Mineralcorticoid receptor blockers in chronic kidney disease

array:25 ["pii" => "S2013251421000675" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2021.08.001" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "785" "copyright" => "Sociedad Española de Nefrología" "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Nefrologia (English Version). 2021;41:258-75" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S021169952030165X" "issn" => "02116995" "doi" => "10.1016/j.nefro.2020.10.001" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "785" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Nefrologia. 2021;41:258-75" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Revisión" "titulo" => "Bloqueantes del receptor mineralcorticoide en la enfermedad renal crónica" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "258" "paginaFinal" => "275" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Mineralcorticoid receptor blockers in chronic kidney disease" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "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" => 1662 "Ancho" => 3000 "Tamanyo" => 499408 ] ] "descripcion" => array:1 [ "es" => "1) En situación basal, el receptor mineralcorticoide (RM) se localiza predominantemente en el citoplasma formando parte de un complejo con la chaperona heat shock protein (Hsp90), que facilita su unión al ligando, y con la inmunofilina FK506-binding protein of 51 kDa (FKBP51). Tras su unión al ligando, la inmunofilina FKBP51 es sustituida por la FBBP52, que facilita el tránsito del complejo RM-ligando desde el citoplasma al núcleo. Una vez en el nucleoplasma, el RM-ligando se disocia de la chaperona y de la inmunofilina para unirse al ADN y formar dímeros. El RM se une a secuencias específicas de ADN denominadas hormone response element (HRE) para regular la transcripción de genes diana (en la figura se exponen algunos de ellos). La actividad transcripcional mediada por RM puede ser aumentada o reprimida por proteínas reguladoras como steroid receptor coactivator 1 (SRC1), cAMP-response element binding protein (CBP) y transcriptional intermediary factor 1a (TIF1a), entre otros. 2. El complejo RM-ligando pueden interactuar con otros factores de transcripción como cAMP response element-binding protein (CREB) y nuclear factor of activated T-cells (NFAT), que pueden influir en la transcripción. La aldosterona también se une al RM anclado en la membrana celular por caveolina (Cav1) y estriatina transactivando receptores de membrana como epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), insulin like growth factor receptor (IGF1R), vascular endotelial growth factor receptor (VEGFR), G protein coupled estrogen receptor (GPER) y angiotensin II receptor type I (AT1R). Todo ello promueve señales que implican, entre otros efectos, activación de cinasas. Estos eventos son responsables de los efectos rápidos, no genómicos, de la aldosterona. 3. Es posible la activación del receptor RM sin concurso del ligando. La activación de Ras-related C3 botulinum toxin substrate 1 (Rac1) por estímulos como estrés oxidativo, glucosa, AII, entre otros, puede promover la translocación del RM al núcleo y su actividad transcripcional." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sara Erraez, Manuel López-Mesa, Pablo Gómez-Fernández" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Sara" "apellidos" => "Erraez" ] 1 => array:2 [ "nombre" => "Manuel" "apellidos" => "López-Mesa" ] 2 => array:2 [ "nombre" => "Pablo" "apellidos" => "Gómez-Fernández" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2013251421000675" "doi" => "10.1016/j.nefroe.2021.08.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251421000675?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S021169952030165X?idApp=UINPBA000064" "url" => "/02116995/0000004100000003/v1_202105080820/S021169952030165X/v1_202105080820/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2013251421000717" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2021.08.004" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "809" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Nefrologia (English Version). 2021;41:276-83" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "FGF23: From academic nephrology to personalized patients’ care" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "276" "paginaFinal" => "283" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "FGF23: de la nefrología de salón a la cabecera del paciente" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1487 "Ancho" => 2500 "Tamanyo" => 296239 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "FGF23, a biomarker of early phosphate retention and a therapeutic target. Therapeutic strategy 1: Faced with the loss of nephrons and klotho, an early adaptive increase in FGF23 occurs (eGFR: 75 mL/min/1.73 m2) to maintain normophosphatemia. When the compensatory phosphaturic capacity of FGF23 plus PTH is exceeded, hyperphosphatemia occurs which is usually observed with (eGFR: 30 mL/min/1.73 m2. and the vascular toxic effect of phosphate is present already. The precocity of its elevation, together with its predictive value of mortality in conditionsof normophosphatemia, supports the usefulness of the quantification of FGF23, especially in the first stages of CKD, allowing to identify those normophosphatemic patients with a “maladaptive increase”, reflecting greater problems to control phosphorus, and that would require the adoption of more rigorous therapeutic measures. Therapeutic strategy 2: In the final stages of CKD, the absence of nephrons and klotho generate resistance to the action of FGF23 and circulating levels of FGF23 are unlimited. These exaggerated values of FGF23 are capable of activating other FGFR receptors producing pathology in other organs and systems that do not express klotho. In this situation, FGF23 becomes a therapeutic target in an attempt to avoid toxicity. CKD: chronic kidney disease; FGF23: fibroblast growth factor 23; FGFR: fibroblast growth factor receptor; PTH: parathyroid hormone." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María Luisa González-Casaus, Emilio Gonzalez-Parra, Pilar Fernandez-Calle, Antonio Buño-Soto" "autores" => array:4 [ 0 => array:2 [ "nombre" => "María Luisa" "apellidos" => "González-Casaus" ] 1 => array:2 [ "nombre" => "Emilio" "apellidos" => "Gonzalez-Parra" ] 2 => array:2 [ "nombre" => "Pilar" "apellidos" => "Fernandez-Calle" ] 3 => array:2 [ "nombre" => "Antonio" "apellidos" => "Buño-Soto" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699520301910" "doi" => "10.1016/j.nefro.2020.09.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699520301910?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251421000717?idApp=UINPBA000064" "url" => "/20132514/0000004100000003/v1_202109180529/S2013251421000717/v1_202109180529/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2013251421000572" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2021.06.003" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "834" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Nefrologia (English Version). 2021;41:244-57" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Interleukin-17A: Potential mediator and therapeutic target in hypertension" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "244" "paginaFinal" => "257" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Interleuquina-17A: potential mediador y diana terapéutica en la hipertensión" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2352 "Ancho" => 2508 "Tamanyo" => 361321 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Molecular mechanisms regulated by IL-17A in vascular smooth muscle cells and in endothelial cells." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Raúl R. Rodrigues-Diez, Antonio Tejera-Muñoz, Macarena Orejudo, Laura Marquez-Exposito, Laura Santos-Sanchez, Sandra Rayego-Mateos, Elena Cantero-Navarro, Lucia Tejedor-Santamaria, Vanessa Marchant, Alberto Ortiz, Jesús Egido, Sergio Mezzano, Rafael Selgas, Juan F. Navarro-González, Jose M. Valdivielso, Carolina Lavoz, Marta Ruiz-Ortega" "autores" => array:17 [ 0 => array:2 [ "nombre" => "Raúl R." "apellidos" => "Rodrigues-Diez" ] 1 => array:2 [ "nombre" => "Antonio" "apellidos" => "Tejera-Muñoz" ] 2 => array:2 [ "nombre" => "Macarena" "apellidos" => "Orejudo" ] 3 => array:2 [ "nombre" => "Laura" "apellidos" => "Marquez-Exposito" ] 4 => array:2 [ "nombre" => "Laura" "apellidos" => "Santos-Sanchez" ] 5 => array:2 [ "nombre" => "Sandra" "apellidos" => "Rayego-Mateos" ] 6 => array:2 [ "nombre" => "Elena" "apellidos" => "Cantero-Navarro" ] 7 => array:2 [ "nombre" => "Lucia" "apellidos" => "Tejedor-Santamaria" ] 8 => array:2 [ "nombre" => "Vanessa" "apellidos" => "Marchant" ] 9 => array:2 [ "nombre" => "Alberto" "apellidos" => "Ortiz" ] 10 => array:2 [ "nombre" => "Jesús" "apellidos" => "Egido" ] 11 => array:2 [ "nombre" => "Sergio" "apellidos" => "Mezzano" ] 12 => array:2 [ "nombre" => "Rafael" "apellidos" => "Selgas" ] 13 => array:2 [ "nombre" => "Juan F." "apellidos" => "Navarro-González" ] 14 => array:2 [ "nombre" => "Jose M." "apellidos" => "Valdivielso" ] 15 => array:2 [ "nombre" => "Carolina" "apellidos" => "Lavoz" ] 16 => array:2 [ "nombre" => "Marta" "apellidos" => "Ruiz-Ortega" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699521000229" "doi" => "10.1016/j.nefro.2020.11.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699521000229?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251421000572?idApp=UINPBA000064" "url" => "/20132514/0000004100000003/v1_202109180529/S2013251421000572/v1_202109180529/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Mineralcorticoid receptor blockers in chronic kidney disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "258" "paginaFinal" => "275" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Sara Erraez, Manuel López-Mesa, Pablo Gómez-Fernández" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Sara" "apellidos" => "Erraez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Manuel" "apellidos" => "López-Mesa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "Pablo" "apellidos" => "Gómez-Fernández" "email" => array:1 [ 0 => "pgomezf@senefro.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Factores de Riesgo Vascular, Nefrología, Hospital Universitario de Jerez, Jerez de la Frontera, Cádiz, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro de salud El Posito, Arcos de la Frontera, Cádiz, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bloqueantes del receptor mineralcorticoide en la enfermedad renal crónica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 899 "Ancho" => 2503 "Tamanyo" => 132879 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanisms of kidney damage produced by aldosterone and the activation of the mineralocorticoid receptor (MR)." ] ] ] "textoCompleto" => "IntroductionConsiderable evidence implicates the renin-angiotensin-aldosterone system (RAAS) in the progression of chronic kidney disease (CKD) Blocking the generation and action of angiotensin II (AII) by AII converting enzyme inhibitors (iACEi) and the A II AT1 receptor blockers (ARA2) have shown to be useful to reduce the progression of diabetic and non-diabetic nephropathy<a class="elsevierStyleCrossRefs" href="#bib0005">1–5</a> and to decrease cardiovascular (CV) morbidity and mortality and mortality of any cause.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Mineralocorticoid receptor (MR) blockade with spironolactone and eplerenone adds an antiproteinuric effect when associated to ACEI or ARA2. However, so far, there is no consistent evidence show in a benefit of MR blockade in the progression of CKD or in reducing CV events and total mortality in CKD. However, MR blockade in patients with heart failure with reduced ejection fraction (EF) decrases CV events and mortality.<a class="elsevierStyleCrossRefs" href="#bib0035">7–9</a>Physiology/pathophysiology of aldosterone/MRAldosterone was isolated in 1953 by Simpson et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> It is produced mainly by glomerulosa cells of the adrenal glands. Under certain circumstances, aldosterone is produced in the heart, blood vessels, and adipocytes.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> Increased expression of aldosterone synthetase (AS) has been shown in human coronary arteries from multi-organ donors, and it is increased in subjects with renal failure and correlates with the vascular expression of the osteoblastic transforming factor: core binding factor alpha 1 (CBFa1).13The A II and an increase in K+ concentration are the main aldosterone secretagogues. However, other factors such as ACTH, catecholamines, endothelin, and adipocyte-derived products, such as leptin, adiponectin, and C1qTNF-related protein 1 (CTRP1), also stimulate adrenal secretion of aldosterone.<a class="elsevierStyleCrossRefs" href="#bib0060">12,14</a>In culture of aortic vascular smooth muscle cells, the presence of phosphorus in the medium induces an increase in the vascular expression of AS.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> This fact may be relevant in CKD. In addition, in adrenal glands it has been demonstrated colocalization of klotho-AS and in klotho haplodeficient animals there is an increase in the expression of AS.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>The MR was cloned in 1997.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> It is a protein of 107 kD encoded by a gene located on chromosome 14. It has three domains: an N-terminal domain, another domain that binds to DNA and a third domain that is assembled to the ligand. Certain coactivators and co-repressors bind some domains, that can be tissue-specific and modulate specific actions in certain organs.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> There are MR in the renal collecting duct and colon (classic sites), and also in other locations<a class="elsevierStyleCrossRefs" href="#bib0090">18–25</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Cortisol also binds to MR. In epithelial cells and vascular endothelium, the enzyme 11-βOH-steroid dehydrogenase converts cortisol into cortisone, thus preventing its binding to MR.The MR is not inserted directly into the cell membrane. In a basal state, not bound to the ligand, the RM is located predominantly in the cytoplasm bound to chaperones that facilitate its binding to the ligand and serve as shuttles of the RM-ligand complex to the nucleus.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> The aldosterone-RM binding promotes several effects: (1) the RM complex and its ligand are translocated to the nucleus where it forms dimers and activates genes encoding certain proteins (genomic effects) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); There may be interaction with other cytoplasmic transcription factors such as nuclear factor of activated T-cells (NAFT) and cAMP response element-binding protein (CREB) that can modify genomic signals; (2) in addition to the genomic effects, there may be fast non-genomic effects. The aldosterone-MR complex can directly activate cytoplasmic kinases through its interaction with membrane receptors.<a class="elsevierStyleCrossRefs" href="#bib0130">25,26</a> Aldosterone binds to MR that is anchored in the membrane by caveolin and striatin and interacts with membrane receptors such as epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), insulin like growth factor receptor (IGF1R), vascular endothelial growth factor receptor (VEGFR), G protein coupled estrogen receptor (GPER) and angiotensin II receptor type I (AT1R). This interaction is responsible for the non-genomic effects of aldosterone mainly related with electrolyte transport and vasomotor tone (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The genomic signals of MR-aldosterone can be modified by epigenetic signals and undergo post-transcriptional changes. Also the redox status and the amount of reactive oxygen species (ROS) influence the cellular processes and even the activation mechanism triggered by the activation of MR.The activation and transcriptional effect of MR may occur without its binding to the ligand (aldosterone or cortisol). Activation of ras-related C3 botulinum substrate 1 (Rac1) may cause MR stimulation with its transcriptional activity independently of aldosterone<a class="elsevierStyleCrossRef" href="#bib0135">27</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Rac1 is a member of the RhoGTPase subfamily that transduces extracellular signals from G protein-coupled receptors, integrins, and growth factors to effector molecules that modulate multiple signaling pathways. Various stimuli, such as mechanical stretching, inflammatory cytokines, growth factors, glucose, aldosterone, and oxidative stress, among others, activate Rac1.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> In vitro studies show that Rac1 improves the transcriptional activity of MR by increasing its nuclear translocation.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Studies in animal models with increased Rac1 activation, the Rac1-MR interaction is associated with proteinuria and podocyte damage, without changes in aldosterone levels. Pharmacological inhibition of Rac or the use of MR antagonist inhibits the hyperactivity of MR and reduced renal histological changes and proteinuria.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Mesangial cells cultured in high glucose increase Rac1 activity, and mayenhance the transcriptional activity of the MR induced by aldosterone; also it may increase transcriptional activity of the RM in the absence of aldosterone in the medium.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> In animal models of obesity-related diabetic nephropathy in which there is an increase in plasma aldosterone concentration and renal Rac1 activity, administration of a specific Rac inhibitor suppressed renal Rac1, decreased MR activation, and attenuated renal damage, all without changes in the aldosterone level.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> In the murine model of salt-sensitive HT, the high-salt diet increases renal Rac1 activity and produces MR activation at the renal level, and induces HTN and kidney damage despite low plasma aldosterone levels. The opposed, Rac inhibition prevented hypertension and kidney damage. The infusion of aldosterone enhanced the activation of the MR by Rac1 which demonstrate an additive effect of Rac1 and aldosterone.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>In most of these studies, the increase in MR transcriptional activity induced by Rac1 was due to an increase in nuclear translocation of MR. There are other mechanisms could participate in the increase in MR signals mediated by Rac1: both the amount and modifications of signals (phosphorylation, acetylation, sumoylation (small ubiquitin-related modifier) of MR, changes in its efficacy after activation due to epigenetic modifications or recruitment of co-regulators, among others.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Aldosterone-independent MR modulation by Rac1 may be of great relevance not only because it enhances the MR activation exerted by aldosterone, but also because it activates MR, promoting organ dysfunction in situations in which the plasma concentration of aldosterone is normal or reduced, as frequently occurs in DM with renal involvement and in salt-sensitive HT, among others. It would also explain that the effect of MR antagonists is not correlated on many occasions with the plasma concentration of aldosterone.Effects of aldosterone on the renal tubuleThe first action described of aldosterone was on the main cells of the renal collecting duct. After translocation to the nucleus, the aldosterone-MR complex interacts with a large number of genes that encode proteins such as the alpha subunit of the epithelial sodium channel (ENaC) and serum and gluco-corticoid-regulated kinase 1 (SGK1), which control the amount and the activity of ENaC in the apical part of the membrane and of the Na-K-ATPase pump in the basolateral membrane. The electrogenic increase in tubular reabsorption of Na+ secondary to the activation of ENaC favors the secretion of K+ by the renal outer medullary K+ channel (ROMK).<a class="elsevierStyleCrossRef" href="#bib0160">32</a> Recent findings show that in the presence of hypokalemia, aldosterone activates the pendrin, ATPase dependent H+ secretion and the thiazide sensitive cotransporter Na+–Cl− (NCC).<a class="elsevierStyleCrossRefs" href="#bib0165">33–35</a>Aldosterone exerts tubular effects that affect the afferent arteriole and, therefore, glomerular filtration (GFR). The macula densa (MD) contains MR whose activation by aldosterone increases nitric oxide production with attenuation of the tubulo-glomerular feedback (TGF) response (decrease in the afferent arteriole vasoconstrictor response induced by the delivery of Na+ to MD).<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In addition, by activating ENaC and increasing distal Na+ reabsorption, it induces vasodilation of the afferent arteriole (tubule connecting-glomerulus feedback [TCGF]), which also antagonizes TGF.<a class="elsevierStyleCrossRefs" href="#bib0185">37,38</a>Vascular effects of aldosteroneIn addition to this indirect effect on glomerular hemodynamics, aldosterone has a direct impact on the systemic and renal vasculature. There are MR on the endothelium and the smooth muscle cell. In blood vessels, it regulates genes involved in fibrosis, calcification, and inflammation. The degree of regulation depends on other factors, such as type of flow (laminar/turbulent) and oxidative stress, among others. Endothelial MR activation produces an increase in endothelial ENaC expression, intensifies oxidative stress and inflammation, contributing to endothelial dysfunction and increased arterial stiffness.<a class="elsevierStyleCrossRefs" href="#bib0200">39,40</a>In the vascular smooth muscle cell, MR activation contributes to the regulation of vascular tone through a series of events (activation Src kinase, Rho kinase and placental growth factor [PlGF], among others) that induce proliferation, fibrosis, remodeling and increase of arterial stiffness.<a class="elsevierStyleCrossRefs" href="#bib0135">26,39</a> Consequently, activation of vascular MR produces target organ damage, HTN, coronary vascular dysfunction, cardiac fibrosis, alterations in renal hemodynamics, and kidney damage. Many of the effects of MR activation are not genomic.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> There is intimate interaction and synergy between genomic and non-genomic effects of aldosterone such that non-genomic effects may provide support to genomic actions.Experimental data on the effects of aldosterone and MR block in models of kidney damageThere are many studies on the effect of aldosterone and the pharmacological blockade or deletion of MR in animal models of kidney damage and in vitro investigations in various types of kidney cells (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). We highlight the most relevant on the different renal structures and in the systemic vasculature.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Effects of aldosterone on renal hemodynamics and acute tubular damageAldosterone causes renal vasoconstriction by increasing Rho kinase activity, endothelin, and the AT1 receptors of AII. In animal models of renal damage induced by ischemia-reperfusion, the administration of spironolactone prior to or within 6 h of the onset of ischemia attenuates renal hypoperfusion, reduces oxidative stress and prevents structural damage (tubular necrosis) and decreases tubular damage markers such as kidney injury molecule (KIM-1) and heat shock protein (HSP72).<a class="elsevierStyleCrossRef" href="#bib0205">41</a> In the model of renal damage induced by cyclosporine, in which there is vasoconstriction of the afferent arteriole, the MR of vascular smooth muscle cells also participates by modulating the phosphorylation of their contractile proteins and the activity of their calcium L channels. Deletion of the MR of vascular smooth muscle cell prevents histological damage, vacuolization of the proximal tubular cells and overexpression of - neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>Effect on the renal interstitium. Production of interstitial fibrosisThere are several mechanisms involved in the genesis of renal interstitial fibrosis and chronic kidney damage: transformation of tubular cells into mesenchymal cells, inflammation, and inadequate tissue repair after acute kidney injury (AKI). All of these have been shown to be involved in the renal profibrotic effects of aldosterone. Human proximal tubular cells exposed to aldosterone undergo epithelial-mesenchymal transformation by activation of extracellular regulated kinases (ERK1 and 2) secondary to the generation of mitochondrial ROS.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> This increase in mitochondrial ROS is also responsible for the activation of the inflammasome nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3), which is as associated with an increase in fibrogenic interleukins IL-1b and IL-18 that is observed when proximal tubular cells HK-2 are cultured in aldosterone medium. Both the mesenchymal transition and the activation of the inflammasome are blocked by aldosterone antagonists.<a class="elsevierStyleCrossRefs" href="#bib0220">43,44</a>There is evidence that AKI can be a factor in the development of interstitial fibrosis and CKD.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> This AKI-interstitial fibrosis interconnection is mediated, in part, by the early appearance of inflammatory cells that play an important role in defective repair after AKI. In the model of AKI due to ischemia-reperfusion, finerenone, an MR antagonist, decreases interstitial fibrosis by activating the signals mediated by the IL-4 receptor, increasing anti-inflammatory M2 macrophages and decreasing the pro-inflammatory macrophage phenotype.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> In animal models of ischemia induced AKI, spironolactone administration, before or after ischemia, prevents the development of CKD by preventing the activation of inflammatory and profibrotic processes.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>Effect on glomerular cellsAldosterone participates in the alterations of various glomerular cells that possess MR and are able to produce functional and structural alterations of the glomerulus.The podocyte is a fundamental component of the glomerular filtration barrier. Alterations in the function and structure of the podocyte constitute the pathophysiological basis of many glomerular diseases including diabetic nephropathy.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> The podocyte participates in aldosterone-induced glomerular damage. In uninephrectomized rat fed a high-salt diet, the administration of aldosterone induces proteinuria, structural alterations of the podocyte and a decrease in the gene expression of the podocyte proteins nephrin and podocin. Podocyte damage is associated with increased oxidative stress and SGK1 activation. Epleronone treatment prevents podocyte damage.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> In podocyte culture, aldosterone stimulates oxidative stress and the expression of SGK1, which is inhibited by epleronone and bysuperoxide dismutase, suggesting that aldosterone affects podocyte function through oxidative stress and SGK1.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>The inflammasome NLRP3 is also involved in aldosterone-induced podocyte damage. The inflammasome activates procaspase 1 which in turn induce activation of IL-1b and IL-18. In podocytes incubated with aldosterone, it is observed an increase in the expression of NLRP3 which increases the expression of caspase 1 and the concentration of IL-1b and IL-18). The increase in oxidative stress participates in the activation of NLRP3, since it is attenuated if N-acetylcysteine is added to the medium.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Similar results are observed in in vivo experiments. The administration of aldosterone to experimental animals also induces an increase in the expression of NLPR3 in podocytes and also produces damage of the podocyte with loss of nephrin and podocin, alterations that are not observed in animals with a deletion of the NLRP3 gene.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Aldosterone contributes to the generation of glomerular inflammation and fibrosis, two fundamental processes involved in glomerular sclerosis. Both in vivo and in vitro, aldosterone stimulates the expression and activity of SGK1 in the mesangium, which is involved in the transcription of connective tissue growth factor (CTGF) and intercellular adhesion molecule (ICAM-1), which are related to the fibrosis and glomerular inflammation, respectively. These phenomena are attenuated by the administration of epleronone.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>Aldosterone also contributes to the glomerular inflammation seen in experimental glomerulonephritis (GN). In animal models of rapidly progressive GN, deletion of MR in myeloid cells, as well as therapy with RM antagonists reduced the early neutrophil infiltration of the glomerulus and later on, the glomerular recruitment of macrophage with the corresponding decreased expression of proinflammatory cytokines, diminution of crescents and better preservation of renal function.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>Systemic vascular effectsAldosterone exerts systemic vascular effects that may be relevant in CV morbidity and mortality of CKD patients. Aldosterone increases oxidative stress, promotes phenotypic changes in vascular smooth muscle cells and fibrosis of the vascular wall.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The infusion of aldosterone to experimental animals worsens endothelial function and vasodilation mediated by adenosine by reducing the A2a receptor dependent of calcium-activated K channels.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> This is relevant because the microvascular dysfunction evidenced by decrease in coronary reserve mediated by A2a predicts cardiovascular mortality in CKD patients on dialysis.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>Vascular calcifications are very frequent in the different stages of CKD, these calcifications have hemodynamic consequences and predict CV events and mortality. Important to note that in adenine - induced CKD animal model of vascular calcification, spironolactone administration attenuates vascular calcification by suppression of osteogenic transdifferentiation of vascular smooth muscle cells.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Effects of MR blockade in CKD. Clinical studiesMR blockade and HTNOne of the factors that promote CKD progression is hypertension. Aldosterone favors Na+ retention, increases blood volume, produces vasoconstriction, endothelial dysfunction, increases arterial stiffness, and alters the baroreflex response. MR blockade reduces blood pressure (BP).<a class="elsevierStyleCrossRefs" href="#bib0285">56,57</a> In resistant HTN, the addition of spironolactone to the therapeutic triad: diuretic-ARS blockade-calcium antagonist produced a greater reduction of BP than the addition of doxazosin or beta-blocker.<a class="elsevierStyleCrossRef" href="#bib0290">58</a>Resistant HTN is common in CKD. Even in CKD with well controlled BP, administration of spironolactone slows pulse wave velocity, a marker of arterial stiffness and LVH.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> The decrease in arterial stiffness benefits the heart because it reduces the central systolic BP and also favors the kidney. A rigid aorta that is not capable to mitigate the pulsatile flow generated by ventricular ejection, the fluctuations of pulsatile flow will be transmitted without attenuation to the capillaries in those organs with a low vascular resistance such as the kidney. Increased arterial stiffness is associated with a decrease in GFR.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>Plasma aldosterone values and renal expression of MR in CKDIn CKD there is an increase in plasma aldosterone which is inversely related to the GFR.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> Although, as in normal subjects, there is an inverse relationship between Na+ intake and aldosterone. However, in renal failure there is inadequate suppression of aldosterone.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> CKD is a state of relative hyperaldosteronism. The underlying cause of the increase in aldosterone when the GFR decreases, that persists despite the blockade with ACEi or ARA2, is not clear.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> There is a direct relationship between PTH/FGF23 and aldosterone, and an inverse relationship between klotho and aldosterone.<a class="elsevierStyleCrossRef" href="#bib0320">64</a> A decrease in klotho values can increase aldosterone synthesis.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The existence of imperceptibly elevated K+ values could also contribute to aldosterone elevation. In another sense, the association between elevated aldosterone values and a decrease in GFR could be due to the renal damage induced by aldosterone.In the proteinuric nephropathies it has been also demonstrated increased renal expression of the MR which correlates with the presence of inflammatory markers.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>All this, together with the experimental data, reaffirms the association between CKD and aldosterone, and raises a probable nephroprotective effect of a reduction of aldosterone values or a blockade of its effects.Aldosterone escape with drugs that block RASThe most important secretagogue of aldosterone is AII. The use and optimization of doses of drugs that block the generation or action of AII is associated with a decrease in the development and progression of CKD and death.<a class="elsevierStyleCrossRefs" href="#bib0330">66,67</a> The dual blockade of the RAS (ACEi + ARA2) reduces proteinuria compared to monotherapy, but iy is associated with a higher risk of hyperkalemia.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> In all these studies, despite therapy with ACEI, ARA2 or their combination, it persists a high residual risk of CKD progression and death.This residual risk may be in part due to the so-called aldosterone “escape”: elevation of plasma aldosterone levels, after an initial decrease, when an RAS blocker is administered. In CKD, this occurs frequently, in 40–53% of cases,<a class="elsevierStyleCrossRef" href="#bib0345">69</a> and it is associated with reappearance or the increase in proteinuria and a decrease in GFR.<a class="elsevierStyleCrossRefs" href="#bib0350">70,71</a> The cause of the aldosterone escape is unknown. An increase in serum K+ and ACTH, a decrease in atrial natriuretic peptide,<a class="elsevierStyleCrossRef" href="#bib0360">72</a> or a lack of inhibition of the receptor AT1 of the A II receptor bound to ®-arrestin1 may contribute to escape.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> The involvement of aldosterone in this phenomenon is reinforced by the finding that the administration of spironolactone reduces proteinuria after its relapse.<a class="elsevierStyleCrossRef" href="#bib0350">70</a>Effect of MR blockade on proteinuria and GFR in CKDThe first study on the effect of MR blockade in proteinuric nephropathy included 8 patients. The addition of spironolactone to ACEi achieved a 45% reduction in proteinuria, without changes in BP.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> In another study with 165 patients with non-diabetic proteinuric nephropathy treated with ACEI or ARA2, the administration of spironolactone 25 mg/day for one year reduced proteinuria by 50%. In the group receiving spironolactone it was observed that the GFR initially decreased with subsequent stabilization, while the control group showed a progressive decrease in GFR.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> This pattern of GFR behavior mimics that found with drugs that reduce hyperfiltration, an effect that, in the case of MR blockers, probably derives from their action on glomerular hemodynamics.<a class="elsevierStyleCrossRefs" href="#bib0180">36–38</a> In another study in subjects receiving RAS blockers with residual proteinuria, addition of spironolactone therapy for 2 years produced a progressive reduction in proteinuria, to a 63%. The evolution of the GFR was better in those in which the initial decrease was greater.<a class="elsevierStyleCrossRef" href="#bib0380">76</a> Various meta-analyzes have shown that aldosterone antagonists added to ACEI or ARA2 produce a significant decrease in proteinuria, a reduction in BP, but an increased risk of hyperkalemia (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0385">77–79</a>In an analysis of a database from subjects with CKD stages 3–4, the comparative study, after adequate adjustment of variables, between patients on spironolactone (n = 693) vs those who did not receive (n = 1386) showed that patients receiving spironolactone had less progression to CKD with less dialysis requirements (hazard ratio [HR] 0.66; 95% CI, 0.51−0.84; p < 0.001) and a higher risk of hospitalization due to hyperkalemia (HR 3.17; 95% CI 2.41–4.17; p < 0.001).<a class="elsevierStyleCrossRef" href="#bib0400">80</a>Recently, a probable nephroprotective effect of the sodium-glucose cotransporter type 2 (iSGLT2) inhibitor dapagliflozin has been observed in non-diabetic CKD. The DAPA-CKD (The effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease) clinical trial<a class="elsevierStyleCrossRef" href="#bib0405">81</a> included 4245 subjects with CKD stages 2–4 with increased urinary albumin excretion, with a maximum tolerated dose of ACEi or ARA2. Patients were randomized to dapagliflozin 10 mg/day or placebo. The primary endpoint was a decrease of the by GFR ≥50%, advanced CKD (FG < 15 ml/min, dialysis or renal transplant) or renal and cardiovascular death. On March 30, 2020, the trial was discontinued because it was observed, ahead of schedule, the probable benefits in the dapagliflozin branch. Although the results are not published yet, it seems presumable to attribute the early suspension of the trial to the superiority of dapagliflozin in reducing events.One of the mechanisms involved in the nephroprotective effect of iSGLT2 is the decrease in intraglomerular pressure secondary to the vasoconstriction of the afferent arteriole induced by the increased supply of Na+ to MD.<a class="elsevierStyleCrossRef" href="#bib0410">82</a> Coadministration of ACEi or ARA2 would enhance the decrease in intraglomerular pressure, by decreasing the vasoconstriction of the efferent arteriole. Theoretically, the administration of loop diuretics, by inhibiting Na+ reabsorption in MD, could reduce the renal hemodynamic effect of iSGLT2. However, the co-administration of antialdosteronic agents, by decreasing the distal reabsorption of Na+, inhibits the connective tubule-glomerular feedback, inducing vasoconstriction of the afferent arteriole and enhancing the effect of iSGLT2 on glomerular hemodynamics.<a class="elsevierStyleCrossRefs" href="#bib0180">36,37,83</a> Thus, the combination of ACEi or ARA2, iSGLT2 and MR antagonists could enhance the nephroprotective effects. Studies are needed to explore this hypothesis.The effect of MR blockers on CV events and mortality in CKD paties is analyzed in the BARACK D<a class="elsevierStyleCrossRef" href="#bib0420">84</a> clinical trial (Benefits of aldosterone receptor antagonism in chronic kidney disease), currently in progress, with a 3-year follow-up (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).Effect of MR blockade on proteinuria and GFR in type 2 DMMost of the referred studies included subgroups of patients with DM2. There are, however, others who have specifically looked at the effect of MR blockade on diabetic nephropathy.The effect of ACEi, ARA2, antirenin drugs or a combination of them on the different stages of diabetic nephropathy has been evaluated.<a class="elsevierStyleCrossRefs" href="#bib0435">85–94</a> Compared with conventional antihypertensive therapy, the ARA2 reduce the risk of kidney disease progression and mortality. However still persists a high residual risk for these events.<a class="elsevierStyleCrossRefs" href="#bib0475">93,94</a>The combination ACE1-spironolactone, compared to the combination ACEi-ARA2, produces a greater decrease in proteinuria, similar effects on BP and GFR, and higher values of serum K+.<a class="elsevierStyleCrossRef" href="#bib0475">95</a>In DM2, it is frequent to observe reduced serum levels of renin and aldosterone<a class="elsevierStyleCrossRefs" href="#bib0480">96,97</a>; in this situation, it would seem reasonable to predict an attenuated response to aldosterone antagonists. However, both in animals with experimental diabetes and in subjects with DM2, the administration of spironolactone reduces alterations of podocyte and proteinuria.<a class="elsevierStyleCrossRefs" href="#bib0490">98,99</a> In an experimental model of diabetic rats with hypoaldosteronism, the administration of spironolactone prevents oxidative stress, podocyte apoptosis and proteinuria. in vitro, glucose, through MR, increases NADPH oxidase activity, ROS generation and SGK1 expression, producing podocyte damage, all of this is inhibited by spironolactone.<a class="elsevierStyleCrossRef" href="#bib0500">100</a> The increased activity of podocyte AS and Rac1 could mediate the activation of MR by glucose, independent of the systemic aldosterone.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29,101,102</a> Therefore, even in situations of low plasma aldosterone values, the administration of MR antagonists may be useful for renal protection.Several meta-analyzes showed that in subjects with diabetic nephropathy the co-administration of an aldosterone antagonist with ACEI or ARB2, versus monotherapy with ACEI or ARB2, reduced albuminuria and BP, in addition to the increased risk of hyperkalemia, which was lower with the antagonist finerenone. of 3rd generation aldosterone antagonist<a class="elsevierStyleCrossRefs" href="#bib0515">103,104</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Although the cited studies have some limitations, it can be concluded that in mild-to-moderate diabetic and non-diabetic CKD (stages 2–3) with proteinuria, the addition of aldosterone antagonists to ACEI or ARB2, compared with monotherapy with ACEI or ARB2, reduces proteinuria and BP, and increases the risk of hyperkalemia.In patients with DM2, prevention of the development of nephropathy is very important. Adequate metabolic control, BP values, weight, ACEi or ARA2 and iSGLT2 are effective in reducing the appearance of albuminuria in patients with DM2.<a class="elsevierStyleCrossRefs" href="#bib0525">105–107</a> In the PRIORITY clinical trial (Proteomic prediction and renin angiotensin aldosterone system inhibition prevention of early diabetic nephropathy in type 2 diabetic patients with normoalbuminuria),<a class="elsevierStyleCrossRef" href="#bib0540">108</a> 1175 subjects with DM2 and normoalbuminuria were classified, using a urine proteomic biomarker pan (CKD273), at high and low risk of developing albuminuria. 216 subjects classified as high risk were randomized to spironolactone more conventional therapy 25 mg/day and more conventional therapy placebo. The follow-up was 2.57 years and the primary endpoint was the development of albuminuria. The results were presented at the 55th meeting of the European Association for the Study of Diabetes (EASD), held in Barcelona in September 2019. No significant reduction in the appearance of albuminuria was observed, although there was some suggestion of benefit spironolactone from the last year. The serum K+ rate > 5.5 mEq/l was higher in the spironolactone group.There is enough evidence about the renoprotective effect of iSGLT2 in DM2<a class="elsevierStyleCrossRefs" href="#bib0545">109–111</a>; given in combination with ACEi or ARA2, produces a decrease the development and progression of nephropathy in DM2. There are pathophysiological considerations, even with more argumentative force than those discussed in CKD, which raise the possibility that the triple combination of aldosterone antagonists, ACEIs or ARA2 and iSGLT2 offers greater protection in diabetic nephropathy.<a class="elsevierStyleCrossRefs" href="#bib0170">33,34,82,83</a>MR blockade in CKD patients on dialysis therapyCKD patients on HD frequently present vascular calcifications. In a small study of 5 patients on HD the administration of spironolactone 50 mg/day for 3 years produced a significant decrease in aortic calcifications.<a class="elsevierStyleCrossRef" href="#bib0560">112</a>In CKD patients on peritoneal dialysis (PD), biopsy of the peritoneum showed that the administration of 25 mg/day of spironolactone was associated with a reduction in the amount of type IV collagen and CD20 lymphocytes in the peritoneum.<a class="elsevierStyleCrossRef" href="#bib0565">113</a> A lesser degree of fibrosis which improves peritoneal function in these patients.Apart from these facts, the use of aldosterone antagonists in CKD patients treated with dialysis is relevant since it has been demonstrate an association between plasma aldosterone levels and mortality, including sudden death.<a class="elsevierStyleCrossRef" href="#bib0570">114</a>One of the largest clinical trials is the DOHAS (Dialysis outcomes heart failure aldactone study),<a class="elsevierStyleCrossRef" href="#bib0575">115</a> in which 309 subjects on HD were randomized to receive spironolactone 25 mg/day or conventional therapy during 3 years. It was observed that in the spironolactone group there was a significant reduction in mortality or admissions for CV events 95%, from; p (HR 0.40; 95% CI, 0.20–0.80; p = 0.017).A 1.9% of the patients treated with spironolactone had severe hyperkalemia and 10.2% had gynecomastia or mastodynia.Similar results were obtained in 2 metaanalysis that included HD and PD patients in which the effect of aldosterone antagonists was compared with placebo or conventional therapy<a class="elsevierStyleCrossRefs" href="#bib0580">116,117</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).The great reduction in CV events and total mortality achieved by aldosterone antagonists in dialysis CKD patients on dialysis is prominent when compared to the observed in CKD subjects who are not on dialysis. However, the limitations of the included studies must be taken into consideration (open design, small number of patients, short follow-up, few events of CV mortality, as well as high relative risk variability demonstrated by sensitivity analysis). All this make us think that, currently, there is no definitive evidence of a benefit of MR antagonists in dialysis patients. There are two randomized trials, currently underway, may provide more certainty: one of them, ALCHEMIST (Aldosterone antagonist chronic hemodyalisis interventional survival trial), includes 825 high-risk vascular subjects with kidney failure on HD. Its duration will be 2 years and the primary objective is to analyze the effect of spironolactone 25 mg/day versus placebo on CV death and events.<a class="elsevierStyleCrossRef" href="#bib0590">118</a> The other trial, ACHIEVE (Aldosterone blockade for health improvement evaluation in end-stage renal disease), tries to determine whether spironolactone 25 mg/day, as compared with placebo, reduces mortality and hospitalization due to heart failure (HF) in 2750 patients with CKD on dialysis treatment<a class="elsevierStyleCrossRef" href="#bib0595">119</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).MR antagonists in HF with CKDThe benefits of MR antagonists in patients with heart failure with reduced eyection fraction (EF) are well established.<a class="elsevierStyleCrossRefs" href="#bib0035">7–9</a> Even in HF with preserved EF, MR antagonists can reduce admissions for heart failure.<a class="elsevierStyleCrossRef" href="#bib0600">120</a> More than 50% of patients with heart failure have CKD and their mortality increases with the decrease in GFR.<a class="elsevierStyleCrossRef" href="#bib0605">121</a> A large percentage of patients with heart failure and CKD do not receive MR blocker therapy because of the concern of hyperkalemia.<a class="elsevierStyleCrossRef" href="#bib0610">122</a> In the RALES trial, the relative risk of total mortality and hospitalization for heart failure in subjects treated with spironolactone was similar in those with and without a decrease in GFR (0.68, 95% CI, 056−0.84 and 0.64; 95% CI, 0.52−0.72 vs 0.71, 95% CI, 0.57−0.90 and 0.67, 95% CI, 0.56−0,81, respectively). The reduction of absolute risk for mortality and admission for heart failure was greater in the presence of renal failure. As expected, the aldosterone antagonists produced hyperkalemia more frequently if the GFR was reduced (25.6% vs 15.4%)<a class="elsevierStyleCrossRef" href="#bib0615">123</a>.Non-steroidal MR blockers with a better safety profile (less hyperkalemia) and new intestinal K+ linkers may facilitate the use of aldosterone antagonists in CKD patients with heart failure.<a class="elsevierStyleCrossRefs" href="#bib0620">121,124</a>The ongoing FINESSE clinical trial compares the effect of finerenone versus eplerenone on CV mortality and admission for heart failure in subjects with chronic heart failure with reduced EF and DM-2 or CKD<a class="elsevierStyleCrossRef" href="#bib0625">125</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).MR antagonists and hyperkalemiaIn contrast to the consistent evidence of the CV and mortality benefits of aldosterone antagonists in cardiology<a class="elsevierStyleCrossRefs" href="#bib0035">7–9</a>, there are few specific studies of the effect of these drugs on these events in nephrology. It is possible that one of the hyperkalemia, especially in situations of renal failure, has been a constrain for the frequent use of these drugs in CKD.As observed in clinical trials and in real life studies, the combination of aldosterone antagonists with ACEI or ARA2 increases the risk of hyperkalemia.<a class="elsevierStyleCrossRefs" href="#bib0520">104,116,126</a>This fact is important since in conditions frequently associated with abnormal regulation of K, such as heart failure, DM and CKD, there is a U shape relationship between serum K+ and mortality.<a class="elsevierStyleCrossRef" href="#bib0635">127</a>In subjects with less capacity to excrete K+ in the urine due to a reduction in the diuresis, aldosterone antagonists also increase serum K+. Compared with subjects with normal renal function, patients with severe CKD have an increased expression of K+ channels (BK channels) in colon enterocytes that increases their capacity for intestinal elimination of K+.<a class="elsevierStyleCrossRef" href="#bib0640">128</a> Aldosterone stimulates colonic K+ secretion through BK channels, secretion that is inhibited by spironolactone.<a class="elsevierStyleCrossRefs" href="#bib0645">129,130</a>The association of aldosterone antagonists with ACEI or ARA2 contributes to hyperkalemia, but in these patients there may also concur other causes of elevated serum K+.<a class="elsevierStyleCrossRef" href="#bib0655">131</a>Given the occurrence of hyperkalemia in subjects who receive RAAS blockers for processes in which they have shown benefit, frequently the dose has to be reduced or even suppressed. This fact may condition an increase in CV and renal events, and mortality.<a class="elsevierStyleCrossRef" href="#bib0660">132</a> The use of the new oral K+ binders as patiromer and zirconium cyclosilicate is likely to improve tolerability and minimize discontinuation of RAAS<a class="elsevierStyleCrossRefs" href="#bib0665">133–135</a> blockers. On the other hand, the new non-steroidal aldosterone antagonists induce less hyperkalemia than the classic antagonists.<a class="elsevierStyleCrossRef" href="#bib0680">136</a>Nonsteroidal aldosterone antagonistsMost studies with aldosterone antagonists have used the classic steroid antagonists: spironolactone, which has low specificity of action on MR, and eplerenone, which is more selective.Nonsteroidal aldosterone antagonists have a different chemical structure from that of steroids, which determines differences in physicochemical properties, pharmacological actions, tissue penetration and distribution, the mode of binding to the ligand and the ability to bind to co-regulators, among others.<a class="elsevierStyleCrossRef" href="#bib0685">137</a> All this may condition special effects on organ protection and attenuation of adverse effects.To date, 7 nonsteroidal aldosterone antagonists has been tested in clinical trials in different phases, some of them being discontinued for various reasons. Others have completed phase 1 trials or are recruiting patients for phase 2.<a class="elsevierStyleCrossRefs" href="#bib0690">138–141</a>The most advanced nonsteroidal aldosterone antagonists are: apararenone (MT3995, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan), exaserenone (CS3150, Exelisis, California, USA, and Daiichi Sankio, Tokyo, Japan) and finerenone.Aphase 2 clinical trial with Apararerone has completed in subjects with diabetic nephropathy.<a class="elsevierStyleCrossRef" href="#bib0710">142</a> Esxerenone, whose maximum 50% inhibitory concentration (IC50) of MR transcriptional activation is 9.4 nM, is a more potent, more selective and specific inhibitor than spironolactone and epleronone. In a randomized clinical trial, Esxerenone has been shown to be effective and well tolerated in patients with HTN.<a class="elsevierStyleCrossRef" href="#bib0715">143</a>The finerenona has an IC50 of 18 nM (much lower than spironolactone and eplerenone and therefore more powerful). It is much more selective for MR than spironolactone and epleronone and, unlike those predominantly distributed in the kidney, finerenone is equally distributed in the kidney and heart.<a class="elsevierStyleCrossRef" href="#bib0680">136</a>Experimental studies show that finerenone produces renal and vascular protection by reducing oxidative stress and attenuating endothelial dysfunction, among other effects.<a class="elsevierStyleCrossRefs" href="#bib0720">144,145</a>In the clinical trial ARTS (The mineralocorticoid receptor antagonist tolerability study), there were 782 included with heart failure and reduced EF and CKD stages 2−3. Fineronona 5−10 mg/day, compared with spironolactone 25−50 mg/day, produced the same effect on the reduction of NT-pro-BNP and albuminuria, less deterioration of renal function and less elevation of serum K+ with a lower incidence of hyperkalemia (5% vs. 13%) <a class="elsevierStyleCrossRef" href="#bib0730">146</a>.In a similar patient population, different doses of finerenone, compared with epleronone 25−50 mg/day, produced a similar reduction in NT-pro-BNP and a lower increase in serum K+; and in doses of 20 mg/day, finerenone produces a greater reduction in CV events and mortality than epleronone. However, as it was a short study, these variables were considered exploratory.<a class="elsevierStyleCrossRef" href="#bib0735">147</a>In the test ARTS-DN (Minerlocorticoid receptor antagonist tolerability study- diabetic nephropathy), 823 patients with diabetic nephropathy treated blockers of the Renin Angiotensin system (ACEi or ARA2) were randomized to different doses of finerenona or placebo. The main objective was the modification of proteinuria. Fineronone induced a significant dose-dependent reduction in proteinuria (50% reduction in proteinuria in 40% of patients with 20 mg/day), with a slight non-significant decrease in GFR, reversible after stopping the drug, and a decrease in BP. It was observed a low frequency of hyperkalemia (K+ > 5.6 mEq/l) (1.6% of the group treated with 20 mg/day of finerenone vs. 1.5% of the placebo group).<a class="elsevierStyleCrossRef" href="#bib0740">148</a>These are short-term studies that analyze the effect of nonsteroidal aldosterone antagonists on intermediate variables. In patients with heart failure and reduced EF, the Classic MR antagonists have achieved benefits relative to CV events and mortality despite an increase in hyperkalemia. Activation of MR produces harmful cardiorenal effects by various mechanisms that have been discussed in this review. It is possible that nonsteroidal aldosterone antagonists, with a theoretical greater cardiorenal protective capacity and with less risk of hyperkalemia, more benefits will be obtained in important CV and renal variables.The definitive answer will be provided by 2 clinical trials with finerenone. The FIDELIO-DKD (Finerenone in reducing kidney failure and disease progression in diabetic kidney disease) trial investigates the efficacy of finerenone compared to placebo in reducing major renal and CV events in subjects with DM-2 and CKD treated with ACEI or ARA2. The primary endpoint is the time elapsed until the onset of advanced kidney disease, decreased eGFR sustained ≥40% or renal death<a class="elsevierStyleCrossRef" href="#bib0745">149</a>. There were 5734 patients randomized, ending the follow-up in 2020. The study has been published recently. Finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 [95% CI, 0.75−0.99]; p = 0.034), with no significant interaction between patients with and without CVD. The incidence of treatment-emergent adverse events was similar in both arms.The FIGARO- DKD (Finerenone in reducing CV mortality and morbidity in diabetic kidney disease) investigates, in subjects with DM2 and CKD, the efficacy and safety of finerenone compared with placebo, to reduce clinically relevant CV and renal events.<a class="elsevierStyleCrossRef" href="#bib0750">150</a> The primary endpoint is the composite of CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. 7437 patients were recruited, currently under follow-up, waiting for results in 2021.Key concepts<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1In addition to the classic sites, such as distal renal and connecting tubule, and colon, there are MR in other locations, such as podocyte, mesangium, macula densa, endothelium, vascular smooth muscle cell, myocardiocyte, adipocyte, macrophage, among others. In certain situations, MR can be activated by mechanisms independent of aldosterone.</li><li class="elsevierStyleListItem" id="lsti0010">2Activation of MR by aldosterone increases distal renal tubular Na+ reabsorption and K+ secretion. In addition to systemic hemodynamic effects (increased BP and arterial stiffness), aldosterone modifies intraglomerular hemodynamics by modulating the tubulo-glomerular and connecting tubule-glomerulus feedbacks.</li><li class="elsevierStyleListItem" id="lsti0015">3Activation of vascular MRI (endothelium, smooth muscle fiber) produces increased oxidative stress, endothelial dysfunction, fibrosis, vascular remodeling, and increased arterial stiffness.</li><li class="elsevierStyleListItem" id="lsti0020">4In experimental models, aldosterone and MR activation produce kidney damage by various mechanisms (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025">5In CKD with decreased GFR and proteinuria, there is an increase in plasma aldosterone values and in renal expression of MR.</li><li class="elsevierStyleListItem" id="lsti0030">6A high percentage of subjects with CKD treated with ACEi or ARA2 present aldosterone leakage, which is associated with a reappearance or increase in proteinuria and a greater decrease in GFR.</li><li class="elsevierStyleListItem" id="lsti0035">7Many short-follow-up studies have shown that in diabetic and non-diabetic CKD patient with proteinuria, classic aldosterone antagonists (spironolactone, eplerenone) reduce proteinuria and increase the risk of hyperkalemia. There are several clinical trials currently underway that attempt to study the effect of spironolactone administration on mortality and CV events in subjects with CKD stages 3b and 5d.</li><li class="elsevierStyleListItem" id="lsti0040">8ACEi and ARA2, and the association of iSGLT2, have been shown to improve nephroprotection in diabetic and non-diabetic nephropathy. There are pathophysiological considerations that raise the possibility that the combination of ACEi or ARA2, iSGLT2, and MR blockers may enhance nephroprotection.</li><li class="elsevierStyleListItem" id="lsti0045">9Compared with steroidal MR blockers, the more modern non-steroidal MR blockers have higher potency and selectivity, and produce less elevation of serum K+. The underway clinical trials (FIGARO-DCK and FIDELIO-DCK just completed) will determine whether in subjects with DM2 and nephropathy and with a maximum tolerated dose of ACEi or ARA2, the non-steroidal MR blocker, finerenone, 10−20 mg/day, reduces mortality, CV events and the progression of kidney disease.</li></ul>Conflict of interestsDr. Pablo Gómez-Fernández has participated as principal investigator in the following Bayer-sponsored trials.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0050">-Mineralocorticoid rec eptor antagonist tolerability study-diabetic nephropathy (ARTS-DN; ClinicalTrials.gov identifier NCT01874431).</li><li class="elsevierStyleListItem" id="lsti0055">-Finerenone in reducing kidney failure and disease progression in diabetic kidney disease (FIDELIO-DKD, ClinicalTrials.gov identifier: NCT02540993).</li><li class="elsevierStyleListItem" id="lsti0060">-Finerenone in reducing CV mortality and morbidity in diabetic kidney disease (FIGARO-DKD; ClinicalTrials.gov identifier NCT02545049).</li></ul>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1574099" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1418413" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1574098" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1418414" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Physiology/pathophysiology of aldosterone/MR" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Effects of aldosterone on the renal tubule" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Vascular effects of aldosterone" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Experimental data on the effects of aldosterone and MR block in models of kidney damage" ] 4 => array:2 [ "identificador" => "sec0030" "titulo" => "Effects of aldosterone on renal hemodynamics and acute tubular damage" ] 5 => array:2 [ "identificador" => "sec0035" "titulo" => "Effect on the renal interstitium. Production of interstitial fibrosis" ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Effect on glomerular cells" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Systemic vascular effects" ] ] ] 5 => array:3 [ "identificador" => "sec0050" "titulo" => "Effects of MR blockade in CKD. Clinical studies" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "MR blockade and HTN" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Plasma aldosterone values and renal expression of MR in CKD" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Aldosterone escape with drugs that block RAS" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Effect of MR blockade on proteinuria and GFR in CKD" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Effect of MR blockade on proteinuria and GFR in type 2 DM" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "MR blockade in CKD patients on dialysis therapy" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "MR antagonists in HF with CKD" ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "MR antagonists and hyperkalemia" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Nonsteroidal aldosterone antagonists" ] ] ] 6 => array:2 [ "identificador" => "sec0100" "titulo" => "Key concepts" ] 7 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-04-17" "fechaAceptado" => "2020-10-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1418413" "palabras" => array:5 [ 0 => "Mineralcorticoid receptor blockers" 1 => "Aldosterone" 2 => "Chronic kidney disease" 3 => "Diabetic kidney disease" 4 => "Finerenone" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1418414" "palabras" => array:5 [ 0 => "Bloqueantes de receptor mineralcorticoide" 1 => "Aldosterona" 2 => "Enfermedad renal crónica" 3 => "Nefropatía diabética" 4 => "Finerenona" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "There are many experimental data supporting the involvement of aldosterone and mineralcorticoid receptor (MR) activation in the genesis and progression of chronic kidney disease (CKD) and cardiovascular damage.Many studies have shown that in diabetic and non-diabetic CKD, blocking the renin-angiotensin-aldosterone (RAAS) system with conversion enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) decreases proteinuria, progression of CKD and mortality, but there is still a significant residual risk of developing these events.In subjects treated with ACEi or ARBs there may be an aldosterone breakthrough whose prevalence in subjects with CKD can reach 50%. Several studies have shown that in CKD, the aldosterone antagonists (spironolactone, eplerenone) added to ACEi or ARBs, reduce proteinuria, but increase the risk of hyperkalemia. Other studies in subjects treated with dialysis suggest a possible beneficial effect of antialdosteronic drugs on CV events and mortality. Newer potassium binders drugs can prevent/decrease hyperkalemia induced by RAAS blockade, and may reduce the high discontinuation rates or dose reduction of RAAS-blockers.The nonsteroidal MR blockers, with more potency and selectivity than the classic ones, reduce proteinuria and have a lower risk of hyperkalemia. Several clinical trials, currently underway, will determine the effect of classic MR blockers on CV events and mortality in subjects with stage 3b CKD and in dialysis patients, and whether in patients with type 2 diabetes mellitus and CKD, optimally treated and with high risk of CV and kidney events, the addition of finerenone to their treatment produces cardiorenal benefits.Large randomized trials have shown that sodium glucose type 2 cotransporter inhibitors (SGLT2i) reduce mortality and the development and progression of diabetic and nondiabetic CKD. There are pathophysiological arguments, which raise the possibility that the triple combination ACEi or ARBs, SGLT2i and aldosterone antagonist provide additional renal and cardiovascular protection." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Hay abundantes datos experimentales que sustentan la participación de la aldosterona y la estimulación del receptor mineralcorticoide (RM) en la génesis y progresión de la enfermedad renal crónica (ERC) y en el daño cardiovascular.Muchos estudios han demostrado que en la ERC diabética y no diabética, el bloqueo del sistema renina angiotensina-aldosterona (SRAA) con inhibidores de enzima de conversión (iECA) ó antagonistas del receptor de angiotensina II (ARA2) disminuye la proteinuria, la progresión de la ERC y la mortalidad, pero persiste todavía importante riesgo residual de desarrollo de estos eventos.En sujetos tratados con iECA ó ARA2 puede haber un escape de la aldosterona cuya prevalencia en sujetos con ERC puede alcanzar el 50 %. Diversos estudios han demostrado que, en la ERC, los fármacos antialdosterónicos clásicos (espironolactona, eplerenona) añadidos a iECA ó ARA2, reducen la proteinuria, pero aumentan el riesgo de hiperkaliemia. Otros estudios en sujetos tratados con diálisis sugieren un posible efecto beneficioso de los antialadosterónicos sobre eventos CV y mortalidad. Los nuevos ligadores intestinales de K+ pueden prevenir ó reducir la hiperkaliemia inducida por el bloqueo del SRAA, y disminuir la desprescripción o la reducción de dosis de fármacos bloqueantes del SRAA.Los bloqueantes del RM no esteroideos, con más potencia y selectividad que los clásicos, reducen la proteinuria y tienen menos riesgo de hiperkaliemia. Varios ensayos clínicos, actualmente en realización, determinarán el efecto de los bloqueantes clásicos del RM sobre eventos CV y mortalidad en sujetos con ERC estadio 3b y en enfermos en diálisis, y si en enfermos con diabetes mellitus tipo 2 y ERC, óptimamente tratados y con elevado riesgo de eventos CV y renales, la adición de finerenona a su tratamiento produce beneficios cardiorrenales.Los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) han demos-trado reducir la mortalidad y el desarrollo y progresión de la nefropatía diabética y no diabética. Hay argumentos fisiopatológicos, que suscitan la posibilidad de que la triple combinación, iECA ó ARA2, iSGLT2 y antagonista de aldosterona ofrezca mayor protección renal y vascular." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Erraez S, López-Mesa M, Gómez-Fernández P. Bloqueantes del receptor mineralcorticoide en la enfermedad renal crónica. Nefrologia. 2021;41:258–275." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1662 "Ancho" => 3000 "Tamanyo" => 504720 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "At a basal state, the mineralocorticoid receptor (MR) is predominantly located in the cytoplasm, forming part of a complex with the chaperone heat shock protein (Hsp90), which facilitates its binding to the ligand, and with the immunophilin FK506-binding protein of 51 kDa (FKBP51). After binding to the ligand, immunophilin FKBP51 is replaced by FBBP52, which facilitates the transit of the RM-ligand complex from the cytoplasm to the nucleus. Once in the nucleoplasm, the RM-ligand dissociates from the chaperone and immunophilin to bind to DNA and form dimers. MR binds to specific DNA sequences, the hormone response element (HRE) to regulate the transcription of target genes (some of these are shown in the figure). MR-mediated transcriptional activity can be increased or repressed by regulatory proteins such as steroid receptor coactivator 1 (SRC1), cAMP-response element binding protein (CBP), and transcriptional intermediary factor 1a (TIF1a), among others. 2. The RM-ligand complex can interact with other transcription factors such as cAMP response element-binding protein (CREB) and nuclear factor of activated T-cells (NFAT), which can influence transcription. Aldosterone also binds to MR anchored in the cell membrane by caveolin (Cav1) and striatin, transactivating membrane receptors such as epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), insulin like growth factor receptor (IGF1R), vascular endothelial growth factor receptor (VEGFR), G protein coupled estrogen receptor (GPER) and angiotensin II receptor type I (AT1R). All this promotes signals that involve, among other effects, kinase activation. These events are responsible for the rapid, non-genomic effects of aldosterone. 3. Activation of the RM receptor is possible without the ligand. The activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) by stimuli such as oxidative stress, glucose, AII, among others, can promote the translocation of the RM to the nucleus and trigger its transcriptional activity." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 899 "Ancho" => 2503 "Tamanyo" => 132879 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanisms of kidney damage produced by aldosterone and the activation of the mineralocorticoid receptor (MR)." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Distal convoluted tubule and connecting tubule \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Cardiomyocytes \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">Dense macula \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">Adipocytes \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">Podocytes \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">Fibroblasts \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">Mesangium \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">Macrophages \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">Colon \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">Limbic neurons of the hypothalamus \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">Vascular smooth muscle cells \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">Salivary glands \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">Endothelial cells \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">Sweat glands \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2697146.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Mineralcorticoid receptor locations." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CTGF; connective tissue growth factor; CKD: chronic kidney disease; ETB: endothelin B; ERK1/2: extracellular signal-regulated kinases; HK-2: human kidney 2; I/R: ischemia/reperfusion; ICAM-1: intercellular adhesion molecule-1; IL: interleukins; NFk-B: nuclear factor kappa-light chain enhancer of activated B cells; NGAL: neutrophil gelatinase-associated lipocalin; NLRP3: nucleotide-binding domain and leucine-rich repeat containing PYD-3; MR: mineralocorticoid receptor; ROS: reactive oxygen species; Runx2: runt-related transcription factor 2; Sgk-1: serum and glucocorticoid regulated kinase 1; TNFalpha: tumor necrosis factor alpha." "tablatextoimagen" => array:1 [ 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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Experimental model \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect of aldosterone/MRI block \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Effect on acute kidney injury</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">Sánchez Pozos et al., 2012<a class="elsevierStyleCrossRef" href="#bib0210">41</a> \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">Acute kidney injury by I/R \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">Spironolactone \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">Prevents the decrease of the ETB vasodilator receptor \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"> \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"> \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"> \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">Spironolactone prevents kidney dysfunction, tubular damage, and oxidative stress \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">Amador et al., 2016<a class="elsevierStyleCrossRef" href="#bib0215">42</a> \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">Kidney damage from cyclosporin \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">MR deletion in vascular smooth muscle cells \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">Deletion of MR prevents renal dysfunction, tubular cell vacuolization, and overexpression of NGAL. MR deletion reduces cyclosporine-induced vasoconstriction due to decreased Ca++ L channel activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Effect on transition from acute kidney injury to CKD</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">Zhang et al., 2007<a class="elsevierStyleCrossRef" href="#bib0220">43</a> \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">Culture of human tubular epithelial cells \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">Aldosterone \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">Aldosterone induces epithelial-mesenchymal transition by increasing mitochondrial ROS production via ERK1/2 activation \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">Barrera-Chimal et al., 2013<a class="elsevierStyleCrossRef" href="#bib0240">47</a> \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">Acute kidney injury by I/R \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">Spironolactone \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">Decreased progression of CKD and pro-inflammatory fibrosis and IL markers \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">Ding et al., 2016<a class="elsevierStyleCrossRef" href="#bib0225">44</a> \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">Culture of human renal tubular cells (HK-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">Aldosterone \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">Aldosterone induces cell damage by stimulating mitochondrial ROS production and NLRP3 inflammasome activation \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">Barrera-Chimal et al., 2018<a class="elsevierStyleCrossRef" href="#bib0235">46</a> \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">Acute kidney injury by I/R \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">Fineronone or MR deletion in myeloid cells \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">Decreased renal dysfunction, renal fibrosis, and pro-inflammatory macrophages (M1) \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"> \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"> \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"> \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">Increased macrophages with anti-inflammatory phenotype (M2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Effect on glomerular cells (podocytes, mesangial cells, parietal epithelium)</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">Shibata et al., 2007<a class="elsevierStyleCrossRef" href="#bib0095">19</a> \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">Uninephrectomized rats \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">Aldosterone administration and high salt diet \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">Development of proteinuria and reduction of nephrin and podocin in podocytes. Increased SGK1 activity and oxidative stress of podocytes Administration of epleronone prevents podocyte damage \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"> \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"> \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">Eplerenone \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"> \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">Terada et al., 2008<a class="elsevierStyleCrossRef" href="#bib0260">51</a> \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">Mesangial cell culture \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">Aldosterone in the culture media or aldosterone administration \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">Increased expression-activity of Sgk-1 and NFk-B, ICAM-1, CTGF. Aldosterone administration produces an increase in glomerular expression of all these factors, accompanied by glomerulosclerosis and inflammation. \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"> \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">Rectomized uninefrectomized \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"> \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"> \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">Huang et al., 2014<a class="elsevierStyleCrossRef" href="#bib0265">52</a> \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">Experimental model of rapidly progressive glomerulonephritis \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">MR deletion in myeloid cells, epleronone \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">Both MR deletion and epleronone are associated with reduced crescent formation and expression of pro-inflammatory molecules at the renal level, reduction of tubular damage and renal fibrosis \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">Bai et al., 2017<a class="elsevierStyleCrossRef" href="#bib0255">50</a> \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">Podocyte culture \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">Exposure to aldosterone \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">Exposure of podocytes to aldosterone increases expression of NLRP3 lymphoma, caspase1 and IL-18 in podocytes. In vivo, administration of aldosterone to mice produces NLRP3 activation and decreased podocyte nephrin; epleronone blocks NLRP3 inflammasome activation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular effects</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">Tsatsumoto et al., 2015<a class="elsevierStyleCrossRef" href="#bib0280">55</a> \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">Experimental model of adenine-induced chronic kidney damage \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">Spironolactone \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">Spironolactone reduces aortic calcification together with the aortic expression of Runx2 and the sodium-phosphorus cotransporter (Pit-1), TNFa and Sgk-1 \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">Khan et al., 2019<a class="elsevierStyleCrossRef" href="#bib0270">53</a> \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">Coronary Artery Function Investigated Using Myography \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">Subpression of aldosterone \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">Decreased the vasodilation dependent of adenosine A 2A receptors by down-regulation of K Ca receptors (calcium-dependent K + channels) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2697144.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Some experimental data on renal effects of aldosterone and mineralocorticoid receptor (MR) blockade/deletion." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Alb/creat: urine albumin/creatinine; ARA2: angiotensin II receptor antagonist; IQR: interquartile range; Eple: eplerenone; CKD: chronic kidney disease; Spir: spironolactone; ACEi: angiotensin converting enzyme inhibitor; DN: diabetic nephropathy; NDN: non-diabetic nephropathy; SBP: systolic blood pressure; DBP: diastolic blood pressure; RR (CI): relative risk (confidence interval)." "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 " colspan="9" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-diabetic and diabetic CKD (anti-aldosterone agents added to ACEi or ARA2 vs. ACEi or ARA2)</th></tr><tr title="table-row"><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">Author/year \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">No. studies/No. subjects \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">Type of CKD \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">Median month follow-up (IQR) \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">Antidosterone drug \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">ΔAlb/creat. mg/g × (95% CI) \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">ΔGFR ml/min/1.73 m2 × (95% CI) \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">ΔSBP/DBP mmHg × (95% CI) \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">Hyperkalemia RR (95% CI) \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">Navaneeth a et al., 2009 <a class="elsevierStyleCrossRef" href="#bib0385">77</a><a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">11/991 \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">DN/NDN \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 (10) \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">9: Spir. 2: Eple. \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">–0.80 (–1.3; –0.3)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \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">–0.70 (–4.3, 3.3)<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \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">–3.4 (–5.1, –1.7)/–1.8 (–2.9, –0.6) \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">3.06 (1.26−7.41) \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">Bolignano et al., 2014 <a class="elsevierStyleCrossRef" href="#bib0390">78</a><a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">27 /1549 \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">NDN/DN \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">3.5 (10) \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: Spir 5: Eple. \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">–0.61 (–1.1; –0.1)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \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">–2.55 (–5.7, 0.5) <a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \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">–3.4 (–5.0, –1.8)/–1.7 (–2.8, –0.6) \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">2.00 (1.25−3.2) \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">Currie et al., 2016<a class="elsevierStyleCrossRef" href="#bib0400">79</a> \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">19/2016 \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">NDN// DN \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 (10) \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">14: Spir. 5: Eple \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">–31 (–35; –37)<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \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">–3.15 (–5.4; –0.9) \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">–5.7 (–9.0, –2.3)/–1.7 (–3.4, –0.1) \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">3.21 (1.19−8.71) \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">Sun et al., 2017<a class="elsevierStyleCrossRef" href="#bib0530">103</a> \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">18/1786 \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">DN \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">3 (7) \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">15: Spir. 2: Eple \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">–216 (–409; –22) \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">4.32 (–3.6, 12.2) \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">–4.8 (–9.5; –0.16)/–3.3 (–5.9; –0.56) \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">3.74 (2.30−6.09) \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">Zuo and Xu, 2019<a class="elsevierStyleCrossRef" href="#bib0535">104</a> \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">17/1838 \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">DN \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">3 (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">13: Spir. 2: Eple \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">−202 (-580; 175) \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">–2.1 (–5.2, 1.0) \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">5.06 (–0.74, 10.9)/1.60 (0.26, 2.96) \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">Esp.: 4.58 (2.6−8.0), epl.: 2.81 (1.0−7.7), fin.: 2.22 (0.1−38) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2697148.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="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Advanced CKD on dialysis therapy (antialdosteronic drugs vs. placebo or conventional therapy)</th></tr><tr title="table-row"><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">Author/year \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">No. studies/no. subjects \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">Median month follow-up (IQR) \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">Antidosteronic \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">CV mortality RR (95% CI) \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">All-cause mortality RR (95% CI) \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">Hyperkalemia RR (95% CI) \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">RR gynecomastia (95% CI) \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">Li et al., 2019<a class="elsevierStyleCrossRef" href="#bib0600">117</a> \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">10/1172 \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 (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">9: Spir. 1: Eple. \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">0.42 (0.26−0.65) \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">0.46 (0.32−0.66) \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">1.70 (1.0−2.9) \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">8.0 (2.4−26) \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">Quach et al., 2016<a class="elsevierStyleCrossRef" href="#bib0595">116</a> \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">9/829 \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 (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">8: Spir. 1: Eple \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">0.34 (0.15−0.75) \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">0.40 (0.23−0.69) \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">3.05 (1.2−7.7) \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">5.6 (1.3−24)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2697145.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Some of the included studies use ACEi + ARA2 as a comparison." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "only 1 of the studies." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "g/24 h." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Percentage reduction in proteinuria or albuminuria." ] ] ] "descripcion" => array:1 [ "en" => "Meta-analysis on renal effects and mortality of antialdosterone drugs in CKD." ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ARA2: angiotensin II receptor antagonists; CV: cardiovascular; DM: diabetes mellitus; DM2: type 2 diabetes mellitus; CKD: chronic kidney disease; EF: ejection fraction; eGFR: estimated glomerular filtration rate; LVH: left ventricular hypertrophy; CHF: congestive heart failure; HF: heart failure; iECA: angiotensin converting enzyme inhibitors; MI: myocardial infarction." "tablatextoimagen" => array:1 [ 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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Identifier/acronym/query date \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">Study population \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">Drugs compared \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">Objective 1 \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">Eudract: 2012-002672-13/BARACK D/12-.04-2020<a class="elsevierStyleCrossRef" href="#bib0430">84</a> \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">Stage 3b CKD (eGFR 30−44 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">Conventional therapy + spironolactone 25 mg/day vs. conventional therapy \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">Mortality and CV events \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">NCT01848639/ALCHEMIST/12-.04-2020<a class="elsevierStyleCrossRef" href="#bib0605">118</a> \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">Advanced CKD in hemodialysis + DM2 or ↓ EF or history of CV event or LVH \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">Spironolactone 25 mg/day vs. placebo \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">Non-fatal MI/non-fatal stroke/acute coronary syndrome/hospitalization for HF/CV death \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">NCT03020303/ACHIEVE/04-12-2020<a class="elsevierStyleCrossRef" href="#bib0610">119</a> \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">Advanced CKD in dialysis \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">Spironolactone 25 mg/day vs. placebo \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">CV death/hospitalization due to HF \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">Eudract: 2015-002168-17/FINESSE HF 04-12-2020<a class="elsevierStyleCrossRef" href="#bib0640">125</a> \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">CHF with reduced EF + DM or CKD \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">iECA or ARA2 + finerenone 10−20 mg/day vs. iECA or ARA2+ eplerenone 25−50 mg/day \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">CV death/hospitalization due to HF \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">NCT02540993/FIDELIO-DKD/04-12-2020<a class="elsevierStyleCrossRef" href="#bib0745">149</a> \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">DM2 with diabetic kidney disease and maximum tolerated dose of ACEI or ARA2 \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">Finerenone 10−20 mg/day vs. placebo \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">Development of advanced CKD/sustained ↓ in eGFR ≥ 40%/renal death \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">NCT02545049/FIGARO-DKD/12-04-2020<a class="elsevierStyleCrossRef" href="#bib0750">150</a> \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">DM2 with diabetic kidney disease and maximum tolerated dose of ACEI or ARA2 \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">Finerenone 10−20 mg/day vs. placebo \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">CV death/non-fatal CV events \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2697147.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Phase III clinical trials on mineralocorticoid receptor blockers in CKD, currently in progress." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:150 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa011161" "Revista" => array:5 [ …5] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa011303" "Revista" => array:6 [ …6] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibition in progressive renal Insufficiency study group" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199604113341502" "Revista" => array:6 [ …6] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-135-2-200107170-00007" "Revista" => array:6 [ …6] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.285.21.2719" "Revista" => array:5 [ …5] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of a multifactorial intervention on mortality in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0706245" "Revista" => array:6 [ …6] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized aldactone evaluation study investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199909023411001" "Revista" => array:6 [ …6] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eplerenone in patients with systolic heart failure and mild symptoms" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1009492" "Revista" => array:6 [ …6] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa030207" "Revista" => array:6 [ …6] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/bf02155834" "Revista" => array:6 [ …6] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone in congestive heart failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra000050" "Revista" => array:6 [ …6] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adipocytes, aldosterone and obesity-related hypertension" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JME-16-0025" "Revista" => array:6 [ …6] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Involvement of vascular aldosterone synthase In phosphate-induced osteogenic transformation of vascular smooth muscle cells" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-017-01882-2" "Revista" => array:5 [ …5] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of aldosterone secretion: current concepts and newer aspects" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antiaging gene Klotho regulates CYP11B2 expression and aldosterone synthesis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2015010093" "Revista" => array:5 [ …5] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.3037703" "Revista" => array:6 [ …6] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The mineralocorticoid receptor and its coregulators" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1677/JME-09-0031" "Revista" => array:7 [ …7] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.HYP. 0000154681. 38944.9a" "Revista" => array:6 [ …6] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.HYP.0000255636.11931.a2" "Revista" => array:6 [ …6] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification and role of aldosterone receptors in the cardiovascular system" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Func-tional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCRESAHA.108 174235" "Revista" => array:6 [ …6] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pivotal role of the mineralocorticoid receptor in corticosteroid induced adipogenesis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1096/fj.06-7970com" "Revista" => array:6 [ …6] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deletion of mineralocorticoid receptors from macrophages protects against deoxycor-ticosterone/salt-induced cardiac fibrosis and increased blood pressure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTENSIONAHA.109.131110" "Revista" => array:6 [ …6] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The coming out of the brain mineralocorticoid receptor" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tins.2007.10.005" "Revista" => array:5 [ …5] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JME-15-0318" "Revista" => array:6 [ …6] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Grossmann C.30 Nongenomic effects via the mineralocorticoid receptor" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JOE-16-0659" "Revista" => array:6 [ …6] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrneph. 2012.282" "Revista" => array:5 [ …5] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTENSIONAHA.111.185520" "Revista" => array:6 [ …6] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nm.1879" "Revista" => array:5 [ …5] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Local mineralocorticoid receptor activation and the role of Rac1 in obesity-related diabetic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000358758" "Revista" => array:5 [ …5] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI43124" "Revista" => array:7 [ …7] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JOE-16-0669" "Revista" => array:6 [ …6] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypokalemia and Pendrin induction by aldosterone" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTENSIONAHA.116.08519" "Revista" => array:6 [ …6] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone stimulates vacuolar H(+)-ATPase activity in renal acid-secretory intercalated cells mainly via a protein kinase C-dependent pathway" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajpcell.00076.2011" "Revista" => array:6 [ …6] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone mediates activation of the thiazide-sensitive Na–Cl cotransporter through an SGK1 and WNK4 signaling pathway" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI38323" "Revista" => array:6 [ …6] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTENSIONAHA.111.173195" "Revista" => array:6 [ …6] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Connecting tubule glomerular feedback in hypertension" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTENSIONA HA.113.01846" "Revista" => array:6 [ …6] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel mechanism of renal microcirculation regulation: connecting tubule-glomerular feedback" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11906-019-0911-5" "Revista" => array:5 [ …5] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of the mineralocorticoid receptor in the vasculature" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JOE-17-0009" "Revista" => array:6 [ …6] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epitelial sodium channel in aldosterone-induced endothelium stiffness and aortic dysfunction" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTEN-SIONAHA.118.11339" "Revista" => array:6 [ …6] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recovery from ischemic acute injury by spironolactone administration" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfs014" "Revista" => array:6 [ …6] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ki.2015.312" "Revista" => array:6 [ …6] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajprenal.00480.2006" "Revista" => array:5 [ …5] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mitochondrial – reactive oxygen species mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.18632/oncotarget.8243" "Revista" => array:6 [ …6] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute kidney injury and chronic kidney disease as interconnected syndromes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1214243" "Revista" => array:5 [ …5] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The myeloid mineralcorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin 4 receptor signaling" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.kint.2017.12.016" "Revista" => array:5 [ …5] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone prevents chronic kidney disease caused by Ischemic acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ki.2012.352" "Revista" => array:6 [ …6] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "From podocyte biology to novel cures for glomerular disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.kint.2019.05.015" "Revista" => array:6 [ …6] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Podocyte as the target for aldosterone: roles  of oxidative stress and Sgk1" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.HYP.0000255636.11931.a2" "Revista" => array:6 [ …6] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NLRP3 inflammasome activation contributes to aldosterone induced podocyte injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajprenal.00332.2016" "Revista" => array:5 [ …5] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2007050531" "Revista" => array:6 [ …6] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2012111094" "Revista" => array:6 [ …6] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca2-activated K-channels" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajpheart.00081.2019" "Revista" => array:5 [ …5] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognostic value of coronary flow reserve in patients with dialysis-dependent ESRD" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2015030301" "Revista" => array:6 [ …6] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone ameliorates arteria medial calcification in uremic rats medial calcification: the role of mineralocorticoid receptor signaling in vascular calcification" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajprenal.00669.2014" "Revista" => array:7 [ …7] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone blunts the baroreflex response in man" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1042/cs0950687" "Revista" => array:5 [ …5] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of aldosterone receptor blockade compared with thiazide therapy on sympathetic nervous system function in geriatric hypertension" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/HYPERTEN-SIONAHA.109.147058" "Revista" => array:6 [ …6] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(15)00257-3" "Revista" => array:7 [ …7] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2009.03.066" "Revista" => array:6 [ …6] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mediation analysis of aortic stiffness and renal microvascular function" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2014050450" "Revista" => array:6 [ …6] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma aldosterone concentrations in chronic renal disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ki.1982.14" "Revista" => array:6 [ …6] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mineralocorticoid receptor blockade in chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11906-011-0202-2" "Revista" => array:6 [ …6] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12882-017-0789-x" "Revista" => array:4 [ …4] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2010121251" "Revista" => array:7 [ …7] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased expression of mineral-corticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/circulationHA.105.539122" "Revista" => array:6 [ …6] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of benazepril for advanced chronic renal insufficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa053107" "Revista" => array:5 [ …5] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renoprotection of optimal antiproteinuric doses (ROAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2006121372" "Revista" => array:6 [ …6] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bmj.f360" "Revista" => array:5 [ …5] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The incidence and implications of aldosterone breakthrough" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ncpneph0575" "Revista" => array:6 [ …6] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjhyper.2007.09.001" "Revista" => array:6 [ …6] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-004-1542-0" "Revista" => array:6 [ …6] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction between atrial natriuretic peptide and the renin angiotensin aldosterone system. Endogenous antagonists" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0002-9343(89)90087-9" "Revista" => array:6 [ …6] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: implications for heart failure therapy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4330/wjc.v9.i3.200" "Revista" => array:6 [ …6] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM200109203451215" "Revista" => array:6 [ …6] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0375" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.ki.5001854" "Revista" => array:6 [ …6] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0380" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfs429" "Revista" => array:4 [ …4] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0385" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2215/CJN.04750908" "Revista" => array:6 [ …6] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0390" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone antagonists for preventing the progression of chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/14651 858.CD007004.pub3" "Revista" => array:3 [ …3] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0395" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of mineralcorticoid receptor antagonist on proteinuria and progression of chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12882-016-0337-0" "Revista" => array:5 [ …5] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0400" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long term effects of spironolactone on kidney function and hyperkalemia-associated hospitalization in patients with chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/jcm7110459" "Revista" => array:5 [ …5] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0405" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfz290" "Revista" => array:6 [ …6] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0410" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jdiacomp.2018.04.011" "Revista" => array:6 [ …6] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0415" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajprenal.00605.2014" "Revista" => array:6 [ …6] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0420" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Benefits of aldosterone receptor antagonism in chronic kidney disease (BARACK D)trial a multicentre prospective randomised open blinded endpoint, 36 month study of 2.616 patients within primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25 mg once daily in addition to routine care on mortality and cardiovascularoutcomes versus routine care alone: study protocol for a randomized controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1745-6215-15-160" "Revista" => array:5 [ …5] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0425" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preventing microalbuminuria in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa042167" "Revista" => array:6 [ …6] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0430" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa-1007994" "Revista" => array:5 [ …5] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0435" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(07)61303-8" "Revista" => array:6 [ …6] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0440" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Irbesartan in patients with type 2 diabetes and microalbuminuria. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa011489" "Revista" => array:6 [ …6] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0445" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal outcomes with aliskiren in patients with type 2 diabetes: a prespecified secondary analysis of the ALTITUDE randomised controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(15)00469-6" "Revista" => array:4 [ …4] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0450" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aliskiren combined with losartan in type 2 diabetes and nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0708379" "Revista" => array:5 [ …5] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0455" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combined angiotensin inhibition for the treatment of diabetic nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1303154" "Revista" => array:6 [ …6] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib0460" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Makino H; Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-011-2325-z" "Revista" => array:6 [ …6] ] ] ] ] ] 92 => array:3 [ "identificador" => "bib0465" "etiqueta" => "93" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reno-protective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa011303" "Revista" => array:6 [ …6] ] ] ] ] ] 93 => array:3 [ "identificador" => "bib0470" "etiqueta" => "94" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa011161" "Revista" => array:6 [ …6] ] ] ] ] ] 94 => array:3 [ "identificador" => "bib0475" "etiqueta" => "95" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2009070737" "Revista" => array:6 [ …6] ] ] ] ] ] 95 => array:3 [ "identificador" => "bib0480" "etiqueta" => "96" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyporeninemic hypoaldosteronism and diabetes mellitus: pathophysiology assumptions, clinical aspects and implications for management" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4239/wjd.v7.i5.101" "Revista" => array:5 [ …5] ] ] ] ] ] 96 => array:3 [ "identificador" => "bib0485" "etiqueta" => "97" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Angiotensin II and its receptors in the diabetic kidney" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/ajkd.2000.16192" "Revista" => array:5 [ …5] ] ] ] ] ] 97 => array:3 [ "identificador" => "bib0490" "etiqueta" => "98" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1523-1755.2004.00913.x" "Revista" => array:6 [ …6] ] ] ] ] ] 98 => array:3 [ "identificador" => "bib0495" "etiqueta" => "99" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Beneficial impact of spironolactone on nephrotic range" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.ki.5001580" "Revista" => array:6 [ …6] ] ] ] ] ] 99 => array:3 [ "identificador" => "bib0500" "etiqueta" => "100" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone inhibits hyperglycemia induced podocyte injury by attenuating ROS production" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfq750" "Revista" => array:6 [ …6] ] ] ] ] ] 100 => array:3 [ "identificador" => "bib0505" "etiqueta" => "101" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajprenal.00101.2009" "Revista" => array:6 [ …6] ] ] ] ] ] 101 => array:3 [ "identificador" => "bib0510" "etiqueta" => "102" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.freeradbiomed.2005.03.031" "Revista" => array:6 [ …6] ] ] ] ] ] 102 => array:3 [ "identificador" => "bib0515" "etiqueta" => "103" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jdi.12629" "Revista" => array:5 [ …5] ] ] ] ] ] 103 => array:3 [ "identificador" => "bib0520" "etiqueta" => "104" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of mineralcorticoid receptor antagonists with ACEI/ARB treatment for diabetic nephropathy: a metaanalysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ijcp.13413" "Revista" => array:3 [ …3] ] ] ] ] ] 104 => array:3 [ "identificador" => "bib0525" "etiqueta" => "105" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0140-6736(98)07368-1" "Revista" => array:5 [ …5] ] ] ] ] ] 105 => array:3 [ "identificador" => "bib0530" "etiqueta" => "106" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pre-venting microalbuminuria in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa042167" "Revista" => array:5 [ …5] ] ] ] ] ] 106 => array:3 [ "identificador" => "bib0535" "etiqueta" => "107" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of sodium-glucose cotransporter 2 Inhibitors on renal outcomes in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-019-49525-y" "Revista" => array:4 [ …4] ] ] ] ] ] 107 => array:3 [ "identificador" => "bib0540" "etiqueta" => "108" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Clinical Trials Gov. Proteomic prediction and reninangiotensin aldosterone system inhibition prevention of early diabetic nephropathy in type 2 diabetic patients withnormoalbuminuria (PRIORITY) [Accessed 17 August 2020] NCT02040441." ] ] ] 108 => array:3 [ "identificador" => "bib0545" "etiqueta" => "109" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Canagliflozin and renal outcomes in type 2 diabetes and nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1811744" "Revista" => array:5 [ …5] ] ] ] ] ] 109 => array:3 [ "identificador" => "bib0550" "etiqueta" => "110" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Empagliflozin and progression of kidney disease in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1515920" "Revista" => array:6 [ …6] ] ] ] ] ] 110 => array:3 [ "identificador" => "bib0555" "etiqueta" => "111" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomized trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(19)30180-30189" "Revista" => array:6 [ …6] ] ] ] ] ] 111 => array:3 [ "identificador" => "bib0560" "etiqueta" => "112" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone blockade and vascular calcification in hemodialysis patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0002-9343(03)00293-296" "Revista" => array:5 [ …5] ] ] ] ] ] 112 => array:3 [ "identificador" => "bib0565" "etiqueta" => "113" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone to prevent peritoneal fibrosis in peritoneal dialysis patients: a randomized controlled trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2014.01.426" "Revista" => array:5 [ …5] ] ] ] ] ] 113 => array:3 [ "identificador" => "bib0570" "etiqueta" => "114" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehs361" "Revista" => array:6 [ …6] ] ] ] ] ] 114 => array:3 [ "identificador" => "bib0575" "etiqueta" => "115" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2013.09.056" "Revista" => array:6 [ …6] ] ] ] ] ] 115 => array:3 [ "identificador" => "bib0580" "etiqueta" => "116" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The safety and efficacy of mineralocorticoid receptor antagonists in patients who require dialysis: a systematic review and meta-analysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2016.04.011" "Revista" => array:6 [ …6] ] ] ] ] ] 116 => array:3 [ "identificador" => "bib0585" "etiqueta" => "117" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone antagonists reduce the risk of cardiovascular mortality in dialysis patients: a meta-analysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2019/1925243" "Revista" => array:2 [ …2] ] ] ] ] ] 117 => array:3 [ "identificador" => "bib0590" "etiqueta" => "118" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Aldosterone antagonist chronic hemodiálysis interventional survival trial) (ALCHEMIST)NCT01848639 Clinical trial.gov." ] ] ] 118 => array:3 [ "identificador" => "bib0595" "etiqueta" => "119" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Clinical Trial Gov. Aldosterone blockade for health Improvement evaluation in end-stage renal disease (ACHIEVE) NCT03020303." ] ] ] 119 => array:3 [ "identificador" => "bib0600" "etiqueta" => "120" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIR-CULATIONAHA.114.013255" "Revista" => array:6 [ …6] ] ] ] ] ] 120 => array:3 [ "identificador" => "bib0605" "etiqueta" => "121" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of heart failure in advancing CKD: core curriculum 2018" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2017.12.006" "Revista" => array:5 [ …5] ] ] ] ] ] 121 => array:3 [ "identificador" => "bib0610" "etiqueta" => "122" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2018.04.070" "Revista" => array:6 [ …6] ] ] ] ] ] 122 => array:3 [ "identificador" => "bib0615" "etiqueta" => "123" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RALES Investigators. Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2012.07.048" "Revista" => array:6 [ …6] ] ] ] ] ] 123 => array:3 [ "identificador" => "bib0620" "etiqueta" => "124" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ejhf.402" "Revista" => array:6 [ …6] ] ] ] ] ] 124 => array:3 [ "identificador" => "bib0625" "etiqueta" => "125" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "EudraCT 2015-002168-17.FINESSE-HF. 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Bloqueantes del receptor mineralcorticoide en la enfermedad renal crónica

Sara Erraeza, Manuel López-Mesab, Pablo Gómez-Fernándeza,

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pgomezf@senefro.org

Corresponding author.

a Unidad de Factores de Riesgo Vascular, Nefrología, Hospital Universitario de Jerez, Jerez de la Frontera, Cádiz, Spain

b Centro de salud El Posito, Arcos de la Frontera, Cádiz, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Considerable evidence implicates the renin-angiotensin-aldosterone system &#40;RAAS&#41; in the progression of chronic kidney disease &#40;CKD&#41; Blocking the generation and action of angiotensin II &#40;A<span class="elsevierStyleInf">II</span>&#41; by A<span class="elsevierStyleInf">II</span> converting enzyme inhibitors &#40;iACEi&#41; and the A <span class="elsevierStyleInf">II</span> AT1 receptor blockers &#40;ARA2&#41; have shown to be useful to reduce the progression of diabetic and non-diabetic nephropathy<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;5</span></a> and to decrease cardiovascular &#40;CV&#41; morbidity and mortality and mortality of any cause&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Mineralocorticoid receptor &#40;MR&#41; blockade with spironolactone and eplerenone adds an antiproteinuric effect when associated to ACEI or ARA2&#46; However&#44; so far&#44; there is no consistent evidence show in a benefit of MR blockade in the progression of CKD or in reducing CV events and total mortality in CKD&#46; However&#44; MR blockade in patients with heart failure with reduced ejection fraction &#40;EF&#41; decrases CV events and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a></p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Physiology&#47;pathophysiology of aldosterone&#47;MR</span><p id="par0010" class="elsevierStylePara elsevierViewall">Aldosterone was isolated in 1953 by Simpson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> It is produced mainly by glomerulosa cells of the adrenal glands&#46; Under certain circumstances&#44; aldosterone is produced in the heart&#44; blood vessels&#44; and adipocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> Increased expression of aldosterone synthetase &#40;AS&#41; has been shown in human coronary arteries from multi-organ donors&#44; and it is increased in subjects with renal failure and correlates with the vascular expression of the osteoblastic transforming factor&#58; <span class="elsevierStyleItalic">core binding factor alpha 1</span> &#40;CBFa1&#41;&#46;<span class="elsevierStyleSup">13</span></p><p id="par0015" class="elsevierStylePara elsevierViewall">The A <span class="elsevierStyleInf">II</span> and an increase in K<span class="elsevierStyleSup">&#43;</span> concentration are the main aldosterone secretagogues&#46; However&#44; other factors such as ACTH&#44; catecholamines&#44; endothelin&#44; and adipocyte-derived products&#44; such as leptin&#44; adiponectin&#44; and <span class="elsevierStyleItalic">C1qTNF-related protein 1</span> &#40;CTRP1&#41;&#44; also stimulate adrenal secretion of aldosterone&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;14</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In culture of aortic vascular smooth muscle cells&#44; the presence of phosphorus in the medium induces an increase in the vascular expression of AS&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This fact may be relevant in CKD&#46; In addition&#44; in adrenal glands it has been demonstrated colocalization of klotho-AS and in klotho haplodeficient animals there is an increase in the expression of AS&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The MR was cloned in 1997&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> It is a protein of 107&#8239;kD encoded by a gene located on chromosome 14&#46; It has three domains&#58; an N-terminal domain&#44; another domain that binds to DNA and a third domain that is assembled to the ligand&#46; Certain coactivators and co-repressors bind some domains&#44; that can be tissue-specific and modulate specific actions in certain organs&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> There are MR in the renal collecting duct and colon &#40;classic sites&#41;&#44; and also in other locations<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Cortisol also binds to MR&#46; In epithelial cells and vascular endothelium&#44; the enzyme 11-&#946;OH-steroid dehydrogenase converts cortisol into cortisone&#44; thus preventing its binding to MR&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The MR is not inserted directly into the cell membrane&#46; In a basal state&#44; not bound to the ligand&#44; the RM is located predominantly in the cytoplasm bound to chaperones that facilitate its binding to the ligand and serve as shuttles of the RM-ligand complex to the nucleus&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The aldosterone-RM binding promotes several effects&#58; <span class="elsevierStyleItalic">&#40;1&#41;</span> the RM complex and its ligand are translocated to the nucleus where it forms dimers and activates genes encoding certain proteins &#40;genomic effects&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#59; There may be interaction with other cytoplasmic transcription factors such as <span class="elsevierStyleItalic">nuclear factor of activated T-cells</span> &#40;NAFT&#41; and <span class="elsevierStyleItalic">cAMP response element-binding protein</span> &#40;CREB&#41; that can modify genomic signals&#59; <span class="elsevierStyleItalic">&#40;2&#41; in</span> addition to the genomic effects&#44; there may be fast non-genomic effects&#46; The aldosterone-MR complex can directly activate cytoplasmic kinases through its interaction with membrane receptors&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">25&#44;26</span></a> Aldosterone binds to MR that is anchored in the membrane by caveolin and striatin and interacts with membrane receptors such as <span class="elsevierStyleItalic">epidermal growth factor receptor</span> &#40;EGFR&#41;&#44; <span class="elsevierStyleItalic">platelet derived growth factor receptor</span> &#40;PDGFR&#41;&#44; <span class="elsevierStyleItalic">insulin like growth factor receptor</span> &#40;IGF1R&#41;&#44; <span class="elsevierStyleItalic">vascular endothelial growth factor receptor</span> &#40;VEGFR&#41;&#44; <span class="elsevierStyleItalic">G protein coupled estrogen receptor</span> &#40;GPER&#41; and <span class="elsevierStyleItalic">angiotensin II receptor type I</span> &#40;AT1R&#41;&#46; This interaction is responsible for the non-genomic effects of aldosterone mainly related with electrolyte transport and vasomotor tone &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The genomic signals of MR-aldosterone can be modified by epigenetic signals and undergo post-transcriptional changes&#46; Also the redox status and the amount of <span class="elsevierStyleItalic">reactive oxygen species</span> &#40;ROS&#41; influence the cellular processes and even the activation mechanism triggered by the activation of MR&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The activation and transcriptional effect of MR may occur without its binding to the ligand &#40;aldosterone or cortisol&#41;&#46; Activation of <span class="elsevierStyleItalic">ras-related C3 botulinum substrate 1</span> &#40;Rac1&#41; may cause MR stimulation with its transcriptional activity independently of aldosterone<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Rac1 is a member of the RhoGTPase subfamily that transduces extracellular signals from G protein-coupled receptors&#44; integrins&#44; and growth factors to effector molecules that modulate multiple signaling pathways&#46; Various stimuli&#44; such as mechanical stretching&#44; inflammatory cytokines&#44; growth factors&#44; glucose&#44; aldosterone&#44; and oxidative stress&#44; among others&#44; activate Rac1&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> In vitro studies show that Rac1 improves the transcriptional activity of MR by increasing its nuclear translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Studies in animal models with increased Rac1 activation&#44; the Rac1-MR interaction is associated with proteinuria and podocyte damage&#44; without changes in aldosterone levels&#46; Pharmacological inhibition of Rac or the use of MR antagonist inhibits the hyperactivity of MR and reduced renal histological changes and proteinuria&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Mesangial cells cultured in high glucose increase Rac1 activity&#44; and mayenhance the transcriptional activity of the MR induced by aldosterone&#59; also it may increase transcriptional activity of the RM in the absence of aldosterone in the medium&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In animal models of obesity-related diabetic nephropathy in which there is an increase in plasma aldosterone concentration and renal Rac1 activity&#44; administration of a specific Rac inhibitor suppressed renal Rac1&#44; decreased MR activation&#44; and attenuated renal damage&#44; all without changes in the aldosterone level&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In the murine model of salt-sensitive HT&#44; the high-salt diet increases renal Rac1 activity and produces MR activation at the renal level&#44; and induces HTN and kidney damage despite low plasma aldosterone levels&#46; The opposed&#44; Rac inhibition prevented hypertension and kidney damage&#46; The infusion of aldosterone enhanced the activation of the MR by Rac1 which demonstrate an additive effect of Rac1 and aldosterone&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In most of these studies&#44; the increase in MR transcriptional activity induced by Rac1 was due to an increase in nuclear translocation of MR&#46; There are other mechanisms could participate in the increase in MR signals mediated by Rac1&#58; both the amount and modifications of signals &#40;phosphorylation&#44; acetylation&#44; <span class="elsevierStyleItalic">sumoylation</span> &#40;small ubiquitin-related modifier&#41; of MR&#44; changes in its efficacy after activation due to epigenetic modifications or recruitment of co-regulators&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Aldosterone-independent MR modulation by Rac1 may be of great relevance not only because it enhances the MR activation exerted by aldosterone&#44; but also because it activates MR&#44; promoting organ dysfunction in situations in which the plasma concentration of aldosterone is normal or reduced&#44; as frequently occurs in DM with renal involvement and in salt-sensitive HT&#44; among others&#46; It would also explain that the effect of MR antagonists is not correlated on many occasions with the plasma concentration of aldosterone&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Effects of aldosterone on the renal tubule</span><p id="par0065" class="elsevierStylePara elsevierViewall">The first action described of aldosterone was on the main cells of the renal collecting duct&#46; After translocation to the nucleus&#44; the aldosterone-MR complex interacts with a large number of genes that encode proteins such as the alpha subunit of the epithelial sodium channel &#40;ENaC&#41; and <span class="elsevierStyleItalic">serum and gluco-corticoid-regulated kinase 1</span> &#40;SGK1&#41;&#44; which control the amount and the activity of ENaC in the apical part of the membrane and of the Na-K-ATPase pump in the basolateral membrane&#46; The electrogenic increase in tubular reabsorption of Na<span class="elsevierStyleSup">&#43;</span> secondary to the activation of ENaC favors the secretion of K<span class="elsevierStyleSup">&#43;</span> by the <span class="elsevierStyleItalic">renal outer medullary K<span class="elsevierStyleSup">&#43;</span> channel</span> &#40;ROMK&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Recent findings show that in the presence of hypokalemia&#44; aldosterone activates the pendrin&#44; ATPase dependent H<span class="elsevierStyleSup">&#43;</span> secretion and the thiazide sensitive cotransporter Na<span class="elsevierStyleSup">&#43;</span>&#8211;Cl<span class="elsevierStyleSup">&#8722;</span> &#40;NCC&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Aldosterone exerts tubular effects that affect the afferent arteriole and&#44; therefore&#44; glomerular filtration &#40;GFR&#41;&#46; The macula densa &#40;MD&#41; contains MR whose activation by aldosterone increases nitric oxide production with attenuation of the tubulo-glomerular <span class="elsevierStyleItalic">feedback</span> &#40;TGF&#41; response &#40;decrease in the afferent arteriole vasoconstrictor response induced by the delivery of Na<span class="elsevierStyleSup">&#43;</span> to MD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In addition&#44; by activating ENaC and increasing distal Na<span class="elsevierStyleSup">&#43;</span> reabsorption&#44; it induces vasodilation of the afferent arteriole &#40;tubule connecting-glomerulus <span class="elsevierStyleItalic">feedback</span> &#91;TCGF&#93;&#41;&#44; which also antagonizes TGF&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Vascular effects of aldosterone</span><p id="par0075" class="elsevierStylePara elsevierViewall">In addition to this indirect effect on glomerular hemodynamics&#44; aldosterone has a direct impact on the systemic and renal vasculature&#46; There are MR on the endothelium and the smooth muscle cell&#46; In blood vessels&#44; it regulates genes involved in fibrosis&#44; calcification&#44; and inflammation&#46; The degree of regulation depends on other factors&#44; such as type of flow &#40;laminar&#47;turbulent&#41; and oxidative stress&#44; among others&#46; Endothelial MR activation produces an increase in endothelial ENaC expression&#44; intensifies oxidative stress and inflammation&#44; contributing to endothelial dysfunction and increased arterial stiffness&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">39&#44;40</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In the vascular smooth muscle cell&#44; MR activation contributes to the regulation of vascular tone through a series of events &#40;activation Src kinase&#44; Rho kinase and <span class="elsevierStyleItalic">placental growth factor</span> &#91;PlGF&#93;&#44; among others&#41; that induce proliferation&#44; fibrosis&#44; remodeling and increase of arterial stiffness&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">26&#44;39</span></a> Consequently&#44; activation of vascular MR produces target organ damage&#44; HTN&#44; coronary vascular dysfunction&#44; cardiac fibrosis&#44; alterations in renal hemodynamics&#44; and kidney damage&#46; Many of the effects of MR activation are not genomic&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> There is intimate interaction and synergy between genomic and non-genomic effects of aldosterone such that non-genomic effects may provide support to genomic actions&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Experimental data on the effects of aldosterone and MR block in models of kidney damage</span><p id="par0085" class="elsevierStylePara elsevierViewall">There are many studies on the effect of aldosterone and the pharmacological blockade or deletion of MR in animal models of kidney damage and in vitro investigations in various types of kidney cells &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; We highlight the most relevant on the different renal structures and in the systemic vasculature&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Effects of aldosterone on renal hemodynamics and acute tubular damage</span><p id="par0090" class="elsevierStylePara elsevierViewall">Aldosterone causes renal vasoconstriction by increasing Rho kinase activity&#44; endothelin&#44; and the AT1 receptors of A<span class="elsevierStyleInf">II</span>&#46; In animal models of renal damage induced by ischemia-reperfusion&#44; the administration of spironolactone prior to or within 6&#8239;h of the onset of ischemia attenuates renal hypoperfusion&#44; reduces oxidative stress and prevents structural damage &#40;tubular necrosis&#41; and decreases tubular damage markers such as <span class="elsevierStyleItalic">kidney injury molecule</span> &#40;KIM-1&#41; and <span class="elsevierStyleItalic">heat shock protein</span> &#40;HSP72&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> In the model of renal damage induced by cyclosporine&#44; in which there is vasoconstriction of the afferent arteriole&#44; the MR of vascular smooth muscle cells also participates by modulating the phosphorylation of their contractile proteins and the activity of their calcium L channels&#46; Deletion of the MR of vascular smooth muscle cell prevents histological damage&#44; vacuolization of the proximal tubular cells and overexpression of <span class="elsevierStyleItalic">- neutrophil gelatinase associated lipocalin</span> &#40;NGAL&#41;&#44; a marker of tubular damage&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Effect on the renal interstitium&#46; Production of interstitial fibrosis</span><p id="par0095" class="elsevierStylePara elsevierViewall">There are several mechanisms involved in the genesis of renal interstitial fibrosis and chronic kidney damage&#58; transformation of tubular cells into mesenchymal cells&#44; inflammation&#44; and inadequate tissue repair after acute kidney injury &#40;AKI&#41;&#46; All of these have been shown to be involved in the renal profibrotic effects of aldosterone&#46; Human proximal tubular cells exposed to aldosterone undergo epithelial-mesenchymal transformation by activation of <span class="elsevierStyleItalic">extracellular regulated kinases</span> &#40;ERK1 and 2&#41; secondary to the generation of mitochondrial ROS&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> This increase in mitochondrial ROS is also responsible for the activation of the <span class="elsevierStyleItalic">inflammasome nucleotide-binding domain and leucine-rich repeat containing PYD-3</span> &#40;NLRP3&#41;&#44; which is as associated with an increase in fibrogenic interleukins IL-1b and IL-18 that is observed when proximal tubular cells HK-2 are cultured in aldosterone medium&#46; Both the mesenchymal transition and the activation of the inflammasome are blocked by aldosterone antagonists&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">43&#44;44</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There is evidence that AKI can be a factor in the development of interstitial fibrosis and CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> This AKI-interstitial fibrosis interconnection is mediated&#44; in part&#44; by the early appearance of inflammatory cells that play an important role in defective repair after AKI&#46; In the model of AKI due to ischemia-reperfusion&#44; finerenone&#44; an MR antagonist&#44; decreases interstitial fibrosis by activating the signals mediated by the IL-4 receptor&#44; increasing anti-inflammatory M2 macrophages and decreasing the pro-inflammatory macrophage phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> In animal models of ischemia induced AKI&#44; spironolactone administration&#44; before or after ischemia&#44; prevents the development of CKD by preventing the activation of inflammatory and profibrotic processes&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Effect on glomerular cells</span><p id="par0105" class="elsevierStylePara elsevierViewall">Aldosterone participates in the alterations of various glomerular cells that possess MR and are able to produce functional and structural alterations of the glomerulus&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The podocyte is a fundamental component of the glomerular filtration barrier&#46; Alterations in the function and structure of the podocyte constitute the pathophysiological basis of many glomerular diseases including diabetic nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> The podocyte participates in aldosterone-induced glomerular damage&#46; In uninephrectomized rat fed a high-salt diet&#44; the administration of aldosterone induces proteinuria&#44; structural alterations of the podocyte and a decrease in the gene expression of the podocyte proteins nephrin and podocin&#46; Podocyte damage is associated with increased oxidative stress and SGK1 activation&#46; Epleronone treatment prevents podocyte damage&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> In podocyte culture&#44; aldosterone stimulates oxidative stress and the expression of SGK1&#44; which is inhibited by epleronone and bysuperoxide dismutase&#44; suggesting that aldosterone affects podocyte function through oxidative stress and SGK1&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The inflammasome NLRP3 is also involved in aldosterone-induced podocyte damage&#46; The inflammasome activates procaspase 1 which in turn induce activation of IL-1b and IL-18&#46; In podocytes incubated with aldosterone&#44; it is observed an increase in the expression of NLRP3 which increases the expression of caspase 1 and the concentration of IL-1b and IL-18&#41;&#46; The increase in oxidative stress participates in the activation of NLRP3&#44; since it is attenuated if <span class="elsevierStyleItalic">N</span>-acetylcysteine is added to the medium&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Similar results are observed in <span class="elsevierStyleItalic">in vivo</span> experiments&#46; The administration of aldosterone to experimental animals also induces an increase in the expression of NLPR3 in podocytes and also produces damage of the podocyte with loss of nephrin and podocin&#44; alterations that are not observed in animals with a deletion of the NLRP3 gene&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Aldosterone contributes to the generation of glomerular inflammation and fibrosis&#44; two fundamental processes involved in glomerular sclerosis&#46; Both <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#44; aldosterone stimulates the expression and activity of SGK1 in the mesangium&#44; which is involved in the transcription of connective tissue growth factor &#40;CTGF&#41; and intercellular adhesion molecule &#40;ICAM-1&#41;&#44; which are related to the fibrosis and glomerular inflammation&#44; respectively&#46; These phenomena are attenuated by the administration of epleronone&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Aldosterone also contributes to the glomerular inflammation seen in experimental glomerulonephritis &#40;GN&#41;&#46; In animal models of rapidly progressive GN&#44; deletion of MR in myeloid cells&#44; as well as therapy with RM antagonists reduced the early neutrophil infiltration of the glomerulus and later on&#44; the glomerular recruitment of macrophage with the corresponding decreased expression of proinflammatory cytokines&#44; diminution of crescents and better preservation of renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Systemic vascular effects</span><p id="par0130" class="elsevierStylePara elsevierViewall">Aldosterone exerts systemic vascular effects that may be relevant in CV morbidity and mortality of CKD patients&#46; Aldosterone increases oxidative stress&#44; promotes phenotypic changes in vascular smooth muscle cells and fibrosis of the vascular wall&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The infusion of aldosterone to experimental animals worsens endothelial function and vasodilation mediated by adenosine by reducing the A2a receptor dependent of calcium-activated K channels&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> This is relevant because the microvascular dysfunction evidenced by decrease in coronary reserve mediated by A2a predicts cardiovascular mortality in CKD patients on dialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Vascular calcifications are very frequent in the different stages of CKD&#44; these calcifications have hemodynamic consequences and predict CV events and mortality&#46; Important to note that in adenine - induced CKD animal model of vascular calcification&#44; spironolactone administration attenuates vascular calcification by suppression of osteogenic transdifferentiation of vascular smooth muscle cells&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Effects of MR blockade in CKD&#46; Clinical studies</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">MR blockade and HTN</span><p id="par0145" class="elsevierStylePara elsevierViewall">One of the factors that promote CKD progression is hypertension&#46; Aldosterone favors Na<span class="elsevierStyleSup">&#43;</span> retention&#44; increases blood volume&#44; produces vasoconstriction&#44; endothelial dysfunction&#44; increases arterial stiffness&#44; and alters the baroreflex response&#46; MR blockade reduces blood pressure &#40;BP&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">56&#44;57</span></a> In resistant HTN&#44; the addition of spironolactone to the therapeutic triad&#58; diuretic-ARS blockade-calcium antagonist produced a greater reduction of BP than the addition of doxazosin or beta-blocker&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Resistant HTN is common in CKD&#46; Even in CKD with well controlled BP&#44; administration of spironolactone slows pulse wave velocity&#44; a marker of arterial stiffness and LVH&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> The decrease in arterial stiffness benefits the heart because it reduces the central systolic BP and also favors the kidney&#46; A rigid aorta that is not capable to mitigate the pulsatile flow generated by ventricular ejection&#44; the fluctuations of pulsatile flow will be transmitted without attenuation to the capillaries in those organs with a low vascular resistance such as the kidney&#46; Increased arterial stiffness is associated with a decrease in GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Plasma aldosterone values and renal expression of MR in CKD</span><p id="par0155" class="elsevierStylePara elsevierViewall">In CKD there is an increase in plasma aldosterone which is inversely related to the GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Although&#44; as in normal subjects&#44; there is an inverse relationship between Na<span class="elsevierStyleSup">&#43;</span> intake and aldosterone&#46; However&#44; in renal failure there is inadequate suppression of aldosterone&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> CKD is a state of relative hyperaldosteronism&#46; The underlying cause of the increase in aldosterone when the GFR decreases&#44; that persists despite the blockade with ACEi or ARA2&#44; is not clear&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> There is a direct relationship between PTH&#47;FGF23 and aldosterone&#44; and an inverse relationship between klotho and aldosterone&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> A decrease in klotho values can increase aldosterone synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The existence of imperceptibly elevated K<span class="elsevierStyleSup">&#43;</span> values could also contribute to aldosterone elevation&#46; In another sense&#44; the association between elevated aldosterone values and a decrease in GFR could be due to the renal damage induced by aldosterone&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In the proteinuric nephropathies it has been also demonstrated increased renal expression of the MR which correlates with the presence of inflammatory markers&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">All this&#44; together with the experimental data&#44; reaffirms the association between CKD and aldosterone&#44; and raises a probable nephroprotective effect of a reduction of aldosterone values or a blockade of its effects&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Aldosterone escape with drugs that block RAS</span><p id="par0170" class="elsevierStylePara elsevierViewall">The most important secretagogue of aldosterone is A<span class="elsevierStyleInf">II&#46;</span> The use and optimization of doses of drugs that block the generation or action of A<span class="elsevierStyleInf">II</span> is associated with a decrease in the development and progression of CKD and death&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">66&#44;67</span></a> The dual blockade of the RAS &#40;ACEi&#8239;&#43;&#8239;ARA2&#41; reduces proteinuria compared to monotherapy&#44; but iy is associated with a higher risk of hyperkalemia&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> In all these studies&#44; despite therapy with ACEI&#44; ARA2 or their combination&#44; it persists a high residual risk of CKD progression and death&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">This residual risk may be in part due to the so-called aldosterone &#8220;escape&#8221;&#58; elevation of plasma aldosterone levels&#44; after an initial decrease&#44; when an RAS blocker is administered&#46; In CKD&#44; this occurs frequently&#44; in 40&#8211;53&#37; of cases&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> and it is associated with reappearance or the increase in proteinuria and a decrease in GFR&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">70&#44;71</span></a> The cause of the aldosterone escape is unknown&#46; An increase in serum K<span class="elsevierStyleSup">&#43;</span> and ACTH&#44; a decrease in atrial natriuretic peptide&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> or a lack of inhibition of the receptor AT<span class="elsevierStyleInf">1</span> of the A <span class="elsevierStyleInf">II</span> receptor bound to &#174;-arrestin<span class="elsevierStyleInf">1</span> may contribute to escape&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> The involvement of aldosterone in this phenomenon is reinforced by the finding that the administration of spironolactone reduces proteinuria after its relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Effect of MR blockade on proteinuria and GFR in CKD</span><p id="par0180" class="elsevierStylePara elsevierViewall">The first study on the effect of MR blockade in proteinuric nephropathy included 8 patients&#46; The addition of spironolactone to ACEi achieved a 45&#37; reduction in proteinuria&#44; without changes in BP&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> In another study with 165 patients with non-diabetic proteinuric nephropathy treated with ACEI or ARA2&#44; the administration of spironolactone 25&#8239;mg&#47;day for one year reduced proteinuria by 50&#37;&#46; In the group receiving spironolactone it was observed that the GFR initially decreased with subsequent stabilization&#44; while the control group showed a progressive decrease in GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> This pattern of GFR behavior mimics that found with drugs that reduce hyperfiltration&#44; an effect that&#44; in the case of MR blockers&#44; probably derives from their action on glomerular hemodynamics&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;38</span></a> In another study in subjects receiving RAS blockers with residual proteinuria&#44; addition of spironolactone therapy for 2 years produced a progressive reduction in proteinuria&#44; to a 63&#37;&#46; The evolution of the GFR was better in those in which the initial decrease was greater&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> Various meta-analyzes have shown that aldosterone antagonists added to ACEI or ARA2 produce a significant decrease in proteinuria&#44; a reduction in BP&#44; but an increased risk of hyperkalemia &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#8211;79</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">In an analysis of a database from subjects with CKD stages 3&#8211;4&#44; the comparative study&#44; after adequate adjustment of variables&#44; between patients on spironolactone &#40;n&#8239;&#61;&#8239;693&#41; vs those who did not receive &#40;n&#8239;&#61;&#8239;1386&#41; showed that patients receiving spironolactone had less progression to CKD with less dialysis requirements <span class="elsevierStyleItalic">&#40;hazard ratio</span> &#91;HR&#93; 0&#46;66&#59; 95&#37; CI&#44; 0&#46;51&#8722;0&#46;84&#59; p&#8239;&#60;&#8239;0&#46;001&#41; and a higher risk of hospitalization due to hyperkalemia &#40;HR 3&#46;17&#59; 95&#37; CI 2&#46;41&#8211;4&#46;17&#59; p&#8239;&#60;&#8239;0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Recently&#44; a probable nephroprotective effect of the sodium-glucose cotransporter type 2 &#40;iSGLT2&#41; inhibitor dapagliflozin has been observed in non-diabetic CKD&#46; The DAPA-CKD <span class="elsevierStyleItalic">&#40;The effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease&#41;</span> clinical trial<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> included 4245 subjects with CKD stages 2&#8211;4 with increased urinary albumin excretion&#44; with a maximum tolerated dose of ACEi or ARA2&#46; Patients were randomized to dapagliflozin 10&#8239;mg&#47;day or placebo&#46; The primary endpoint was a decrease of the by GFR &#8805;50&#37;&#44; advanced CKD &#40;FG&#8239;&#60;&#8239;15&#8239;ml&#47;min&#44; dialysis or renal transplant&#41; or renal and cardiovascular death&#46; On March 30&#44; 2020&#44; the trial was discontinued because it was observed&#44; ahead of schedule&#44; the probable benefits in the dapagliflozin branch&#46; Although the results are not published yet&#44; it seems presumable to attribute the early suspension of the trial to the superiority of dapagliflozin in reducing events&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">One of the mechanisms involved in the nephroprotective effect of iSGLT2 is the decrease in intraglomerular pressure secondary to the vasoconstriction of the afferent arteriole induced by the increased supply of Na<span class="elsevierStyleSup">&#43;</span> to MD&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> Coadministration of ACEi or ARA2 would enhance the decrease in intraglomerular pressure&#44; by decreasing the vasoconstriction of the efferent arteriole&#46; Theoretically&#44; the administration of loop diuretics&#44; by inhibiting Na<span class="elsevierStyleSup">&#43;</span> reabsorption in MD&#44; could reduce the renal hemodynamic effect of iSGLT2&#46; However&#44; the co-administration of antialdosteronic agents&#44; by decreasing the distal reabsorption of Na<span class="elsevierStyleSup">&#43;</span>&#44; inhibits the connective tubule-glomerular <span class="elsevierStyleItalic">feedback</span>&#44; inducing vasoconstriction of the afferent arteriole and enhancing the effect of iSGLT2 on glomerular hemodynamics&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37&#44;83</span></a> Thus&#44; the combination of ACEi or ARA2&#44; iSGLT2 and MR antagonists could enhance the nephroprotective effects&#46; Studies are needed to explore this hypothesis&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The effect of MR blockers on CV events and mortality in CKD paties is analyzed in the BARACK D<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> clinical trial <span class="elsevierStyleItalic">&#40;Benefits of aldosterone receptor antagonism in chronic kidney disease&#41;&#44;</span> currently in progress&#44; with a 3-year follow-up &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Effect of MR blockade on proteinuria and GFR in type 2 DM</span><p id="par0205" class="elsevierStylePara elsevierViewall">Most of the referred studies included subgroups of patients with DM2&#46; There are&#44; however&#44; others who have specifically looked at the effect of MR blockade on diabetic nephropathy&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The effect of ACEi&#44; ARA2&#44; antirenin drugs or a combination of them on the different stages of diabetic nephropathy has been evaluated&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">85&#8211;94</span></a> Compared with conventional antihypertensive therapy&#44; the ARA2 reduce the risk of kidney disease progression and mortality&#46; However still persists a high residual risk for these events&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">93&#44;94</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The combination ACE1-spironolactone&#44; compared to the combination ACEi-ARA2&#44; produces a greater decrease in proteinuria&#44; similar effects on BP and GFR&#44; and higher values of serum K<span class="elsevierStyleSup">&#43;</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">In DM2&#44; it is frequent to observe reduced serum levels of renin and aldosterone<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">96&#44;97</span></a>&#59; in this situation&#44; it would seem reasonable to predict an attenuated response to aldosterone antagonists&#46; However&#44; both in animals with experimental diabetes and in subjects with DM2&#44; the administration of spironolactone reduces alterations of podocyte and proteinuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">98&#44;99</span></a> In an experimental model of diabetic rats with hypoaldosteronism&#44; the administration of spironolactone prevents oxidative stress&#44; podocyte apoptosis and proteinuria&#46; <span class="elsevierStyleItalic">in vitro</span>&#44; glucose&#44; through MR&#44; increases NADPH oxidase activity&#44; ROS generation and SGK1 expression&#44; producing podocyte damage&#44; all of this is inhibited by spironolactone&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> The increased activity of podocyte AS and Rac1 could mediate the activation of MR by glucose&#44; independent of the systemic aldosterone&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29&#44;101&#44;102</span></a> Therefore&#44; even in situations of low plasma aldosterone values&#44; the administration of MR antagonists may be useful for renal protection&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Several meta-analyzes showed that in subjects with diabetic nephropathy the co-administration of an aldosterone antagonist with ACEI or ARB2&#44; versus monotherapy with ACEI or ARB2&#44; reduced albuminuria and BP&#44; in addition to the increased risk of hyperkalemia&#44; which was lower with the antagonist finerenone&#46; of 3rd generation aldosterone antagonist<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">103&#44;104</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0230" class="elsevierStylePara elsevierViewall">Although the cited studies have some limitations&#44; it can be concluded that in mild-to-moderate diabetic and non-diabetic CKD &#40;stages 2&#8211;3&#41; with proteinuria&#44; the addition of aldosterone antagonists to ACEI or ARB2&#44; compared with monotherapy with ACEI or ARB2&#44; reduces proteinuria and BP&#44; and increases the risk of hyperkalemia&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">In patients with DM2&#44; prevention of the development of nephropathy is very important&#46; Adequate metabolic control&#44; BP values&#44; weight&#44; ACEi or ARA2 and iSGLT2 are effective in reducing the appearance of albuminuria in patients with DM2&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">105&#8211;107</span></a> In the PRIORITY clinical trial <span class="elsevierStyleItalic">&#40;Proteomic prediction and renin angiotensin aldosterone system inhibition prevention of early diabetic nephropathy in type 2 diabetic patients with normoalbuminuria&#41;</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> 1175 subjects with DM2 and normoalbuminuria were classified&#44; using a urine proteomic biomarker pan &#40;CKD273&#41;&#44; at high and low risk of developing albuminuria&#46; 216 subjects classified as high risk were randomized to spironolactone more conventional therapy 25&#8239;mg&#47;day and more conventional therapy placebo&#46; The follow-up was 2&#46;57 years and the primary endpoint was the development of albuminuria&#46; The results were presented at the 55th meeting of the European Association for the Study of Diabetes &#40;EASD&#41;&#44; held in Barcelona in September 2019&#46; No significant reduction in the appearance of albuminuria was observed&#44; although there was some suggestion of benefit spironolactone from the last year&#46; The serum K<span class="elsevierStyleSup">&#43;</span> rate&#8239;&#62;&#8239;5&#46;5&#8239;mEq&#47;l was higher in the spironolactone group&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">There is enough evidence about the renoprotective effect of iSGLT<span class="elsevierStyleInf">2</span> in DM2<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">109&#8211;111</span></a>&#59; given in combination with ACEi or ARA2&#44; produces a decrease the development and progression of nephropathy in DM2&#46; There are pathophysiological considerations&#44; even with more argumentative force than those discussed in CKD&#44; which raise the possibility that the triple combination of aldosterone antagonists&#44; ACEIs or ARA2 and iSGLT2 offers greater protection in diabetic nephropathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">33&#44;34&#44;82&#44;83</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">MR blockade in CKD patients on dialysis therapy</span><p id="par0245" class="elsevierStylePara elsevierViewall">CKD patients on HD frequently present vascular calcifications&#46; In a small study of 5 patients on HD the administration of spironolactone 50&#8239;mg&#47;day for 3 years produced a significant decrease in aortic calcifications&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">In CKD patients on peritoneal dialysis &#40;PD&#41;&#44; biopsy of the peritoneum showed that the administration of 25&#8239;mg&#47;day of spironolactone was associated with a reduction in the amount of type IV collagen and CD20 lymphocytes in the peritoneum&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">113</span></a> A lesser degree of fibrosis which improves peritoneal function in these patients&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Apart from these facts&#44; the use of aldosterone antagonists in CKD patients treated with dialysis is relevant since it has been demonstrate an association between plasma aldosterone levels and mortality&#44; including sudden death&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">One of the largest clinical trials is the DOHAS <span class="elsevierStyleItalic">&#40;Dialysis outcomes heart failure aldactone study&#41;</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> in which 309 subjects on HD were randomized to receive spironolactone 25&#8239;mg&#47;day or conventional therapy during 3 years&#46; It was observed that in the spironolactone group there was a significant reduction in mortality or admissions for CV events 95&#37;&#44; from&#59; p &#40;HR 0&#46;40&#59; 95&#37; CI&#44; 0&#46;20&#8211;0&#46;80&#59; p&#8239;&#61;&#8239;0&#46;017&#41;&#46;A 1&#46;9&#37; of the patients treated with spironolactone had severe hyperkalemia and 10&#46;2&#37; had gynecomastia or mastodynia&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Similar results were obtained in 2 metaanalysis that included HD and PD patients in which the effect of aldosterone antagonists was compared with placebo or conventional therapy<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">116&#44;117</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">The great reduction in CV events and total mortality achieved by aldosterone antagonists in dialysis CKD patients on dialysis is prominent when compared to the observed in CKD subjects who are not on dialysis&#46; However&#44; the limitations of the included studies must be taken into consideration &#40;open design&#44; small number of patients&#44; short follow-up&#44; few events of CV mortality&#44; as well as high relative risk variability demonstrated by sensitivity analysis&#41;&#46; All this make us think that&#44; currently&#44; there is no definitive evidence of a benefit of MR antagonists in dialysis patients&#46; There are two randomized trials&#44; currently underway&#44; may provide more certainty&#58; one of them&#44; ALCHEMIST <span class="elsevierStyleItalic">&#40;Aldosterone antagonist chronic hemodyalisis interventional survival trial&#41;</span>&#44; includes 825 high-risk vascular subjects with kidney failure on HD&#46; Its duration will be 2 years and the primary objective is to analyze the effect of spironolactone 25&#8239;mg&#47;day versus placebo on CV death and events&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> The other trial&#44; ACHIEVE <span class="elsevierStyleItalic">&#40;Aldosterone blockade for health improvement evaluation in end-stage renal disease&#41;</span>&#44; tries to determine whether spironolactone 25&#8239;mg&#47;day&#44; as compared with placebo&#44; reduces mortality and hospitalization due to heart failure &#40;HF&#41; in 2750 patients with CKD on dialysis treatment<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">119</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">MR antagonists in HF with CKD</span><p id="par0275" class="elsevierStylePara elsevierViewall">The benefits of MR antagonists in patients with heart failure with reduced eyection fraction &#40;EF&#41; are well established&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a> Even in HF with preserved EF&#44; MR antagonists can reduce admissions for heart failure&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a> More than 50&#37; of patients with heart failure have CKD and their mortality increases with the decrease in GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> A large percentage of patients with heart failure and CKD do not receive MR blocker therapy because of the concern of hyperkalemia&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a> In the RALES trial&#44; the relative risk of total mortality and hospitalization for heart failure in subjects treated with spironolactone was similar in those with and without a decrease in GFR &#40;0&#46;68&#44; 95&#37; CI&#44; 056&#8722;0&#46;84 and 0&#46;64&#59; 95&#37; CI&#44; 0&#46;52&#8722;0&#46;72 vs 0&#46;71&#44; 95&#37; CI&#44; 0&#46;57&#8722;0&#46;90 and 0&#46;67&#44; 95&#37; CI&#44; 0&#46;56&#8722;0&#44;81&#44; respectively&#41;&#46; The reduction of absolute risk for mortality and admission for heart failure was greater in the presence of renal failure&#46; As expected&#44; the aldosterone antagonists produced hyperkalemia more frequently if the GFR was reduced &#40;25&#46;6&#37; vs 15&#46;4&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a>&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Non-steroidal MR blockers with a better safety profile &#40;less hyperkalemia&#41; and new intestinal K<span class="elsevierStyleSup">&#43;</span> linkers may facilitate the use of aldosterone antagonists in CKD patients with heart failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">121&#44;124</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The ongoing FINESSE clinical trial compares the effect of finerenone versus eplerenone on CV mortality and admission for heart failure in subjects with chronic heart failure with reduced EF and DM-2 or CKD<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">MR antagonists and hyperkalemia</span><p id="par0290" class="elsevierStylePara elsevierViewall">In contrast to the consistent evidence of the CV and mortality benefits of aldosterone antagonists in cardiology<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a>&#44; there are few specific studies of the effect of these drugs on these events in nephrology&#46; It is possible that one of the hyperkalemia&#44; especially in situations of renal failure&#44; has been a constrain for the frequent use of these drugs in CKD&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">As observed in clinical trials and in real life studies&#44; the combination of aldosterone antagonists with ACEI or ARA2 increases the risk of hyperkalemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">104&#44;116&#44;126</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">This fact is important since in conditions frequently associated with abnormal regulation of K&#44; such as heart failure&#44; DM and CKD&#44; there is a U shape relationship between serum K<span class="elsevierStyleSup">&#43;</span> and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">In subjects with less capacity to excrete K<span class="elsevierStyleSup">&#43;</span> in the urine due to a reduction in the diuresis&#44; aldosterone antagonists also increase serum K<span class="elsevierStyleSup">&#43;</span>&#46; Compared with subjects with normal renal function&#44; patients with severe CKD have an increased expression of K<span class="elsevierStyleSup">&#43;</span> channels &#40;BK channels&#41; in colon enterocytes that increases their capacity for intestinal elimination of K<span class="elsevierStyleSup">&#43;</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a> Aldosterone stimulates colonic K<span class="elsevierStyleSup">&#43;</span> secretion through BK channels&#44; secretion that is inhibited by spironolactone&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">129&#44;130</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">The association of aldosterone antagonists with ACEI or ARA2 contributes to hyperkalemia&#44; but in these patients there may also concur other causes of elevated serum K<span class="elsevierStyleSup">&#43;</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">131</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Given the occurrence of hyperkalemia in subjects who receive RAAS blockers for processes in which they have shown benefit&#44; frequently the dose has to be reduced or even suppressed&#46; This fact may condition an increase in CV and renal events&#44; and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">132</span></a> The use of the new oral K<span class="elsevierStyleSup">&#43;</span> binders as patiromer and zirconium cyclosilicate is likely to improve tolerability and minimize discontinuation of RAAS<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">133&#8211;135</span></a> blockers&#46; On the other hand&#44; the new non-steroidal aldosterone antagonists induce less hyperkalemia than the classic antagonists&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">136</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Nonsteroidal aldosterone antagonists</span><p id="par0320" class="elsevierStylePara elsevierViewall">Most studies with aldosterone antagonists have used the classic steroid antagonists&#58; spironolactone&#44; which has low specificity of action on MR&#44; and eplerenone&#44; which is more selective&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Nonsteroidal aldosterone antagonists have a different chemical structure from that of steroids&#44; which determines differences in physicochemical properties&#44; pharmacological actions&#44; tissue penetration and distribution&#44; the mode of binding to the ligand and the ability to bind to co-regulators&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> All this may condition special effects on organ protection and attenuation of adverse effects&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">To date&#44; 7 nonsteroidal aldosterone antagonists has been tested in clinical trials in different phases&#44; some of them being discontinued for various reasons&#46; Others have completed phase 1 trials or are recruiting patients for phase 2&#46;<a class="elsevierStyleCrossRefs" href="#bib0690"><span class="elsevierStyleSup">138&#8211;141</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">The most advanced nonsteroidal aldosterone antagonists are&#58; apararenone &#40;MT3995&#44; Mitsubishi Tanabe Pharma Corporation&#44; Osaka&#44; Japan&#41;&#44; exaserenone &#40;CS3150&#44; Exelisis&#44; California&#44; USA&#44; and Daiichi Sankio&#44; Tokyo&#44; Japan&#41; and finerenone&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">Aphase 2 clinical trial with Apararerone has completed in subjects with diabetic nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">142</span></a> Esxerenone&#44; whose maximum 50&#37; inhibitory concentration &#40;IC<span class="elsevierStyleInf">50</span>&#41; of MR transcriptional activation is 9&#46;4&#8239;nM&#44; is a more potent&#44; more selective and specific inhibitor than spironolactone and epleronone&#46; In a randomized clinical trial&#44; Esxerenone has been shown to be effective and well tolerated in patients with HTN&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">143</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">The finerenona has an IC<span class="elsevierStyleInf">50</span> of 18&#8239;nM &#40;much lower than spironolactone and eplerenone and therefore more powerful&#41;&#46; It is much more selective for MR than spironolactone and epleronone and&#44; unlike those predominantly distributed in the kidney&#44; finerenone is equally distributed in the kidney and heart&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">136</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall">Experimental studies show that finerenone produces renal and vascular protection by reducing oxidative stress and attenuating endothelial dysfunction&#44; among other effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">144&#44;145</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">In the clinical trial ARTS <span class="elsevierStyleItalic">&#40;The mineralocorticoid receptor antagonist tolerability study&#41;&#44;</span> there were 782 included with heart failure and reduced EF and CKD stages 2&#8722;3&#46; Fineronona 5&#8722;10&#8239;mg&#47;day&#44; compared with spironolactone 25&#8722;50&#8239;mg&#47;day&#44; produced the same effect on the reduction of NT-pro-BNP and albuminuria&#44; less deterioration of renal function and less elevation of serum K<span class="elsevierStyleSup">&#43;</span> with a lower incidence of hyperkalemia &#40;5&#37; vs&#46; 13&#37;&#41; <a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">146</span></a>&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">In a similar patient population&#44; different doses of finerenone&#44; compared with epleronone 25&#8722;50&#8239;mg&#47;day&#44; produced a similar reduction in NT-pro-BNP and a lower increase in serum K<span class="elsevierStyleSup">&#43;</span>&#59; and in doses of 20&#8239;mg&#47;day&#44; finerenone produces a greater reduction in CV events and mortality than epleronone&#46; However&#44; as it was a short study&#44; these variables were considered exploratory&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">147</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">In the test ARTS-DN <span class="elsevierStyleItalic">&#40;Minerlocorticoid receptor antagonist tolerability study- diabetic nephropathy&#41;&#44;</span> 823 patients with diabetic nephropathy treated blockers of the Renin Angiotensin system &#40;ACEi or ARA2&#41; were randomized to different doses of finerenona or placebo&#46; The main objective was the modification of proteinuria&#46; Fineronone induced a significant dose-dependent reduction in proteinuria &#40;50&#37; reduction in proteinuria in 40&#37; of patients with 20&#8239;mg&#47;day&#41;&#44; with a slight non-significant decrease in GFR&#44; reversible after stopping the drug&#44; and a decrease in BP&#46; It was observed a low frequency of hyperkalemia &#40;K<span class="elsevierStyleSup">&#43;</span>&#8239;&#62;&#8239;5&#46;6 mEq&#47;l&#41; &#40;1&#46;6&#37; of the group treated with 20&#8239;mg&#47;day of finerenone vs&#46; 1&#46;5&#37; of the placebo group&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">These are short-term studies that analyze the effect of nonsteroidal aldosterone antagonists on intermediate variables&#46; In patients with heart failure and reduced EF&#44; the Classic MR antagonists have achieved benefits relative to CV events and mortality despite an increase in hyperkalemia&#46; Activation of MR produces harmful cardiorenal effects by various mechanisms that have been discussed in this review&#46; It is possible that nonsteroidal aldosterone antagonists&#44; with a theoretical greater cardiorenal protective capacity and with less risk of hyperkalemia&#44; more benefits will be obtained in important CV and renal variables&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">The definitive answer will be provided by 2 clinical trials with finerenone&#46; The FIDELIO-DKD <span class="elsevierStyleItalic">&#40;Finerenone in reducing kidney failure and disease progression in diabetic kidney disease&#41;</span> trial investigates the efficacy of finerenone compared to placebo in reducing major renal and CV events in subjects with DM-2 and CKD treated with ACEI or ARA2&#46; The primary endpoint is the time elapsed until the onset of advanced kidney disease&#44; decreased eGFR sustained &#8805;40&#37; or renal death<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">149</span></a>&#46; There were 5734 patients randomized&#44; ending the follow-up in 2020&#46; The study has been published recently&#46; Finerenone reduced the risk of the composite cardiovascular outcome compared with placebo &#40;hazard ratio&#44; 0&#46;86 &#91;95&#37; CI&#44; 0&#46;75&#8722;0&#46;99&#93;&#59; <span class="elsevierStyleItalic">p</span>&#8239;&#61;&#8239;0&#46;034&#41;&#44; with no significant interaction between patients with and without CVD&#46; The incidence of treatment-emergent adverse events was similar in both arms&#46;</p><p id="par0380" class="elsevierStylePara elsevierViewall">The FIGARO- DKD <span class="elsevierStyleItalic">&#40;Finerenone in reducing CV mortality and morbidity in diabetic kidney disease&#41;</span> investigates&#44; in subjects with DM2 and CKD&#44; the efficacy and safety of finerenone compared with placebo&#44; to reduce clinically relevant CV and renal events&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">150</span></a> The primary endpoint is the composite of CV death&#44; non-fatal myocardial infarction&#44; non-fatal stroke&#44; and hospitalization for heart failure&#46; 7437 patients were recruited&#44; currently under follow-up&#44; waiting for results in 2021&#46;</p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Key concepts</span><p id="par0385" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0390" class="elsevierStylePara elsevierViewall">In addition to the classic sites&#44; such as distal renal and connecting tubule&#44; and colon&#44; there are MR in other locations&#44; such as podocyte&#44; mesangium&#44; macula densa&#44; endothelium&#44; vascular smooth muscle cell&#44; myocardiocyte&#44; adipocyte&#44; macrophage&#44; among others&#46; In certain situations&#44; MR can be activated by mechanisms independent of aldosterone&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0395" class="elsevierStylePara elsevierViewall">Activation of MR by aldosterone increases distal renal tubular Na<span class="elsevierStyleSup">&#43;</span> reabsorption and K<span class="elsevierStyleSup">&#43;</span> secretion&#46; In addition to systemic hemodynamic effects &#40;increased BP and arterial stiffness&#41;&#44; aldosterone modifies intraglomerular hemodynamics by modulating the tubulo-glomerular and connecting tubule-glomerulus feedbacks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0400" class="elsevierStylePara elsevierViewall">Activation of vascular MRI &#40;endothelium&#44; smooth muscle fiber&#41; produces increased oxidative stress&#44; endothelial dysfunction&#44; fibrosis&#44; vascular remodeling&#44; and increased arterial stiffness&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0405" class="elsevierStylePara elsevierViewall">In experimental models&#44; aldosterone and MR activation produce kidney damage by various mechanisms &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5</span><p id="par0410" class="elsevierStylePara elsevierViewall">In CKD with decreased GFR and proteinuria&#44; there is an increase in plasma aldosterone values and in renal expression of MR&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">6</span><p id="par0415" class="elsevierStylePara elsevierViewall">A high percentage of subjects with CKD treated with ACEi or ARA2 present aldosterone leakage&#44; which is associated with a reappearance or increase in proteinuria and a greater decrease in GFR&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">7</span><p id="par0420" class="elsevierStylePara elsevierViewall">Many short-follow-up studies have shown that in diabetic and non-diabetic CKD patient with proteinuria&#44; classic aldosterone antagonists &#40;spironolactone&#44; eplerenone&#41; reduce proteinuria and increase the risk of hyperkalemia&#46; There are several clinical trials currently underway that attempt to study the effect of spironolactone administration on mortality and CV events in subjects with CKD stages 3b and 5d&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">8</span><p id="par0425" class="elsevierStylePara elsevierViewall">ACEi and ARA2&#44; and the association of iSGLT2&#44; have been shown to improve nephroprotection in diabetic and non-diabetic nephropathy&#46; There are pathophysiological considerations that raise the possibility that the combination of ACEi or ARA2&#44; iSGLT2&#44; and MR blockers may enhance nephroprotection&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">9</span><p id="par0430" class="elsevierStylePara elsevierViewall">Compared with steroidal MR blockers&#44; the more modern non-steroidal MR blockers have higher potency and selectivity&#44; and produce less elevation of serum K<span class="elsevierStyleSup">&#43;</span>&#46; The underway clinical trials &#40;FIGARO-DCK and FIDELIO-DCK just completed&#41; will determine whether in subjects with DM2 and nephropathy and with a maximum tolerated dose of ACEi or ARA2&#44; the non-steroidal MR blocker&#44; finerenone&#44; 10&#8722;20&#8239;mg&#47;day&#44; reduces mortality&#44; CV events and the progression of kidney disease&#46;</p></li></ul></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interests</span><p id="par0435" class="elsevierStylePara elsevierViewall">Dr&#46; Pablo G&#243;mez-Fern&#225;ndez has participated as principal investigator in the following Bayer-sponsored trials&#46;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0440" class="elsevierStylePara elsevierViewall">Mineralocorticoid rec eptor antagonist tolerability study-diabetic nephropathy &#40;ARTS-DN&#59; ClinicalTrials&#46;gov identifier NCT01874431&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0445" class="elsevierStylePara elsevierViewall">Finerenone in reducing kidney failure and disease progression in diabetic kidney disease &#40;FIDELIO-DKD&#44; ClinicalTrials&#46;gov identifier&#58; NCT02540993&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0450" class="elsevierStylePara elsevierViewall">Finerenone in reducing CV mortality and morbidity in diabetic kidney disease &#40;FIGARO-DKD&#59; ClinicalTrials&#46;gov identifier NCT02545049&#41;&#46;</p></li></ul></p></span></span>"
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          "titulo" => "Introduction"
          "secciones" => array:8 [
            0 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Physiology&#47;pathophysiology of aldosterone&#47;MR"
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            1 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Effects of aldosterone on the renal tubule"
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            2 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Vascular effects of aldosterone"
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            3 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Experimental data on the effects of aldosterone and MR block in models of kidney damage"
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              "identificador" => "sec0030"
              "titulo" => "Effects of aldosterone on renal hemodynamics and acute tubular damage"
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              "titulo" => "Effect on the renal interstitium&#46; Production of interstitial fibrosis"
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              "titulo" => "Effect on glomerular cells"
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              "titulo" => "Systemic vascular effects"
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          "titulo" => "Effects of MR blockade in CKD&#46; Clinical studies"
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              "identificador" => "sec0055"
              "titulo" => "MR blockade and HTN"
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              "titulo" => "Plasma aldosterone values and renal expression of MR in CKD"
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            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Aldosterone escape with drugs that block RAS"
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              "titulo" => "Effect of MR blockade on proteinuria and GFR in CKD"
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            4 => array:2 [
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              "titulo" => "Effect of MR blockade on proteinuria and GFR in type 2 DM"
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              "identificador" => "sec0080"
              "titulo" => "MR blockade in CKD patients on dialysis therapy"
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              "identificador" => "sec0085"
              "titulo" => "MR antagonists in HF with CKD"
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              "identificador" => "sec0090"
              "titulo" => "MR antagonists and hyperkalemia"
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            8 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Nonsteroidal aldosterone antagonists"
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          "titulo" => "Key concepts"
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          "titulo" => "References"
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    "fechaRecibido" => "2020-04-17"
    "fechaAceptado" => "2020-10-17"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:5 [
            0 => "Mineralcorticoid receptor blockers"
            1 => "Aldosterone"
            2 => "Chronic kidney disease"
            3 => "Diabetic kidney disease"
            4 => "Finerenone"
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          "palabras" => array:5 [
            0 => "Bloqueantes de receptor mineralcorticoide"
            1 => "Aldosterona"
            2 => "Enfermedad renal cr&#243;nica"
            3 => "Nefropat&#237;a diab&#233;tica"
            4 => "Finerenona"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">There are many experimental data supporting the involvement of aldosterone and mineralcorticoid receptor &#40;MR&#41; activation in the genesis and progression of chronic kidney disease &#40;CKD&#41; and cardiovascular damage&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Many studies have shown that in diabetic and non-diabetic CKD&#44; blocking the renin-angiotensin-aldosterone &#40;RAAS&#41; system with conversion enzyme inhibitors &#40;ACEi&#41; or angiotensin II receptor blockers &#40;ARBs&#41; decreases proteinuria&#44; progression of CKD and mortality&#44; but there is still a significant residual risk of developing these events&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">In subjects treated with ACEi or ARBs there may be an aldosterone breakthrough whose prevalence in subjects with CKD can reach 50&#37;&#46; Several studies have shown that in CKD&#44; the aldosterone antagonists &#40;spironolactone&#44; eplerenone&#41; added to ACEi or ARBs&#44; reduce proteinuria&#44; but increase the risk of hyperkalemia&#46; Other studies in subjects treated with dialysis suggest a possible beneficial effect of antialdosteronic drugs on CV events and mortality&#46; Newer potassium binders drugs can prevent&#47;decrease hyperkalemia induced by RAAS blockade&#44; and may reduce the high discontinuation rates or dose reduction of RAAS-blockers&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The nonsteroidal MR blockers&#44; with more potency and selectivity than the classic ones&#44; reduce proteinuria and have a lower risk of hyperkalemia&#46; Several clinical trials&#44; currently underway&#44; will determine the effect of classic MR blockers on CV events and mortality in subjects with stage 3b CKD and in dialysis patients&#44; and whether in patients with type 2 diabetes mellitus and CKD&#44; optimally treated and with high risk of CV and kidney events&#44; the addition of finerenone to their treatment produces cardiorenal benefits&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Large randomized trials have shown that sodium glucose type 2 cotransporter inhibitors &#40;SGLT2i&#41; reduce mortality and the development and progression of diabetic and nondiabetic CKD&#46; There are pathophysiological arguments&#44; which raise the possibility that the triple combination ACEi or ARBs&#44; SGLT2i and aldosterone antagonist provide additional renal and cardiovascular protection&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Hay abundantes datos experimentales que sustentan la participaci&#243;n de la aldosterona y la estimulaci&#243;n del receptor mineralcorticoide &#40;RM&#41; en la g&#233;nesis y progresi&#243;n de la enfermedad renal cr&#243;nica &#40;ERC&#41; y en el da&#241;o cardiovascular&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Muchos estudios han demostrado que en la ERC diab&#233;tica y no diab&#233;tica&#44; el bloqueo del sistema renina angiotensina-aldosterona &#40;SRAA&#41; con inhibidores de enzima de conversi&#243;n &#40;iECA&#41; &#243; antagonistas del receptor de angiotensina II &#40;ARA2&#41; disminuye la proteinuria&#44; la progresi&#243;n de la ERC y la mortalidad&#44; pero persiste todav&#237;a importante riesgo residual de desarrollo de estos eventos&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">En sujetos tratados con iECA &#243; ARA2 puede haber un escape de la aldosterona cuya prevalencia en sujetos con ERC puede alcanzar el 50 &#37;&#46; Diversos estudios han demostrado que&#44; en la ERC&#44; los f&#225;rmacos antialdoster&#243;nicos cl&#225;sicos &#40;espironolactona&#44; eplerenona&#41; a&#241;adidos a iECA &#243; ARA2&#44; reducen la proteinuria&#44; pero aumentan el riesgo de hiperkaliemia&#46; Otros estudios en sujetos tratados con di&#225;lisis sugieren un posible efecto beneficioso de los antialadoster&#243;nicos sobre eventos CV y mortalidad&#46; Los nuevos ligadores intestinales de K<span class="elsevierStyleSup">&#43;</span> pueden prevenir &#243; reducir la hiperkaliemia inducida por el bloqueo del SRAA&#44; y disminuir la desprescripci&#243;n o la reducci&#243;n de dosis de f&#225;rmacos bloqueantes del SRAA&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Los bloqueantes del RM no esteroideos&#44; con m&#225;s potencia y selectividad que los cl&#225;sicos&#44; reducen la proteinuria y tienen menos riesgo de hiperkaliemia&#46; Varios ensayos cl&#237;nicos&#44; actualmente en realizaci&#243;n&#44; determinar&#225;n el efecto de los bloqueantes cl&#225;sicos del RM sobre eventos CV y mortalidad en sujetos con ERC estadio 3b y en enfermos en di&#225;lisis&#44; y si en enfermos con diabetes mellitus tipo 2 y ERC&#44; &#243;ptimamente tratados y con elevado riesgo de eventos CV y renales&#44; la adici&#243;n de finerenona a su tratamiento produce beneficios cardiorrenales&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Los inhibidores del cotransportador sodio-glucosa tipo 2 &#40;iSGLT2&#41; han demos-trado reducir la mortalidad y el desarrollo y progresi&#243;n de la nefropat&#237;a diab&#233;tica y no diab&#233;tica&#46; Hay argumentos fisiopatol&#243;gicos&#44; que suscitan la posibilidad de que la triple combinaci&#243;n&#44; iECA &#243; ARA2&#44; iSGLT2 y antagonista de aldosterona ofrezca mayor protecci&#243;n renal y vascular&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; Erraez S&#44; L&#243;pez-Mesa M&#44; G&#243;mez-Fern&#225;ndez P&#46; Bloqueantes del receptor mineralcorticoide en la enfermedad renal cr&#243;nica&#46; Nefrologia&#46; 2021&#59;41&#58;258&#8211;275&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">At a basal state&#44; the mineralocorticoid receptor &#40;MR&#41; is predominantly located in the cytoplasm&#44; forming part of a complex with the chaperone <span class="elsevierStyleItalic">heat shock protein</span> &#40;Hsp90&#41;&#44; which facilitates its binding to the ligand&#44; and with the immunophilin <span class="elsevierStyleItalic">FK506-binding protein of 51 kDa</span> &#40;FKBP51&#41;&#46; After binding to the ligand&#44; immunophilin FKBP51 is replaced by FBBP52&#44; which facilitates the transit of the RM-ligand complex from the cytoplasm to the nucleus&#46; Once in the nucleoplasm&#44; the RM-ligand dissociates from the chaperone and immunophilin to bind to DNA and form dimers&#46; MR binds to specific DNA sequences&#44; the <span class="elsevierStyleItalic">hormone response element</span> &#40;HRE&#41; to regulate the transcription of target genes &#40;some of these are shown in the figure&#41;&#46; MR-mediated transcriptional activity can be increased or repressed by regulatory proteins such as <span class="elsevierStyleItalic">steroid receptor coactivator 1</span> &#40;SRC1&#41;&#44; <span class="elsevierStyleItalic">cAMP-response element binding protein</span> &#40;CBP&#41;&#44; and <span class="elsevierStyleItalic">transcriptional intermediary factor 1a</span> &#40;TIF1a&#41;&#44; among others&#46; 2&#46; The RM-ligand complex can interact with other transcription factors such as <span class="elsevierStyleItalic">cAMP response element-binding protein</span> &#40;CREB&#41; and nuclear factor of activated T-cells &#40;NFAT&#41;&#44; which can influence transcription&#46; Aldosterone also binds to MR anchored in the cell membrane by caveolin &#40;Cav1&#41; and striatin&#44; transactivating membrane receptors such as <span class="elsevierStyleItalic">epidermal growth factor receptor</span> &#40;EGFR&#41;&#44; <span class="elsevierStyleItalic">platelet derived growth factor receptor</span> &#40;PDGFR&#41;&#44; <span class="elsevierStyleItalic">insulin like growth factor receptor</span> &#40;IGF1R&#41;&#44; <span class="elsevierStyleItalic">vascular endothelial growth factor receptor</span> &#40;VEGFR&#41;&#44; <span class="elsevierStyleItalic">G protein coupled estrogen receptor</span> &#40;GPER&#41; and <span class="elsevierStyleItalic">angiotensin II receptor type I</span> &#40;AT1R&#41;&#46; All this promotes signals that involve&#44; among other effects&#44; kinase activation&#46; These events are responsible for the rapid&#44; non-genomic effects of aldosterone&#46; 3&#46; Activation of the RM receptor is possible without the ligand&#46; The activation of <span class="elsevierStyleItalic">Ras-related C3 botulinum toxin substrate 1</span> &#40;Rac1&#41; by stimuli such as oxidative stress&#44; glucose&#44; A<span class="elsevierStyleInf">II</span>&#44; among others&#44; can promote the translocation of the RM to the nucleus and trigger its transcriptional activity&#46;</p>"
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                  \t\t\t\t" scope="col">Distal convoluted tubule and connecting tubule&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Mesangium&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mineralcorticoid receptor locations&#46;</p>"
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        "etiqueta" => "Table 2"
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          0 => array:3 [
            "identificador" => "at0020"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">CTGF&#59; <span class="elsevierStyleItalic">connective tissue growth factor</span>&#59; CKD&#58; chronic kidney disease&#59; ETB&#58; endothelin B&#59; ERK1&#47;2&#58; <span class="elsevierStyleItalic">extracellular signal-regulated kinases</span>&#59; HK-2&#58; human kidney 2&#59; I&#47;R&#58; ischemia&#47;reperfusion&#59; ICAM-1&#58; <span class="elsevierStyleItalic">intercellular adhesion molecule-1</span>&#59; IL&#58; interleukins&#59; NFk-B&#58; <span class="elsevierStyleItalic">nuclear factor kappa-light chain enhancer of activated B cells</span>&#59; NGAL&#58; <span class="elsevierStyleItalic">neutrophil gelatinase-associated lipocalin</span>&#59; NLRP3&#58; <span class="elsevierStyleItalic">nucleotide-binding domain and leucine-rich repeat containing PYD-3</span>&#59; MR&#58; mineralocorticoid receptor&#59; ROS&#58; <span class="elsevierStyleItalic">reactive oxygen species</span>&#59; Runx2&#58; <span class="elsevierStyleItalic">runt-related transcription factor 2</span>&#59; Sgk-1&#58; <span class="elsevierStyleItalic">serum and glucocorticoid regulated kinase 1</span>&#59; TNFalpha&#58; tumor necrosis factor alpha&#46;</p>"
          "tablatextoimagen" => array:1 [
            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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Experimental model&nbsp;\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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect of aldosterone&#47;MRI block&nbsp;\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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome&nbsp;\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 " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Effect on acute kidney injury</span></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">S&#225;nchez Pozos et al&#46;&#44; 2012<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">41</span></a>&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">Acute kidney injury by I&#47;R&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">Spironolactone&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">Prevents the decrease of the ETB vasodilator receptor&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">&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">&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">&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">Spironolactone prevents kidney dysfunction&#44; tubular damage&#44; and oxidative stress&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">Amador et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">42</span></a>&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">Kidney damage from cyclosporin&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">MR deletion in vascular smooth muscle cells&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">Deletion of MR prevents renal dysfunction&#44; tubular cell vacuolization&#44; and overexpression of NGAL&#46; MR deletion reduces cyclosporine-induced vasoconstriction due to decreased Ca&#43;&#43; L channel activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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 " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Effect on transition from acute kidney injury to CKD</span></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">Zhang et al&#46;&#44; 2007<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">43</span></a>&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">Culture of human tubular epithelial cells&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">Aldosterone&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">Aldosterone induces epithelial-mesenchymal transition by increasing mitochondrial ROS production via ERK1&#47;2 activation&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">Barrera-Chimal et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">47</span></a>&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">Acute kidney injury by I&#47;R&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">Spironolactone&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">Decreased progression of CKD and pro-inflammatory fibrosis and IL markers&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">Ding et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">44</span></a>&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">Culture of human renal tubular cells &#40;HK-2&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aldosterone&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">Aldosterone induces cell damage by stimulating mitochondrial ROS production and NLRP3 inflammasome activation&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">Barrera-Chimal et al&#46;&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">46</span></a>&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">Acute kidney injury by I&#47;R&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">Fineronone or MR deletion in myeloid cells&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">Decreased renal dysfunction&#44; renal fibrosis&#44; and pro-inflammatory macrophages &#40;M1&#41;&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">&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">&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">&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">Increased macrophages with anti-inflammatory phenotype &#40;M2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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 " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Effect on glomerular cells &#40;podocytes&#44; mesangial cells&#44; parietal epithelium&#41;</span></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">Shibata et al&#46;&#44; 2007<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&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">Uninephrectomized rats&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">Aldosterone administration and high salt diet&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">Development of proteinuria and reduction of nephrin and podocin in podocytes&#46; Increased SGK1 activity and oxidative stress of podocytes Administration of epleronone prevents podocyte damage&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">&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">&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">Eplerenone&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">&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">Terada et al&#46;&#44; 2008<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">51</span></a>&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">Mesangial cell culture&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">Aldosterone in the culture media or aldosterone administration&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">Increased expression-activity of Sgk-1 and NFk-B&#44; ICAM-1&#44; CTGF&#46; Aldosterone administration produces an increase in glomerular expression of all these factors&#44; accompanied by glomerulosclerosis and inflammation&#46;&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">&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">Rectomized uninefrectomized&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">&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">&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">Huang et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">52</span></a>&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">Experimental model of rapidly progressive glomerulonephritis&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">MR deletion in myeloid cells&#44; epleronone&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">Both MR deletion and epleronone are associated with reduced crescent formation and expression of pro-inflammatory molecules at the renal level&#44; reduction of tubular damage and renal fibrosis&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">Bai et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">50</span></a>&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">Podocyte culture&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">Exposure to aldosterone&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">Exposure of podocytes to aldosterone increases expression of NLRP3 lymphoma&#44; caspase1 and IL-18 in podocytes<span class="elsevierStyleItalic">&#46; In vivo</span>&#44; administration of aldosterone to mice produces NLRP3 activation and decreased podocyte nephrin&#59; epleronone blocks NLRP3 inflammasome activation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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 " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Vascular effects</span></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">Tsatsumoto et al&#46;&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">55</span></a>&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">Experimental model of adenine-induced chronic kidney damage&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">Spironolactone&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">Spironolactone reduces aortic calcification together with the aortic expression of Runx2 and the sodium-phosphorus cotransporter &#40;Pit-1&#41;&#44; TNFa and Sgk-1&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">Khan et al&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">53</span></a>&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">Coronary Artery Function Investigated Using Myography&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">Subpression of aldosterone&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">Decreased the vasodilation dependent of adenosine A 2A receptors by down-regulation of K Ca receptors &#40;calcium-dependent K&#8239;&#43;&#8239;channels&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Alb&#47;creat&#58; urine albumin&#47;creatinine&#59; ARA2&#58; angiotensin II receptor antagonist&#59; IQR&#58; interquartile range&#59; Eple&#58; eplerenone&#59; CKD&#58; chronic kidney disease&#59; Spir&#58; spironolactone&#59; ACEi&#58; angiotensin converting enzyme inhibitor&#59; DN&#58; diabetic nephropathy&#59; NDN&#58; non-diabetic nephropathy&#59; SBP&#58; systolic blood pressure&#59; DBP&#58; diastolic blood pressure&#59; RR &#40;CI&#41;&#58; relative risk &#40;confidence interval&#41;&#46;</p>"
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                  <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="9" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-diabetic and diabetic CKD &#40;anti-aldosterone agents added to ACEi or ARA2 vs&#46; ACEi or ARA2&#41;</th></tr><tr title="table-row"><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">Author&#47;year&nbsp;\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">No&#46; studies&#47;No&#46; subjects&nbsp;\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">Type of CKD&nbsp;\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">Median month follow-up &#40;IQR&#41;&nbsp;\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">Antidosterone drug&nbsp;\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">&#916;Alb&#47;creat&#46; mg&#47;g&#8239;&#215;&#8239;&#40;95&#37; CI&#41;&nbsp;\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">&#916;GFR ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#8239;&#215;&#8239;&#40;95&#37; CI&#41;&nbsp;\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">&#916;SBP&#47;DBP mmHg&#8239;&#215;&#8239;&#40;95&#37; CI&#41;&nbsp;\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">Hyperkalemia RR &#40;95&#37; CI&#41;&nbsp;\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">Navaneeth a et al&#46;&#44; 2009 <a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">11&#47;991&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">DN&#47;NDN&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">6 &#40;10&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#58; Spir&#46; 2&#58; Eple&#46;&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">&#8211;0&#46;80 &#40;&#8211;1&#46;3&#59; &#8211;0&#46;3&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&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">&#8211;0&#46;70 &#40;&#8211;4&#46;3&#44; 3&#46;3&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&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">&#8211;3&#46;4 &#40;&#8211;5&#46;1&#44; &#8211;1&#46;7&#41;&#47;&#8211;1&#46;8 &#40;&#8211;2&#46;9&#44; &#8211;0&#46;6&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;06 &#40;1&#46;26&#8722;7&#46;41&#41;&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">Bolignano et al&#46;&#44; 2014 <a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">27 &#47;1549&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">NDN&#47;DN&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">3&#46;5 &#40;10&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#58; Spir 5&#58; Eple&#46;&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">&#8211;0&#46;61 &#40;&#8211;1&#46;1&#59; &#8211;0&#46;1&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&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">&#8211;2&#46;55 &#40;&#8211;5&#46;7&#44; 0&#46;5&#41; <a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&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">&#8211;3&#46;4 &#40;&#8211;5&#46;0&#44; &#8211;1&#46;8&#41;&#47;&#8211;1&#46;7 &#40;&#8211;2&#46;8&#44; &#8211;0&#46;6&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;00 &#40;1&#46;25&#8722;3&#46;2&#41;&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">Currie et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">79</span></a>&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">19&#47;2016&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">NDN&#47;&#47; DN&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">4 &#40;10&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#58; Spir&#46; 5&#58; Eple&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">&#8211;31 &#40;&#8211;35&#59; &#8211;37&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&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">&#8211;3&#46;15 &#40;&#8211;5&#46;4&#59; &#8211;0&#46;9&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;5&#46;7 &#40;&#8211;9&#46;0&#44; &#8211;2&#46;3&#41;&#47;&#8211;1&#46;7 &#40;&#8211;3&#46;4&#44; &#8211;0&#46;1&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;21 &#40;1&#46;19&#8722;8&#46;71&#41;&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">Sun et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">103</span></a>&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">18&#47;1786&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">DN&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">3 &#40;7&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#58; Spir&#46; 2&#58; Eple&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">&#8211;216 &#40;&#8211;409&#59; &#8211;22&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;32 &#40;&#8211;3&#46;6&#44; 12&#46;2&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;4&#46;8 &#40;&#8211;9&#46;5&#59; &#8211;0&#46;16&#41;&#47;&#8211;3&#46;3 &#40;&#8211;5&#46;9&#59; &#8211;0&#46;56&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;74 &#40;2&#46;30&#8722;6&#46;09&#41;&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">Zuo and Xu&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">104</span></a>&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">17&#47;1838&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">DN&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">3 &#40;9&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#58; Spir&#46; 2&#58; Eple&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">&#8722;202 &#40;-580&#59; 175&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;2&#46;1 &#40;&#8211;5&#46;2&#44; 1&#46;0&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;06 &#40;&#8211;0&#46;74&#44; 10&#46;9&#41;&#47;1&#46;60 &#40;0&#46;26&#44; 2&#46;96&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Esp&#46;&#58; 4&#46;58 &#40;2&#46;6&#8722;8&#46;0&#41;&#44; epl&#46;&#58; 2&#46;81 &#40;1&#46;0&#8722;7&#46;7&#41;&#44; fin&#46;&#58; 2&#46;22 &#40;0&#46;1&#8722;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Advanced CKD on dialysis therapy &#40;antialdosteronic drugs vs&#46; placebo or conventional therapy&#41;</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author&#47;year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median month follow-up &#40;IQR&#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\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CV mortality RR &#40;95&#37; CI&#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\ttop\n
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                  \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">Hyperkalemia RR &#40;95&#37; CI&#41;&nbsp;\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">RR gynecomastia &#40;95&#37; CI&#41;&nbsp;\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">Li et al&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">117</span></a>&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">10&#47;1172&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">6 &#40;18&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#58; Spir&#46; 1&#58; Eple&#46;&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">0&#46;42 &#40;0&#46;26&#8722;0&#46;65&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;46 &#40;0&#46;32&#8722;0&#46;66&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;70 &#40;1&#46;0&#8722;2&#46;9&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;0 &#40;2&#46;4&#8722;26&#41;&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">Quach et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">116</span></a>&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">9&#47;829&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">6 &#40;20&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#58; Spir&#46; 1&#58; Eple&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">0&#46;34 &#40;0&#46;15&#8722;0&#46;75&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;40 &#40;0&#46;23&#8722;0&#46;69&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;05 &#40;1&#46;2&#8722;7&#46;7&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;6 &#40;1&#46;3&#8722;24&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">ARA2&#58; angiotensin II receptor antagonists&#59; CV&#58; cardiovascular&#59; DM&#58; diabetes mellitus&#59; DM2&#58; type 2 diabetes mellitus&#59; CKD&#58; chronic kidney disease&#59; EF&#58; ejection fraction&#59; eGFR&#58; estimated glomerular filtration rate&#59; LVH&#58; left ventricular hypertrophy&#59; CHF&#58; congestive heart failure&#59; HF&#58; heart failure&#59; iECA&#58; angiotensin converting enzyme inhibitors&#59; MI&#58; myocardial infarction&#46;</p>"
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                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
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Identifier&#47;acronym&#47;query date&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" scope="col" style="border-bottom: 2px solid black">Study population&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" scope="col" style="border-bottom: 2px solid black">Drugs compared&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">Objective 1&nbsp;\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">Eudract&#58; 2012-002672-13&#47;BARACK D&#47;12-&#46;04-2020<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">84</span></a>&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">Stage 3b CKD &#40;eGFR 30&#8722;44&#8239;ml&#47;min&#47;1&#46;73&#8239;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
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Conventional therapy&#8239;&#43;&#8239;spironolactone 25&#8239;mg&#47;day vs&#46; conventional therapy&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">Mortality and CV events&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">NCT01848639&#47;ALCHEMIST&#47;12-&#46;04-2020<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">118</span></a>&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">Advanced CKD in hemodialysis&#8239;&#43;&#8239;DM2 or &#8595; EF or history of CV event or LVH&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">Spironolactone 25&#8239;mg&#47;day vs&#46; placebo&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">Non-fatal MI&#47;non-fatal stroke&#47;acute coronary syndrome&#47;hospitalization for HF&#47;CV death&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">NCT03020303&#47;ACHIEVE&#47;04-12-2020<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">119</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Advanced CKD in dialysis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CV death&#47;hospitalization due to HF&nbsp;\t\t\t\t\t\t\n
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                      "doi" => "10.1056/NEJMoa011161"
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                      "titulo" => "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes"
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                    ]
                  ]
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                    0 => array:2 [
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                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.7326/0003-4819-135-2-200107170-00007"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
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                    ]
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                    0 => array:2 [
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                  ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0706245"
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                    ]
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              "identificador" => "bib0050"
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                      "titulo" => "Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/bf02155834"
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                    ]
                  ]
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              "identificador" => "bib0055"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone in congestive heart failure"
                      "autores" => array:1 [ …1]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMra000050"
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                      "doi" => "10.1530/JME-16-0025"
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                      "autores" => array:1 [ …1]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0070"
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                    0 => array:2 [
                      "titulo" => "Regulation of aldosterone secretion&#58; current concepts and newer aspects"
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antiaging gene Klotho regulates CYP11B2 expression and aldosterone synthesis"
                      "autores" => array:1 [ …1]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2015010093"
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                  ]
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                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.3037703"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
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              "identificador" => "bib0085"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The mineralocorticoid receptor and its coregulators"
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                    0 => array:2 [
                      "doi" => "10.1677/JME-09-0031"
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                  ]
                ]
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              "identificador" => "bib0090"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.HYP. 0000154681. 38944.9a"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
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              "identificador" => "bib0095"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Podocyte as the target for aldosterone&#58; roles of oxidative stress and Sgk1"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.HYP.0000255636.11931.a2"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
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            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification and role of aldosterone receptors in the cardiovascular system"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
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            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Func-tional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCRESAHA.108 174235"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pivotal role of the mineralocorticoid receptor in corticosteroid induced adipogenesis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.06-7970com"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Deletion of mineralocorticoid receptors from macrophages protects against deoxycor-ticosterone&#47;salt-induced cardiac fibrosis and increased blood pressure"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/HYPERTENSIONAHA.109.131110"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The coming out of the brain mineralocorticoid receptor"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.tins.2007.10.005"
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mineralocorticoid regulation of cell function&#58; the role of rapid signalling and gene transcription pathways"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/JME-15-0318"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Grossmann C&#46;30 Nongenomic effects via the mineralocorticoid receptor"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/JOE-16-0659"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrneph. 2012.282"
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0140"
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                0 => array:2 [
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                    ]
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                      "Revista" => array:6 [ …6]
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                  ]
                ]
              ]
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              "identificador" => "bib0145"
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                    0 => array:2 [
                      "doi" => "10.1038/nm.1879"
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                    0 => array:2 [
                      "titulo" => "Local mineralocorticoid receptor activation and the role of Rac1 in obesity-related diabetic kidney disease"
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                    0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway"
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                  "host" => array:1 [
                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron"
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                    0 => array:2 [
                      "doi" => "10.1530/JOE-16-0669"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypokalemia and Pendrin induction by aldosterone"
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                    0 => array:2 [
                      "doi" => "10.1161/HYPERTENSIONAHA.116.08519"
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              "identificador" => "bib0170"
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                0 => array:2 [
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                    0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Aldosterone mediates activation of the thiazide-sensitive Na&#8211;Cl cotransporter through an SGK1 and WNK4 signaling pathway"
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                    0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/HYPERTENSIONAHA.111.173195"
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                    ]
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              "identificador" => "bib0185"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Connecting tubule glomerular feedback in hypertension"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1161/HYPERTENSIONA HA.113.01846"
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                    ]
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              "identificador" => "bib0190"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel mechanism of renal microcirculation regulation&#58; connecting tubule-glomerular feedback"
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                    ]
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                    0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of the mineralocorticoid receptor in the vasculature"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1530/JOE-17-0009"
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              "identificador" => "bib0200"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epitelial sodium channel in aldosterone-induced endothelium stiffness and aortic dysfunction"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/HYPERTEN-SIONAHA.118.11339"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recovery from ischemic acute injury by spironolactone administration"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfs014"
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                  ]
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              "identificador" => "bib0210"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1038/ki.2015.312"
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                    ]
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              "identificador" => "bib0215"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1152/ajprenal.00480.2006"
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              "identificador" => "bib0220"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mitochondrial &#8211; reactive oxygen species mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury"
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                    0 => array:2 [
                      "doi" => "10.18632/oncotarget.8243"
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              "identificador" => "bib0225"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute kidney injury and chronic kidney disease as interconnected syndromes"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1214243"
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              "identificador" => "bib0230"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The myeloid mineralcorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin 4 receptor signaling"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.kint.2017.12.016"
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              "identificador" => "bib0235"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spironolactone prevents chronic kidney disease caused by Ischemic acute kidney injury"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ki.2012.352"
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                    ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "From podocyte biology to novel cures for glomerular disease"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.kint.2019.05.015"
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                    ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Podocyte as the target for aldosterone&#58; roles&#8239;&#8239;of oxidative stress and Sgk1"
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                  "host" => array:1 [
                    0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NLRP3 inflammasome activation contributes to aldosterone induced podocyte injury"
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                    0 => array:2 [
                      "doi" => "10.1152/ajprenal.00332.2016"
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                    ]
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            50 => array:3 [
              "identificador" => "bib0255"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2007050531"
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            51 => array:3 [
              "identificador" => "bib0260"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease"
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca<span class="elsevierStyleInf">2</span>-activated K-channels"
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                    0 => array:2 [
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              "identificador" => "bib0270"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognostic value of coronary flow reserve in patients with dialysis-dependent ESRD"
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Spironolactone ameliorates arteria medial calcification in uremic rats medial calcification&#58; the role of mineralocorticoid receptor signaling in vascular calcification"
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                    0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone blunts the baroreflex response in man"
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Impact of aldosterone receptor blockade compared with thiazide therapy on sympathetic nervous system function in geriatric hypertension"
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                  "host" => array:1 [
                    0 => array:2 [
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              "identificador" => "bib0290"
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                0 => array:2 [
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                    0 => array:2 [
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                    0 => array:2 [
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            59 => array:3 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mediation analysis of aortic stiffness and renal microvascular function"
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Plasma aldosterone concentrations in chronic renal disease"
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                    0 => array:2 [
                      "doi" => "10.1038/ki.1982.14"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mineralocorticoid receptor blockade in chronic kidney disease"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels"
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                    0 => array:2 [
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                0 => array:2 [
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                      "titulo" => "Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease"
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                0 => array:2 [
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                    0 => array:2 [
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
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                    0 => array:2 [
                      "doi" => "10.1136/bmj.f360"
                      "Revista" => array:5 [ …5]
                    ]
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                ]
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              "identificador" => "bib0345"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The incidence and implications of aldosterone breakthrough"
                      "autores" => array:1 [ …1]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ncpneph0575"
                      "Revista" => array:6 [ …6]
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                ]
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              "identificador" => "bib0350"
              "etiqueta" => "70"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjhyper.2007.09.001"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0355"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate"
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                    0 => array:2 [
                      "doi" => "10.1007/s00125-004-1542-0"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
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            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interaction between atrial natriuretic peptide and the renin angiotensin aldosterone system&#46; Endogenous antagonists"
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                    0 => array:2 [
                      "doi" => "10.1016/0002-9343(89)90087-9"
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                    ]
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              "identificador" => "bib0365"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production&#58; implications for heart failure therapy"
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                    0 => array:2 [
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                    ]
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            73 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "74"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM200109203451215"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
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              ]
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            74 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "75"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.ki.5001854"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
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              ]
            ]
            75 => array:3 [
              "identificador" => "bib0380"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfs429"
                      "Revista" => array:4 [ …4]
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                  ]
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              "identificador" => "bib0385"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone antagonists for preventing the progression of chronic kidney disease&#58; a systematic review and meta-analysis"
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                    0 => array:2 [
                      "doi" => "10.2215/CJN.04750908"
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                  ]
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            77 => array:3 [
              "identificador" => "bib0390"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone antagonists for preventing the progression of chronic kidney disease"
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                    0 => array:2 [
                      "doi" => "10.1002/14651 858.CD007004.pub3"
                      "Revista" => array:3 [ …3]
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            78 => array:3 [
              "identificador" => "bib0395"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of mineralcorticoid receptor antagonist on proteinuria and progression of chronic kidney disease"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12882-016-0337-0"
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
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            79 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long term effects of spironolactone on kidney function and hyperkalemia-associated hospitalization in patients with chronic kidney disease"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/jcm7110459"
                      "Revista" => array:5 [ …5]
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                ]
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            80 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in Chronic Kidney Disease &#40;DAPA-CKD&#41; randomized controlled trial"
                      "autores" => array:1 [ …1]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfz290"
                      "Revista" => array:6 [ …6]
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                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jdiacomp.2018.04.011"
                      "Revista" => array:6 [ …6]
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                  ]
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              ]
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            82 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron"
                      "autores" => array:1 [ …1]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajprenal.00605.2014"
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                ]
              ]
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            83 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Benefits of aldosterone receptor antagonism in chronic kidney disease &#40;BARACK D&#41;trial a multicentre prospective randomised open blinded endpoint&#44; 36 month study of 2&#46;616 patients within primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25 mg once daily in addition to routine care on mortality and cardiovascularoutcomes versus routine care alone&#58; study protocol for a randomized controlled trial"
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                    0 => array:2 [
                      "doi" => "10.1186/1745-6215-15-160"
                      "Revista" => array:5 [ …5]
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            84 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preventing microalbuminuria in type 2 diabetes"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa042167"
                      "Revista" => array:6 [ …6]
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            85 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa-1007994"
                      "Revista" => array:5 [ …5]
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                  ]
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            86 => array:3 [
              "identificador" => "bib0435"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus &#40;the ADVANCE trial&#41;&#58; a randomised controlled trial"
                      "autores" => array:1 [ …1]
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                    0 => array:2 [
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                      "Revista" => array:6 [ …6]
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            87 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Irbesartan in patients with type 2 diabetes and microalbuminuria&#46; The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes"
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                    0 => array:2 [
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              "identificador" => "bib0445"
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                0 => array:2 [
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                    0 => array:2 [
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              "identificador" => "bib0450"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aliskiren combined with losartan in type 2 diabetes and nephropathy"
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0708379"
                      "Revista" => array:5 [ …5]
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              "identificador" => "bib0455"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Combined angiotensin inhibition for the treatment of diabetic nephropathy"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1303154"
                      "Revista" => array:6 [ …6]
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            91 => array:3 [
              "identificador" => "bib0460"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Makino H&#59; Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy&#58; a multicentre&#44; randomised&#44; placebo-controlled study"
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                    0 => array:2 [
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            92 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "93"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reno-protective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes"
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                  "host" => array:1 [
                    0 => array:2 [
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              "identificador" => "bib0470"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy"
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                    0 => array:2 [
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              "identificador" => "bib0475"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2009070737"
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              "identificador" => "bib0480"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyporeninemic hypoaldosteronism and diabetes mellitus&#58; pathophysiology assumptions&#44; clinical aspects and implications for management"
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                    0 => array:2 [
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            96 => array:3 [
              "identificador" => "bib0485"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Angiotensin II and its receptors in the diabetic kidney"
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                    0 => array:2 [
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            97 => array:3 [
              "identificador" => "bib0490"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats"
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                    0 => array:2 [
                      "doi" => "10.1111/j.1523-1755.2004.00913.x"
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                ]
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            98 => array:3 [
              "identificador" => "bib0495"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Beneficial impact of spironolactone on nephrotic range"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.ki.5001580"
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                  ]
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              "identificador" => "bib0500"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spironolactone inhibits hyperglycemia induced podocyte injury by attenuating ROS production"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfq750"
                      "Revista" => array:6 [ …6]
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              "identificador" => "bib0505"
              "etiqueta" => "101"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions"
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                    0 => array:2 [
                      "doi" => "10.1152/ajprenal.00101.2009"
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            101 => array:3 [
              "identificador" => "bib0510"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement"
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                    0 => array:2 [
                      "doi" => "10.1016/j.freeradbiomed.2005.03.031"
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                    ]
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                ]
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              "identificador" => "bib0515"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy"
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                    0 => array:2 [
                      "doi" => "10.1111/jdi.12629"
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              "identificador" => "bib0520"
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                  "contribucion" => array:1 [
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                      "titulo" => "Efficacy and safety of mineralcorticoid receptor antagonists with ACEI&#47;ARB treatment for diabetic nephropathy&#58; a metaanalysis"
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              "identificador" => "bib0525"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria&#58; the Steno type 2 randomised study"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Pre-venting microalbuminuria in type 2 diabetes"
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Article information

ISSN: 20132514
Original language: English

DOI:10.1016/j.nefroe.2021.08.001

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