" => "Pediatr Surg Int"
                        "fecha" => "2011"
                        "volumen" => "27"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21748651"
                            "web" => "Medline"
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                      "titulo" => "Long-term risk of end stage renal disease in patients with posterior urethral valves"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46; Heikkila"
                            1 => "C&#46; Holmberg"
                            2 => "L&#46; Kyllonen"
                            3 => "R&#46; Rintala"
                            4 => "S&#46; Taskinen"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.juro.2011.07.109"
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              ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46; Kousidis"
                            1 => "D&#46;F&#46; Thomas"
                            2 => "H&#46; Morgan"
                            3 => "N&#46; Haider"
                            4 => "R&#46; Subramaniam"
                            5 => "S&#46; Feather"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                ]
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                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46; Thakkar"
                            1 => "A&#46;V&#46; Deshpande"
                            2 => "S&#46;E&#46; Kennedy"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/pr.2014.134"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Res"
                        "fecha" => "2014"
                        "volumen" => "76"
                        "paginaInicial" => "560"
                        "paginaFinal" => "563"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25198372"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Posterior urethral valve in fetuses&#58; evidence for the role of inflammatory molecules"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;L&#46; Vieira"
                            1 => "N&#46; Pessoa Rocha"
                            2 => "F&#46; Macedo Bastos"
                            3 => "K&#46;D&#46; da Silveira"
                            4 => "A&#46;K&#46; Pereira"
                            5 => "E&#46; Araujo Oliveira"
                          ]
                        ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00467-017-3614-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Nephrol"
                        "fecha" => "2017"
                        "volumen" => "32"
                        "paginaInicial" => "1391"
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                            4 => "S&#46; Kagami"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10157-014-0977-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Nephrol"
                        "fecha" => "2015"
                        "volumen" => "19"
                        "paginaInicial" => "293"
                        "paginaFinal" => "297"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24792728"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack409660"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0115" class="elsevierStylePara elsevierViewall">The authors would like to acknowledge the participation of volunteers in this study and are indebted to the pregnant women and parents of the fetuses&#47;newborns for their magnificent support&#46; They also would like to thanks the members of LIIM for their skilled comments&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/00217557/0000009500000003/v1_201905310725/S0021755717311646/v1_201905310725/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "10179"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/00217557/0000009500000003/v1_201905310725/S0021755717311646/v1_201905310725/en/main.pdf?idApp=UINPBA000049&text.app=https://jped.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755717311646?idApp=UINPBA000049"
]

Article information

ISSN: 00217557
Original language: English

DOI:10.1016/j.jped.2018.02.003

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	6	4	10
2024 October	19	28	47
2024 September	35	21	56
2024 August	37	30	67
2024 July	40	38	78
2024 June	24	15	39
2024 May	19	14	33
2024 April	25	30	55
2024 March	19	21	40
2024 February	16	31	47
2024 January	15	22	37
2023 December	39	27	66
2023 November	37	33	70
2023 October	26	42	68
2023 September	40	43	83
2023 August	27	13	40
2023 July	31	9	40
2023 June	17	16	33
2023 May	49	21	70
2023 April	30	8	38
2023 March	58	26	84
2023 February	52	12	64
2023 January	31	16	47
2022 December	63	26	89
2022 November	26	29	55
2022 October	47	35	82
2022 September	16	27	43
2022 August	21	32	53
2022 July	18	35	53
2022 June	16	29	45
2022 May	23	31	54
2022 April	36	39	75
2022 March	28	40	68
2022 February	24	24	48
2022 January	13	16	29
2021 December	27	13	40
2021 November	16	18	34
2021 October	11	14	25
2021 September	5	6	11
2021 August	4	10	14
2021 July	3	8	11
2021 June	8	6	14
2021 May	11	21	32
2021 April	4	9	13
2021 March	10	31	41
2021 February	2	9	11
2021 January	8	7	15
2020 December	10	6	16
2020 November	6	15	21
2020 October	10	5	15
2020 September	9	13	22
2020 August	3	2	5
2020 July	4	4	8
2020 June	7	4	11
2020 May	7	9	16
2020 April	5	12	17
2020 March	3	16	19
2020 February	13	12	25
2020 January	13	14	27
2019 December	6	4	10
2019 November	5	12	17
2019 October	16	15	31
2019 September	12	11	23
2019 August	24	11	35
2019 July	30	13	43
2019 June	19	15	34
2019 May	15	13	28
2019 April	18	6	24
2019 March	9	6	15
2019 February	9	3	12
2019 January	6	9	15
2018 December	12	5	17
2018 November	13	6	19
2018 October	19	14	33
2018 September	7	4	11
2018 August	5	2	7
2018 July	4	5	9
2018 June	4	3	7
2018 May	0	8	8

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