Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches

array:25 ["pii" => "S2013251418300051" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2018.01.003" "estado" => "S300" "fechaPublicacion" => "2018-01-01" "aid" => "397" "copyright" => "Sociedad Española de Nefrología" "copyrightAnyo" => "2017" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "ssu" "cita" => "Nefrologia (English Version). 2018;38:13-26" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6603 "formatos" => array:3 [ "EPUB" => 295 "HTML" => 5501 "PDF" => 807 ] ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0211699517301327" "issn" => "02116995" "doi" => "10.1016/j.nefro.2017.05.009" "estado" => "S300" "fechaPublicacion" => "2018-01-01" "aid" => "397" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "ssu" "cita" => "Nefrologia. 2018;38:13-26" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 10931 "formatos" => array:3 [ "EPUB" => 375 "HTML" => 8916 "PDF" => 1640 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Revisión" "titulo" => "Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "13" "paginaFinal" => "26" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches" ] ] "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" => 2753 "Ancho" => 1727 "Tamanyo" => 319876 ] ] "descripcion" => array:1 [ "es" => "Principales causas de hemoglobinuria y rabdomiólisis." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Melania Guerrero-Hue, Alfonso Rubio-Navarro, Ángel Sevillano, Claudia Yuste, Eduardo Gutiérrez, Alejandra Palomino-Antolín, Elena Román, Manuel Praga, Jesús Egido, Juan Antonio Moreno" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Melania" "apellidos" => "Guerrero-Hue" ] 1 => array:2 [ "nombre" => "Alfonso" "apellidos" => "Rubio-Navarro" ] 2 => array:2 [ "nombre" => "Ángel" "apellidos" => "Sevillano" ] 3 => array:2 [ "nombre" => "Claudia" "apellidos" => "Yuste" ] 4 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Gutiérrez" ] 5 => array:2 [ "nombre" => "Alejandra" "apellidos" => "Palomino-Antolín" ] 6 => array:2 [ "nombre" => "Elena" "apellidos" => "Román" ] 7 => array:2 [ "nombre" => "Manuel" "apellidos" => "Praga" ] 8 => array:2 [ "nombre" => "Jesús" "apellidos" => "Egido" ] 9 => array:2 [ "nombre" => "Juan Antonio" "apellidos" => "Moreno" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2013251418300051" "doi" => "10.1016/j.nefroe.2018.01.003" "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/S2013251418300051?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699517301327?idApp=UINPBA000064" "url" => "/02116995/0000003800000001/v1_201801090621/S0211699517301327/v1_201801090621/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2013251417302158" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2017.04.018" "estado" => "S300" "fechaPublicacion" => "2018-01-01" "aid" => "383" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "ssu" "cita" => "Nefrologia (English Version). 2018;38:27-33" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3003 "formatos" => array:3 [ "EPUB" => 269 "HTML" => 2196 "PDF" => 538 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Brief review" "titulo" => "Advances in the evaluation of bone health in kidney transplant patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "27" "paginaFinal" => "33" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Avances en la valoración de la salud ósea en el trasplantado renal" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1981 "Ancho" => 2865 "Tamanyo" => 281712 ] ] "descripcion" => array:1 [ "en" => "Comparison between the different diagnostic tests to estimate bone health." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María José Pérez-Sáez, Daniel Prieto-Alhambra, Adolfo Díez-Pérez, Julio Pascual" "autores" => array:4 [ 0 => array:2 [ "nombre" => "María José" "apellidos" => "Pérez-Sáez" ] 1 => array:2 [ "nombre" => "Daniel" "apellidos" => "Prieto-Alhambra" ] 2 => array:2 [ "nombre" => "Adolfo" "apellidos" => "Díez-Pérez" ] 3 => array:2 [ "nombre" => "Julio" "apellidos" => "Pascual" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699517301030" "doi" => "10.1016/j.nefro.2017.04.002" "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/S0211699517301030?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251417302158?idApp=UINPBA000064" "url" => "/20132514/0000003800000001/v1_201802180616/S2013251417302158/v1_201802180616/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2013251418300191" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2018.01.007" "estado" => "S300" "fechaPublicacion" => "2018-01-01" "aid" => "426" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2018;38:8-12" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 17530 "formatos" => array:3 [ "EPUB" => 317 "HTML" => 14257 "PDF" => 2956 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "8" "paginaFinal" => "12" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anemia en la enfermedad renal crónica: Protocolo de estudio, manejo y derivación a Nefrología" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1921 "Ancho" => 2865 "Tamanyo" => 432464 ] ] "descripcion" => array:1 [ "en" => "Work up algorithm and referral to Nephrology of patients with anemia of renal origin." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Aleix Cases, M. Isabel Egocheaga, Salvador Tranche, Vicente Pallarés, Raquel Ojeda, José Luis Górriz, José María Portolés" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Aleix" "apellidos" => "Cases" ] 1 => array:2 [ "nombre" => "M. Isabel" "apellidos" => "Egocheaga" ] 2 => array:2 [ "nombre" => "Salvador" "apellidos" => "Tranche" ] 3 => array:2 [ "nombre" => "Vicente" "apellidos" => "Pallarés" ] 4 => array:2 [ "nombre" => "Raquel" "apellidos" => "Ojeda" ] 5 => array:2 [ "nombre" => "José Luis" "apellidos" => "Górriz" ] 6 => array:2 [ "nombre" => "José María" "apellidos" => "Portolés" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699517301881" "doi" => "10.1016/j.nefro.2017.09.004" "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/S0211699517301881?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251418300191?idApp=UINPBA000064" "url" => "/20132514/0000003800000001/v1_201802180616/S2013251418300191/v1_201802180616/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "13" "paginaFinal" => "26" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Melania Guerrero-Hue, Alfonso Rubio-Navarro, Ángel Sevillano, Claudia Yuste, Eduardo Gutiérrez, Alejandra Palomino-Antolín, Elena Román, Manuel Praga, Jesús Egido, Juan Antonio Moreno" "autores" => array:10 [ 0 => array:3 [ "nombre" => "Melania" "apellidos" => "Guerrero-Hue" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "◊" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Alfonso" "apellidos" => "Rubio-Navarro" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "◊" "identificador" => "fn0005" ] ] ] 2 => array:3 [ "nombre" => "Ángel" "apellidos" => "Sevillano" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Claudia" "apellidos" => "Yuste" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Eduardo" "apellidos" => "Gutiérrez" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Alejandra" "apellidos" => "Palomino-Antolín" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Elena" "apellidos" => "Román" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 7 => array:3 [ "nombre" => "Manuel" "apellidos" => "Praga" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 8 => array:3 [ "nombre" => "Jesús" "apellidos" => "Egido" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 9 => array:4 [ "nombre" => "Juan Antonio" "apellidos" => "Moreno" "email" => array:1 [ 0 => "jamoreno@fjd.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Laboratorio de Nefrología Experimental, Patología Vascular y Diabetes, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Red de Investigación Renal (REDINREN), Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Nefrología, Hospital 12 de Octubre, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Nefrología Pediátrica, Hospital La Fe, Valencia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1220 "Ancho" => 3102 "Tamanyo" => 260256 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of renal damage caused by haemoproteins." ] ] ] "textoCompleto" => "IntroductionHaemoglobin (Hb) and myoglobin (Mb) are haemoproteins that play a crucial role in the body's homeostasis, by oxygenating tissues and participating in the regulation of blood pH levels. Hb has a molecular weight of 64.5kDa and is composed of four polypeptide chains known as globins.<a class="elsevierStyleCrossRef" href="#bib0775">1</a> Each globin contains a haem group with an iron atom in its interior, which is responsible for its functional properties. Mb is a smaller protein with a molecular weight of 17kDa, which is formed by a single globin. In physiological conditions, both Hb and Mb are found inside erythrocytes and muscle cells, respectively. However, in certain pathological conditions, these molecules are released into the blood stream and may enter and accumulate in the kidneys, where they are cytotoxic, especially for the proximal tubule epithelium. In fact, the renal accumulation of haemoproteins may induce acute kidney injury (AKI) and chronic kidney disease (CKD). In recent years, new mechanisms have been identified which are involved in kidney damage linked to these molecules, which have helped to develop experimental treatments that have already yielded positive results in recently published studies or in ongoing clinical trials, as described in more detail below.Origin of the renal accumulation of haemoproteinsMb builds up in the kidneys as a result of severe muscular damage (rhabdomyolysis), whereas Hb accumulates due to the intravascular haemolysis of red blood cells or the rupture of red blood cells that cross the glomerular membrane in diseases with glomerular haematuria, such as IgA nephropathy (IgAN), lupus or Alport syndrome. In this review, we will focus on myoglobinuria and haemoglobinuria due to space limitations.MyoglobinuriaMyoglobinuria is the presence of Mb in urine, for which the main cause is rhabdomyolysis or the rupture of skeletal muscle.<a class="elsevierStyleCrossRef" href="#bib0780">2</a> Rhabdomyolysis may be caused by severe trauma, situations of prolonged ischaemia, metabolic disorders, intense physical activity, alcohol abuse and some toxic compounds of chemical or biological origin<a class="elsevierStyleCrossRef" href="#bib0785">3</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The incidence of rhabdomyolysis is not entirely clear, but it has been estimated that it could affect 7–10% of patients presenting with an AKI.<a class="elsevierStyleCrossRefs" href="#bib0785">3,4</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>HaemoglobinuriaHaemoglobinuria is the presence of Hb in urine as a result of intravascular haemolysis. This causes a renal overload of Hb, especially when there is recurring exposure to free Hb.<a class="elsevierStyleCrossRef" href="#bib0795">5</a> Some of the main aetiological causes of haemoglobinuria include hereditary conditions, such as paroxysmal nocturnal haemoglobinuria, thrombotic thrombocytopenic purpura, haemolytic-uraemic syndrome (HUS), sickle-cell anaemia (SCA), cell membrane defects (elliptocytosis, spherocytosis, etc.), enzymatic defects (glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency), severe haemolytic anaemia caused by massive transfusion reactions, as well as other causes acquired from HUS and thrombotic microangiopathies of various origins<a class="elsevierStyleCrossRef" href="#bib0800">6</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).Haemoproteins and acute kidney injuryAKI is a common complication in patients with haemoglobinuria or rhabdomyolysis, especially if they were already suffering from kidney disease. Up to 50% of patients suffering from rhabdomyolysis develop AKI, depending on what is the causes.<a class="elsevierStyleCrossRefs" href="#bib0805">7,8</a> Therefore, rhabdomyolysis is one of the main causes of AKI (5–25%) and results in death in 2–46% of cases in the absence of dialysis.<a class="elsevierStyleCrossRefs" href="#bib0785">3,4</a> On many occasions, situations associated with intravascular haemolysis may also induce AKI.<a class="elsevierStyleCrossRefs" href="#bib0815">9,10</a>Haemoproteins and chronic kidney diseaseThe onset of kidney disease in patients with renal accumulation of haemoproteins is well documented. It has been reported that haemoglobinuria is an independent risk factor for the onset and progression of CKD in people suffering with SCA.<a class="elsevierStyleCrossRef" href="#bib0825">11</a> Something similar occurs in paroxysmal nocturnal haemoglobinuria, a disease in which CKD secondary to the onset of renal vein thrombosis and haemoglobinuria is one of its most significant complications, which may affect 64% of patients and cause 18% of deaths.<a class="elsevierStyleCrossRef" href="#bib0830">12</a> In the absence of treatment, the prognosis for atypical HUS (aHUS) is also poor, with a mortality rate during outbreak of 25%, and progression to CKD in over half of the patients the year after the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0835">13</a>Pathophysiological mechanisms involved in haemoproteins induced renal damageThe main effect of haemoproteins on the kidneys is their direct tubule cell toxicity, regardless of what causes their release (haemo- or myoglobinuria) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Under normal conditions, Hb binds to haptoglobin and forms the Hb–haptoglobin complex in the plasma.<a class="elsevierStyleCrossRef" href="#bib0840">14</a> This complex is too large to be filtered by the glomerulus, and is therefore broken down by the spleen, bone marrow and liver. However, during intravascular haemolysis, the massive release of Hb causes haptoglobin to be consumed. As a result, Hb remains in the plasma for longer periods of time and is more likely to dissociate into dimers, which are more easily filtered by the glomerulus. Unlike Hb, Mb directly crosses the glomerular filtration membrane due to its smaller molecular size.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Once in the lumen of the tubule, the haemoproteins can be reabsorbed by the proximal tubules through the megalin/cubilin receptors complex,<a class="elsevierStyleCrossRef" href="#bib0840">14</a> or even break down by releasing the haem group and free iron, which also have deleterious actions such as nitric oxide neutralisation, vasoconstriction and ischaemia.<a class="elsevierStyleCrossRef" href="#bib0845">15</a> The reduced bioavailability of nitric oxide causes the deregulation of factors that control vascular tone, such as endothelin-1, thromboxane A2, tumour necrosis factor and isoprostanes.<a class="elsevierStyleCrossRefs" href="#bib0850">16,17</a> Hb and Mb are also powerful vasoconstrictors because they also react with nitric oxide, as described in diseases associated with intravascular haemolysis and rhabdomyolysis.<a class="elsevierStyleCrossRefs" href="#bib0860">18–20</a> When present in the lumen of the tubule, both Mb and Hb can precipitate and bind to the Tamm-Horsfall protein and give rise to RBC casts, which cause intratubular obstruction in the distal nephron segments.<a class="elsevierStyleCrossRef" href="#bib0875">21</a> This obstruction is assisted by the acidic pH found in urine, which increases the stability of the links between the haemoproteins and the Tamm-Horsfall protein.<a class="elsevierStyleCrossRefs" href="#bib0880">22,23</a>Inside the tubule cells, the haemoproteins dissociate by releasing globins and the haem group, which induces oxidative stress, cell death and the production of inflammatory cytokines and fibrosis, as discussed in more detail below.Oxidative stressHaemoproteins present various redox forms and are an endogenous source of reactive oxygen species.<a class="elsevierStyleCrossRef" href="#bib0890">24</a> When haemoproteins are captured by tubule cells, the haem group is oxidised from Fe2+ to Fe3+ and produces hydroxyl radicals.<a class="elsevierStyleCrossRef" href="#bib0895">25</a> In the presence of peroxides, Fe3+ oxidises to Fe4+ and generates hydroperoxyl radicals, which are highly reactive and contribute to the formation of new reactive oxygen species in the kidneys.<a class="elsevierStyleCrossRefs" href="#bib0900">26,27</a> All of these radicals promote the lipid peroxidation of plasma membranes and generate malondialdehyde, which intervenes in the oxidation of proteins and genetic material.<a class="elsevierStyleCrossRefs" href="#bib0790">4,28,29</a> This process leads to the production of isoprostanes, proinflammatory cytokines and the expression of adhesion molecules, which increases inflammatory response.<a class="elsevierStyleCrossRef" href="#bib0920">30</a>InflammationThe haem group acts as a TLR-4 agonist and induces inflammatory response by activating the transcription factor NF-kB.<a class="elsevierStyleCrossRefs" href="#bib0925">31,32</a> After binding to the pattern recognition receptor, Hb promotes the activation of several signal transduction pathways such as c-Jun N-terminal, p38 and MAP kinases.<a class="elsevierStyleCrossRef" href="#bib0935">33</a> Another involved pathway is mediated by the activation of the NLRP3 (nitrogen permease regulator-like 3) inflammasome, which is responsible for releasing different cytokines and chemokines involved in the monocyte/macrophage recruitment.<a class="elsevierStyleCrossRef" href="#bib0940">34</a> The presence of proinflammatory macrophages (M1) has been reported in early phases in experimental models of AKI due to the accumulation of haemoproteins, which differ from anti-inflammatory macrophages (M2) in later phases.<a class="elsevierStyleCrossRefs" href="#bib0945">35,36</a> These M2 macrophages are found in renal biopsies of patients suffering from rhabdomyolysis, favism, paroxysmal nocturnal haemoglobinuria and outbreaks of macroscopic haematuria associated with IgAN.<a class="elsevierStyleCrossRefs" href="#bib0955">37–39</a>Cell deathThere have been reports of several types of cell death in the epithelial tubule of patients and in experimental models associated with the accumulation of haemoproteins.<a class="elsevierStyleCrossRefs" href="#bib0790">4,39–43</a> Necrosis and apoptosis are the types of death that have been studied at a greater depth.<a class="elsevierStyleCrossRefs" href="#bib0940">34,44–46</a> The molecular mechanisms causing death by apoptosis are associated with mitochondrial dysfunction and an increase in pro-apoptotic proteins (BAX and BAD), as well as the activation of caspase-3, the main effector caspase,<a class="elsevierStyleCrossRefs" href="#bib0940">34,47</a> and endoplasmic reticulum stress proteins.<a class="elsevierStyleCrossRef" href="#bib1010">48</a> Other types of cell death have been described in these diseases, such as pyroptosis (cell death mediated by caspase-1 which leads to DNA fragmentation and cell lysis) and ferroptosis (iron-dependent cell death). Caspase-1 activation has been observed in experimental rat models of rhabdomyolysis,<a class="elsevierStyleCrossRef" href="#bib0940">34</a> whereas the use of ferroptosis inhibitors in these rats reduced cell death of proximal tubules.<a class="elsevierStyleCrossRef" href="#bib1015">49</a> Lastly, the accumulation of haemoproteins and their derivatives may induce autophagy as a defence mechanism.<a class="elsevierStyleCrossRefs" href="#bib1000">46,50,51</a>FibrosisRenal fibrosis is another mechanism involved in renal damage caused by haemoproteins. In fact, patients with SCA present with renal fibrosis and increased TGF-β in urine, which is one of the main profibrotic mediators.<a class="elsevierStyleCrossRef" href="#bib1030">52</a> Even though fibroblasts and tubule cells play a very important role in the production of extracellular matrix proteins, recent studies show that macrophages may increase profibrotic response due to the production of mediators such as CTGF and TGF-β during rhabdomyolysis.<a class="elsevierStyleCrossRefs" href="#bib0945">35,36</a>Renal tubules are considered as the main sites of Hb toxicity. However, the presence of proteinuria has been reported in experimental models of recurring exposure to haemoproteins.<a class="elsevierStyleCrossRef" href="#bib1035">53</a> There have also been reports of the presence of focal segmental glomerulosclerosis in experimental models of SCA<a class="elsevierStyleCrossRef" href="#bib1040">54</a> and in patients with chronic and recurring haemolysis, such as paroxysmal nocturnal haemoglobinuria, HUS and SCA.<a class="elsevierStyleCrossRef" href="#bib1045">55</a> These patients develop proteinuria<a class="elsevierStyleCrossRef" href="#bib1050">56</a> and suffer from a chronic reduction of glomerular filtration.<a class="elsevierStyleCrossRefs" href="#bib0830">12,57</a> These data suggest that there is a link between intravascular haemolysis and glomerular dysfunction. The physiopathological mechanisms, however, are not clear. There are indications that the haemodynamic changes linked to this disease may be responsible for proteinuria and progressive renal damage; however, there is no definitive proof for this theory.<a class="elsevierStyleCrossRef" href="#bib1060">58</a> Given that focal segmental glomerulosclerosis entails a loss of podocytes, these cells may also suffer from haemoprotein-mediated injury. In this sense, unpublished data from our group show that podocytes are capable of capturing Hb, which induces oxidative stress and causes these cells to die, as well as a loss of proteins involved in the glomerular filtration process such as synaptopodin and nephrin.Defence mechanisms against the renal toxicity of haemoproteinsThere are two types of defence mechanisms that work against the harmful effects of haemoproteins: direct and indirect. The direct mechanisms promote the catabolism of haemoproteins and by-products, whereas the indirect mechanisms reduce oxidative stress resulting from the presence of these molecules, thus eliminating the reactive oxygen species or repairing the possible damage caused (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Below is an analysis of each of these defence mechanisms relating to renal damage caused by haemoproteins.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Direct mechanismsHaptoglobinHaptoglobin (Hp) is a glycoprotein found in high concentrations in plasma (0.3–3g/l) and is mainly secreted by hepatocytes, although it is also synthesised in other tissues such as kidneys. Hp irreversibly binds to Hb and impedes its filtration in the kidneys<a class="elsevierStyleCrossRef" href="#bib1065">59</a> and its translocation to the endothelium,<a class="elsevierStyleCrossRef" href="#bib1070">60</a> which counteracts its harmful effects.<a class="elsevierStyleCrossRef" href="#bib1075">61</a> Hp can also bind to Mb, but with less affinity that it does to Hb.<a class="elsevierStyleCrossRef" href="#bib1080">62</a> The Hb–Hp binding promotes the interaction and subsequent internalisation of this complex through the CD163 receptor of the membrane, which is present in monocytes and macrophages.<a class="elsevierStyleCrossRef" href="#bib1085">63</a> Hp levels are highly reduced in patients with chronic haemolysis, such as SCA,<a class="elsevierStyleCrossRef" href="#bib1090">64</a> because Hp breaks down after being endocited.<a class="elsevierStyleCrossRef" href="#bib1095">65</a> The importance of this protein for Hp has been reported in gene knockout studies in rats, which are more sensitive to damage from haemolysis.<a class="elsevierStyleCrossRef" href="#bib1065">59</a> Studies in animal models of SCA and rhabdomyolysis have shown that the administration of Hp reduces vaso-occlusion,<a class="elsevierStyleCrossRef" href="#bib0925">31</a> oxidative stress<a class="elsevierStyleCrossRef" href="#bib1100">66</a> and renal damage.<a class="elsevierStyleCrossRefs" href="#bib1070">60,67,68</a>CD163CD163 is a receptor found on the surface of circulating monocytes and macrophages, whose main function is Hb clearance in tissue.<a class="elsevierStyleCrossRef" href="#bib1085">63</a> CD163 has a high affinity for Hb–Hp complexes, although it can also bind to free Hb.<a class="elsevierStyleCrossRef" href="#bib1115">69</a> The macrophages that express CD163 have reduced hydrogen peroxide release and important anti-inflammatory functions through the production of IL-10 and HO-1 stimulation.<a class="elsevierStyleCrossRef" href="#bib1120">70</a> Our group has observed an increase in the macrophages expressing CD163 in renal biopsies of patients with massive haemolysis, such as paroxysmal nocturnal haemoglobinuria<a class="elsevierStyleCrossRef" href="#bib0955">37</a> and favism.<a class="elsevierStyleCrossRef" href="#bib0965">39</a> The renal expression of CD163 was higher in areas where iron had accumulated and where oxidative stress markers were found. We have recently written about the presence of CD163 in the kidneys of patients and experimental models of rhabdomyolysis.<a class="elsevierStyleCrossRef" href="#bib0945">35</a> Since the anti-inflammatory and antioxidant functions of CD163 are well known, these data suggest that CD163 could play a nephroprotective role in response to the renal accumulation of haemoproteins.Haem oxygenaseHaem oxygenase (HO) is one of the main defence mechanisms in situations of renal overload of Mb and Hb. HO is the enzyme responsible for breaking down the haem group, and thus releasing biliverdin, Fe2+ and carbon monoxide,<a class="elsevierStyleCrossRef" href="#bib1125">71</a> which are powerful anti-inflammatory and antioxidant molecules that enhance the beneficial effects of HO.<a class="elsevierStyleCrossRefs" href="#bib1130">72,73</a> There are three isoforms of HO (HO-1, HO-2 and HO-3) which differ in their tissue distribution, regulation and function. Unlike other isoforms, the expression of HO-1 is induced in conditions of oxidative stress, and is expressed in many tissues, including the kidneys.<a class="elsevierStyleCrossRef" href="#bib1140">74</a> The renal expression of HO-1 is increased in experimental models of haemoglobinuria and rhabdomyolysis, as well as in patients with intravascular haemolysis.<a class="elsevierStyleCrossRefs" href="#bib1100">66,75,76</a> The deficiency of this enzyme in patients with intravascular haemolysis increases tubular and glomerular damage.<a class="elsevierStyleCrossRef" href="#bib1155">77</a> Similarly, animals used in gene knockout studies for HO-1 have shown greater sensitivity to rhabdomyolysis, higher levels of creatinine and higher mortality rates.<a class="elsevierStyleCrossRef" href="#bib1160">78</a>TransferrinTransferrin (Tf) is a glycoprotein that is mainly secreted by the liver, and which binds to free iron to mitigate its adverse effects.<a class="elsevierStyleCrossRef" href="#bib1165">79</a> Depending on the iron concentration, the tubule cells express the Tf receptor (TfR1), which plays an essential role in the metabolism of this molecule in the kidneys.<a class="elsevierStyleCrossRef" href="#bib1170">80</a> Its expression is regulated by the iron-regulatory proteins 1 and 2, which are highly expressed in the proximal tubules and which act as sensors of iron levels.<a class="elsevierStyleCrossRefs" href="#bib1175">81–83</a> Under normal conditions, approximately 30% of the Tf iron-binding sites are saturated. However, these levels increase in the presence of iron accumulation disorders,<a class="elsevierStyleCrossRef" href="#bib1190">84</a> such as severe haemochromatosis, in which case Tf saturation exceeds 60%.<a class="elsevierStyleCrossRefs" href="#bib1195">85,86</a> In addition, patients or experimental models of hypotransferrinaemia have low levels of Tf, which promotes renal overload of iron.<a class="elsevierStyleCrossRefs" href="#bib1205">87,88</a>HaemopexinHaemopexin (Hx) is a plasma protein that complexes to the haem group for its subsequent internalisation and hepatic clearance through its binding to the LDL receptor-related protein-1 (LRP1) receptor.<a class="elsevierStyleCrossRefs" href="#bib1215">89–91</a> In haemolysis, the Hb oxidises and releases the haem group into the bloodstream to later bind to the serum albumin, which transfers the haem group to the Hx and releases the complex in the liver. Once in hepatocytes, the Hx–haem complex breaks down in lysosomes, although a small amount of Hx is recycled and returned to the bloodstream. Therefore, in patients with haemolytic events, the plasma concentrations of serum Hx are reduced<a class="elsevierStyleCrossRefs" href="#bib1230">92–95</a> as it builds up in the renal cortex and increases its levels in urine.<a class="elsevierStyleCrossRef" href="#bib1250">96</a> Hx plays a protective role against the harmful effects of the haem group.<a class="elsevierStyleCrossRefs" href="#bib0925">31,32,97</a> Rats used in gene knockout studies for Hx have a poor recovery of renal function after suffering an intravascular haemolysis event, because they have a greater renal accumulation of iron and, therefore, higher oxidative stress levels.<a class="elsevierStyleCrossRefs" href="#bib1260">98,99</a>FerritinFerritin is a protein consisting of 24 subunits, forming a hollow spherical structure.<a class="elsevierStyleCrossRef" href="#bib1270">100</a> Its primary function is to store iron, so it has a protective capacity against the toxicity caused by iron and haemoproteins. After the HO-1-catalysed reaction, the iron is released from the haem group and is stored inside the ferritin.<a class="elsevierStyleCrossRef" href="#bib1275">101</a> The expression of ferritin is regulated by the concentration of iron and the HO-1 activity.<a class="elsevierStyleCrossRef" href="#bib1280">102</a> This protein plays a crucial role in diseases related to haemoproteins, as ferritin-deficient rats show notable renal damage,<a class="elsevierStyleCrossRef" href="#bib1285">103</a> and it is a good serum marker for SCA.<a class="elsevierStyleCrossRef" href="#bib1290">104</a> Plasma levels of Tf are also higher in ferritin-deficient rats that are subjected to rhabdomyolysis.<a class="elsevierStyleCrossRef" href="#bib1285">103</a>Nrf2Nrf2 is a transcription factor that controls the expression of several antioxidant genes such as HO-1 and ferritin.<a class="elsevierStyleCrossRefs" href="#bib1295">105,106</a> Under normal conditions, Nrf2 is found in the cytoplasm bound to its repressor Keap1, which is susceptible to changes in the redox state and is subjected to proteolytic degradation through the proteasome. In the presence of oxidative stress, Nrf2 is released from Keap1 and translocates to the nucleus, where it activates the expression of antioxidant genes.<a class="elsevierStyleCrossRefs" href="#bib1305">107–112</a> The activation of Nrf2 has a positive effect against renal damage linked to the accumulation of haemoproteins in experimental models and patients with haemolytic anaemia.<a class="elsevierStyleCrossRefs" href="#bib1335">113–115</a>Indirect mechanismsThis second group is composed of antioxidant molecules and various antioxidant enzymes.Non-enzymatic mechanismsThere are many molecules in the body that have an antioxidant action, such as vitamins, melatonin and bilirubin. These molecules neutralise free radicals and are involved in the protection against renal damage caused by haemoproteins.Vitamins are an important antioxidant group. One such example is vitamin C, which reacts with the superoxide anion and lipid peroxides, thus reducing the oxidative stress induced by the in vitro<a class="elsevierStyleCrossRef" href="#bib1350">116</a> and in vivo<a class="elsevierStyleCrossRef" href="#bib1355">117</a> RBC lysis. Similarly, treatment with vitamin C was effective in a context of AKI caused by haemoglobinaemia in a patient with glucose-6-phosphate dehydrogenase deficiency.<a class="elsevierStyleCrossRef" href="#bib1360">118</a> The levels of vitamin C decrease after the development of rhabdomyolysis, and its administration has partially reduced histological disorders and renal function in experimental models of rhabdomyolysis.<a class="elsevierStyleCrossRef" href="#bib1365">119</a> Vitamin E is another important vitamin because it plays a significant role in maintaining the redox balance and the integrity of cell membranes, acting on peroxyl and hydroperoxyl radicals. The administration of vitamin E inhibited the RBC lysis of patients suffering from paroxysmal nocturnal haemoglobinuria, which suggests that this vitamin is an effective treatment for these patients.<a class="elsevierStyleCrossRefs" href="#bib1370">120,121</a> Vitamin E has not been as effective as vitamin C, however, in the treatment of rhabdomyolysis.<a class="elsevierStyleCrossRef" href="#bib1380">122</a>Melatonin is a hormone secreted by the pineal gland which has several antioxidant properties, as it neutralises free radicals such as hydrogen peroxide, the hydroxyl radical, peroxynitrite and the superoxide anion. This molecule also stimulates the expression of other antioxidant molecules, such as superoxide dismutase, glutathione peroxidase and glutathione reductase. Several studies have shown that this hormone plays a protective role in models of AKI caused by rhabdomyolysis or intravascular haemolysis by reducing tubular necrosis and lipid peroxidation associated with these conditions.<a class="elsevierStyleCrossRefs" href="#bib1355">117,123</a>Glutathione, in its reduced state (GSH), is a powerful cell antioxidant that can be oxidised to glutathione disulfide (GSSG) through several enzymatic reactions. Several experimental models of myoglobinuria and haemoglobinuria, as well as studies in patients with HUS and SCA, show decreased levels of GSH in the kidneys.<a class="elsevierStyleCrossRefs" href="#bib1355">117,123–128</a> The depletion of GSH increases toxicity mediated by oxidative stress in these diseases, because, by restoring the GSH levels, treatment with N-acetylcysteine reduces histological disorders and inhibits cell death associated with these conditions.<a class="elsevierStyleCrossRefs" href="#bib1415">129,130</a>Enzymatic mechanismsThis group includes molecules with enzymatic activity that reduce the content of intracellular reactive oxygen species and, therefore, protect cells from oxidative damage. Superoxide dismutase (SOD) is able to dismutate O2− in O2 and H2O2. For the elimination of H2O2, there are other enzymes with peroxidase activity. These include catalase, glutathione peroxidase (GPx) and reduced thioredoxin (Trx). Catalase is an oxidoreductase that catalyses the decomposition reaction of H2O2 in O2 and water. GPx catalyses the decomposition of H2O2 through the oxidation of GSH to GSSG and water. The GPx, catalase and SOD activity is reduced in experimental models of intravascular haemolysis<a class="elsevierStyleCrossRef" href="#bib1355">117</a> and rhabdomyolysis.<a class="elsevierStyleCrossRefs" href="#bib1395">125,128,131–134</a> Furthermore, the plasma levels of GPx and SOD show a negative correlation with albuminuria in patients with SCA.<a class="elsevierStyleCrossRef" href="#bib1445">135</a> Lastly, Trx protects from renal damage associated with rhabdomyolysis through the reduction of oxidative stress and inflammation.<a class="elsevierStyleCrossRef" href="#bib1450">136</a>TreatmentsThere is currently no specific treatment for preventing the damage induced by ferroportins in their different forms of clinical presentation. The alkalisation of urine may be beneficial by reducing the dissociation of the iron found in haemoproteins. This alkalisation can be carried out with oral bicarbonate, while monitoring the urine and serum pH levels. However, no clear benefits have been reliably proven. The use of calcium channel blockers in experimental models has shown an increase in the urinary excretion of iron by mechanisms that remain unknown, which results in a decrease in the renal accumulation of iron.<a class="elsevierStyleCrossRef" href="#bib1455">137</a>The use of iron-chelating agents in diseases associated with the accumulation of this molecule reduces oxidative damage<a class="elsevierStyleCrossRef" href="#bib1460">138</a> and also avoids iron deposition.<a class="elsevierStyleCrossRef" href="#bib1465">139</a> Prophylactically administered deferoxamine reduces oxidative stress resulting from the presence of Hb.<a class="elsevierStyleCrossRef" href="#bib1470">140</a> Iron-chelating agents reduce the toxicity produced by the massive deposition of iron in multitransfused patients,<a class="elsevierStyleCrossRef" href="#bib1475">141</a> although recent studies question their nephroprotective capacity in haemoglobin-induced AKI.<a class="elsevierStyleCrossRef" href="#bib1480">142</a> It should be noted that certain iron-chelating agents, such as deferasirox<a class="elsevierStyleCrossRef" href="#bib1485">143</a> and deferoxamine,<a class="elsevierStyleCrossRef" href="#bib1490">144</a> are potential nephrotoxic agents, requiring strict monitoring during their use.<a class="elsevierStyleCrossRef" href="#bib1495">145</a>Prophylactic treatment with antioxidants such as N-acetylcysteine has yielded positive results in preventing tubular damage secondary to myoglobinuria or haemoglobinuria.<a class="elsevierStyleCrossRef" href="#bib1500">146</a> Other antioxidants, such as acetaminophen, were also effective.<a class="elsevierStyleCrossRefs" href="#bib0905">27,147</a> The possible protective role of vitamin E<a class="elsevierStyleCrossRef" href="#bib1510">148</a> and vitamin C,<a class="elsevierStyleCrossRef" href="#bib0905">27</a> in addition to polyphenols,<a class="elsevierStyleCrossRef" href="#bib1515">149</a> flavonoids<a class="elsevierStyleCrossRefs" href="#bib1410">128,150–152</a> and l-carnitine,<a class="elsevierStyleCrossRef" href="#bib1535">153</a> has also been investigated, yielding disparate results, as mentioned earlier. Recent studies have also addressed the use of stem cells and have produced positive results, especially in models of rhabdomyolysis.<a class="elsevierStyleCrossRef" href="#bib1540">154</a>Clinical trialsOngoing clinical trials for the treatment of disorders caused by haemoproteins are focused on two aspects. First, treating the underlying disease to prevent the release of haemoproteins into the plasma, and second, mitigating the damage potentially caused by haemoproteins once they are released. As such, in diseases such as aHUS and paroxysmal nocturnal haemoglobinuria, the majority of trials test drugs that act on the complement system, mainly eculizumab, or even new molecules that act in other ways. These include: CCX168 (C5aR antagonist); conversin (protein that prevents action on its C5 convertase); TT30 (ALXN1102 and ALXN1103; recombinant proteins containing Factor H domains 1–5 and which reduce the complement's convertase activity and activate Factor I); LFG316 (anti-C5 monoclonal antibody); APL-2 (C3 inhibitor) and ALN-CC5 (hepatic inhibitor of C5 synthesis) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In aHUS, antibodies are also being developed that work against MASP-2, known as OMS 723. In SCA there are trials involving drugs such as SCD 101 and ICA-17043 (which stop red blood cells from turning into falciform cells); decitabine, vorinostat and panobinostat (to increase foetal haemoglobin); and statins, sodium nitrate and ambrisentan (type A-selective endothelin receptor antagonist) to improve endothelial dysfunction, maintain good tissue perfusion during crises and avoid the rupture of red blood cells. SCD 101 has also been used in beta thalassaemia.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Once haemoproteins are released into the plasma, the trials focus on two strategies. The first strategy is to try to clear these molecules from the plasma. This has been done in several trials in patients suffering from rhabdomyolysis who require renal replacement therapy, in which the effects of continuous techniques, high cut-off haemofilters and immunoabsorption techniques (CytoSorb®) have been analysed in order to remove Mb from plasma as quickly as possible. The second strategy is based on reducing their toxic effect. To do this, efforts are being made to prevent haemoglobinuria-induced oxidation in malaria using paracetamol, and myoglobinuria-induced oxidation using N-acetylcysteine. Trials are also under way that use iron-chelating agents (deferasirox or a combination of exjade and desferal) in thalassaemia to prevent iron deposition in target organs.ConclusionThe accumulation of haemoproteins in the kidneys is nephrotoxic. There is evidence showing the short-term adverse effects and the chronic loss of renal function. Even though several adverse effects have been reported about these molecules, we must continue to determine the pathogenic mechanisms of haemoproteins to identify new therapeutic targets and prevent their adverse effects. In this sense, podocytes may constitute new cellular targets of the harmful effects of haemoproteins. From a therapeutic perspective, the data currently available are primarily based on studies in animal models. Therapeutic measures aimed at reducing myoglobinuria or haemoglobinuria will be hugely important to prevent renal damage caused by these molecules.FundingThis study was funded using grants from: the Spanish Society of Nephrology (Sociedad Española de Nefrología), the Spanish Health Research Fund (Fondo de Investigaciones Sanitarias, FIS) (ISCIII/FEDER) (Miguel Servet Programme: CP10/00479 and CPII16/00017; PI13/00802 and PI14/00883) and Fundación Renal Íñigo Álvarez de Toledo (FRIAT) (grants given to JAM); Fundación Conchita Rábago (grant given to MGH); REDinREN (RD012/0021), FIS PI13/02502 and ICI14/00350 (grants given to MP); and FIS/FEDER PI14/00386 and Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas asociadas, CIBERDEM) (grants given to JE).Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres985558" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec953213" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres985559" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec953212" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Origin of the renal accumulation of haemoproteins" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Myoglobinuria" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Haemoglobinuria" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Haemoproteins and acute kidney injury" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Haemoproteins and chronic kidney disease" ] 8 => array:3 [ "identificador" => "sec0035" "titulo" => "Pathophysiological mechanisms involved in haemoproteins induced renal damage" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Oxidative stress" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Inflammation" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Cell death" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Fibrosis" ] ] ] 9 => array:3 [ "identificador" => "sec0060" "titulo" => "Defence mechanisms against the renal toxicity of haemoproteins" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0065" "titulo" => "Direct mechanisms" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Haptoglobin" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "CD163" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Haem oxygenase" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Transferrin" ] 4 => array:2 [ "identificador" => "sec0090" "titulo" => "Haemopexin" ] 5 => array:2 [ "identificador" => "sec0095" "titulo" => "Ferritin" ] 6 => array:2 [ "identificador" => "sec0100" "titulo" => "Nrf2" ] ] ] 1 => array:3 [ "identificador" => "sec0105" "titulo" => "Indirect mechanisms" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0110" "titulo" => "Non-enzymatic mechanisms" ] 1 => array:2 [ "identificador" => "sec0115" "titulo" => "Enzymatic mechanisms" ] ] ] ] ] 10 => array:2 [ "identificador" => "sec0120" "titulo" => "Treatments" ] 11 => array:2 [ "identificador" => "sec0125" "titulo" => "Clinical trials" ] 12 => array:2 [ "identificador" => "sec0130" "titulo" => "Conclusion" ] 13 => array:2 [ "identificador" => "sec0135" "titulo" => "Funding" ] 14 => array:2 [ "identificador" => "sec0140" "titulo" => "Conflicts of interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-07" "fechaAceptado" => "2017-05-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec953213" "palabras" => array:7 [ 0 => "Haemoglobin" 1 => "Myoglobin" 2 => "Haemoglobinuria" 3 => "Rhabdomyolysis" 4 => "Haematuria" 5 => "Acute kidney failure" 6 => "Chronic kidney disease" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec953212" "palabras" => array:7 [ 0 => "Hemoglobina" 1 => "Mioglobina" 2 => "Hemoglobinuria" 3 => "Rabdomiólisis" 4 => "Hematuria" 5 => "Fracaso renal agudo" 6 => "Enfermedad renal crónica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La hemoglobina y la mioglobina son hemoproteínas que juegan un papel fundamental en el organismo ya que participan en el transporte de oxígeno. Sin embargo, debido a su estructura química, estas moléculas pueden ejercer efectos deletéreos cuando se liberan al torrente sanguíneo de forma masiva, como sucede en determinadas condiciones patológicas asociadas a rabdomiólisis o hemólisis intravascular. Una vez en el plasma, estas hemoproteínas se pueden filtrar y acumular en el riñón, donde resultan citotóxicas, principalmente para el epitelio tubular, e inducen fracaso renal agudo y enfermedad renal crónica. En la presente revisión analizaremos los distintos contextos patológicos que provocan la acumulación renal de estas hemoproteínas, su relación con la pérdida de función renal a corto y largo plazo, los mecanismos fisiopatólogicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones. Por último, describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terapéuticas basadas en la identificación de nuevas dianas celulares y moleculares, prestando especial atención a los diversos ensayos clínicos que se encuentran en marcha en la actualidad." ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "◊" "nota" => "Both authors share authorship as first authors." "identificador" => "fn0005" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Guerrero-Hue M, Rubio-Navarro A, Sevillano A, Yuste C, Gutiérrez E, Palomino-Antolín A, et al. Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas. Nefrologia. 2018;38:13–26." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2753 "Ancho" => 1727 "Tamanyo" => 295162 ] ] "descripcion" => array:1 [ "en" => "Main causes of haemoglobinuria and rhabdomyolysis." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1220 "Ancho" => 3102 "Tamanyo" => 260256 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of renal damage caused by haemoproteins." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1135 "Ancho" => 1663 "Tamanyo" => 119129 ] ] "descripcion" => array:1 [ "en" => "Main defence mechanisms and adverse effects of the renal accumulation of haemoproteins." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mode of action \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Trial treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical trial number \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="16" align="left" valign="top">Treatment of underlying disease</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">HUS</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Inhibition of complement</td><td class="td" title="table-entry " align="left" valign="top">Eculizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00838513 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CCX168 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02464891 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antibody against MASP-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">OMS 721 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02222545 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Paroxysmal nocturnal haemoglobinuria</td><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Inhibition of complement</td><td class="td" title="table-entry " align="left" valign="top">Conversin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02591862 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01335165 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LFG316 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02534909 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">APL2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02588833 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ALN-CC5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02352493 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="8" align="left" valign="top">Sickle-cell anaemia</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Covalent modifiers of haemoglobin</td><td class="td" title="table-entry " align="left" valign="top">SCD-101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02380079 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ICA-17043 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00294541 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Increase in foetal haemoglobin production</td><td class="td" title="table-entry " align="left" valign="top">Decitabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01375608 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vorinostat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01000155 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Panobinostat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01245179 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Improvement of endothelium function</td><td class="td" title="table-entry " align="left" valign="top">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00508027 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sodium nitrate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00095472 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ambrisentan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02712346 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Prevention of damage caused by haemoproteins</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Rhabdomyolysis</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Elimination of myoglobin through renal replacement therapies</td><td class="td" title="table-entry " align="left" valign="top">Continuous therapies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00391911 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High cut-off HicoRhabdo filters \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01467180 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunoabsorption (CytoSorb®) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT02111018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decreased oxidation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N-acetylcysteine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00391911 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Malaria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Decreased oxidation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paracetamol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT01641289 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Beta thalassaemia</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Iron-chelating agents</td><td class="td" title="table-entry " align="left" valign="top">Deferasirox \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00560820 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Exjade-desferal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCT00901199 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1672053.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical trials in diseases associated with the renal accumulation of haemoproteins." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:154 [ 0 => array:3 [ "identificador" => "bib0775" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18990801" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-Å resolution, obtained by X-ray analysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0780" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://link.springer.com/10.1007/s10545-015-9827-7" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute rhabdomyolysis and inflammation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0785" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://link.springer.com/10.1007/s11739-007-0060-8" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rhabdomyolysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0790" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.karger.com/?doi=10.1159/000368528" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mechanisms and novel therapeutic approaches to rhabdomyolysis-induced acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0795" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://cjasn.asnjournals.org/cgi/doi/10.2215/CJN.01970211" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0800" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.13.1653" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0805" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/16267412" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rhabdomyolysis: an evaluation of 475 hospitalized patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0810" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/11430535" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis and treatment of renal dysfunction in rhabdomyolysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0815" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/26456110" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0820" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/1445988" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute renal failure in patients with severe falciparum malaria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0825" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1111/bjh.12690" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0830" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1002/ajh.21757" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0835" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9621299" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The pathogenesis and treatment of hemolytic uremic syndrome" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0840" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jasn.org/cgi/doi/10.1681/ASN.2006080894" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Physiology and pathophysiology of heme: implications for kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0845" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/7566565" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute renal failure in glomerular bleeding: a puzzling phenomenon" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0850" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.liebertonline.com/doi/abs/10.1089/ars.2004.6.954" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The radical and redox chemistry of myoglobin and hemoglobin: from in vitro studies to human pathology" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0855" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/12874476" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in the pathophysiology of ischemic acute renal failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0860" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.nature.com/doifinder/10.1038/nm799" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0865" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2006-12-061697" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0870" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.110.008698" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0875" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0272638614011901" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intratubular hemoglobin casts in hemolysis-associated acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0880" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/8821813" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rhabdomyolysis and myohemoglobinuric acute renal failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0885" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/14518093" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "[Rhabdomyolysis – development, causes, sequelae and therapy] [article in Czech]" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0890" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.liebertonline.com/doi/abs/10.1089/ars.2005.7.1755" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Redox biology of blood revisited: the role of red blood cells in maintaining circulatory reductive capacity" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0895" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://pubs.acs.org/doi/abs/10.1021/jf011394w" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myoglobin-induced lipid oxidation. A review" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0900" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/2423372" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0905" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/21034813" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0910" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jbc.org/cgi/doi/10.1074/jbc.M609955200" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structural basis of peroxide-mediated changes in human hemoglobin: a novel oxidative pathway" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0915" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S1471491410001097" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemoglobin-based oxygen carriers: from mechanisms of toxicity and clearance to rational drug design" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0920" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9822635" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0925" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/24277079" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0930" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103623" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0935" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18650913" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Origin and physiological roles of inflammation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0940" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.nature.com/articles/srep10901" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of NLRP3 inflammasomes for rhabdomyolysis-induced acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0945" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.thno.org/v06p0896.htm" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CD163-macrophages are involved in rhabdomyolysis-induced kidney injury and may be detected by MRI with targeted gold-coated iron oxide nanoparticles" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0950" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jasn.org/cgi/doi/10.1681/ASN.2014040320" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0955" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/21771756" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0960" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.karger.com/doi/10.1159/000342385" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative stress macrophage infiltration and CD163 expression are determinants of long-term renal outcome in macrohematuria-induced acute kidney injury of IgA nephropathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0965" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.dustri.com/article_response_page.html?artId=10009&doi=10.5414/CN107520&L=0" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mediators of favism-induced acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0970" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0217-z" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute kidney injury induced by thrombotic microangiopathy in a patient with hemophagocytic lymphohistiocytosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0975" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0085253815522709" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute renal failure in a patient with paroxysmal nocturnal hemoglobinuria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0980" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.karger.com?doi=10.1159/000351345" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal involvement in paroxysmal nocturnal hemoglobinuria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0985" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/1635582" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rhabdomyolysis with acute tubular necrosis – a nonglomerular cause of dysmorphic hematuria" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0990" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jci.org/articles/view/59770" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0995" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajprenal.physiology.org/cgi/doi/10.1152/ajprenal.00300.2003" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heme: a determinant of life and death in renal tubular epithelial cells" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib1000" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.jasn.org/cgi/doi/10.1681/ASN.2013030281" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib1005" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ndt.oxfordjournals.org/cgi/doi/10.1093/ndt/gfp659" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib1010" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.nature.com/doifinder/10.1038/cddis.2015.392" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib1015" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://pubs.acs.org/doi/abs/10.1021/ja411006a" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib1020" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajprenal.physiology.org/cgi/doi/10.1152/ajprenal.00035.2011" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Persistent disruption of mitochondrial homeostasis after acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib1025" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajpheart.physiology.org/cgi/doi/10.1152/ajpheart.00584.2011" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib1030" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S1875957215001229" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Urinary transforming growth factor β-1 as a marker of renal dysfunction in sickle cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib1035" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/10844611" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal response to repetitive exposure to heme proteins: chronic injury induced by an acute insult" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib1040" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/7853792" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The transgenic SAD mouse: a model of human sickle cell glomerulopathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib1045" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/8971879" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Development of focal segmental sclerosis and hyalinosis in hemolytic uremic syndrome" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib1050" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25599621" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Podocyte dysfunction in atypical haemolytic uraemic syndrome" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib1055" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25393378" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib1060" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9708603" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early glomerular dysfunction in patients with sickle cell anemia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib1065" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9731043" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased susceptibility in Hp knockout mice during acute hemolysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib1070" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/23418677" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human Hp 1-1 and Hp 2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib1075" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/2980525" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of a 99Tcm bound brain scanning agent for single photon emission computed tomography" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib1080" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/3756181" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human haptoglobin binds to human myoglobin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib1085" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/11196644" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of the haemoglobin scavenger receptor" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib1090" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/5687939" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib1095" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/19659436" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemoglobin and heme scavenger receptors" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib1100" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S1079979614001569" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib1105" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/19620788" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib1110" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25582460" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib1115" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/16189277" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib1120" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00041433-201210000-00008" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib1125" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/3715920" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of sorbic acid and sorbic acid-nitrite in vivo on bone marrow chromosomes of mice" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib1130" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://journal.frontiersin.org/article/10.3389/fphar.2012.00030/Abstract" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Direct antioxidant properties of bilirubin and biliverdin is there a role for biliverdin reductase?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ …3] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib1135" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajpheart.physiology.org/cgi/doi/10.1152/ajpheart.00327.2009" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib1140" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00041552-201401000-00004" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heme oxygenase-1 and acute kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib1145" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/27329933" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of myoglobin degradation in nephrotoxicity after rhabdomyolysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib1150" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv147" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib1155" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/10793020" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib1160" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0002944010650249" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib1165" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9444770" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transferrin, the transferrin receptor, and the uptake of iron by cells" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib1170" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15345587" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib1175" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/9484220" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron regulatory element and internal loop/bulge structure for ferritin mRNA studied by cobalt(III) hexammine binding, molecular modeling, and NMR spectroscopy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib1180" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0022283697913772" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structure and dynamics of the iron responsive element RNA: implications for binding of the RNA by iron regulatory binding proteins" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib1185" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://emboj.embopress.org/cgi/doi/10.1038/sj.emboj.7600041" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib1190" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/20603012" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two to tango: regulation of mammalian iron metabolism" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib1195" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/3733737" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of non-transferrin-bound iron clearance by rat liver" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib1200" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0304416511002674" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of iron transport and the role of transferrin" …1 ] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 86 => array:3 [ "identificador" => "bib1205" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/10910930" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 87 => array:3 [ "identificador" => "bib1210" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/22294463" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 88 => array:3 [ "identificador" => "bib1215" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/12690199" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 89 => array:3 [ "identificador" => "bib1220" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15947085" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 90 => array:3 [ "identificador" => "bib1225" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/16102056" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 91 => array:3 [ "identificador" => "bib1230" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/4921465" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 92 => array:3 [ "identificador" => "bib1235" "etiqueta" => "93" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25389409" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 93 => array:3 [ "identificador" => "bib1240" "etiqueta" => "94" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/666618" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 94 => array:3 [ "identificador" => "bib1245" "etiqueta" => "95" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/188189" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 95 => array:3 [ "identificador" => "bib1250" "etiqueta" => "96" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/22993068" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 96 => array:3 [ "identificador" => "bib1255" "etiqueta" => "97" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/23446829" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 97 => array:3 [ "identificador" => "bib1260" "etiqueta" => "98" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/10572107" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 98 => array:3 [ "identificador" => "bib1265" "etiqueta" => "99" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18556779" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 99 => array:3 [ "identificador" => "bib1270" "etiqueta" => "100" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/26518749" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 100 => array:3 [ "identificador" => "bib1275" "etiqueta" => "101" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25874599" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 101 => array:3 [ "identificador" => "bib1280" "etiqueta" => "102" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18805612" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 102 => array:3 [ "identificador" => "bib1285" "etiqueta" => "103" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/24018561" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 103 => array:3 [ "identificador" => "bib1290" "etiqueta" => "104" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/24319218" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 104 => array:3 [ "identificador" => "bib1295" "etiqueta" => "105" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/8962164" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 105 => array:3 [ "identificador" => "bib1300" "etiqueta" => "106" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15110384" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 106 => array:3 [ "identificador" => "bib1305" "etiqueta" => "107" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/12446695" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 107 => array:3 [ "identificador" => "bib1310" "etiqueta" => "108" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/12441344" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 108 => array:3 [ "identificador" => "bib1315" "etiqueta" => "109" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15581590" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 109 => array:3 [ "identificador" => "bib1320" "etiqueta" => "110" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/14764898" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 110 => array:3 [ "identificador" => "bib1325" "etiqueta" => "111" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/14612418" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 111 => array:3 [ "identificador" => "bib1330" "etiqueta" => "112" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/14585973" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 112 => array:3 [ "identificador" => "bib1335" "etiqueta" => "113" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "e0152895. Available in: http://www.ncbi.nlm.nih.gov/pubmed/27071063" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 113 => array:3 [ "identificador" => "bib1340" "etiqueta" => "114" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/26371321" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 114 => array:3 [ "identificador" => "bib1345" "etiqueta" => "115" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/26914345" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 115 => array:3 [ "identificador" => "bib1350" "etiqueta" => "116" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1002/cbf.1255" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 116 => array:3 [ "identificador" => "bib1355" "etiqueta" => "117" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.degruyter.com/view/j/jcim.2017.14.issue-1/jcim-2015-0082/jcim-2015-0082.xml" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 117 => array:3 [ "identificador" => "bib1360" "etiqueta" => "118" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ajhp.org/cgi/doi/10.2146/ajhp150591" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 118 => array:3 [ "identificador" => "bib1365" "etiqueta" => "119" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.tandfonline.com/doi/full/10.1080/08860220802212965" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 119 => array:3 [ "identificador" => "bib1370" "etiqueta" => "120" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0301472X07006935" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 120 => array:3 [ "identificador" => "bib1375" "etiqueta" => "121" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/1145115" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 121 => array:3 [ "identificador" => "bib1380" "etiqueta" => "122" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.tandfonline.com/doi/full/10.3109/10715762.2011.590137" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 122 => array:3 [ "identificador" => "bib1385" "etiqueta" => "123" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/12472196" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 123 => array:3 [ "identificador" => "bib1390" "etiqueta" => "124" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/1946409" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 124 => array:3 [ "identificador" => "bib1395" "etiqueta" => "125" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.tandfonline.com/doi/full/10.3109/0886022X.2013.835223" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 125 => array:3 [ "identificador" => "bib1400" "etiqueta" => "126" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1111/cei.12124" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 126 => array:3 [ "identificador" => "bib1405" "etiqueta" => "127" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajpregu.physiology.org/cgi/doi/10.1152/ajpregu.00611.2009" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 127 => array:3 [ "identificador" => "bib1410" "etiqueta" => "128" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0300483X04002628" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 128 => array:3 [ "identificador" => "bib1415" "etiqueta" => "129" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15600251" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 129 => array:3 [ "identificador" => "bib1420" "etiqueta" => "130" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfp659" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 130 => array:3 [ "identificador" => "bib1425" "etiqueta" => "131" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1111/j. 1440-1681.2004.04050.x" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 131 => array:3 [ "identificador" => "bib1430" "etiqueta" => "132" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://ajprenal.physiology.org/lookup/doi/10.1152/ajprenal.00546.2016" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 132 => array:3 [ "identificador" => "bib1435" "etiqueta" => "133" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://linkinghub.elsevier.com/retrieve/pii/S0940299310000242" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 133 => array:3 [ "identificador" => "bib1440" "etiqueta" => "134" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1002/jat.1449" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 134 => array:3 [ "identificador" => "bib1445" "etiqueta" => "135" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-016-0398-0" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 135 => array:3 [ "identificador" => "bib1450" "etiqueta" => "136" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.nature.com/articles/srep14471" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 136 => array:3 [ "identificador" => "bib1455" "etiqueta" => "137" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/17293870" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 137 => array:3 [ "identificador" => "bib1460" "etiqueta" => "138" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18067870" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 138 => array:3 [ "identificador" => "bib1465" "etiqueta" => "139" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/27626608" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 139 => array:3 [ "identificador" => "bib1470" "etiqueta" => "140" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/18215735" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 140 => array:3 [ "identificador" => "bib1475" "etiqueta" => "141" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/24726864" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 141 => array:3 [ "identificador" => "bib1480" "etiqueta" => "142" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15987753" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 142 => array:3 [ "identificador" => "bib1485" "etiqueta" => "143" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/21439361" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 143 => array:3 [ "identificador" => "bib1490" "etiqueta" => "144" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/21320071" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 144 => array:3 [ "identificador" => "bib1495" "etiqueta" => "145" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/25402221" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 145 => array:3 [ "identificador" => "bib1500" "etiqueta" => "146" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/23576637" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 146 => array:3 [ "identificador" => "bib1505" "etiqueta" => "147" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/20133658" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 147 => array:3 [ "identificador" => "bib1510" "etiqueta" => "148" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/15774072" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 148 => array:3 [ "identificador" => "bib1515" "etiqueta" => "149" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/22343418" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 149 => array:3 [ "identificador" => "bib1520" "etiqueta" => "150" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfh369" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 150 => array:3 [ "identificador" => "bib1525" "etiqueta" => "151" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.karger.com/?doi=10.1159/000081074" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 151 => array:3 [ "identificador" => "bib1530" "etiqueta" => "152" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/10586425" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 152 => array:3 [ "identificador" => "bib1535" "etiqueta" => "153" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://doi.wiley.com/10.1111/j. 1440-1681.2006.04336.x" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] 153 => array:3 [ "identificador" => "bib1540" "etiqueta" => "154" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: http://www.ncbi.nlm.nih.gov/pubmed/19389847" "contribucion" => array:1 [ 0 => array:2 [ …2] ] "host" => array:1 [ 0 => array:1 [ …1] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003800000001/v1_201802180616/S2013251418300051/v1_201802180616/en/main.assets" "Apartado" => array:4 [ "identificador" => "35443" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003800000001/v1_201802180616/S2013251418300051/v1_201802180616/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251418300051?idApp=UINPBA000064"]

Statistics

Review

Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas

Melania Guerrero-Huea,◊, Alfonso Rubio-Navarroa,◊, Ángel Sevillanob,c, Claudia Yusteb,c, Eduardo Gutiérrezb,c, Alejandra Palomino-Antolína, Elena Románd, Manuel Pragab,c, Jesús Egidoa, Juan Antonio Morenoa,

Corresponding author

jamoreno@fjd.es

Corresponding author.

a Laboratorio de Nefrología Experimental, Patología Vascular y Diabetes, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain

b Red de Investigación Renal (REDINREN), Madrid, Spain

c Departamento de Nefrología, Hospital 12 de Octubre, Madrid, Spain

d Departamento de Nefrología Pediátrica, Hospital La Fe, Valencia, Spain

Read

18486

Times
was read the article

4372

Total PDF

14114

Total HTML

Share statistics

 array:25 [
  "pii" => "S2013251418300051"
  "issn" => "20132514"
  "doi" => "10.1016/j.nefroe.2018.01.003"
  "estado" => "S300"
  "fechaPublicacion" => "2018-01-01"
  "aid" => "397"
  "copyright" => "Sociedad Espa&#241;ola de Nefrolog&#237;a"
  "copyrightAnyo" => "2017"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "ssu"
  "cita" => "Nefrologia &#40;English Version&#41;. 2018;38:13-26"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 6603
    "formatos" => array:3 [
      "EPUB" => 295
      "HTML" => 5501
      "PDF" => 807
    ]
  ]
  "Traduccion" => array:1 [
    "es" => array:20 [
      "pii" => "S0211699517301327"
      "issn" => "02116995"
      "doi" => "10.1016/j.nefro.2017.05.009"
      "estado" => "S300"
      "fechaPublicacion" => "2018-01-01"
      "aid" => "397"
      "copyright" => "Sociedad Espa&#241;ola de Nefrolog&#237;a"
      "documento" => "article"
      "crossmark" => 0
      "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
      "subdocumento" => "ssu"
      "cita" => "Nefrologia. 2018;38:13-26"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 10931
        "formatos" => array:3 [
          "EPUB" => 375
          "HTML" => 8916
          "PDF" => 1640
        ]
      ]
      "es" => array:13 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">Revisi&#243;n</span>"
        "titulo" => "Efectos adversos de la acumulaci&#243;n renal de hemoprote&#237;nas&#46; Nuevas herramientas terap&#233;uticas"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "13"
            "paginaFinal" => "26"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Adverse effects of the renal accumulation of haem proteins&#46; Novel therapeutic approaches"
          ]
        ]
        "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" => 2753
                "Ancho" => 1727
                "Tamanyo" => 319876
              ]
            ]
            "descripcion" => array:1 [
              "es" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Principales causas de hemoglobinuria y rabdomi&#243;lisis&#46;</p>"
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "Melania Guerrero-Hue, Alfonso Rubio-Navarro, &#193;ngel Sevillano, Claudia Yuste, Eduardo Guti&#233;rrez, Alejandra Palomino-Antol&#237;n, Elena Rom&#225;n, Manuel Praga, Jes&#250;s Egido, Juan Antonio Moreno"
            "autores" => array:10 [
              0 => array:2 [
                "nombre" => "Melania"
                "apellidos" => "Guerrero-Hue"
              ]
              1 => array:2 [
                "nombre" => "Alfonso"
                "apellidos" => "Rubio-Navarro"
              ]
              2 => array:2 [
                "nombre" => "&#193;ngel"
                "apellidos" => "Sevillano"
              ]
              3 => array:2 [
                "nombre" => "Claudia"
                "apellidos" => "Yuste"
              ]
              4 => array:2 [
                "nombre" => "Eduardo"
                "apellidos" => "Guti&#233;rrez"
              ]
              5 => array:2 [
                "nombre" => "Alejandra"
                "apellidos" => "Palomino-Antol&#237;n"
              ]
              6 => array:2 [
                "nombre" => "Elena"
                "apellidos" => "Rom&#225;n"
              ]
              7 => array:2 [
                "nombre" => "Manuel"
                "apellidos" => "Praga"
              ]
              8 => array:2 [
                "nombre" => "Jes&#250;s"
                "apellidos" => "Egido"
              ]
              9 => array:2 [
                "nombre" => "Juan Antonio"
                "apellidos" => "Moreno"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S2013251418300051"
          "doi" => "10.1016/j.nefroe.2018.01.003"
          "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/S2013251418300051?idApp=UINPBA000064"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699517301327?idApp=UINPBA000064"
      "url" => "/02116995/0000003800000001/v1_201801090621/S0211699517301327/v1_201801090621/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:20 [
    "pii" => "S2013251417302158"
    "issn" => "20132514"
    "doi" => "10.1016/j.nefroe.2017.04.018"
    "estado" => "S300"
    "fechaPublicacion" => "2018-01-01"
    "aid" => "383"
    "copyright" => "Sociedad Espa&#241;ola de Nefrolog&#237;a"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "ssu"
    "cita" => "Nefrologia &#40;English Version&#41;. 2018;38:27-33"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 3003
      "formatos" => array:3 [
        "EPUB" => 269
        "HTML" => 2196
        "PDF" => 538
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Brief review</span>"
      "titulo" => "Advances in the evaluation of bone health in kidney transplant patients"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "27"
          "paginaFinal" => "33"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Avances en la valoraci&#243;n de la salud &#243;sea en el trasplantado renal"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Fig&#46; 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 1981
              "Ancho" => 2865
              "Tamanyo" => 281712
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Comparison between the different diagnostic tests to estimate bone health&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Mar&#237;a Jos&#233; P&#233;rez-S&#225;ez, Daniel Prieto-Alhambra, Adolfo D&#237;ez-P&#233;rez, Julio Pascual"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "Mar&#237;a Jos&#233;"
              "apellidos" => "P&#233;rez-S&#225;ez"
            ]
            1 => array:2 [
              "nombre" => "Daniel"
              "apellidos" => "Prieto-Alhambra"
            ]
            2 => array:2 [
              "nombre" => "Adolfo"
              "apellidos" => "D&#237;ez-P&#233;rez"
            ]
            3 => array:2 [
              "nombre" => "Julio"
              "apellidos" => "Pascual"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0211699517301030"
        "doi" => "10.1016/j.nefro.2017.04.002"
        "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/S0211699517301030?idApp=UINPBA000064"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251417302158?idApp=UINPBA000064"
    "url" => "/20132514/0000003800000001/v1_201802180616/S2013251417302158/v1_201802180616/en/main.assets"
  ]
  "itemAnterior" => array:20 [
    "pii" => "S2013251418300191"
    "issn" => "20132514"
    "doi" => "10.1016/j.nefroe.2018.01.007"
    "estado" => "S300"
    "fechaPublicacion" => "2018-01-01"
    "aid" => "426"
    "copyright" => "Sociedad Espa&#241;ola de Nefrolog&#237;a"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Nefrologia &#40;English Version&#41;. 2018;38:8-12"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 17530
      "formatos" => array:3 [
        "EPUB" => 317
        "HTML" => 14257
        "PDF" => 2956
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>"
      "titulo" => "Anemia of chronic kidney disease&#58; Protocol of study&#44; management and referral to Nephrology"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "8"
          "paginaFinal" => "12"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Anemia en la enfermedad renal cr&#243;nica&#58; Protocolo de estudio&#44; manejo y derivaci&#243;n a Nefrolog&#237;a"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 1921
              "Ancho" => 2865
              "Tamanyo" => 432464
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Work up algorithm and referral to Nephrology of patients with anemia of renal origin&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Aleix Cases, M&#46; Isabel Egocheaga, Salvador Tranche, Vicente Pallar&#233;s, Raquel Ojeda, Jos&#233; Luis G&#243;rriz, Jos&#233; Mar&#237;a Portol&#233;s"
          "autores" => array:7 [
            0 => array:2 [
              "nombre" => "Aleix"
              "apellidos" => "Cases"
            ]
            1 => array:2 [
              "nombre" => "M&#46; Isabel"
              "apellidos" => "Egocheaga"
            ]
            2 => array:2 [
              "nombre" => "Salvador"
              "apellidos" => "Tranche"
            ]
            3 => array:2 [
              "nombre" => "Vicente"
              "apellidos" => "Pallar&#233;s"
            ]
            4 => array:2 [
              "nombre" => "Raquel"
              "apellidos" => "Ojeda"
            ]
            5 => array:2 [
              "nombre" => "Jos&#233; Luis"
              "apellidos" => "G&#243;rriz"
            ]
            6 => array:2 [
              "nombre" => "Jos&#233; Mar&#237;a"
              "apellidos" => "Portol&#233;s"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0211699517301881"
        "doi" => "10.1016/j.nefro.2017.09.004"
        "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/S0211699517301881?idApp=UINPBA000064"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251418300191?idApp=UINPBA000064"
    "url" => "/20132514/0000003800000001/v1_201802180616/S2013251418300191/v1_201802180616/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review</span>"
    "titulo" => "Adverse effects of the renal accumulation of haem proteins&#46; Novel therapeutic approaches"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "13"
        "paginaFinal" => "26"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Melania Guerrero-Hue, Alfonso Rubio-Navarro, &#193;ngel Sevillano, Claudia Yuste, Eduardo Guti&#233;rrez, Alejandra Palomino-Antol&#237;n, Elena Rom&#225;n, Manuel Praga, Jes&#250;s Egido, Juan Antonio Moreno"
        "autores" => array:10 [
          0 => array:3 [
            "nombre" => "Melania"
            "apellidos" => "Guerrero-Hue"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#9674;</span>"
                "identificador" => "fn0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Alfonso"
            "apellidos" => "Rubio-Navarro"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#9674;</span>"
                "identificador" => "fn0005"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "&#193;ngel"
            "apellidos" => "Sevillano"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Claudia"
            "apellidos" => "Yuste"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Eduardo"
            "apellidos" => "Guti&#233;rrez"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Alejandra"
            "apellidos" => "Palomino-Antol&#237;n"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "Elena"
            "apellidos" => "Rom&#225;n"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
          7 => array:3 [
            "nombre" => "Manuel"
            "apellidos" => "Praga"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          8 => array:3 [
            "nombre" => "Jes&#250;s"
            "apellidos" => "Egido"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          9 => array:4 [
            "nombre" => "Juan Antonio"
            "apellidos" => "Moreno"
            "email" => array:1 [
              0 => "jamoreno&#64;fjd&#46;es"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Laboratorio de Nefrolog&#237;a Experimental&#44; Patolog&#237;a Vascular y Diabetes&#44; Fundaci&#243;n Instituto de Investigaci&#243;n Sanitaria-Fundaci&#243;n Jim&#233;nez D&#237;az&#44; Universidad Aut&#243;noma&#44; Madrid&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Red de Investigaci&#243;n Renal &#40;REDINREN&#41;&#44; Madrid&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Departamento de Nefrolog&#237;a&#44; Hospital 12 de Octubre&#44; Madrid&#44; Spain"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "Departamento de Nefrolog&#237;a Pedi&#225;trica&#44; Hospital La Fe&#44; Valencia&#44; Spain"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Efectos adversos de la acumulaci&#243;n renal de hemoprote&#237;nas&#46; Nuevas herramientas terap&#233;uticas"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1220
            "Ancho" => 3102
            "Tamanyo" => 260256
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of renal damage caused by haemoproteins&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Haemoglobin &#40;Hb&#41; and myoglobin &#40;Mb&#41; are haemoproteins that play a crucial role in the body&#39;s homeostasis&#44; by oxygenating tissues and participating in the regulation of blood pH levels&#46; Hb has a molecular weight of 64&#46;5<span class="elsevierStyleHsp" style=""></span>kDa and is composed of four polypeptide chains known as globins&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">1</span></a> Each globin contains a haem group with an iron atom in its interior&#44; which is responsible for its functional properties&#46; Mb is a smaller protein with a molecular weight of 17<span class="elsevierStyleHsp" style=""></span>kDa&#44; which is formed by a single globin&#46; In physiological conditions&#44; both Hb and Mb are found inside erythrocytes and muscle cells&#44; respectively&#46; However&#44; in certain pathological conditions&#44; these molecules are released into the blood stream and may enter and accumulate in the kidneys&#44; where they are cytotoxic&#44; especially for the proximal tubule epithelium&#46; In fact&#44; the renal accumulation of haemoproteins may induce acute kidney injury &#40;AKI&#41; and chronic kidney disease &#40;CKD&#41;&#46; In recent years&#44; new mechanisms have been identified which are involved in kidney damage linked to these molecules&#44; which have helped to develop experimental treatments that have already yielded positive results in recently published studies or in ongoing clinical trials&#44; as described in more detail below&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Origin of the renal accumulation of haemoproteins</span><p id="par0010" class="elsevierStylePara elsevierViewall">Mb builds up in the kidneys as a result of severe muscular damage &#40;rhabdomyolysis&#41;&#44; whereas Hb accumulates due to the intravascular haemolysis of red blood cells or the rupture of red blood cells that cross the glomerular membrane in diseases with glomerular haematuria&#44; such as IgA nephropathy &#40;IgAN&#41;&#44; lupus or Alport syndrome&#46; In this review&#44; we will focus on myoglobinuria and haemoglobinuria due to space limitations&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Myoglobinuria</span><p id="par0015" class="elsevierStylePara elsevierViewall">Myoglobinuria is the presence of Mb in urine&#44; for which the main cause is rhabdomyolysis or the rupture of skeletal muscle&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">2</span></a> Rhabdomyolysis may be caused by severe trauma&#44; situations of prolonged ischaemia&#44; metabolic disorders&#44; intense physical activity&#44; alcohol abuse and some toxic compounds of chemical or biological origin<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">3</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The incidence of rhabdomyolysis is not entirely clear&#44; but it has been estimated that it could affect 7&#8211;10&#37; of patients presenting with an AKI&#46;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">3&#44;4</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Haemoglobinuria</span><p id="par0020" class="elsevierStylePara elsevierViewall">Haemoglobinuria is the presence of Hb in urine as a result of intravascular haemolysis&#46; This causes a renal overload of Hb&#44; especially when there is recurring exposure to free Hb&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">5</span></a> Some of the main aetiological causes of haemoglobinuria include hereditary conditions&#44; such as paroxysmal nocturnal haemoglobinuria&#44; thrombotic thrombocytopenic purpura&#44; haemolytic-uraemic syndrome &#40;HUS&#41;&#44; sickle-cell anaemia &#40;SCA&#41;&#44; cell membrane defects &#40;elliptocytosis&#44; spherocytosis&#44; etc&#46;&#41;&#44; enzymatic defects &#40;glucose-6-phosphate dehydrogenase deficiency&#44; pyruvate kinase deficiency&#41;&#44; severe haemolytic anaemia caused by massive transfusion reactions&#44; as well as other causes acquired from HUS and thrombotic microangiopathies of various origins<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Haemoproteins and acute kidney injury</span><p id="par0025" class="elsevierStylePara elsevierViewall">AKI is a common complication in patients with haemoglobinuria or rhabdomyolysis&#44; especially if they were already suffering from kidney disease&#46; Up to 50&#37; of patients suffering from rhabdomyolysis develop AKI&#44; depending on what is the causes&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">7&#44;8</span></a> Therefore&#44; rhabdomyolysis is one of the main causes of AKI &#40;5&#8211;25&#37;&#41; and results in death in 2&#8211;46&#37; of cases in the absence of dialysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">3&#44;4</span></a> On many occasions&#44; situations associated with intravascular haemolysis may also induce AKI&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">9&#44;10</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Haemoproteins and chronic kidney disease</span><p id="par0030" class="elsevierStylePara elsevierViewall">The onset of kidney disease in patients with renal accumulation of haemoproteins is well documented&#46; It has been reported that haemoglobinuria is an independent risk factor for the onset and progression of CKD in people suffering with SCA&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">11</span></a> Something similar occurs in paroxysmal nocturnal haemoglobinuria&#44; a disease in which CKD secondary to the onset of renal vein thrombosis and haemoglobinuria is one of its most significant complications&#44; which may affect 64&#37; of patients and cause 18&#37; of deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">12</span></a> In the absence of treatment&#44; the prognosis for atypical HUS &#40;aHUS&#41; is also poor&#44; with a mortality rate during outbreak of 25&#37;&#44; and progression to CKD in over half of the patients the year after the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pathophysiological mechanisms involved in haemoproteins induced renal damage</span><p id="par0035" class="elsevierStylePara elsevierViewall">The main effect of haemoproteins on the kidneys is their direct tubule cell toxicity&#44; regardless of what causes their release &#40;haemo- or myoglobinuria&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Under normal conditions&#44; Hb binds to haptoglobin and forms the Hb&#8211;haptoglobin complex in the plasma&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">14</span></a> This complex is too large to be filtered by the glomerulus&#44; and is therefore broken down by the spleen&#44; bone marrow and liver&#46; However&#44; during intravascular haemolysis&#44; the massive release of Hb causes haptoglobin to be consumed&#46; As a result&#44; Hb remains in the plasma for longer periods of time and is more likely to dissociate into dimers&#44; which are more easily filtered by the glomerulus&#46; Unlike Hb&#44; Mb directly crosses the glomerular filtration membrane due to its smaller molecular size&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Once in the lumen of the tubule&#44; the haemoproteins can be reabsorbed by the proximal tubules through the megalin&#47;cubilin receptors complex&#44;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">14</span></a> or even break down by releasing the haem group and free iron&#44; which also have deleterious actions such as nitric oxide neutralisation&#44; vasoconstriction and ischaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">15</span></a> The reduced bioavailability of nitric oxide causes the deregulation of factors that control vascular tone&#44; such as endothelin-1&#44; thromboxane A2&#44; tumour necrosis factor and isoprostanes&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">16&#44;17</span></a> Hb and Mb are also powerful vasoconstrictors because they also react with nitric oxide&#44; as described in diseases associated with intravascular haemolysis and rhabdomyolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0860"><span class="elsevierStyleSup">18&#8211;20</span></a> When present in the lumen of the tubule&#44; both Mb and Hb can precipitate and bind to the Tamm-Horsfall protein and give rise to RBC casts&#44; which cause intratubular obstruction in the distal nephron segments&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">21</span></a> This obstruction is assisted by the acidic pH found in urine&#44; which increases the stability of the links between the haemoproteins and the Tamm-Horsfall protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0880"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Inside the tubule cells&#44; the haemoproteins dissociate by releasing globins and the haem group&#44; which induces oxidative stress&#44; cell death and the production of inflammatory cytokines and fibrosis&#44; as discussed in more detail below&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oxidative stress</span><p id="par0050" class="elsevierStylePara elsevierViewall">Haemoproteins present various redox forms and are an endogenous source of reactive oxygen species&#46;<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">24</span></a> When haemoproteins are captured by tubule cells&#44; the haem group is oxidised from Fe<span class="elsevierStyleSup">2&#43;</span> to Fe<span class="elsevierStyleSup">3&#43;</span> and produces hydroxyl radicals&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">25</span></a> In the presence of peroxides&#44; Fe<span class="elsevierStyleSup">3&#43;</span> oxidises to Fe<span class="elsevierStyleSup">4&#43;</span> and generates hydroperoxyl radicals&#44; which are highly reactive and contribute to the formation of new reactive oxygen species in the kidneys&#46;<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">26&#44;27</span></a> All of these radicals promote the lipid peroxidation of plasma membranes and generate malondialdehyde&#44; which intervenes in the oxidation of proteins and genetic material&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">4&#44;28&#44;29</span></a> This process leads to the production of isoprostanes&#44; proinflammatory cytokines and the expression of adhesion molecules&#44; which increases inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Inflammation</span><p id="par0055" class="elsevierStylePara elsevierViewall">The haem group acts as a TLR-4 agonist and induces inflammatory response by activating the transcription factor NF-kB&#46;<a class="elsevierStyleCrossRefs" href="#bib0925"><span class="elsevierStyleSup">31&#44;32</span></a> After binding to the pattern recognition receptor&#44; Hb promotes the activation of several signal transduction pathways such as c-Jun N-terminal&#44; p38 and MAP kinases&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">33</span></a> Another involved pathway is mediated by the activation of the NLRP3 &#40;nitrogen permease regulator-like 3&#41; inflammasome&#44; which is responsible for releasing different cytokines and chemokines involved in the monocyte&#47;macrophage recruitment&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">34</span></a> The presence of proinflammatory macrophages &#40;M1&#41; has been reported in early phases in experimental models of AKI due to the accumulation of haemoproteins&#44; which differ from anti-inflammatory macrophages &#40;M2&#41; in later phases&#46;<a class="elsevierStyleCrossRefs" href="#bib0945"><span class="elsevierStyleSup">35&#44;36</span></a> These M2 macrophages are found in renal biopsies of patients suffering from rhabdomyolysis&#44; favism&#44; paroxysmal nocturnal haemoglobinuria and outbreaks of macroscopic haematuria associated with IgAN&#46;<a class="elsevierStyleCrossRefs" href="#bib0955"><span class="elsevierStyleSup">37&#8211;39</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Cell death</span><p id="par0060" class="elsevierStylePara elsevierViewall">There have been reports of several types of cell death in the epithelial tubule of patients and in experimental models associated with the accumulation of haemoproteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">4&#44;39&#8211;43</span></a> Necrosis and apoptosis are the types of death that have been studied at a greater depth&#46;<a class="elsevierStyleCrossRefs" href="#bib0940"><span class="elsevierStyleSup">34&#44;44&#8211;46</span></a> The molecular mechanisms causing death by apoptosis are associated with mitochondrial dysfunction and an increase in pro-apoptotic proteins &#40;BAX and BAD&#41;&#44; as well as the activation of caspase-3&#44; the main effector caspase&#44;<a class="elsevierStyleCrossRefs" href="#bib0940"><span class="elsevierStyleSup">34&#44;47</span></a> and endoplasmic reticulum stress proteins&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">48</span></a> Other types of cell death have been described in these diseases&#44; such as pyroptosis &#40;cell death mediated by caspase-1 which leads to DNA fragmentation and cell lysis&#41; and ferroptosis &#40;iron-dependent cell death&#41;&#46; Caspase-1 activation has been observed in experimental rat models of rhabdomyolysis&#44;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">34</span></a> whereas the use of ferroptosis inhibitors in these rats reduced cell death of proximal tubules&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">49</span></a> Lastly&#44; the accumulation of haemoproteins and their derivatives may induce autophagy as a defence mechanism&#46;<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">46&#44;50&#44;51</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Fibrosis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Renal fibrosis is another mechanism involved in renal damage caused by haemoproteins&#46; In fact&#44; patients with SCA present with renal fibrosis and increased TGF-&#946; in urine&#44; which is one of the main profibrotic mediators&#46;<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">52</span></a> Even though fibroblasts and tubule cells play a very important role in the production of extracellular matrix proteins&#44; recent studies show that macrophages may increase profibrotic response due to the production of mediators such as CTGF and TGF-&#946; during rhabdomyolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0945"><span class="elsevierStyleSup">35&#44;36</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Renal tubules are considered as the main sites of Hb toxicity&#46; However&#44; the presence of proteinuria has been reported in experimental models of recurring exposure to haemoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">53</span></a> There have also been reports of the presence of focal segmental glomerulosclerosis in experimental models of SCA<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">54</span></a> and in patients with chronic and recurring haemolysis&#44; such as paroxysmal nocturnal haemoglobinuria&#44; HUS and SCA&#46;<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">55</span></a> These patients develop proteinuria<a class="elsevierStyleCrossRef" href="#bib1050"><span class="elsevierStyleSup">56</span></a> and suffer from a chronic reduction of glomerular filtration&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">12&#44;57</span></a> These data suggest that there is a link between intravascular haemolysis and glomerular dysfunction&#46; The physiopathological mechanisms&#44; however&#44; are not clear&#46; There are indications that the haemodynamic changes linked to this disease may be responsible for proteinuria and progressive renal damage&#59; however&#44; there is no definitive proof for this theory&#46;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">58</span></a> Given that focal segmental glomerulosclerosis entails a loss of podocytes&#44; these cells may also suffer from haemoprotein-mediated injury&#46; In this sense&#44; unpublished data from our group show that podocytes are capable of capturing Hb&#44; which induces oxidative stress and causes these cells to die&#44; as well as a loss of proteins involved in the glomerular filtration process such as synaptopodin and nephrin&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Defence mechanisms against the renal toxicity of haemoproteins</span><p id="par0075" class="elsevierStylePara elsevierViewall">There are two types of defence mechanisms that work against the harmful effects of haemoproteins&#58; direct and indirect&#46; The direct mechanisms promote the catabolism of haemoproteins and by-products&#44; whereas the indirect mechanisms reduce oxidative stress resulting from the presence of these molecules&#44; thus eliminating the reactive oxygen species or repairing the possible damage caused &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Below is an analysis of each of these defence mechanisms relating to renal damage caused by haemoproteins&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Direct mechanisms</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Haptoglobin</span><p id="par0080" class="elsevierStylePara elsevierViewall">Haptoglobin &#40;Hp&#41; is a glycoprotein found in high concentrations in plasma &#40;0&#46;3&#8211;3<span class="elsevierStyleHsp" style=""></span>g&#47;l&#41; and is mainly secreted by hepatocytes&#44; although it is also synthesised in other tissues such as kidneys&#46; Hp irreversibly binds to Hb and impedes its filtration in the kidneys<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">59</span></a> and its translocation to the endothelium&#44;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">60</span></a> which counteracts its harmful effects&#46;<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">61</span></a> Hp can also bind to Mb&#44; but with less affinity that it does to Hb&#46;<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">62</span></a> The Hb&#8211;Hp binding promotes the interaction and subsequent internalisation of this complex through the CD163 receptor of the membrane&#44; which is present in monocytes and macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib1085"><span class="elsevierStyleSup">63</span></a> Hp levels are highly reduced in patients with chronic haemolysis&#44; such as SCA&#44;<a class="elsevierStyleCrossRef" href="#bib1090"><span class="elsevierStyleSup">64</span></a> because Hp breaks down after being endocited&#46;<a class="elsevierStyleCrossRef" href="#bib1095"><span class="elsevierStyleSup">65</span></a> The importance of this protein for Hp has been reported in gene knockout studies in rats&#44; which are more sensitive to damage from haemolysis&#46;<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">59</span></a> Studies in animal models of SCA and rhabdomyolysis have shown that the administration of Hp reduces vaso-occlusion&#44;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">31</span></a> oxidative stress<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">66</span></a> and renal damage&#46;<a class="elsevierStyleCrossRefs" href="#bib1070"><span class="elsevierStyleSup">60&#44;67&#44;68</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">CD163</span><p id="par0085" class="elsevierStylePara elsevierViewall">CD163 is a receptor found on the surface of circulating monocytes and macrophages&#44; whose main function is Hb clearance in tissue&#46;<a class="elsevierStyleCrossRef" href="#bib1085"><span class="elsevierStyleSup">63</span></a> CD163 has a high affinity for Hb&#8211;Hp complexes&#44; although it can also bind to free Hb&#46;<a class="elsevierStyleCrossRef" href="#bib1115"><span class="elsevierStyleSup">69</span></a> The macrophages that express CD163 have reduced hydrogen peroxide release and important anti-inflammatory functions through the production of IL-10 and HO-1 stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib1120"><span class="elsevierStyleSup">70</span></a> Our group has observed an increase in the macrophages expressing CD163 in renal biopsies of patients with massive haemolysis&#44; such as paroxysmal nocturnal haemoglobinuria<a class="elsevierStyleCrossRef" href="#bib0955"><span class="elsevierStyleSup">37</span></a> and favism&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">39</span></a> The renal expression of CD163 was higher in areas where iron had accumulated and where oxidative stress markers were found&#46; We have recently written about the presence of CD163 in the kidneys of patients and experimental models of rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">35</span></a> Since the anti-inflammatory and antioxidant functions of CD163 are well known&#44; these data suggest that CD163 could play a nephroprotective role in response to the renal accumulation of haemoproteins&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Haem oxygenase</span><p id="par0090" class="elsevierStylePara elsevierViewall">Haem oxygenase &#40;HO&#41; is one of the main defence mechanisms in situations of renal overload of Mb and Hb&#46; HO is the enzyme responsible for breaking down the haem group&#44; and thus releasing biliverdin&#44; Fe<span class="elsevierStyleSup">2&#43;</span> and carbon monoxide&#44;<a class="elsevierStyleCrossRef" href="#bib1125"><span class="elsevierStyleSup">71</span></a> which are powerful anti-inflammatory and antioxidant molecules that enhance the beneficial effects of HO&#46;<a class="elsevierStyleCrossRefs" href="#bib1130"><span class="elsevierStyleSup">72&#44;73</span></a> There are three isoforms of HO &#40;HO-1&#44; HO-2 and HO-3&#41; which differ in their tissue distribution&#44; regulation and function&#46; Unlike other isoforms&#44; the expression of HO-1 is induced in conditions of oxidative stress&#44; and is expressed in many tissues&#44; including the kidneys&#46;<a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">74</span></a> The renal expression of HO-1 is increased in experimental models of haemoglobinuria and rhabdomyolysis&#44; as well as in patients with intravascular haemolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib1100"><span class="elsevierStyleSup">66&#44;75&#44;76</span></a> The deficiency of this enzyme in patients with intravascular haemolysis increases tubular and glomerular damage&#46;<a class="elsevierStyleCrossRef" href="#bib1155"><span class="elsevierStyleSup">77</span></a> Similarly&#44; animals used in gene knockout studies for HO-1 have shown greater sensitivity to rhabdomyolysis&#44; higher levels of creatinine and higher mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib1160"><span class="elsevierStyleSup">78</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Transferrin</span><p id="par0095" class="elsevierStylePara elsevierViewall">Transferrin &#40;Tf&#41; is a glycoprotein that is mainly secreted by the liver&#44; and which binds to free iron to mitigate its adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">79</span></a> Depending on the iron concentration&#44; the tubule cells express the Tf receptor &#40;TfR1&#41;&#44; which plays an essential role in the metabolism of this molecule in the kidneys&#46;<a class="elsevierStyleCrossRef" href="#bib1170"><span class="elsevierStyleSup">80</span></a> Its expression is regulated by the iron-regulatory proteins 1 and 2&#44; which are highly expressed in the proximal tubules and which act as sensors of iron levels&#46;<a class="elsevierStyleCrossRefs" href="#bib1175"><span class="elsevierStyleSup">81&#8211;83</span></a> Under normal conditions&#44; approximately 30&#37; of the Tf iron-binding sites are saturated&#46; However&#44; these levels increase in the presence of iron accumulation disorders&#44;<a class="elsevierStyleCrossRef" href="#bib1190"><span class="elsevierStyleSup">84</span></a> such as severe haemochromatosis&#44; in which case Tf saturation exceeds 60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib1195"><span class="elsevierStyleSup">85&#44;86</span></a> In addition&#44; patients or experimental models of hypotransferrinaemia have low levels of Tf&#44; which promotes renal overload of iron&#46;<a class="elsevierStyleCrossRefs" href="#bib1205"><span class="elsevierStyleSup">87&#44;88</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Haemopexin</span><p id="par0100" class="elsevierStylePara elsevierViewall">Haemopexin &#40;Hx&#41; is a plasma protein that complexes to the haem group for its subsequent internalisation and hepatic clearance through its binding to the LDL receptor-related protein-1 &#40;LRP1&#41; receptor&#46;<a class="elsevierStyleCrossRefs" href="#bib1215"><span class="elsevierStyleSup">89&#8211;91</span></a> In haemolysis&#44; the Hb oxidises and releases the haem group into the bloodstream to later bind to the serum albumin&#44; which transfers the haem group to the Hx and releases the complex in the liver&#46; Once in hepatocytes&#44; the Hx&#8211;haem complex breaks down in lysosomes&#44; although a small amount of Hx is recycled and returned to the bloodstream&#46; Therefore&#44; in patients with haemolytic events&#44; the plasma concentrations of serum Hx are reduced<a class="elsevierStyleCrossRefs" href="#bib1230"><span class="elsevierStyleSup">92&#8211;95</span></a> as it builds up in the renal cortex and increases its levels in urine&#46;<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">96</span></a> Hx plays a protective role against the harmful effects of the haem group&#46;<a class="elsevierStyleCrossRefs" href="#bib0925"><span class="elsevierStyleSup">31&#44;32&#44;97</span></a> Rats used in gene knockout studies for Hx have a poor recovery of renal function after suffering an intravascular haemolysis event&#44; because they have a greater renal accumulation of iron and&#44; therefore&#44; higher oxidative stress levels&#46;<a class="elsevierStyleCrossRefs" href="#bib1260"><span class="elsevierStyleSup">98&#44;99</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ferritin</span><p id="par0105" class="elsevierStylePara elsevierViewall">Ferritin is a protein consisting of 24 subunits&#44; forming a hollow spherical structure&#46;<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">100</span></a> Its primary function is to store iron&#44; so it has a protective capacity against the toxicity caused by iron and haemoproteins&#46; After the HO-1-catalysed reaction&#44; the iron is released from the haem group and is stored inside the ferritin&#46;<a class="elsevierStyleCrossRef" href="#bib1275"><span class="elsevierStyleSup">101</span></a> The expression of ferritin is regulated by the concentration of iron and the HO-1 activity&#46;<a class="elsevierStyleCrossRef" href="#bib1280"><span class="elsevierStyleSup">102</span></a> This protein plays a crucial role in diseases related to haemoproteins&#44; as ferritin-deficient rats show notable renal damage&#44;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">103</span></a> and it is a good serum marker for SCA&#46;<a class="elsevierStyleCrossRef" href="#bib1290"><span class="elsevierStyleSup">104</span></a> Plasma levels of Tf are also higher in ferritin-deficient rats that are subjected to rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">103</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Nrf2</span><p id="par0110" class="elsevierStylePara elsevierViewall">Nrf2 is a transcription factor that controls the expression of several antioxidant genes such as HO-1 and ferritin&#46;<a class="elsevierStyleCrossRefs" href="#bib1295"><span class="elsevierStyleSup">105&#44;106</span></a> Under normal conditions&#44; Nrf2 is found in the cytoplasm bound to its repressor Keap1&#44; which is susceptible to changes in the redox state and is subjected to proteolytic degradation through the proteasome&#46; In the presence of oxidative stress&#44; Nrf2 is released from Keap1 and translocates to the nucleus&#44; where it activates the expression of antioxidant genes&#46;<a class="elsevierStyleCrossRefs" href="#bib1305"><span class="elsevierStyleSup">107&#8211;112</span></a> The activation of Nrf2 has a positive effect against renal damage linked to the accumulation of haemoproteins in experimental models and patients with haemolytic anaemia&#46;<a class="elsevierStyleCrossRefs" href="#bib1335"><span class="elsevierStyleSup">113&#8211;115</span></a></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Indirect mechanisms</span><p id="par0115" class="elsevierStylePara elsevierViewall">This second group is composed of antioxidant molecules and various antioxidant enzymes&#46;</p><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Non-enzymatic mechanisms</span><p id="par0120" class="elsevierStylePara elsevierViewall">There are many molecules in the body that have an antioxidant action&#44; such as vitamins&#44; melatonin and bilirubin&#46; These molecules neutralise free radicals and are involved in the protection against renal damage caused by haemoproteins&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Vitamins are an important antioxidant group&#46; One such example is vitamin C&#44; which reacts with the superoxide anion and lipid peroxides&#44; thus reducing the oxidative stress induced by the <span class="elsevierStyleItalic">in vitro</span><a class="elsevierStyleCrossRef" href="#bib1350"><span class="elsevierStyleSup">116</span></a> and <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib1355"><span class="elsevierStyleSup">117</span></a> RBC lysis&#46; Similarly&#44; treatment with vitamin C was effective in a context of AKI caused by haemoglobinaemia in a patient with glucose-6-phosphate dehydrogenase deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib1360"><span class="elsevierStyleSup">118</span></a> The levels of vitamin C decrease after the development of rhabdomyolysis&#44; and its administration has partially reduced histological disorders and renal function in experimental models of rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib1365"><span class="elsevierStyleSup">119</span></a> Vitamin E is another important vitamin because it plays a significant role in maintaining the redox balance and the integrity of cell membranes&#44; acting on peroxyl and hydroperoxyl radicals&#46; The administration of vitamin E inhibited the RBC lysis of patients suffering from paroxysmal nocturnal haemoglobinuria&#44; which suggests that this vitamin is an effective treatment for these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib1370"><span class="elsevierStyleSup">120&#44;121</span></a> Vitamin E has not been as effective as vitamin C&#44; however&#44; in the treatment of rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib1380"><span class="elsevierStyleSup">122</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Melatonin is a hormone secreted by the pineal gland which has several antioxidant properties&#44; as it neutralises free radicals such as hydrogen peroxide&#44; the hydroxyl radical&#44; peroxynitrite and the superoxide anion&#46; This molecule also stimulates the expression of other antioxidant molecules&#44; such as superoxide dismutase&#44; glutathione peroxidase and glutathione reductase&#46; Several studies have shown that this hormone plays a protective role in models of AKI caused by rhabdomyolysis or intravascular haemolysis by reducing tubular necrosis and lipid peroxidation associated with these conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib1355"><span class="elsevierStyleSup">117&#44;123</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Glutathione&#44; in its reduced state &#40;GSH&#41;&#44; is a powerful cell antioxidant that can be oxidised to glutathione disulfide &#40;GSSG&#41; through several enzymatic reactions&#46; Several experimental models of myoglobinuria and haemoglobinuria&#44; as well as studies in patients with HUS and SCA&#44; show decreased levels of GSH in the kidneys&#46;<a class="elsevierStyleCrossRefs" href="#bib1355"><span class="elsevierStyleSup">117&#44;123&#8211;128</span></a> The depletion of GSH increases toxicity mediated by oxidative stress in these diseases&#44; because&#44; by restoring the GSH levels&#44; treatment with N-acetylcysteine reduces histological disorders and inhibits cell death associated with these conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib1415"><span class="elsevierStyleSup">129&#44;130</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Enzymatic mechanisms</span><p id="par0140" class="elsevierStylePara elsevierViewall">This group includes molecules with enzymatic activity that reduce the content of intracellular reactive oxygen species and&#44; therefore&#44; protect cells from oxidative damage&#46; Superoxide dismutase &#40;SOD&#41; is able to dismutate O<span class="elsevierStyleInf">2</span>&#8722; in O<span class="elsevierStyleInf">2</span> and H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#46; For the elimination of H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#44; there are other enzymes with peroxidase activity&#46; These include catalase&#44; glutathione peroxidase &#40;GPx&#41; and reduced thioredoxin &#40;Trx&#41;&#46; Catalase is an oxidoreductase that catalyses the decomposition reaction of H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> in O<span class="elsevierStyleInf">2</span> and water&#46; GPx catalyses the decomposition of H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> through the oxidation of GSH to GSSG and water&#46; The GPx&#44; catalase and SOD activity is reduced in experimental models of intravascular haemolysis<a class="elsevierStyleCrossRef" href="#bib1355"><span class="elsevierStyleSup">117</span></a> and rhabdomyolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib1395"><span class="elsevierStyleSup">125&#44;128&#44;131&#8211;134</span></a> Furthermore&#44; the plasma levels of GPx and SOD show a negative correlation with albuminuria in patients with SCA&#46;<a class="elsevierStyleCrossRef" href="#bib1445"><span class="elsevierStyleSup">135</span></a> Lastly&#44; Trx protects from renal damage associated with rhabdomyolysis through the reduction of oxidative stress and inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib1450"><span class="elsevierStyleSup">136</span></a></p></span></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Treatments</span><p id="par0145" class="elsevierStylePara elsevierViewall">There is currently no specific treatment for preventing the damage induced by ferroportins in their different forms of clinical presentation&#46; The alkalisation of urine may be beneficial by reducing the dissociation of the iron found in haemoproteins&#46; This alkalisation can be carried out with oral bicarbonate&#44; while monitoring the urine and serum pH levels&#46; However&#44; no clear benefits have been reliably proven&#46; The use of calcium channel blockers in experimental models has shown an increase in the urinary excretion of iron by mechanisms that remain unknown&#44; which results in a decrease in the renal accumulation of iron&#46;<a class="elsevierStyleCrossRef" href="#bib1455"><span class="elsevierStyleSup">137</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The use of iron-chelating agents in diseases associated with the accumulation of this molecule reduces oxidative damage<a class="elsevierStyleCrossRef" href="#bib1460"><span class="elsevierStyleSup">138</span></a> and also avoids iron deposition&#46;<a class="elsevierStyleCrossRef" href="#bib1465"><span class="elsevierStyleSup">139</span></a> Prophylactically administered deferoxamine reduces oxidative stress resulting from the presence of Hb&#46;<a class="elsevierStyleCrossRef" href="#bib1470"><span class="elsevierStyleSup">140</span></a> Iron-chelating agents reduce the toxicity produced by the massive deposition of iron in multitransfused patients&#44;<a class="elsevierStyleCrossRef" href="#bib1475"><span class="elsevierStyleSup">141</span></a> although recent studies question their nephroprotective capacity in haemoglobin-induced AKI&#46;<a class="elsevierStyleCrossRef" href="#bib1480"><span class="elsevierStyleSup">142</span></a> It should be noted that certain iron-chelating agents&#44; such as deferasirox<a class="elsevierStyleCrossRef" href="#bib1485"><span class="elsevierStyleSup">143</span></a> and deferoxamine&#44;<a class="elsevierStyleCrossRef" href="#bib1490"><span class="elsevierStyleSup">144</span></a> are potential nephrotoxic agents&#44; requiring strict monitoring during their use&#46;<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">145</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Prophylactic treatment with antioxidants such as N-acetylcysteine has yielded positive results in preventing tubular damage secondary to myoglobinuria or haemoglobinuria&#46;<a class="elsevierStyleCrossRef" href="#bib1500"><span class="elsevierStyleSup">146</span></a> Other antioxidants&#44; such as acetaminophen&#44; were also effective&#46;<a class="elsevierStyleCrossRefs" href="#bib0905"><span class="elsevierStyleSup">27&#44;147</span></a> The possible protective role of vitamin E<a class="elsevierStyleCrossRef" href="#bib1510"><span class="elsevierStyleSup">148</span></a> and vitamin C&#44;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">27</span></a> in addition to polyphenols&#44;<a class="elsevierStyleCrossRef" href="#bib1515"><span class="elsevierStyleSup">149</span></a> flavonoids<a class="elsevierStyleCrossRefs" href="#bib1410"><span class="elsevierStyleSup">128&#44;150&#8211;152</span></a> and <span class="elsevierStyleSmallCaps">l</span>-carnitine&#44;<a class="elsevierStyleCrossRef" href="#bib1535"><span class="elsevierStyleSup">153</span></a> has also been investigated&#44; yielding disparate results&#44; as mentioned earlier&#46; Recent studies have also addressed the use of stem cells and have produced positive results&#44; especially in models of rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib1540"><span class="elsevierStyleSup">154</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Clinical trials</span><p id="par0160" class="elsevierStylePara elsevierViewall">Ongoing clinical trials for the treatment of disorders caused by haemoproteins are focused on two aspects&#46; First&#44; treating the underlying disease to prevent the release of haemoproteins into the plasma&#44; and second&#44; mitigating the damage potentially caused by haemoproteins once they are released&#46; As such&#44; in diseases such as aHUS and paroxysmal nocturnal haemoglobinuria&#44; the majority of trials test drugs that act on the complement system&#44; mainly eculizumab&#44; or even new molecules that act in other ways&#46; These include&#58; CCX168 &#40;C5aR antagonist&#41;&#59; conversin &#40;protein that prevents action on its C5 convertase&#41;&#59; TT30 &#40;ALXN1102 and ALXN1103&#59; recombinant proteins containing Factor H domains 1&#8211;5 and which reduce the complement&#39;s convertase activity and activate Factor I&#41;&#59; LFG316 &#40;anti-C5 monoclonal antibody&#41;&#59; APL-2 &#40;C3 inhibitor&#41; and ALN-CC5 &#40;hepatic inhibitor of C5 synthesis&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In aHUS&#44; antibodies are also being developed that work against MASP-2&#44; known as OMS 723&#46; In SCA there are trials involving drugs such as SCD 101 and ICA-17043 &#40;which stop red blood cells from turning into falciform cells&#41;&#59; decitabine&#44; vorinostat and panobinostat &#40;to increase foetal haemoglobin&#41;&#59; and statins&#44; sodium nitrate and ambrisentan &#40;type A-selective endothelin receptor antagonist&#41; to improve endothelial dysfunction&#44; maintain good tissue perfusion during crises and avoid the rupture of red blood cells&#46; SCD 101 has also been used in beta thalassaemia&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">Once haemoproteins are released into the plasma&#44; the trials focus on two strategies&#46; The first strategy is to try to clear these molecules from the plasma&#46; This has been done in several trials in patients suffering from rhabdomyolysis who require renal replacement therapy&#44; in which the effects of continuous techniques&#44; high cut-off haemofilters and immunoabsorption techniques &#40;CytoSorb&#174;&#41; have been analysed in order to remove Mb from plasma as quickly as possible&#46; The second strategy is based on reducing their toxic effect&#46; To do this&#44; efforts are being made to prevent haemoglobinuria-induced oxidation in malaria using paracetamol&#44; and myoglobinuria-induced oxidation using N-acetylcysteine&#46; Trials are also under way that use iron-chelating agents &#40;deferasirox or a combination of exjade and desferal&#41; in thalassaemia to prevent iron deposition in target organs&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusion</span><p id="par0170" class="elsevierStylePara elsevierViewall">The accumulation of haemoproteins in the kidneys is nephrotoxic&#46; There is evidence showing the short-term adverse effects and the chronic loss of renal function&#46; Even though several adverse effects have been reported about these molecules&#44; we must continue to determine the pathogenic mechanisms of haemoproteins to identify new therapeutic targets and prevent their adverse effects&#46; In this sense&#44; podocytes may constitute new cellular targets of the harmful effects of haemoproteins&#46; From a therapeutic perspective&#44; the data currently available are primarily based on studies in animal models&#46; Therapeutic measures aimed at reducing myoglobinuria or haemoglobinuria will be hugely important to prevent renal damage caused by these molecules&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">This study was funded using grants from&#58; the Spanish Society of Nephrology &#40;Sociedad Espa&#241;ola de Nefrolog&#237;a&#41;&#44; the Spanish Health Research Fund &#40;Fondo de Investigaciones Sanitarias&#44; FIS&#41; &#40;ISCIII&#47;FEDER&#41; &#40;Miguel Servet Programme&#58; CP10&#47;00479 and CPII16&#47;00017&#59; PI13&#47;00802 and PI14&#47;00883&#41; and Fundaci&#243;n Renal &#205;&#241;igo &#193;lvarez de Toledo &#40;FRIAT&#41; &#40;grants given to JAM&#41;&#59; Fundaci&#243;n Conchita R&#225;bago &#40;grant given to MGH&#41;&#59; REDinREN &#40;RD012&#47;0021&#41;&#44; FIS PI13&#47;02502 and ICI14&#47;00350 &#40;grants given to MP&#41;&#59; and FIS&#47;FEDER PI14&#47;00386 and Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre &#40;Centro de Investigaci&#243;n Biom&#233;dica en Red de Diabetes y Enfermedades Metab&#243;licas asociadas&#44; CIBERDEM&#41; &#40;grants given to JE&#41;&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:16 [
        0 => array:3 [
          "identificador" => "xres985558"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec953213"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres985559"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec953212"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Origin of the renal accumulation of haemoproteins"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Myoglobinuria"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Haemoglobinuria"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Haemoproteins and acute kidney injury"
        ]
        7 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Haemoproteins and chronic kidney disease"
        ]
        8 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Pathophysiological mechanisms involved in haemoproteins induced renal damage"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Oxidative stress"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Inflammation"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Cell death"
            ]
            3 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Fibrosis"
            ]
          ]
        ]
        9 => array:3 [
          "identificador" => "sec0060"
          "titulo" => "Defence mechanisms against the renal toxicity of haemoproteins"
          "secciones" => array:2 [
            0 => array:3 [
              "identificador" => "sec0065"
              "titulo" => "Direct mechanisms"
              "secciones" => array:7 [
                0 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Haptoglobin"
                ]
                1 => array:2 [
                  "identificador" => "sec0075"
                  "titulo" => "CD163"
                ]
                2 => array:2 [
                  "identificador" => "sec0080"
                  "titulo" => "Haem oxygenase"
                ]
                3 => array:2 [
                  "identificador" => "sec0085"
                  "titulo" => "Transferrin"
                ]
                4 => array:2 [
                  "identificador" => "sec0090"
                  "titulo" => "Haemopexin"
                ]
                5 => array:2 [
                  "identificador" => "sec0095"
                  "titulo" => "Ferritin"
                ]
                6 => array:2 [
                  "identificador" => "sec0100"
                  "titulo" => "Nrf2"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "sec0105"
              "titulo" => "Indirect mechanisms"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0110"
                  "titulo" => "Non-enzymatic mechanisms"
                ]
                1 => array:2 [
                  "identificador" => "sec0115"
                  "titulo" => "Enzymatic mechanisms"
                ]
              ]
            ]
          ]
        ]
        10 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Treatments"
        ]
        11 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Clinical trials"
        ]
        12 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Conclusion"
        ]
        13 => array:2 [
          "identificador" => "sec0135"
          "titulo" => "Funding"
        ]
        14 => array:2 [
          "identificador" => "sec0140"
          "titulo" => "Conflicts of interest"
        ]
        15 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-12-07"
    "fechaAceptado" => "2017-05-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec953213"
          "palabras" => array:7 [
            0 => "Haemoglobin"
            1 => "Myoglobin"
            2 => "Haemoglobinuria"
            3 => "Rhabdomyolysis"
            4 => "Haematuria"
            5 => "Acute kidney failure"
            6 => "Chronic kidney disease"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec953212"
          "palabras" => array:7 [
            0 => "Hemoglobina"
            1 => "Mioglobina"
            2 => "Hemoglobinuria"
            3 => "Rabdomi&#243;lisis"
            4 => "Hematuria"
            5 => "Fracaso renal agudo"
            6 => "Enfermedad renal cr&#243;nica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body&#46; However&#44; because of their chemical structure&#44; these molecules can exert harmful effects when they are released massively into the bloodstream&#44; as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis&#46; Once in the plasma&#44; these haem proteins can be filtered and can accumulate in the kidney&#44; where they become cytotoxic&#44; particularly for the tubular epithelium&#44; inducing acute kidney failure and chronic kidney disease&#46; In this review&#44; we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins&#44; their relation to both acute and chronic loss of renal function&#44; the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions&#46; Finally&#44; we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets&#44; with particular emphasis on the numerous clinical trials that are currently ongoing&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La hemoglobina y la mioglobina son hemoprote&#237;nas que juegan un papel fundamental en el organismo ya que participan en el transporte de ox&#237;geno&#46; Sin embargo&#44; debido a su estructura qu&#237;mica&#44; estas mol&#233;culas pueden ejercer efectos delet&#233;reos cuando se liberan al torrente sangu&#237;neo de forma masiva&#44; como sucede en determinadas condiciones patol&#243;gicas asociadas a rabdomi&#243;lisis o hem&#243;lisis intravascular&#46; Una vez en el plasma&#44; estas hemoprote&#237;nas se pueden filtrar y acumular en el ri&#241;&#243;n&#44; donde resultan citot&#243;xicas&#44; principalmente para el epitelio tubular&#44; e inducen fracaso renal agudo y enfermedad renal cr&#243;nica&#46; En la presente revisi&#243;n analizaremos los distintos contextos patol&#243;gicos que provocan la acumulaci&#243;n renal de estas hemoprote&#237;nas&#44; su relaci&#243;n con la p&#233;rdida de funci&#243;n renal a corto y largo plazo&#44; los mecanismos fisiopat&#243;logicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones&#46; Por &#250;ltimo&#44; describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terap&#233;uticas basadas en la identificaci&#243;n de nuevas dianas celulares y moleculares&#44; prestando especial atenci&#243;n a los diversos ensayos cl&#237;nicos que se encuentran en marcha en la actualidad&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:3 [
        "etiqueta" => "&#9674;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Both authors share authorship as first authors&#46;</p>"
        "identificador" => "fn0005"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Guerrero-Hue M&#44; Rubio-Navarro A&#44; Sevillano A&#44; Yuste C&#44; Guti&#233;rrez E&#44; Palomino-Antol&#237;n A&#44; et al&#46; Efectos adversos de la acumulaci&#243;n renal de hemoprote&#237;nas&#46; Nuevas herramientas terap&#233;uticas&#46; Nefrologia&#46; 2018&#59;38&#58;13&#8211;26&#46;</p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2753
            "Ancho" => 1727
            "Tamanyo" => 295162
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main causes of haemoglobinuria and rhabdomyolysis&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1220
            "Ancho" => 3102
            "Tamanyo" => 260256
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of renal damage caused by haemoproteins&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1135
            "Ancho" => 1663
            "Tamanyo" => 119129
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Main defence mechanisms and adverse effects of the renal accumulation of haemoproteins&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mode of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Trial treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical trial number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="16" align="left" valign="top">Treatment of underlying disease</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">HUS</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Inhibition of complement</td><td class="td" title="table-entry  " align="left" valign="top">Eculizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0005" href="ctgov:NCT00838513">NCT00838513</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CCX168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0010" href="ctgov:NCT02464891">NCT02464891</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antibody against MASP-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">OMS 721&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0015" href="ctgov:NCT02222545">NCT02222545</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Paroxysmal nocturnal haemoglobinuria</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Inhibition of complement</td><td class="td" title="table-entry  " align="left" valign="top">Conversin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0020" href="ctgov:NCT02591862">NCT02591862</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0025" href="ctgov:NCT01335165">NCT01335165</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LFG316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0030" href="ctgov:NCT02534909">NCT02534909</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">APL2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0035" href="ctgov:NCT02588833">NCT02588833</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ALN-CC5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0040" href="ctgov:NCT02352493">NCT02352493</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="8" align="left" valign="top">Sickle-cell anaemia</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Covalent modifiers of haemoglobin</td><td class="td" title="table-entry  " align="left" valign="top">SCD-101&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0045" href="ctgov:NCT02380079">NCT02380079</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ICA-17043&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0050" href="ctgov:NCT00294541">NCT00294541</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Increase in foetal haemoglobin production</td><td class="td" title="table-entry  " align="left" valign="top">Decitabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0055" href="ctgov:NCT01375608">NCT01375608</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vorinostat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0060" href="ctgov:NCT01000155">NCT01000155</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Panobinostat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0065" href="ctgov:NCT01245179">NCT01245179</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Improvement of endothelium function</td><td class="td" title="table-entry  " align="left" valign="top">Simvastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0070" href="ctgov:NCT00508027">NCT00508027</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sodium nitrate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0075" href="ctgov:NCT00095472">NCT00095472</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ambrisentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0080" href="ctgov:NCT02712346">NCT02712346</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Prevention of damage caused by haemoproteins</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Rhabdomyolysis</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Elimination of myoglobin through renal replacement therapies</td><td class="td" title="table-entry  " align="left" valign="top">Continuous therapies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0085" href="ctgov:NCT00391911">NCT00391911</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High cut-off HicoRhabdo filters&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0090" href="ctgov:NCT01467180">NCT01467180</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunoabsorption &#40;CytoSorb&#174;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0095" href="ctgov:NCT02111018">NCT02111018</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decreased oxidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N-acetylcysteine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0100" href="ctgov:NCT00391911">NCT00391911</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Malaria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decreased oxidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Paracetamol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0105" href="ctgov:NCT01641289">NCT01641289</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Beta thalassaemia</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Iron-chelating agents</td><td class="td" title="table-entry  " align="left" valign="top">Deferasirox&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0110" href="ctgov:NCT00560820">NCT00560820</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Exjade-desferal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0115" href="ctgov:NCT00901199">NCT00901199</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1672053.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Clinical trials in diseases associated with the renal accumulation of haemoproteins&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:154 [
            0 => array:3 [
              "identificador" => "bib0775"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0125" href="http://www.ncbi.nlm.nih.gov/pubmed/18990801">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18990801</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structure of haemoglobin&#58; a three-dimensional Fourier synthesis at 5&#46;5-&#197; resolution&#44; obtained by X-ray analysis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0780"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0130" href="http://link.springer.com/10.1007/s10545-015-9827-7">http&#58;&#47;&#47;link&#46;springer&#46;com&#47;10&#46;1007&#47;s10545-015-9827-7</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute rhabdomyolysis and inflammation"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0785"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0135" href="http://link.springer.com/10.1007/s11739-007-0060-8">http&#58;&#47;&#47;link&#46;springer&#46;com&#47;10&#46;1007&#47;s11739-007-0060-8</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rhabdomyolysis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0790"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0140" href="http://www.karger.com/?doi=10.1159/000368528">http&#58;&#47;&#47;www&#46;karger&#46;com&#47;&#63;doi&#61;10&#46;1159&#47;000368528</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular mechanisms and novel therapeutic approaches to rhabdomyolysis-induced acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0795"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0145" href="http://cjasn.asnjournals.org/cgi/doi/10.2215/CJN.01970211">http&#58;&#47;&#47;cjasn&#46;asnjournals&#46;org&#47;cgi&#47;doi&#47;10&#46;2215&#47;CJN&#46;01970211</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "AKI associated with macroscopic glomerular hematuria&#58; clinical and pathophysiologic consequences"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0800"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0150" href="http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.13.1653">http&#58;&#47;&#47;jama&#46;jamanetwork&#46;com&#47;article&#46;aspx&#63;doi&#61;10&#46;1001&#47;jama&#46;293&#46;13&#46;1653</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0805"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0155" href="http://www.ncbi.nlm.nih.gov/pubmed/16267412">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;16267412</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rhabdomyolysis&#58; an evaluation of 475 hospitalized patients"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0810"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0160" href="http://www.ncbi.nlm.nih.gov/pubmed/11430535">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;11430535</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathogenesis and treatment of renal dysfunction in rhabdomyolysis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0815"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0165" href="http://www.ncbi.nlm.nih.gov/pubmed/26456110">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;26456110</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An update for atypical haemolytic uraemic syndrome&#58; diagnosis and treatment&#46; A consensus document"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0820"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0170" href="http://www.ncbi.nlm.nih.gov/pubmed/1445988">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;1445988</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure in patients with severe falciparum malaria"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0825"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0175" href="http://doi.wiley.com/10.1111/bjh.12690">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1111&#47;bjh&#46;12690</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0830"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0180" href="http://doi.wiley.com/10.1002/ajh.21757">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1002&#47;ajh&#46;21757</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0835"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0185" href="http://www.ncbi.nlm.nih.gov/pubmed/9621299">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9621299</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pathogenesis and treatment of hemolytic uremic syndrome"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0840"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0190" href="http://www.jasn.org/cgi/doi/10.1681/ASN.2006080894">http&#58;&#47;&#47;www&#46;jasn&#46;org&#47;cgi&#47;doi&#47;10&#46;1681&#47;ASN&#46;2006080894</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Physiology and pathophysiology of heme&#58; implications for kidney disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0845"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0195" href="http://www.ncbi.nlm.nih.gov/pubmed/7566565">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;7566565</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure in glomerular bleeding&#58; a puzzling phenomenon"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0850"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0200" href="http://www.liebertonline.com/doi/abs/10.1089/ars.2004.6.954">http&#58;&#47;&#47;www&#46;liebertonline&#46;com&#47;doi&#47;abs&#47;10&#46;1089&#47;ars&#46;2004&#46;6&#46;954</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The radical and redox chemistry of myoglobin and hemoglobin&#58; from in vitro studies to human pathology"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0855"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0205" href="http://www.ncbi.nlm.nih.gov/pubmed/12874476">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;12874476</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recent advances in the pathophysiology of ischemic acute renal failure"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0860"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0210" href="http://www.nature.com/doifinder/10.1038/nm799">http&#58;&#47;&#47;www&#46;nature&#46;com&#47;doifinder&#47;10&#46;1038&#47;nm799</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0865"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0215" href="http://www.bloodjournal.org/cgi/doi/10.1182/blood-2006-12-061697">http&#58;&#47;&#47;www&#46;bloodjournal&#46;org&#47;cgi&#47;doi&#47;10&#46;1182&#47;blood-2006-12-061697</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Platelet activation in patients with sickle disease&#44; hemolysis-associated pulmonary hypertension&#44; and nitric oxide scavenging by cell-free hemoglobin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0870"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0220" href="http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.110.008698">http&#58;&#47;&#47;circ&#46;ahajournals&#46;org&#47;cgi&#47;doi&#47;10&#46;1161&#47;CIRCULATIONAHA&#46;110&#46;008698</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0875"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0225" href="http://linkinghub.elsevier.com/retrieve/pii/S0272638614011901">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0272638614011901</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intratubular hemoglobin casts in hemolysis-associated acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0880"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0230" href="http://www.ncbi.nlm.nih.gov/pubmed/8821813">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;8821813</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rhabdomyolysis and myohemoglobinuric acute renal failure"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0885"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0235" href="http://www.ncbi.nlm.nih.gov/pubmed/14518093">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;14518093</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#91;Rhabdomyolysis &#8211; development&#44; causes&#44; sequelae and therapy&#93; &#91;article in Czech&#93;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0890"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0240" href="http://www.liebertonline.com/doi/abs/10.1089/ars.2005.7.1755">http&#58;&#47;&#47;www&#46;liebertonline&#46;com&#47;doi&#47;abs&#47;10&#46;1089&#47;ars&#46;2005&#46;7&#46;1755</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Redox biology of blood revisited&#58; the role of red blood cells in maintaining circulatory reductive capacity"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0895"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0245" href="http://pubs.acs.org/doi/abs/10.1021/jf011394w">http&#58;&#47;&#47;pubs&#46;acs&#46;org&#47;doi&#47;abs&#47;10&#46;1021&#47;jf011394w</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myoglobin-induced lipid oxidation&#46; A review"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0900"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0250" href="http://www.ncbi.nlm.nih.gov/pubmed/2423372">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;2423372</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0905"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0255" href="http://www.ncbi.nlm.nih.gov/pubmed/21034813">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;21034813</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0910"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0260" href="http://www.jbc.org/cgi/doi/10.1074/jbc.M609955200">http&#58;&#47;&#47;www&#46;jbc&#46;org&#47;cgi&#47;doi&#47;10&#46;1074&#47;jbc&#46;M609955200</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structural basis of peroxide-mediated changes in human hemoglobin&#58; a novel oxidative pathway"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0915"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0265" href="http://linkinghub.elsevier.com/retrieve/pii/S1471491410001097">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S1471491410001097</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemoglobin-based oxygen carriers&#58; from mechanisms of toxicity and clearance to rational drug design"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0920"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0270" href="http://www.ncbi.nlm.nih.gov/pubmed/9822635">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9822635</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0925"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0275" href="http://www.ncbi.nlm.nih.gov/pubmed/24277079">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;24277079</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0930"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0280" href="http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103623">http&#58;&#47;&#47;www&#46;jimmunol&#46;org&#47;cgi&#47;doi&#47;10&#46;4049&#47;jimmunol&#46;1103623</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0935"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0285" href="http://www.ncbi.nlm.nih.gov/pubmed/18650913">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18650913</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Origin and physiological roles of inflammation"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0940"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0290" href="http://www.nature.com/articles/srep10901">http&#58;&#47;&#47;www&#46;nature&#46;com&#47;articles&#47;srep10901</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of NLRP3 inflammasomes for rhabdomyolysis-induced acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0945"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0295" href="http://www.thno.org/v06p0896.htm">http&#58;&#47;&#47;www&#46;thno&#46;org&#47;v06p0896&#46;htm</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CD163-macrophages are involved in rhabdomyolysis-induced kidney injury and may be detected by MRI with targeted gold-coated iron oxide nanoparticles"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0950"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0300" href="http://www.jasn.org/cgi/doi/10.1681/ASN.2014040320">http&#58;&#47;&#47;www&#46;jasn&#46;org&#47;cgi&#47;doi&#47;10&#46;1681&#47;ASN&#46;2014040320</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0955"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0305" href="http://www.ncbi.nlm.nih.gov/pubmed/21771756">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;21771756</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0960"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0310" href="http://www.karger.com/doi/10.1159/000342385">http&#58;&#47;&#47;www&#46;karger&#46;com&#47;doi&#47;10&#46;1159&#47;000342385</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oxidative stress macrophage infiltration and CD163 expression are determinants of long-term renal outcome in macrohematuria-induced acute kidney injury of IgA nephropathy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0965"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0315" href="http://www.dustri.com/article_response_page.html?artId=10009%26doi=10.5414/CN107520%26L=0">http&#58;&#47;&#47;www&#46;dustri&#46;com&#47;article&#95;response&#95;page&#46;html&#63;artId&#61;10009&#38;doi&#61;10&#46;5414&#47;CN107520&#38;L&#61;0</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular mediators of favism-induced acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0970"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0320" href="http://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0217-z">http&#58;&#47;&#47;bmcnephrol&#46;biomedcentral&#46;com&#47;articles&#47;10&#46;1186&#47;s12882-015-0217-z</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute kidney injury induced by thrombotic microangiopathy in a patient with hemophagocytic lymphohistiocytosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0975"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0325" href="http://linkinghub.elsevier.com/retrieve/pii/S0085253815522709">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0085253815522709</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure in a patient with paroxysmal nocturnal hemoglobinuria"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0980"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0330" href="http://www.karger.com/?doi=10.1159/000351345">http&#58;&#47;&#47;www&#46;karger&#46;com&#63;doi&#61;10&#46;1159&#47;000351345</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renal involvement in paroxysmal nocturnal hemoglobinuria"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0985"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0335" href="http://www.ncbi.nlm.nih.gov/pubmed/1635582">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;1635582</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rhabdomyolysis with acute tubular necrosis &#8211; a nonglomerular cause of dysmorphic hematuria"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0990"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0340" href="http://www.jci.org/articles/view/59770">http&#58;&#47;&#47;www&#46;jci&#46;org&#47;articles&#47;view&#47;59770</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0995"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0345" href="http://ajprenal.physiology.org/cgi/doi/10.1152/ajprenal.00300.2003">http&#58;&#47;&#47;ajprenal&#46;physiology&#46;org&#47;cgi&#47;doi&#47;10&#46;1152&#47;ajprenal&#46;00300&#46;2003</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heme&#58; a determinant of life and death in renal tubular epithelial cells"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib1000"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0350" href="http://www.jasn.org/cgi/doi/10.1681/ASN.2013030281">http&#58;&#47;&#47;www&#46;jasn&#46;org&#47;cgi&#47;doi&#47;10&#46;1681&#47;ASN&#46;2013030281</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib1005"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0355" href="http://ndt.oxfordjournals.org/cgi/doi/10.1093/ndt/gfp659">http&#58;&#47;&#47;ndt&#46;oxfordjournals&#46;org&#47;cgi&#47;doi&#47;10&#46;1093&#47;ndt&#47;gfp659</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib1010"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0360" href="http://www.nature.com/doifinder/10.1038/cddis.2015.392">http&#58;&#47;&#47;www&#46;nature&#46;com&#47;doifinder&#47;10&#46;1038&#47;cddis&#46;2015&#46;392</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [ …4]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib1015"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0365" href="http://pubs.acs.org/doi/abs/10.1021/ja411006a">http&#58;&#47;&#47;pubs&#46;acs&#46;org&#47;doi&#47;abs&#47;10&#46;1021&#47;ja411006a</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib1020"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0370" href="http://ajprenal.physiology.org/cgi/doi/10.1152/ajprenal.00035.2011">http&#58;&#47;&#47;ajprenal&#46;physiology&#46;org&#47;cgi&#47;doi&#47;10&#46;1152&#47;ajprenal&#46;00035&#46;2011</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Persistent disruption of mitochondrial homeostasis after acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib1025"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0375" href="http://ajpheart.physiology.org/cgi/doi/10.1152/ajpheart.00584.2011">http&#58;&#47;&#47;ajpheart&#46;physiology&#46;org&#47;cgi&#47;doi&#47;10&#46;1152&#47;ajpheart&#46;00584&#46;2011</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation&#58; the protective role of autophagy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib1030"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0380" href="http://linkinghub.elsevier.com/retrieve/pii/S1875957215001229">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S1875957215001229</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Urinary transforming growth factor &#946;-1 as a marker of renal dysfunction in sickle cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib1035"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0385" href="http://www.ncbi.nlm.nih.gov/pubmed/10844611">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;10844611</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renal response to repetitive exposure to heme proteins&#58; chronic injury induced by an acute insult"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib1040"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0390" href="http://www.ncbi.nlm.nih.gov/pubmed/7853792">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;7853792</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The transgenic SAD mouse&#58; a model of human sickle cell glomerulopathy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib1045"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0395" href="http://www.ncbi.nlm.nih.gov/pubmed/8971879">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;8971879</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Development of focal segmental sclerosis and hyalinosis in hemolytic uremic syndrome"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib1050"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0400" href="http://www.ncbi.nlm.nih.gov/pubmed/25599621">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25599621</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Podocyte dysfunction in atypical haemolytic uraemic syndrome"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib1055"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0405" href="http://www.ncbi.nlm.nih.gov/pubmed/25393378">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25393378</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib1060"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0410" href="http://www.ncbi.nlm.nih.gov/pubmed/9708603">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9708603</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early glomerular dysfunction in patients with sickle cell anemia"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib1065"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0415" href="http://www.ncbi.nlm.nih.gov/pubmed/9731043">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9731043</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased susceptibility in Hp knockout mice during acute hemolysis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib1070"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0420" href="http://www.ncbi.nlm.nih.gov/pubmed/23418677">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;23418677</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human Hp 1-1 and Hp 2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib1075"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0425" href="http://www.ncbi.nlm.nih.gov/pubmed/2980525">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;2980525</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of a 99Tcm bound brain scanning agent for single photon emission computed tomography"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib1080"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0430" href="http://www.ncbi.nlm.nih.gov/pubmed/3756181">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;3756181</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human haptoglobin binds to human myoglobin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib1085"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0435" href="http://www.ncbi.nlm.nih.gov/pubmed/11196644">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;11196644</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of the haemoglobin scavenger receptor"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib1090"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0440" href="http://www.ncbi.nlm.nih.gov/pubmed/5687939">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;5687939</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasma concentrations of hemopexin&#44; haptoglobin and heme in patients with various hemolytic diseases"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib1095"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0445" href="http://www.ncbi.nlm.nih.gov/pubmed/19659436">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;19659436</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemoglobin and heme scavenger receptors"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib1100"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0450" href="http://linkinghub.elsevier.com/retrieve/pii/S1079979614001569">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S1079979614001569</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib1105"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0455" href="http://www.ncbi.nlm.nih.gov/pubmed/19620788">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;19620788</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib1110"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0460" href="http://www.ncbi.nlm.nih.gov/pubmed/25582460">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25582460</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib1115"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0465" href="http://www.ncbi.nlm.nih.gov/pubmed/16189277">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;16189277</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib1120"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0470" href="http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage%26an=00041433-201210000-00008">http&#58;&#47;&#47;content&#46;wkhealth&#46;com&#47;linkback&#47;openurl&#63;sid&#61;WKPTLP&#58;landingpage&#38;an&#61;00041433-201210000-00008</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib1125"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0475" href="http://www.ncbi.nlm.nih.gov/pubmed/3715920">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;3715920</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of sorbic acid and sorbic acid-nitrite in vivo on bone marrow chromosomes of mice"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib1130"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0480" href="http://journal.frontiersin.org/article/10.3389/fphar.2012.00030/Abstract">http&#58;&#47;&#47;journal&#46;frontiersin&#46;org&#47;article&#47;10&#46;3389&#47;fphar&#46;2012&#46;00030&#47;Abstract</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Direct antioxidant properties of bilirubin and biliverdin is there a role for biliverdin reductase&#63;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [ …3]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib1135"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0485" href="http://ajpheart.physiology.org/cgi/doi/10.1152/ajpheart.00327.2009">http&#58;&#47;&#47;ajpheart&#46;physiology&#46;org&#47;cgi&#47;doi&#47;10&#46;1152&#47;ajpheart&#46;00327&#46;2009</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib1140"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0490" href="http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage%26an=00041552-201401000-00004">http&#58;&#47;&#47;content&#46;wkhealth&#46;com&#47;linkback&#47;openurl&#63;sid&#61;WKPTLP&#58;landingpage&#38;an&#61;00041552-201401000-00004</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heme oxygenase-1 and acute kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib1145"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0495" href="http://www.ncbi.nlm.nih.gov/pubmed/27329933">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;27329933</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of myoglobin degradation in nephrotoxicity after rhabdomyolysis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib1150"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0500" href="https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv147">https&#58;&#47;&#47;academic&#46;oup&#46;com&#47;hmg&#47;article-lookup&#47;doi&#47;10&#46;1093&#47;hmg&#47;ddv147</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib1155"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0505" href="http://www.ncbi.nlm.nih.gov/pubmed/10793020">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;10793020</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib1160"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0510" href="http://linkinghub.elsevier.com/retrieve/pii/S0002944010650249">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0002944010650249</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib1165"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0515" href="http://www.ncbi.nlm.nih.gov/pubmed/9444770">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9444770</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transferrin&#44; the transferrin receptor&#44; and the uptake of iron by cells"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib1170"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0520" href="http://www.ncbi.nlm.nih.gov/pubmed/15345587">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15345587</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib1175"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0525" href="http://www.ncbi.nlm.nih.gov/pubmed/9484220">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;9484220</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron regulatory element and internal loop&#47;bulge structure for ferritin mRNA studied by cobalt&#40;III&#41; hexammine binding&#44; molecular modeling&#44; and NMR spectroscopy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib1180"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0530" href="http://linkinghub.elsevier.com/retrieve/pii/S0022283697913772">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0022283697913772</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structure and dynamics of the iron responsive element RNA&#58; implications for binding of the RNA by iron regulatory binding proteins"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib1185"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0535" href="http://emboj.embopress.org/cgi/doi/10.1038/sj.emboj.7600041">http&#58;&#47;&#47;emboj&#46;embopress&#46;org&#47;cgi&#47;doi&#47;10&#46;1038&#47;sj&#46;emboj&#46;7600041</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib1190"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0540" href="http://www.ncbi.nlm.nih.gov/pubmed/20603012">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;20603012</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Two to tango&#58; regulation of mammalian iron metabolism"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib1195"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0545" href="http://www.ncbi.nlm.nih.gov/pubmed/3733737">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;3733737</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of non-transferrin-bound iron clearance by rat liver"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib1200"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0550" href="http://linkinghub.elsevier.com/retrieve/pii/S0304416511002674">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0304416511002674</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of iron transport and the role of transferrin"
                       …1
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib1205"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0555" href="http://www.ncbi.nlm.nih.gov/pubmed/10910930">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;10910930</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib1210"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0560" href="http://www.ncbi.nlm.nih.gov/pubmed/22294463">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;22294463</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            88 => array:3 [
              "identificador" => "bib1215"
              "etiqueta" => "89"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0565" href="http://www.ncbi.nlm.nih.gov/pubmed/12690199">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;12690199</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            89 => array:3 [
              "identificador" => "bib1220"
              "etiqueta" => "90"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0570" href="http://www.ncbi.nlm.nih.gov/pubmed/15947085">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15947085</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            90 => array:3 [
              "identificador" => "bib1225"
              "etiqueta" => "91"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0575" href="http://www.ncbi.nlm.nih.gov/pubmed/16102056">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;16102056</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            91 => array:3 [
              "identificador" => "bib1230"
              "etiqueta" => "92"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0580" href="http://www.ncbi.nlm.nih.gov/pubmed/4921465">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;4921465</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            92 => array:3 [
              "identificador" => "bib1235"
              "etiqueta" => "93"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0585" href="http://www.ncbi.nlm.nih.gov/pubmed/25389409">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25389409</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            93 => array:3 [
              "identificador" => "bib1240"
              "etiqueta" => "94"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0590" href="http://www.ncbi.nlm.nih.gov/pubmed/666618">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;666618</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            94 => array:3 [
              "identificador" => "bib1245"
              "etiqueta" => "95"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0595" href="http://www.ncbi.nlm.nih.gov/pubmed/188189">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;188189</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            95 => array:3 [
              "identificador" => "bib1250"
              "etiqueta" => "96"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0600" href="http://www.ncbi.nlm.nih.gov/pubmed/22993068">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;22993068</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            96 => array:3 [
              "identificador" => "bib1255"
              "etiqueta" => "97"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0605" href="http://www.ncbi.nlm.nih.gov/pubmed/23446829">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;23446829</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            97 => array:3 [
              "identificador" => "bib1260"
              "etiqueta" => "98"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0610" href="http://www.ncbi.nlm.nih.gov/pubmed/10572107">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;10572107</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            98 => array:3 [
              "identificador" => "bib1265"
              "etiqueta" => "99"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0615" href="http://www.ncbi.nlm.nih.gov/pubmed/18556779">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18556779</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            99 => array:3 [
              "identificador" => "bib1270"
              "etiqueta" => "100"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0620" href="http://www.ncbi.nlm.nih.gov/pubmed/26518749">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;26518749</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            100 => array:3 [
              "identificador" => "bib1275"
              "etiqueta" => "101"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0625" href="http://www.ncbi.nlm.nih.gov/pubmed/25874599">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25874599</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            101 => array:3 [
              "identificador" => "bib1280"
              "etiqueta" => "102"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0630" href="http://www.ncbi.nlm.nih.gov/pubmed/18805612">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18805612</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            102 => array:3 [
              "identificador" => "bib1285"
              "etiqueta" => "103"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0635" href="http://www.ncbi.nlm.nih.gov/pubmed/24018561">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;24018561</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            103 => array:3 [
              "identificador" => "bib1290"
              "etiqueta" => "104"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0640" href="http://www.ncbi.nlm.nih.gov/pubmed/24319218">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;24319218</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            104 => array:3 [
              "identificador" => "bib1295"
              "etiqueta" => "105"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0645" href="http://www.ncbi.nlm.nih.gov/pubmed/8962164">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;8962164</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            105 => array:3 [
              "identificador" => "bib1300"
              "etiqueta" => "106"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0650" href="http://www.ncbi.nlm.nih.gov/pubmed/15110384">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15110384</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            106 => array:3 [
              "identificador" => "bib1305"
              "etiqueta" => "107"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0655" href="http://www.ncbi.nlm.nih.gov/pubmed/12446695">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;12446695</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            107 => array:3 [
              "identificador" => "bib1310"
              "etiqueta" => "108"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0660" href="http://www.ncbi.nlm.nih.gov/pubmed/12441344">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;12441344</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            108 => array:3 [
              "identificador" => "bib1315"
              "etiqueta" => "109"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0665" href="http://www.ncbi.nlm.nih.gov/pubmed/15581590">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15581590</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            109 => array:3 [
              "identificador" => "bib1320"
              "etiqueta" => "110"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0670" href="http://www.ncbi.nlm.nih.gov/pubmed/14764898">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;14764898</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            110 => array:3 [
              "identificador" => "bib1325"
              "etiqueta" => "111"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0675" href="http://www.ncbi.nlm.nih.gov/pubmed/14612418">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;14612418</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            111 => array:3 [
              "identificador" => "bib1330"
              "etiqueta" => "112"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0680" href="http://www.ncbi.nlm.nih.gov/pubmed/14585973">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;14585973</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            112 => array:3 [
              "identificador" => "bib1335"
              "etiqueta" => "113"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "e0152895&#46; Available in&#58; <span class="elsevierStyleInterRef" id="intr0685" href="http://www.ncbi.nlm.nih.gov/pubmed/27071063">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;27071063</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            113 => array:3 [
              "identificador" => "bib1340"
              "etiqueta" => "114"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0690" href="http://www.ncbi.nlm.nih.gov/pubmed/26371321">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;26371321</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            114 => array:3 [
              "identificador" => "bib1345"
              "etiqueta" => "115"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0695" href="http://www.ncbi.nlm.nih.gov/pubmed/26914345">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;26914345</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            115 => array:3 [
              "identificador" => "bib1350"
              "etiqueta" => "116"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0700" href="http://doi.wiley.com/10.1002/cbf.1255">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1002&#47;cbf&#46;1255</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            116 => array:3 [
              "identificador" => "bib1355"
              "etiqueta" => "117"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0705" href="http://www.degruyter.com/view/j/jcim.2017.14.issue-1/jcim-2015-0082/jcim-2015-0082.xml">http&#58;&#47;&#47;www&#46;degruyter&#46;com&#47;view&#47;j&#47;jcim&#46;2017&#46;14&#46;issue-1&#47;jcim-2015-0082&#47;jcim-2015-0082&#46;xml</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            117 => array:3 [
              "identificador" => "bib1360"
              "etiqueta" => "118"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0710" href="http://www.ajhp.org/cgi/doi/10.2146/ajhp150591">http&#58;&#47;&#47;www&#46;ajhp&#46;org&#47;cgi&#47;doi&#47;10&#46;2146&#47;ajhp150591</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            118 => array:3 [
              "identificador" => "bib1365"
              "etiqueta" => "119"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0715" href="http://www.tandfonline.com/doi/full/10.1080/08860220802212965">http&#58;&#47;&#47;www&#46;tandfonline&#46;com&#47;doi&#47;full&#47;10&#46;1080&#47;08860220802212965</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            119 => array:3 [
              "identificador" => "bib1370"
              "etiqueta" => "120"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0720" href="http://linkinghub.elsevier.com/retrieve/pii/S0301472X07006935">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0301472X07006935</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            120 => array:3 [
              "identificador" => "bib1375"
              "etiqueta" => "121"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0725" href="http://www.ncbi.nlm.nih.gov/pubmed/1145115">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;1145115</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            121 => array:3 [
              "identificador" => "bib1380"
              "etiqueta" => "122"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0730" href="http://www.tandfonline.com/doi/full/10.3109/10715762.2011.590137">http&#58;&#47;&#47;www&#46;tandfonline&#46;com&#47;doi&#47;full&#47;10&#46;3109&#47;10715762&#46;2011&#46;590137</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            122 => array:3 [
              "identificador" => "bib1385"
              "etiqueta" => "123"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0735" href="http://www.ncbi.nlm.nih.gov/pubmed/12472196">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;12472196</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            123 => array:3 [
              "identificador" => "bib1390"
              "etiqueta" => "124"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0740" href="http://www.ncbi.nlm.nih.gov/pubmed/1946409">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;1946409</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            124 => array:3 [
              "identificador" => "bib1395"
              "etiqueta" => "125"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0745" href="http://www.tandfonline.com/doi/full/10.3109/0886022X.2013.835223">http&#58;&#47;&#47;www&#46;tandfonline&#46;com&#47;doi&#47;full&#47;10&#46;3109&#47;0886022X&#46;2013&#46;835223</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            125 => array:3 [
              "identificador" => "bib1400"
              "etiqueta" => "126"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0750" href="http://doi.wiley.com/10.1111/cei.12124">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1111&#47;cei&#46;12124</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            126 => array:3 [
              "identificador" => "bib1405"
              "etiqueta" => "127"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0755" href="http://ajpregu.physiology.org/cgi/doi/10.1152/ajpregu.00611.2009">http&#58;&#47;&#47;ajpregu&#46;physiology&#46;org&#47;cgi&#47;doi&#47;10&#46;1152&#47;ajpregu&#46;00611&#46;2009</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            127 => array:3 [
              "identificador" => "bib1410"
              "etiqueta" => "128"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0760" href="http://linkinghub.elsevier.com/retrieve/pii/S0300483X04002628">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0300483X04002628</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            128 => array:3 [
              "identificador" => "bib1415"
              "etiqueta" => "129"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0765" href="http://www.ncbi.nlm.nih.gov/pubmed/15600251">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15600251</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            129 => array:3 [
              "identificador" => "bib1420"
              "etiqueta" => "130"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0770" href="https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfp659">https&#58;&#47;&#47;academic&#46;oup&#46;com&#47;ndt&#47;article-lookup&#47;doi&#47;10&#46;1093&#47;ndt&#47;gfp659</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            130 => array:3 [
              "identificador" => "bib1425"
              "etiqueta" => "131"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0775" href="http://doi.wiley.com/10.1111/j.%201440-1681.2004.04050.x">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1111&#47;j&#46; 1440-1681&#46;2004&#46;04050&#46;x</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            131 => array:3 [
              "identificador" => "bib1430"
              "etiqueta" => "132"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0780" href="http://ajprenal.physiology.org/lookup/doi/10.1152/ajprenal.00546.2016">http&#58;&#47;&#47;ajprenal&#46;physiology&#46;org&#47;lookup&#47;doi&#47;10&#46;1152&#47;ajprenal&#46;00546&#46;2016</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            132 => array:3 [
              "identificador" => "bib1435"
              "etiqueta" => "133"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0785" href="http://linkinghub.elsevier.com/retrieve/pii/S0940299310000242">http&#58;&#47;&#47;linkinghub&#46;elsevier&#46;com&#47;retrieve&#47;pii&#47;S0940299310000242</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            133 => array:3 [
              "identificador" => "bib1440"
              "etiqueta" => "134"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0790" href="http://doi.wiley.com/10.1002/jat.1449">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1002&#47;jat&#46;1449</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            134 => array:3 [
              "identificador" => "bib1445"
              "etiqueta" => "135"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0795" href="http://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-016-0398-0">http&#58;&#47;&#47;bmcnephrol&#46;biomedcentral&#46;com&#47;articles&#47;10&#46;1186&#47;s12882-016-0398-0</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            135 => array:3 [
              "identificador" => "bib1450"
              "etiqueta" => "136"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0800" href="http://www.nature.com/articles/srep14471">http&#58;&#47;&#47;www&#46;nature&#46;com&#47;articles&#47;srep14471</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            136 => array:3 [
              "identificador" => "bib1455"
              "etiqueta" => "137"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0805" href="http://www.ncbi.nlm.nih.gov/pubmed/17293870">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;17293870</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            137 => array:3 [
              "identificador" => "bib1460"
              "etiqueta" => "138"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0810" href="http://www.ncbi.nlm.nih.gov/pubmed/18067870">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18067870</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            138 => array:3 [
              "identificador" => "bib1465"
              "etiqueta" => "139"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0815" href="http://www.ncbi.nlm.nih.gov/pubmed/27626608">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;27626608</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            139 => array:3 [
              "identificador" => "bib1470"
              "etiqueta" => "140"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0820" href="http://www.ncbi.nlm.nih.gov/pubmed/18215735">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;18215735</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            140 => array:3 [
              "identificador" => "bib1475"
              "etiqueta" => "141"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0825" href="http://www.ncbi.nlm.nih.gov/pubmed/24726864">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;24726864</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            141 => array:3 [
              "identificador" => "bib1480"
              "etiqueta" => "142"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0830" href="http://www.ncbi.nlm.nih.gov/pubmed/15987753">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15987753</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            142 => array:3 [
              "identificador" => "bib1485"
              "etiqueta" => "143"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0835" href="http://www.ncbi.nlm.nih.gov/pubmed/21439361">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;21439361</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            143 => array:3 [
              "identificador" => "bib1490"
              "etiqueta" => "144"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0840" href="http://www.ncbi.nlm.nih.gov/pubmed/21320071">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;21320071</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            144 => array:3 [
              "identificador" => "bib1495"
              "etiqueta" => "145"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0845" href="http://www.ncbi.nlm.nih.gov/pubmed/25402221">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;25402221</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            145 => array:3 [
              "identificador" => "bib1500"
              "etiqueta" => "146"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0850" href="http://www.ncbi.nlm.nih.gov/pubmed/23576637">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;23576637</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            146 => array:3 [
              "identificador" => "bib1505"
              "etiqueta" => "147"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0855" href="http://www.ncbi.nlm.nih.gov/pubmed/20133658">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;20133658</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            147 => array:3 [
              "identificador" => "bib1510"
              "etiqueta" => "148"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0860" href="http://www.ncbi.nlm.nih.gov/pubmed/15774072">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;15774072</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            148 => array:3 [
              "identificador" => "bib1515"
              "etiqueta" => "149"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0865" href="http://www.ncbi.nlm.nih.gov/pubmed/22343418">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;22343418</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            149 => array:3 [
              "identificador" => "bib1520"
              "etiqueta" => "150"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0870" href="https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfh369">https&#58;&#47;&#47;academic&#46;oup&#46;com&#47;ndt&#47;article-lookup&#47;doi&#47;10&#46;1093&#47;ndt&#47;gfh369</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            150 => array:3 [
              "identificador" => "bib1525"
              "etiqueta" => "151"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0875" href="http://www.karger.com/?doi=10.1159/000081074">http&#58;&#47;&#47;www&#46;karger&#46;com&#47;&#63;doi&#61;10&#46;1159&#47;000081074</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            151 => array:3 [
              "identificador" => "bib1530"
              "etiqueta" => "152"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0880" href="http://www.ncbi.nlm.nih.gov/pubmed/10586425">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;10586425</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            152 => array:3 [
              "identificador" => "bib1535"
              "etiqueta" => "153"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0885" href="http://doi.wiley.com/10.1111/j.%201440-1681.2006.04336.x">http&#58;&#47;&#47;doi&#46;wiley&#46;com&#47;10&#46;1111&#47;j&#46; 1440-1681&#46;2006&#46;04336&#46;x</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
            153 => array:3 [
              "identificador" => "bib1540"
              "etiqueta" => "154"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "Available in&#58; <span class="elsevierStyleInterRef" id="intr0890" href="http://www.ncbi.nlm.nih.gov/pubmed/19389847">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;19389847</span>"
                  "contribucion" => array:1 [
                    0 => array:2 [ …2]
                  ]
                  "host" => array:1 [
                    0 => array:1 [ …1]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/20132514/0000003800000001/v1_201802180616/S2013251418300051/v1_201802180616/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "35443"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Reviews"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003800000001/v1_201802180616/S2013251418300051/v1_201802180616/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251418300051?idApp=UINPBA000064"
]

Article information

ISSN: 20132514
Original language: English

DOI:10.1016/j.nefroe.2018.01.003

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	160	98	258
2024 September	233	59	292
2024 August	140	90	230
2024 July	132	32	164
2024 June	160	73	233
2024 May	161	53	214
2024 April	159	98	257
2024 March	130	45	175
2024 February	115	93	208
2024 January	114	35	149
2023 December	118	34	152
2023 November	180	57	237
2023 October	204	40	244
2023 September	134	53	187
2023 August	104	44	148
2023 July	147	58	205
2023 June	122	41	163
2023 May	172	201	373
2023 April	150	52	202
2023 March	157	35	192
2023 February	142	35	177
2023 January	116	49	165
2022 December	135	56	191
2022 November	153	81	234
2022 October	126	123	249
2022 September	134	43	177
2022 August	134	88	222
2022 July	128	99	227
2022 June	119	81	200
2022 May	179	80	259
2022 April	137	85	222
2022 March	179	83	262
2022 February	177	75	252
2022 January	162	67	229
2021 December	160	80	240
2021 November	192	62	254
2021 October	162	55	217
2021 September	137	49	186
2021 August	178	85	263
2021 July	222	80	302
2021 June	116	48	164
2021 May	179	71	250
2021 April	421	191	612
2021 March	253	60	313
2021 February	156	66	222
2021 January	117	41	158
2020 December	131	28	159
2020 November	128	48	176
2020 October	121	33	154
2020 September	172	34	206
2020 August	79	30	109
2020 July	99	29	128
2020 June	72	29	101
2020 May	142	37	179
2020 April	135	25	160
2020 March	152	30	182
2020 February	175	41	216
2020 January	237	40	277
2019 December	171	25	196
2019 November	250	42	292
2019 October	284	31	315
2019 September	418	66	484
2019 August	200	39	239
2019 July	266	42	308
2019 June	79	45	124
2019 May	92	44	136
2019 April	119	54	173
2019 March	73	40	113
2019 February	67	31	98
2019 January	96	54	150
2018 December	370	53	423
2018 November	739	23	762
2018 October	578	23	601
2018 September	420	35	455
2018 August	492	16	508
2018 July	99	18	117
2018 June	55	14	69
2018 May	77	12	89
2018 April	68	14	82
2018 March	70	12	82
2018 February	82	11	93

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter