Perfil metabolómico diferenciador asociado a la condición de normoalbuminuria en la población hipertensa

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(J) Diagrammatic representation showing how EMBP1's negative regulation of miR-9-5p may promote pro-proliferative, migratory, and invasive pathways in RCC cells. 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Martinez, Marta Martin-Lorenzo, Gema Ruiz-Hurtado, Maria G Barderas, Julian Segura, Luis M. Ruilope, Gloria Alvarez-Llamas" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Aranzazu" "apellidos" => "Santiago-Hernandez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Paula J." 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"apellidos" => "Ruilope" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 7 => array:4 [ "nombre" => "Gloria" "apellidos" => "Alvarez-Llamas" "email" => array:1 [ 0 => "galvarez@fjd.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Laboratorio de Inmunoalergia y Proteómica, Departamento de Inmunología, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, España" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Laboratorio Traslacional Cardiorrenal, Instituto de Investigación I+12 Hospital Universitario 12 de Octubre/CIBER-CV, Madrid" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Fisiopatología Vascular, Hospital Nacional de Parapléjicos, SESCAM , Toledo, España" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Nefrología, Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Madrid, España" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Escuela de Estudios de Doctorado e Investigación, Universidad Europea de Madrid, Madrid, España" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "REDINREN" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Autor para correspondencia." ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Differential metabolic profile associated with the condition of normoalbuminuria in the hypertensive population" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 768 "Ancho" => 2986 "Tamanyo" => 158883 ] ] "descripcion" => array:1 [ "es" => "Huella metabólica en orina asociada al desarrollo de albuminuria. M: microalbuminuria; N: normo; NA: normal-alta; u.a.: unidades arbitrarias. *p < 0,05. **p < 0,01. ***p < 0,001. ****p < 0,0001." ] ] ] "textoCompleto" => "IntroducciónLa hipertensión es una de las enfermedades con mayor prevalencia en todo el mundo<a class="elsevierStyleCrossRef" href="#bib0165">1</a>. En torno a un 30-40% de la población adulta mundial es hipertensa. Uno de los tratamientos de primera línea para su control es la inhibición crónica del sistema renina angiotensina (SRA) mediante monoterapia o en terapia combinada con otros antihipertensivos, con demostrada eficacia en la reducción de la presión arterial. Sin embargo, un destacable porcentaje de pacientes hipertensos controlados desarrollan albuminuria (16,1% en seguimiento a 3 años)<a class="elsevierStyleCrossRef" href="#bib0170">2</a>. La albuminuria es la expresión clínica de un proceso fisiopatológico multifactorial y complejo que lleva asociado un incremento del riesgo cardiovascular<a class="elsevierStyleCrossRefs" href="#bib0175">3,4</a>. Si bien solo la presencia de albuminuria puede no ser predictiva de progresión de enfermedad renal crónica<a class="elsevierStyleCrossRef" href="#bib0185">5</a>, sí existen evidencias de una asociación entre cambios en los niveles de albuminuria y el desarrollo o agravamiento de la enfermedad renal<a class="elsevierStyleCrossRefs" href="#bib0190">6-8</a>.La albuminuria es un indicador de daño orgánico subclínico. Su desarrollo tiene lugar de forma continuada y como tal deben considerarse sus consecuencias sobre el riesgo cardiovascular y el daño renal<a class="elsevierStyleCrossRef" href="#bib0205">9</a>. Estudios previos muestran como la asociación entre el desarrollo de albuminuria y la existencia de eventos cardiovasculares empieza a niveles de ACR dentro del rango de normoalbuminuria tan bajos como 4,4mg/g<a class="elsevierStyleCrossRef" href="#bib0210">10</a>; 6,6mg/g<a class="elsevierStyleCrossRef" href="#bib0215">11</a> o, en cualquier caso, <10mg/g<a class="elsevierStyleCrossRef" href="#bib0220">12</a>. Particularmente, el riesgo de desarrollar enfermedad cardiovascular en diabéticos aumenta en un factor de 10 si la albuminuria aumenta de 10 a 30mg/d<a class="elsevierStyleCrossRef" href="#bib0225">13</a> y, en la población general, un aumento en 5-10mg/L se asocia a un 29% más de riesgo de mortalidad por enfermedad cardiovascular<a class="elsevierStyleCrossRef" href="#bib0230">14</a>. De la misma forma, predice el desarrollo de hipertensión en el rango normal-alto (<30mg/g)<a class="elsevierStyleCrossRef" href="#bib0235">15</a> y de la enfermedad renal crónica en no diabéticos<a class="elsevierStyleCrossRefs" href="#bib0195">7,8</a>.La mayor dificultad en estrategias de prevención es que no es posible anticiparse a conocer qué sujetos desarrollarán albuminuria. Una de las principales razones es que los mecanismos moleculares que subyacen no se conocen en su totalidad. El valor de la orina en el estudio de la enfermedad cardiovascular ha sido ampliamente demostrado<a class="elsevierStyleCrossRefs" href="#bib0240">16-19</a>. En concreto, en estudios previos identificamos marcadores moleculares en orina asociados a la condición de albuminuria que apuntan a alteraciones en la respuesta inmunitaria, sistema de coagulación, respuesta inflamatoria, remodelado vascular y estrés oxidativo como los principales procesos biológicos implicados<a class="elsevierStyleCrossRefs" href="#bib0260">20-22</a>. En este trabajo exploramos la existencia de un perfil metabolómico diferencial en sujetos clasificados según su nivel de ACR en: a) <10 mg/g (normo); b) 10-30 mg/g en varones o 20-40 mg/g en mujeres (normal-alta); c) 30-200 mg/g o 40-300mg/g, respectivamente (micro). De este modo se diferencia entre individuos que no se espera que desarrollen albuminuria (normo) y aquellos que sí son susceptibles de desarrollarla (normal-alta). Analizamos la huella metabólica previamente identificada para investigar si existe variación metabólica asociada a una condición de albuminuria temprana o incipiente con la finalidad de estratificar el riesgo cardiorrenal a nivel molecular y así adaptar mejor la estrategia terapéutica en estos pacientes.Material y métodosSelección de pacientesEn la Unidad de Hipertensión del Hospital 12 de Octubre de Madrid se seleccionó a un total de 48 pacientes hipertensos controlados bajo supresión crónica del SRA durante un mínimo de 2años. Aquellos pacientes con hipertensión arterial secundaria fueron excluidos del estudio. Se incluyó a pacientes con diabetes mellitus y sin ella de entre 45 y 70 años. El estudio se realizó según las recomendaciones de la Declaración de Helsinki y fue aprobado por el Comité de Ética del Hospital 12 de Octubre, previo consentimiento informado de los pacientes.Los sujetos se clasificaron según el valor de ACR en 3 grupos: normo (N), los individuos con ACR < 10 mg/g, de los que, según el estudio ROADMAP, se sabe que no desarrollarán albuminuria<a class="elsevierStyleCrossRef" href="#bib0275">23</a>; normal-alta (NA), los individuos con ACR = 10-30 mg/g (varones) o 20-40 mg/g (mujeres) y microalbuminuria (M), los individuos con ACR = 30-200 mg/g o 40-300mg/g, respectivamente. Las guías clínicas emplean como criterio de clasificación general un punto de corte de ACR = 30mg/g entre albuminuria y albuminuria moderadamente elevada<a class="elsevierStyleCrossRef" href="#bib0280">24</a>. En el caso de las mujeres, el punto de corte se ha aumentado ligeramente a 40mg/g<a class="elsevierStyleCrossRef" href="#bib0285">25</a>, considerando que la liberación de creatinina en orina se ve influida por la masa muscular. La <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> recoge las características clínicas de los sujetos incluidos en el estudio.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Análisis metabolómico de la orina mediante espectrometría de masas dirigidaSe recogió la primera orina de la mañana, se centrifugó para eliminar restos celulares y se almacenó a −80°C hasta su análisis. El análisis cuantitativo de los metabolitos se realizó mediante cromatografía líquida acoplada a espectrometría de masas dirigida en modo selected reaction monitoring (SRM-LC-MS/MS). Esta metodología fue seleccionada como método del año por la revista Nature Methods 2012<a class="elsevierStyleCrossRef" href="#bib0290">26</a>. Con base en estudios previos de nuestro laboratorio, se extrajeron los metabolitos de la orina tras la eliminación de la fracción proteica por precipitación orgánica<a class="elsevierStyleCrossRefs" href="#bib0295">27,28</a>. El sobrenadante se filtró y se analizó en un espectrómetro de masas Triple Cuadrupolo QQQ6460 (Agilent Technologies) acoplado a un sistema binario de cromatografía líquida (1200 series, Agilent Technologies) controlado por el programa Mass Hunter (v4.0 Agilent Technologies).Análisis estadísticoLa señal correspondiente a cada metabolito se integró mediante el programa Mass Hunter Adquisition Data Qualitative Analysis B.04.00 (Agilent Technologies) y se obtuvo el área de pico. Se realizó un análisis estadístico no paramétrico Mann-Whitney, con un 95% de nivel de confianza y previa detección de outliers mediante el método ROUT (valor Q = 5%). Para el análisis de correlaciones se empleó un test no paramétrico de correlación de Spearman, todo ello mediante el programa GraphPad Prism (versión 6.01).Resultados y discusiónOxalacetato, guanidoacetato y 3-ureidopropionato muestran niveles inferiores en el grupo de individuos con microalbuminuria (M) respecto a aquellos en la condición de normoalbuminuria (N). El malato, en cambio, muestra niveles superiores en M respecto a N (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>). Estos datos confirman observaciones previas en pacientes con albuminuria, bien desarrollada durante los 3 años de seguimiento previos a la toma de muestra (albuminuria de novo) o ya presente con anterioridad (albuminuria mantenida)<a class="elsevierStyleCrossRef" href="#bib0270">22</a>. Cabe destacar que estos 4metabolitos son capaces de diferenciar entre los pacientes N y aquellos en el rango de albuminuria NA y, por lo tanto, permiten una estratificación molecular más temprana de los pacientes.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Paralelamente se realizó un estudio de la correlación entre los niveles de los metabolitos en orina y los valores de ACR para cada paciente, en el que resultó en todos los casos una correlación estadísticamente significativa (<a class="elsevierStyleCrossRef" href="#fig0010">fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Se ha descrito un aumento del estrés oxidativo asociado al desarrollo de albuminuria<a class="elsevierStyleCrossRef" href="#bib0305">29</a>. El estrés oxidativo es causado por una desregulación en la producción y metabolismo de las especies reactivas de oxígeno, en cuya regulación intracelular participa el ciclo de los ácidos tricarboxílicos. Las alteraciones observadas en los niveles de oxalacetato y malato en pacientes con albuminuria en el rango normal-alta y microalbuminuria señalan nuevamente al metabolismo energético como una pieza clave en el manejo de los pacientes hipertensos<a class="elsevierStyleCrossRef" href="#bib0310">30</a>. El guanidoacetato es un intermediario en el metabolismo de la arginina y prolina y precursor de la creatina, un sustrato de la creatinquinasa. Esta enzima se ha relacionado con un fracaso del tratamiento antihipertensivo, sin conocerse en detalle los mecanismos que lo provocan<a class="elsevierStyleCrossRef" href="#bib0315">31</a>. Por otro lado, se ha propuesto el guanidoacetato como marcador de lesión renal: muestra un nivel reducido en la orina de pacientes trasplantados con función renal normal<a class="elsevierStyleCrossRef" href="#bib0320">32</a>. Las alteraciones de estos metabolismos señalan, por tanto, una desregulación temprana de los metabolismos de energía y de la arginina y prolina ya en pacientes con albuminuria en el rango normal-alta.Como limitaciones del estudio cabe destacar diferencias en algunas de las características basales de los grupos clínicos comparados, en particular, en lo que se refiere al porcentaje de individuos diabéticos. Si bien es esperable una mayor presencia de diabetes mellitus en el grupo de sujetos con microalbuminuria, sería de interés evaluar en una mayor cohorte de sujetos únicamente no diabéticos las variaciones metabólicas observadas para determinar exactamente el grado de contribución de la diabetes.ConclusionesEn este estudio hemos confirmado la asociación de los niveles de los metabolitos 3-ureidopropionato, oxalacetato, malato y guanidoacetato con distintos grados de albuminuria. Por vez primera, se ha identificado una huella molecular (panel metabólico) capaz de mostrar variación dentro de la condición de normoalbuminuria, distinguiendo entre sujetos con ACR < 10 mg/g o superior. Este hecho es destacable por cuanto que supone una herramienta con un enorme potencial en el manejo terapéutico de pacientes hipertensos con niveles de ACR considerados «no patológicos» y que, por lo tanto, no reciben una atención médica especial. Sin embargo, son estos pacientes los que más se beneficiarían de una intervención temprana, ya que presentan un mayor riesgo de enfermedad renal o cardiovascular.FinanciaciónInstituto de Salud Carlos III-Fondos FEDER (PI16/01334, PI13/01873, PI17/01193, PI17/01093, IF08/3667-1, CPII15/00027, CP15/00129, PT13/0001/0013, PRB3 (IPT17/0019 ISCIIIS-GEFI/ERDF), REDinREN (RD16/0009)), Ayuda a la Investigación de la Fundación SENEFRO y Fundación Conchita Rábago de Jiménez Díaz.Conflicto de interesesLos autores declaran no tener ningún conflicto de intereses." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1380137" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Pacientes, materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusiones" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1267481" "titulo" => "Palabras clave" ] 2 => array:3 [ "identificador" => "xres1380136" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Background and aim" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Patients, materials and methods" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1267480" "titulo" => "Keywords" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introducción" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material y métodos" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Selección de pacientes" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Análisis metabolómico de la orina mediante espectrometría de masas dirigida" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Análisis estadístico" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Resultados y discusión" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusiones" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Financiación" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicto de intereses" ] 10 => array:2 [ "identificador" => "xack479639" "titulo" => "Agradecimientos" ] 11 => array:1 [ "titulo" => "Bibliografía" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-06-21" "fechaAceptado" => "2019-10-24" "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1267481" "palabras" => array:7 [ 0 => "Albuminuria" 1 => "Riesgo cardiovascular" 2 => "Hipertensión" 3 => "Sistema renina-angiotensina" 4 => "Metabolómica" 5 => "Biomarcadores" 6 => "Metabolitos" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1267480" "palabras" => array:7 [ 0 => "Albuminuria" 1 => "Cardiovascular risk" 2 => "Hypertension" 3 => "Renin-angiotensin system" 4 => "Metabolomics" 5 => "Biomarkers" 6 => "Metabolites" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivoLa albuminuria es un indicador de daño orgánico subclínico y un marcador de riesgo cardiovascular y de enfermedad renal. Un porcentaje de pacientes hipertensos desarrollan albuminuria a pesar de estar bajo supresión crónica del sistema renina-angiotensina (SRA). Previamente identificamos metabolitos en orina asociados al desarrollo de albuminuria. En este estudio, investigamos alteraciones metabólicas que reflejen distintos niveles dentro de la condición de normoalbuminuria. Pacientes, materiales y métodosSe analizó la orina de 48 pacientes hipertensos con supresión crónica del SRA. Se clasificaron según el cociente albúmina/creatinina (ACR) en 3 grupos: normoalbuminuria (<10mg/g); normal-alta (10-30mg/g en varones, o 20-40mg/g en mujeres) y albuminuria moderadamente elevada (microalbuminuria: 30-200mg/g o 40-300mg/g, respectivamente). El metaboloma se analizó mediante espectrometría de masas y se realizó un análisis de correlaciones entre los niveles de los metabolitos alterados y ACR. ResultadosOxalacetato, 3-ureidopropionato, guanidoacetato y malato muestran una variación significativa entre los grupos normo y micro. Además, estos metabolitos son capaces de diferenciar entre los pacientes normo y normal-alta. Igualmente se observó correlación significativa entre el nivel de los metabolitos identificados con el nivel de ACR. Las variaciones observadas señalan una alteración del metabolismo energético ya en pacientes con albuminuria en el rango normal-alta. ConclusionesSe confirma la asociación del panel molecular constituido por 3-ureidopropionato, oxalacetato, malato y guanidoacetato con distintos niveles de albuminuria. Así mismo, se ha identificado una huella metabólica capaz de mostrar variación dentro de la condición de normoalbuminuria, lo que permite una estratificación molecular más temprana de los pacientes." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Pacientes, materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusiones" ] ] ] "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and aimAlbuminuria is an indicator of sub-clinical organ damage and a marker of cardiovascular risk and renal disease. A percentage of hypertensive patients develop albuminuria despite being under chronic suppression of the renin-angiotensin system (RAS). We previously identified urinary metabolites associated with the development of albuminuria. In this study, we searched for metabolic alterations which reflect different levels within the condition of normoalbuminuria. Patients, materials and methodsUrine from 48 hypertensive patients under chronic RAS suppression was analysed. They were classified according to the albumin/creatinine ratio (ACR) into 3groups: Normoalbuminuria (<10mg/g); high-normal (10-30mg/g in men, or 20-40mg/g in women); and moderately high albuminuria (microalbuminuria, 30-200mg/g or 40-300mg/g, respectively). The metabolome was analysed by mass spectrometry and a correlation analysis was performed between altered metabolite levels and ACR. ResultsOxaloacetate, 3-ureidopropionate, guanidoacetate and malate show significant variation between the normo and micro groups. Additionally, these metabolites are able to differentiate between patients in the normo and high-normal range. A significant correlation between metabolites and ACR was found. Observed variations point to alterations in the energy metabolism already in patients with albuminuria in the high-normal range. ConclusionsThe association between the molecular panel consisting of 3-ureidopropionate, oxaloacetate, malate and guanidoacetate and different levels of albuminuria is confirmed. A metabolic fingerprint was also identified showing variations within the condition of normoalbuminuria allowing an earlier molecular stratification of patients." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Background and aim" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Patients, materials and methods" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 768 "Ancho" => 2986 "Tamanyo" => 158883 ] ] "descripcion" => array:1 [ "es" => "Huella metabólica en orina asociada al desarrollo de albuminuria. M: microalbuminuria; N: normo; NA: normal-alta; u.a.: unidades arbitrarias. *p < 0,05. **p < 0,01. ***p < 0,001. ****p < 0,0001." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 780 "Ancho" => 3140 "Tamanyo" => 169380 ] ] "descripcion" => array:1 [ "es" => "Correlaciones observadas entre los metabolitos identificados en orina y el nivel de ACR. Correlación de Spearman. u.a: unidades arbitrarias." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabla 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabla " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ACR se expresa como mediana (rango intercuartílico). El resto de las variables se expresan como frecuencias o como media ± desviación estándar.ACR: cociente albúmina/creatinina; ARA: antagonista de los receptores de angiotensina; eGFR: filtrado glomerular estimado; IECA: inhibidores de la enzima convertidora de angiotensina; PAD: presión arterial diastólica; PAS: presión arterial sistólica." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normo (n = 22) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normal-alta (n = 17) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Microalbuminuria (n = 9) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Edad (años) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 ± 9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 ± 5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 ± 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sexo (% masculino) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">179 ± 38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">166 ± 29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">154 ± 29 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Triglicéridos (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110 ± 33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">125 ± 59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">122 ± 32 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colesterol HDL (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54 ± 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 ± 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 ± 7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colesterol LDL (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">102 ± 31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88 ± 30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91 ± 26 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ácido úrico(mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 ± 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 ± 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 ± 2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">eGFR (ml/min/1,73 m2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86 ± 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 ± 20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 ± 22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ACR (mg/g) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (3-6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (18-31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 (44-99) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes mellitus tipo II (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PAS (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">140 ± 14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">144±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">141 ± 19 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PAD (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85±8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">83±8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 ± 5 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2369698.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tratamiento antihipertensivo (%)</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IECA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ARA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diuréticos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">α-bloqueantes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">β-bloqueantes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bloqueantes del canal de calcio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2369699.png" ] ] ] ] "descripcion" => array:1 [ "es" => "Características clínicas de los pacientes incluidos en el estudio" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliografía" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0165" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2018 ESC/ESH Guidelines for the management of arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. 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Estadísticas

Original breve

Perfil metabolómico diferenciador asociado a la condición de normoalbuminuria en la población hipertensa

Differential metabolic profile associated with the condition of normoalbuminuria in the hypertensive population

Aranzazu Santiago-Hernandeza, Paula J. Martineza, Marta Martin-Lorenzoa, Gema Ruiz-Hurtadob,c, Maria G Barderasc, Julian Segurad, Luis M. Ruilopeb,d,e, Gloria Alvarez-Llamasa,f,

Autor para correspondencia

galvarez@fjd.es

Autor para correspondencia.

a Laboratorio de Inmunoalergia y Proteómica, Departamento de Inmunología, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, España

b Laboratorio Traslacional Cardiorrenal, Instituto de Investigación I+12 Hospital Universitario 12 de Octubre/CIBER-CV, Madrid

c Departamento de Fisiopatología Vascular, Hospital Nacional de Parapléjicos, SESCAM , Toledo, España

d Servicio de Nefrología, Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Madrid, España

e Escuela de Estudios de Doctorado e Investigación, Universidad Europea de Madrid, Madrid, España

f REDINREN

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se ha leído el artículo

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La hipertensi&#243;n es una de las enfermedades con mayor prevalencia en todo el mundo<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a>&#46; En torno a un 30-40&#37; de la poblaci&#243;n adulta mundial es hipertensa&#46; Uno de los tratamientos de primera l&#237;nea para su control es la inhibici&#243;n cr&#243;nica del sistema renina angiotensina &#40;SRA&#41; mediante monoterapia o en terapia combinada con otros antihipertensivos&#44; con demostrada eficacia en la reducci&#243;n de la presi&#243;n arterial&#46; Sin embargo&#44; un destacable porcentaje de pacientes hipertensos controlados desarrollan albuminuria &#40;16&#44;1&#37; en seguimiento a 3 a&#241;os&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a>&#46; La albuminuria es la expresi&#243;n cl&#237;nica de un proceso fisiopatol&#243;gico multifactorial y complejo que lleva asociado un incremento del riesgo cardiovascular<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">3&#44;4</span></a>&#46; Si bien solo la presencia de albuminuria puede no ser predictiva de progresi&#243;n de enfermedad renal cr&#243;nica<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">5</span></a>&#44; s&#237; existen evidencias de una asociaci&#243;n entre cambios en los niveles de albuminuria y el desarrollo o agravamiento de la enfermedad renal<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">6-8</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">La albuminuria es un indicador de da&#241;o org&#225;nico subcl&#237;nico&#46; Su desarrollo tiene lugar de forma continuada y como tal deben considerarse sus consecuencias sobre el riesgo cardiovascular y el da&#241;o renal<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a>&#46; Estudios previos muestran como la asociaci&#243;n entre el desarrollo de albuminuria y la existencia de eventos cardiovasculares empieza a niveles de ACR dentro del rango de normoalbuminuria tan bajos como 4&#44;4<span class="elsevierStyleHsp" style=""></span>mg&#47;g<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a>&#59; 6&#44;6<span class="elsevierStyleHsp" style=""></span>mg&#47;g<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> o&#44; en cualquier caso&#44; &#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;g<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a>&#46; Particularmente&#44; el riesgo de desarrollar enfermedad cardiovascular en diab&#233;ticos aumenta en un factor de 10 si la albuminuria aumenta de 10 a 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">13</span></a> y&#44; en la poblaci&#243;n general&#44; un aumento en 5-10<span class="elsevierStyleHsp" style=""></span>mg&#47;L se asocia a un 29&#37; m&#225;s de riesgo de mortalidad por enfermedad cardiovascular<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a>&#46; De la misma forma&#44; predice el desarrollo de hipertensi&#243;n en el rango normal-alto &#40;&#60;30<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a> y de la enfermedad renal cr&#243;nica en no diab&#233;ticos<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">7&#44;8</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">La mayor dificultad en estrategias de prevenci&#243;n es que no es posible anticiparse a conocer qu&#233; sujetos desarrollar&#225;n albuminuria&#46; Una de las principales razones es que los mecanismos moleculares que subyacen no se conocen en su totalidad&#46; El valor de la orina en el estudio de la enfermedad cardiovascular ha sido ampliamente demostrado<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">16-19</span></a>&#46; En concreto&#44; en estudios previos identificamos marcadores moleculares en orina asociados a la condici&#243;n de albuminuria que apuntan a alteraciones en la respuesta inmunitaria&#44; sistema de coagulaci&#243;n&#44; respuesta inflamatoria&#44; remodelado vascular y estr&#233;s oxidativo como los principales procesos biol&#243;gicos implicados<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">20-22</span></a>&#46; En este trabajo exploramos la existencia de un perfil metabol&#243;mico diferencial en sujetos clasificados seg&#250;n su nivel de ACR en&#58; a&#41; &#60;10&#160;mg&#47;g &#40;normo&#41;&#59; b&#41; 10-30&#160;mg&#47;g en varones o 20-40&#160;mg&#47;g en mujeres &#40;normal-alta&#41;&#59; c&#41; 30-200&#160;mg&#47;g o 40-300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#44; respectivamente &#40;micro&#41;&#46; De este modo se diferencia entre individuos que no se espera que desarrollen albuminuria &#40;normo&#41; y aquellos que s&#237; son susceptibles de desarrollarla &#40;normal-alta&#41;&#46; Analizamos la huella metab&#243;lica previamente identificada para investigar si existe variaci&#243;n metab&#243;lica asociada a una condici&#243;n de albuminuria temprana o incipiente con la finalidad de estratificar el riesgo cardiorrenal a nivel molecular y as&#237; adaptar mejor la estrategia terap&#233;utica en estos pacientes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Selecci&#243;n de pacientes</span><p id="par0020" class="elsevierStylePara elsevierViewall">En la Unidad de Hipertensi&#243;n del Hospital 12 de Octubre de Madrid se seleccion&#243; a un total de 48 pacientes hipertensos controlados bajo supresi&#243;n cr&#243;nica del SRA durante un m&#237;nimo de 2<span class="elsevierStyleHsp" style=""></span>a&#241;os&#46; Aquellos pacientes con hipertensi&#243;n arterial secundaria fueron excluidos del estudio&#46; Se incluy&#243; a pacientes con diabetes mellitus y sin ella de entre 45 y 70 a&#241;os&#46; El estudio se realiz&#243; seg&#250;n las recomendaciones de la Declaraci&#243;n de Helsinki y fue aprobado por el Comit&#233; de &#201;tica del Hospital 12 de Octubre&#44; previo consentimiento informado de los pacientes&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Los sujetos se clasificaron seg&#250;n el valor de ACR en 3 grupos&#58; normo &#40;N&#41;&#44; los individuos con ACR&#160;&#60;&#160;10&#160;mg&#47;g&#44; de los que&#44; seg&#250;n el estudio ROADMAP&#44; se sabe que no desarrollar&#225;n albuminuria<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">23</span></a>&#59; normal-alta &#40;NA&#41;&#44; los individuos con ACR&#160;&#61;&#160;10-30&#160;mg&#47;g &#40;varones&#41; o 20-40&#160;mg&#47;g &#40;mujeres&#41; y microalbuminuria &#40;M&#41;&#44; los individuos con ACR&#160;&#61;&#160;30-200&#160;mg&#47;g o 40-300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#44; respectivamente&#46; Las gu&#237;as cl&#237;nicas emplean como criterio de clasificaci&#243;n general un punto de corte de ACR&#160;&#61;&#160;30<span class="elsevierStyleHsp" style=""></span>mg&#47;g entre albuminuria y albuminuria moderadamente elevada<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">24</span></a>&#46; En el caso de las mujeres&#44; el punto de corte se ha aumentado ligeramente a 40<span class="elsevierStyleHsp" style=""></span>mg&#47;g<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a>&#44; considerando que la liberaci&#243;n de creatinina en orina se ve influida por la masa muscular&#46; La <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> recoge las caracter&#237;sticas cl&#237;nicas de los sujetos incluidos en el estudio&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">An&#225;lisis metabol&#243;mico de la orina mediante espectrometr&#237;a de masas dirigida</span><p id="par0030" class="elsevierStylePara elsevierViewall">Se recogi&#243; la primera orina de la ma&#241;ana&#44; se centrifug&#243; para eliminar restos celulares y se almacen&#243; a &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C hasta su an&#225;lisis&#46; El an&#225;lisis cuantitativo de los metabolitos se realiz&#243; mediante cromatograf&#237;a l&#237;quida acoplada a espectrometr&#237;a de masas dirigida en modo <span class="elsevierStyleItalic">selected reaction monitoring</span> &#40;SRM-LC-MS&#47;MS&#41;&#46; Esta metodolog&#237;a fue seleccionada como m&#233;todo del a&#241;o por la revista <span class="elsevierStyleItalic">Nature Methods</span> 2012<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a>&#46; Con base en estudios previos de nuestro laboratorio&#44; se extrajeron los metabolitos de la orina tras la eliminaci&#243;n de la fracci&#243;n proteica por precipitaci&#243;n org&#225;nica<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">27&#44;28</span></a>&#46; El sobrenadante se filtr&#243; y se analiz&#243; en un espectr&#243;metro de masas Triple Cuadrupolo QQQ6460 &#40;Agilent Technologies&#41; acoplado a un sistema binario de cromatograf&#237;a l&#237;quida &#40;1200 series&#44; Agilent Technologies&#41; controlado por el programa Mass Hunter &#40;v4&#46;0 Agilent Technologies&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">An&#225;lisis estad&#237;stico</span><p id="par0035" class="elsevierStylePara elsevierViewall">La se&#241;al correspondiente a cada metabolito se integr&#243; mediante el programa Mass Hunter Adquisition Data Qualitative Analysis B&#46;04&#46;00 &#40;Agilent Technologies&#41; y se obtuvo el &#225;rea de pico&#46; Se realiz&#243; un an&#225;lisis estad&#237;stico no param&#233;trico Mann-Whitney&#44; con un 95&#37; de nivel de confianza y previa detecci&#243;n de <span class="elsevierStyleItalic">outliers</span> mediante el m&#233;todo ROUT &#40;valor Q&#160;&#61;&#160;5&#37;&#41;&#46; Para el an&#225;lisis de correlaciones se emple&#243; un test no param&#233;trico de correlaci&#243;n de Spearman&#44; todo ello mediante el programa GraphPad Prism &#40;versi&#243;n 6&#46;01&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Resultados y discusi&#243;n</span><p id="par0040" class="elsevierStylePara elsevierViewall">Oxalacetato&#44; guanidoacetato y 3-ureidopropionato muestran niveles inferiores en el grupo de individuos con microalbuminuria &#40;M&#41; respecto a aquellos en la condici&#243;n de normoalbuminuria &#40;N&#41;&#46; El malato&#44; en cambio&#44; muestra niveles superiores en M respecto a N &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Estos datos confirman observaciones previas en pacientes con albuminuria&#44; bien desarrollada durante los 3 a&#241;os de seguimiento previos a la toma de muestra &#40;albuminuria <span class="elsevierStyleItalic">de novo</span>&#41; o ya presente con anterioridad &#40;albuminuria mantenida&#41;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">22</span></a>&#46; Cabe destacar que estos 4<span class="elsevierStyleHsp" style=""></span>metabolitos son capaces de diferenciar entre los pacientes N y aquellos en el rango de albuminuria NA y&#44; por lo tanto&#44; permiten una estratificaci&#243;n molecular m&#225;s temprana de los pacientes&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Paralelamente se realiz&#243; un estudio de la correlaci&#243;n entre los niveles de los metabolitos en orina y los valores de ACR para cada paciente&#44; en el que result&#243; en todos los casos una correlaci&#243;n estad&#237;sticamente significativa &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Se ha descrito un aumento del estr&#233;s oxidativo asociado al desarrollo de albuminuria<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">29</span></a>&#46; El estr&#233;s oxidativo es causado por una desregulaci&#243;n en la producci&#243;n y metabolismo de las especies reactivas de ox&#237;geno&#44; en cuya regulaci&#243;n intracelular participa el ciclo de los &#225;cidos tricarbox&#237;licos&#46; Las alteraciones observadas en los niveles de oxalacetato y malato en pacientes con albuminuria en el rango normal-alta y microalbuminuria se&#241;alan nuevamente al metabolismo energ&#233;tico como una pieza clave en el manejo de los pacientes hipertensos<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a>&#46; El guanidoacetato es un intermediario en el metabolismo de la arginina y prolina y precursor de la creatina&#44; un sustrato de la creatinquinasa&#46; Esta enzima se ha relacionado con un fracaso del tratamiento antihipertensivo&#44; sin conocerse en detalle los mecanismos que lo provocan<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a>&#46; Por otro lado&#44; se ha propuesto el guanidoacetato como marcador de lesi&#243;n renal&#58; muestra un nivel reducido en la orina de pacientes trasplantados con funci&#243;n renal normal<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a>&#46; Las alteraciones de estos metabolismos se&#241;alan&#44; por tanto&#44; una desregulaci&#243;n temprana de los metabolismos de energ&#237;a y de la arginina y prolina ya en pacientes con albuminuria en el rango normal-alta&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Como limitaciones del estudio cabe destacar diferencias en algunas de las caracter&#237;sticas basales de los grupos cl&#237;nicos comparados&#44; en particular&#44; en lo que se refiere al porcentaje de individuos diab&#233;ticos&#46; Si bien es esperable una mayor presencia de diabetes mellitus en el grupo de sujetos con microalbuminuria&#44; ser&#237;a de inter&#233;s evaluar en una mayor cohorte de sujetos &#250;nicamente no diab&#233;ticos las variaciones metab&#243;licas observadas para determinar exactamente el grado de contribuci&#243;n de la diabetes&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusiones</span><p id="par0060" class="elsevierStylePara elsevierViewall">En este estudio hemos confirmado la asociaci&#243;n de los niveles de los metabolitos 3-ureidopropionato&#44; oxalacetato&#44; malato y guanidoacetato con distintos grados de albuminuria&#46; Por vez primera&#44; se ha identificado una huella molecular &#40;panel metab&#243;lico&#41; capaz de mostrar variaci&#243;n dentro de la condici&#243;n de normoalbuminuria&#44; distinguiendo entre sujetos con ACR&#160;&#60;&#160;10&#160;mg&#47;g o superior&#46; Este hecho es destacable por cuanto que supone una herramienta con un enorme potencial en el manejo terap&#233;utico de pacientes hipertensos con niveles de ACR considerados &#171;no patol&#243;gicos&#187; y que&#44; por lo tanto&#44; no reciben una atenci&#243;n m&#233;dica especial&#46; Sin embargo&#44; son estos pacientes los que m&#225;s se beneficiar&#237;an de una intervenci&#243;n temprana&#44; ya que presentan un mayor riesgo de enfermedad renal o cardiovascular&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Financiaci&#243;n</span><p id="par0065" class="elsevierStylePara elsevierViewall">Instituto de Salud Carlos III-Fondos FEDER &#40;PI16&#47;01334&#44; PI13&#47;01873&#44; PI17&#47;01193&#44; PI17&#47;01093&#44; IF08&#47;3667-1&#44; CPII15&#47;00027&#44; CP15&#47;00129&#44; PT13&#47;0001&#47;0013&#44; PRB3 &#40;IPT17&#47;0019 ISCIIIS-GEFI&#47;ERDF&#41;&#44; REDinREN &#40;RD16&#47;0009&#41;&#41;&#44; Ayuda a la Investigaci&#243;n de la Fundaci&#243;n SENEFRO y Fundaci&#243;n Conchita R&#225;bago de Jim&#233;nez D&#237;az&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicto de intereses</span><p id="par0070" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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          "titulo" => "Resultados y discusi&#243;n"
        ]
        7 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Conclusiones"
        ]
        8 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Financiaci&#243;n"
        ]
        9 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflicto de intereses"
        ]
        10 => array:2 [
          "identificador" => "xack479639"
          "titulo" => "Agradecimientos"
        ]
        11 => array:1 [
          "titulo" => "Bibliograf&#237;a"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2019-06-21"
    "fechaAceptado" => "2019-10-24"
    "PalabrasClave" => array:2 [
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1267481"
          "palabras" => array:7 [
            0 => "Albuminuria"
            1 => "Riesgo cardiovascular"
            2 => "Hipertensi&#243;n"
            3 => "Sistema renina-angiotensina"
            4 => "Metabol&#243;mica"
            5 => "Biomarcadores"
            6 => "Metabolitos"
          ]
        ]
      ]
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1267480"
          "palabras" => array:7 [
            0 => "Albuminuria"
            1 => "Cardiovascular risk"
            2 => "Hypertension"
            3 => "Renin-angiotensin system"
            4 => "Metabolomics"
            5 => "Biomarkers"
            6 => "Metabolites"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes y objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La albuminuria es un indicador de da&#241;o org&#225;nico subcl&#237;nico y un marcador de riesgo cardiovascular y de enfermedad renal&#46; Un porcentaje de pacientes hipertensos desarrollan albuminuria a pesar de estar bajo supresi&#243;n cr&#243;nica del sistema renina-angiotensina &#40;SRA&#41;&#46; Previamente identificamos metabolitos en orina asociados al desarrollo de albuminuria&#46; En este estudio&#44; investigamos alteraciones metab&#243;licas que reflejen distintos niveles dentro de la condici&#243;n de normoalbuminuria&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes&#44; materiales y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se analiz&#243; la orina de 48 pacientes hipertensos con supresi&#243;n cr&#243;nica del SRA&#46; Se clasificaron seg&#250;n el cociente alb&#250;mina&#47;creatinina &#40;ACR&#41; en 3 grupos&#58; normoalbuminuria &#40;&#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#41;&#59; normal-alta &#40;10-30<span class="elsevierStyleHsp" style=""></span>mg&#47;g en varones&#44; o 20-40<span class="elsevierStyleHsp" style=""></span>mg&#47;g en mujeres&#41; y albuminuria moderadamente elevada &#40;microalbuminuria&#58; 30-200<span class="elsevierStyleHsp" style=""></span>mg&#47;g o 40-300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#44; respectivamente&#41;&#46; El metaboloma se analiz&#243; mediante espectrometr&#237;a de masas y se realiz&#243; un an&#225;lisis de correlaciones entre los niveles de los metabolitos alterados y ACR&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Oxalacetato&#44; 3-ureidopropionato&#44; guanidoacetato y malato muestran una variaci&#243;n significativa entre los grupos normo y micro&#46; Adem&#225;s&#44; estos metabolitos son capaces de diferenciar entre los pacientes normo y normal-alta&#46; Igualmente se observ&#243; correlaci&#243;n significativa entre el nivel de los metabolitos identificados con el nivel de ACR&#46; Las variaciones observadas se&#241;alan una alteraci&#243;n del metabolismo energ&#233;tico ya en pacientes con albuminuria en el rango normal-alta&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Se confirma la asociaci&#243;n del panel molecular constituido por 3-ureidopropionato&#44; oxalacetato&#44; malato y guanidoacetato con distintos niveles de albuminuria&#46; As&#237; mismo&#44; se ha identificado una huella metab&#243;lica capaz de mostrar variaci&#243;n dentro de la condici&#243;n de normoalbuminuria&#44; lo que permite una estratificaci&#243;n molecular m&#225;s temprana de los pacientes&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Antecedentes y objetivo"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Pacientes&#44; materiales y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Background and aim</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Albuminuria is an indicator of sub-clinical organ damage and a marker of cardiovascular risk and renal disease&#46; A percentage of hypertensive patients develop albuminuria despite being under chronic suppression of the renin-angiotensin system &#40;RAS&#41;&#46; We previously identified urinary metabolites associated with the development of albuminuria&#46; In this study&#44; we searched for metabolic alterations which reflect different levels within the condition of normoalbuminuria&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients&#44; materials and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Urine from 48 hypertensive patients under chronic RAS suppression was analysed&#46; They were classified according to the albumin&#47;creatinine ratio &#40;ACR&#41; into 3<span class="elsevierStyleHsp" style=""></span>groups&#58; Normoalbuminuria &#40;&#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#41;&#59; high-normal &#40;10-30<span class="elsevierStyleHsp" style=""></span>mg&#47;g in men&#44; or 20-40<span class="elsevierStyleHsp" style=""></span>mg&#47;g in women&#41;&#59; and moderately high albuminuria &#40;microalbuminuria&#44; 30-200<span class="elsevierStyleHsp" style=""></span>mg&#47;g or 40-300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#44; respectively&#41;&#46; The metabolome was analysed by mass spectrometry and a correlation analysis was performed between altered metabolite levels and ACR&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Oxaloacetate&#44; 3-ureidopropionate&#44; guanidoacetate and malate show significant variation between the normo and micro groups&#46; Additionally&#44; these metabolites are able to differentiate between patients in the normo and high-normal range&#46; A significant correlation between metabolites and ACR was found&#46; Observed variations point to alterations in the energy metabolism already in patients with albuminuria in the high-normal range&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The association between the molecular panel consisting of 3-ureidopropionate&#44; oxaloacetate&#44; malate and guanidoacetate and different levels of albuminuria is confirmed&#46; A metabolic fingerprint was also identified showing variations within the condition of normoalbuminuria allowing an earlier molecular stratification of patients&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Background and aim"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Patients&#44; materials and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusions"
          ]
        ]
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 768
            "Ancho" => 2986
            "Tamanyo" => 158883
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        "descripcion" => array:1 [
          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Huella metab&#243;lica en orina asociada al desarrollo de albuminuria&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">M&#58; microalbuminuria&#59; N&#58; normo&#59; NA&#58; normal-alta&#59; u&#46;a&#46;&#58; unidades arbitrarias&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#44;05&#46; &#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#44;01&#46; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#44;001&#46; &#42;&#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#44;0001&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figura 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 780
            "Ancho" => 3140
            "Tamanyo" => 169380
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        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Correlaciones observadas entre los metabolitos identificados en orina y el nivel de ACR&#46; Correlaci&#243;n de Spearman&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">u&#46;a&#58; unidades arbitrarias&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Tabla 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Tabla "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ACR se expresa como mediana &#40;rango intercuart&#237;lico&#41;&#46; El resto de las variables se expresan como frecuencias o como media &#177; desviaci&#243;n est&#225;ndar&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ACR&#58; cociente alb&#250;mina&#47;creatinina&#59; ARA&#58; antagonista de los receptores de angiotensina&#59; eGFR&#58; filtrado glomerular estimado&#59; IECA&#58; inhibidores de la enzima convertidora de angiotensina&#59; PAD&#58; presi&#243;n arterial diast&#243;lica&#59; PAS&#58; presi&#243;n arterial sist&#243;lica&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normo &#40;n&#160;&#61;&#160;22&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normal-alta &#40;n&#160;&#61;&#160;17&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Microalbuminuria &#40;n&#160;&#61;&#160;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Edad &#40;a&#241;os&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">57 &#177; 9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">64 &#177; 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">65 &#177; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sexo &#40;&#37; masculino&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Colesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">179 &#177; 38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">166 &#177; 29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">154 &#177; 29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Triglic&#233;ridos &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">110 &#177; 33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">125 &#177; 59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">122 &#177; 32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Colesterol HDL &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">54 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">53 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">50 &#177; 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colesterol LDL &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">102 &#177; 31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#177; 30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">91 &#177; 26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&#193;cido &#250;rico&#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5 &#177; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">6 &#177; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7 &#177; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">eGFR &#40;ml&#47;min&#47;1&#44;73&#160;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">86 &#177; 16&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">85 &#177; 20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">93 &#177; 22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">ACR &#40;mg&#47;g&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4 &#40;3-6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">22 &#40;18-31&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">85 &#40;44-99&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Diabetes mellitus tipo II &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">PAS &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">140 &#177; 14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">144&#177;14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">141 &#177; 19&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PAD &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">85&#177;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">83&#177;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">79 &#177; 5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tratamiento antihipertensivo &#40;&#37;&#41;</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Diur&#233;ticos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&#945;-bloqueantes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-bloqueantes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Bloqueantes del canal de calcio&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">71&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">78&nbsp;\t\t\t\t\t\t\n
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          "es" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas cl&#237;nicas de los pacientes incluidos en el estudio</p>"
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      ]
    ]
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      "titulo" => "Bibliograf&#237;a"
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        0 => array:2 [
          "identificador" => "bibs0015"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2018 ESC&#47;ESH Guidelines for the management of arterial hypertension"
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                        0 => array:2 [
                          "etal" => true
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                            0 => "B&#46; Williams"
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                            2 => "W&#46; Spiering"
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                            5 => "M&#46; Burnier"
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                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehy339"
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                        "tituloSerie" => "Eur Heart J&#46;"
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                        0 => array:2 [
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                            0 => "C&#46; Cerezo"
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                            2 => "J&#46; Segura"
                            3 => "J&#46;A&#46; Garcia-Donaire"
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                      "doi" => "10.1097/HJH.0b013e32834d9e0f"
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                        "tituloSerie" => "J Hypertens&#46;"
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                            2 => "J&#46;B&#46; Meigs"
                            3 => "T&#46;J&#46; Wang"
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                      "doi" => "10.1186/1471-2369-13-37"
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                        "tituloSerie" => "BMC Nephrol&#46;"
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                        "volumen" => "13"
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                      "titulo" => "Microalbuminuria as a risk predictor in diabetes&#58; The continuing saga"
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                          "etal" => false
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Change in albuminuria and subsequent risk of end-stage kidney disease&#58; An individual participant-level consortium meta-analysis of observational studies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Coresh"
                            1 => "H&#46;J&#46;L&#46; Heerspink"
                            2 => "Y&#46; Sang"
                            3 => "K&#46; Matsushita"
                            4 => "J&#46; Arnlov"
                            5 => "B&#46;C&#46; Astor"
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                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet Diabetes Endocrinol&#46;"
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                        "paginaInicial" => "115"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High-normal albuminuria and incident chronic kidney disease in a male nondiabetic population"
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                          "etal" => false
                          "autores" => array:6 [
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Información del artículo

ISSN: 02116995
Idioma original: Español

DOI:10.1016/j.nefro.2019.10.007

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