was read the article
array:21 [ "pii" => "X2013251412001356" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2012.Jan.10928" "estado" => "S300" "fechaPublicacion" => "2012-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2012;32:279-86" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 19888 "formatos" => array:3 [ "EPUB" => 462 "HTML" => 17568 "PDF" => 1858 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699512001359" "issn" => "02116995" "doi" => "10.3265/Nefrologia.pre2012.Jan.10928" "estado" => "S300" "fechaPublicacion" => "2012-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2012;32:279-86" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 45709 "formatos" => array:3 [ "EPUB" => 348 "HTML" => 43675 "PDF" => 1686 ] ] "es" => array:12 [ "idiomaDefecto" => true "titulo" => "Medio ambiente y riñón: nefrotoxicidad por metales pesados" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "279" "paginaFinal" => "286" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Renal health and the environment: heavy metal nephrotoxicity" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10928_108_16137_es_10928_f1.jpg" "Alto" => 346 "Ancho" => 600 "Tamanyo" => 102558 ] ] "descripcion" => array:1 [ "es" => "Mecanismos fisiopatológicos de lesión renal por cadmio" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ernesto Sabath, M. Ludivina Robles-Osorio" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Ernesto" "apellidos" => "Sabath" ] 1 => array:2 [ "nombre" => "M. Ludivina" "apellidos" => "Robles-Osorio" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251412001356" "doi" => "10.3265/Nefrologia.pre2012.Jan.10928" "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/X2013251412001356?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699512001359?idApp=UINPBA000064" "url" => "/02116995/0000003200000003/v0_201502091350/X0211699512001359/v0_201502091350/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X2013251412001348" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2012.Jan.11319" "estado" => "S300" "fechaPublicacion" => "2012-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2012;32:287-94" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 10317 "formatos" => array:3 [ "EPUB" => 340 "HTML" => 8695 "PDF" => 1282 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Pregnancy in women on chronic dialysis: a review" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "287" "paginaFinal" => "294" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Embarazo en mujeres en diálisis crónica: revisión" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11319_16025_28449_en_t1_11319_ing.jpg" "Alto" => 617 "Ancho" => 2186 "Tamanyo" => 399884 ] ] "descripcion" => array:1 [ "en" => "Parameters for pregnancy and new-borns in women on chronic haemodialysis" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Karina Ruth Furaz Czerpak, Karina R. Furaz-Czerpak, Gema Fernández Juárez, Gema Fernández-Juárez, María Angeles Moreno de la Higuera, M. Ángeles Moreno-de la Higuera, Elena Corchete Prats, Elena Corchete-Prats, Adriana Puente García, Adriana Puente-García, Roberto Martín Hernandez, Roberto Martín-Hernández" "autores" => array:12 [ 0 => array:2 [ "nombre" => "Karina Ruth" "apellidos" => "Furaz Czerpak" ] 1 => array:2 [ "nombre" => "Karina R." "apellidos" => "Furaz-Czerpak" ] 2 => array:2 [ "nombre" => "Gema" "apellidos" => "Fernández Juárez" ] 3 => array:2 [ "nombre" => "Gema" "apellidos" => "Fernández-Juárez" ] 4 => array:2 [ "nombre" => "María Angeles" "apellidos" => "Moreno de la Higuera" ] 5 => array:2 [ "nombre" => "M. Ángeles" "apellidos" => "Moreno-de la Higuera" ] 6 => array:2 [ "nombre" => "Elena" "apellidos" => "Corchete Prats" ] 7 => array:2 [ "nombre" => "Elena" "apellidos" => "Corchete-Prats" ] 8 => array:2 [ "nombre" => "Adriana" "apellidos" => "Puente García" ] 9 => array:2 [ "nombre" => "Adriana" "apellidos" => "Puente-García" ] 10 => array:2 [ "nombre" => "Roberto" "apellidos" => "Martín Hernandez" ] 11 => array:2 [ "nombre" => "Roberto" "apellidos" => "Martín-Hernández" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699512001340" "doi" => "10.3265/Nefrologia.pre2012.Jan.11319" "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/X0211699512001340?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251412001348?idApp=UINPBA000064" "url" => "/20132514/0000003200000003/v0_201502091613/X2013251412001348/v0_201502091613/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "X2013251412001364" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2012.Mar.11415" "estado" => "S300" "fechaPublicacion" => "2012-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2012;32:275-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 7187 "formatos" => array:3 [ "EPUB" => 342 "HTML" => 5992 "PDF" => 853 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "FGF23 and mineral metabolism, implications in CKD-MBD" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "275" "paginaFinal" => "278" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11415_108_29534_en_11415_f1.jpg" "Alto" => 272 "Ancho" => 496 "Tamanyo" => 78085 ] ] "descripcion" => array:1 [ "en" => "Hormonal response to hypocalcemia." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Mariano Rodríguez, Ignacio López, Juan Muñoz, Escolástico Aguilera-Tejero, Yolanda Almaden" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Mariano" "apellidos" => "Rodríguez" ] 1 => array:2 [ "nombre" => "Ignacio" "apellidos" => "López" ] 2 => array:2 [ "nombre" => "Juan" "apellidos" => "Muñoz" ] 3 => array:2 [ "nombre" => "Escolástico" "apellidos" => "Aguilera-Tejero" ] 4 => array:2 [ "nombre" => "Yolanda" "apellidos" => "Almaden" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X0211699512001367" "doi" => "10.3265/Nefrologia.pre2012.Mar.11415" "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/X0211699512001367?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251412001364?idApp=UINPBA000064" "url" => "/20132514/0000003200000003/v0_201502091613/X2013251412001364/v0_201502091613/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Renal health and the environment: heavy metal nephrotoxicity" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "279" "paginaFinal" => "286" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Ernesto Sabath, M. Ludivina Robles-Osorio" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Ernesto" "apellidos" => "Sabath" "email" => array:1 [ 0 => "esabath@yahoo.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "M. Ludivina" "apellidos" => "Robles-Osorio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Nefrología, Hospital General de Querétaro, Querétaro, México, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro, México, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Medio ambiente y riñón: nefrotoxicidad por metales pesados" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10928_16025_28802_en_f1_10928.jpg" "Alto" => 1208 "Ancho" => 2112 "Tamanyo" => 440441 ] ] "descripcion" => array:1 [ "en" => "Physiopathological mechanisms of cadmium-induced kidney injury" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Both the incidence and prevalence of chronic renal failure have risen constantly over the last 3 decades, which is now a growing public health problem. Identifying risk factors associated with the disease is essential in order to prevent it from affecting even more patients.</p><p class="elsevierStylePara">Studying the toxic effects of heavy metals on the human body has become especially important in the last 50 years, given that large amounts of these products were disposed of as industrial waste and they are not biodegradable, remaining in the environment for long periods of time. For this reason, despite the fact that strict regulations enforced mainly in Europe and North America limit the disposal of heavy metals, high levels of these elements are still present in soil and sediment, resulting in chronic exposure in the general population.</p><p class="elsevierStylePara">Heavy metals are a poorly defined group of elements. Some are necessary for the human body, such as iron (Fe), cobalt (Co), copper (Cu), manganese (Mn), molybdenum (Mb) and zinc (Zn). It is unknown whether the other metals – lead (Pb), cadmium (Cd) and arsenic (As) – serve any purpose in the body, but they do have a direct effect on the kidneys and they are particularly nephrotoxic, even at “normal” levels. There is no clear evidence of nephrotoxicity due to other metals such as uranium and mercury.<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">The aim of this review is to analyse the epidemiology, physiopathology and clinical manifestations of nephrotoxicity associated with these metals.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">ABSORPTION AND METABOLISM OF DIVALENT METALS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Intestinal absorption of divalent metals such as Cd and Pb is facilitated by divalent metal transporter 1 (DMT-1). DMT-1 is located in the duodenum, erythrocytes, liver and cells in the proximal convoluted tubule (PCT). This protein transports Fe and has a high affinity for other divalent metals such as Cd, Ni (nickel), Pb, Co, Mn, Zn and Cu.<span class="elsevierStyleSup">2 </span>Decreased intake of Fe and Zn results in increased expression of DMT-1, which increases intestinal absorption of Cd and Pb and therefore toxicity by these metals.<span class="elsevierStyleSup">3</span> Experiments in cell lines in which DMT-1 expression has been blocked suggest that there is a different Pb transporter.<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">Heavy metals are metabolised in the liver, where they bind to low molecular weight proteins (<10kDa) called metallothioneins (MT). These proteins are widely distributed throughout the body and contain a large quantity of the amino acid cysteine, which gives them a high affinity for reacting with and storing metals such as Zn, Cd, Hg (mercury), Cu, Pb, Ni, Co and Fe.</p><p class="elsevierStylePara">The main function of MT is to store essential metals such as Zn and Cu in the intracellular medium and transfer them to metalloproteins, transcription factors and enzymes. MT also play a role in the elimination of free radicals and in cellular repair and regeneration processes.<span class="elsevierStyleSup">5</span> Increased intracellular levels of Cd and Pb increases MT expression, and MT knockout mice are more susceptible to toxicity from these metals.<span class="elsevierStyleSup">6</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CADMIUM NEPHROTOXICITY</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Cd is one of the most toxic elements to which humans are exposed. Environmental exposure mainly occurs by contact with tobacco smoke, water and foodstuffs such as vegetables, grains and molluscs.<span class="elsevierStyleSup"> </span>This metal gradually accumulates in the body and levels increase with age given its long half-life, which is more than 20 years.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Epidemiology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Various epidemiological studies have demonstrated that environmental exposure to Cd increases the risk of developing kidney injury. During the 1950s in Japan, doctors began to recognise an association between environmental exposure to Cd and increased numbers of women with kidney disease characterised by tubular dysfunction, chronic kidney disease, and a type of osteomalacia known as “itai-itai”.<span class="elsevierStyleSup">8</span> It was later found that workers suffering from industrial exposure to Cd had an increased risk of developing kidney disease.<span class="elsevierStyleSup">9</span> However, it was not until the publication of Bernard’s studies in Belgium that it was understood that exposure to even low Cd levels had nephrotoxic effects and that up to 7% of the exposed population suffered kidney injury.<span class="elsevierStyleSup">10</span></p><p class="elsevierStylePara">Järup et al<span class="elsevierStyleSup">11</span> studied 1021 people and demonstrated that the prevalence of tubular damage marker alpha 1-microglobulin was significantly higher in subjects whose urinary excretion of Cd was within the high range of normal limits (<span class="elsevierStyleItalic">odds ratio</span> [OR]: 6, 95% confidence interval [CI]: 1.6-22). Noonan et al<span class="elsevierStyleSup">12</span> showed the same relationship between normal-to-high urinary levels of Cd and the presence of NAG (N-acetyl-beta-D-glucosaminidase) and alanine aminopeptidase tubular dysfunction markers. The literature does not currently include reports on the effects of Cd on the progression of chronic kidney injury, although a Swedish study by Hellstrom et al<span class="elsevierStyleSup">13</span> showed a higher incidence rate of patients on dialysis (OR: 18, 95% CI: 1.3-2.3) among people exposed to Cd than among those with no Cd exposure.</p><p class="elsevierStylePara">In addition to its nephrotoxic effect, Cd is also associated with increased risk of developing diabetes,<span class="elsevierStyleSup">14</span> cancer, and cardiovascular disease. In a sample of 13 958 adult participants in NHANES III (National Health and Nutrition Examination Survey III), Menke et al<span class="elsevierStyleSup">15</span> showed that high levels of Cd in urine were associated with higher overall mortality and increased risk of cancer. Exposure to Cd also increases the risk of high blood pressure and it is considered a risk factor for cardiovascular mortality and morbidity.<span class="elsevierStyleSup">16</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Physiopathology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Cd in food is bound to metallothionein and phytochelatin proteins, which are involved in vacuole confinement of heavy metals in vegetables. These proteins are broken down by the action of the gastric juice, releasing Cd that will be absorbed in the intestine by DMT-1 and ZIP-8 transporters.<span class="elsevierStyleSup">17,18</span></p><p class="elsevierStylePara">In circulating blood, it binds to albumin and is transported to the liver, where it binds to glutathione (GSH) and metallothionein-1 (MT-1). The Cd-MT-1 complex is secreted in bile and subsequently reabsorbed into the blood by means of enterohepatic circulation. Cd-MT-1 is a low molecular weight complex (<7kDa) which is easily filtered by the glomerulus and is entirely reabsorbed in the S1 segment of the PCT by endocytosis in a process mediated by the proteins megalin and cubilin.<span class="elsevierStyleSup">19</span></p><p class="elsevierStylePara">The ZIP-8 transporter is also located in PCT cells, and it is able to transport Cd and other divalent metals through the apical membrane of these cells; however, the role it plays in Cd toxicity is unknown.<span class="elsevierStyleSup">17</span></p><p class="elsevierStylePara">Within the intracellular medium of PCT cells, the Cd-MT-1 complex is stored and broken down by lysosomes. Free Cd is then transported to the cytoplasm by lysosomal DMT-1.<span class="elsevierStyleSup">6</span> Activation of protein kinase C increases expression of DMT-1, thereby increasing tubular toxicity by Cd.<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">Free Cd accumulates in mitochondria, blocking the respiratory chain at complex III. This results in mitochondrial dysfunction and the formation of free radicals, which activates caspase enzymes and the apoptosis process. Free Cd also binds to protein sulfhydryl groups and affects the structure and function of the proteins. It has been demonstrated that Cd interferes with enzymatic activities of the calcium-calmodulin complex, inhibits Na+-K+-ATPase activity, and stimulates activity by MAP kinases. In paracellular tight junctions, it affects the distribution of paracellular tight junction proteins and decreases transepithelial resistance.<span class="elsevierStyleSup">21,22 </span></p><p class="elsevierStylePara">Only 10% of filtered Cd is reabsorbed into distal ends of the nephron, and it is possible that the Cd 's hypercalciuric effect is the result of inhibition of calcium channel activity in the distal tubule.<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara">Another nephrotoxicity mechanism is the one mediated by the formation of anti-MT antibodies; exposure to Cd increases MT production in the liver and kidneys, which constitutes a protective response to limit its toxicity. However, once the MT’s capacity for Cd storage has been exceeded, free Cd is able to induce the formation of antibodies against MT, which are also toxic to PCT cells (Figure 1).<span class="elsevierStyleSup">24</span></p><p class="elsevierStylePara">The effect of foetal<span class="elsevierStyleItalic"> </span>exposure to Cd is unknown. Jacquillet et al<span class="elsevierStyleSup">25</span> showed that an offspring of rats exposed to Cd during gestation had decreased renal function, proximal tubular damage and abnormal paracellular tight junctions in the glomeruli in adulthood, as well as PCT characterised by alterations in the expression and arrangement of claudin-2 and claudin-5.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Clinical manifestations</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The main effects of chronic Cd toxicity are kidney injury, bone demineralisation, high blood pressure, pulmonary function disorders (mainly obstructive) and different types of cancer (bladder, lung, etc.)</p><p class="elsevierStylePara">In the kidney, Cd mainly affects PCT cells. This damage manifests clinically as low molecular weight proteinuria, aminoaciduria, bicarbonaturia, glycosuria and phosphaturia. Tubular damage markers such as alpha-1-microglobulin, beta-2-microglobulin, NAG and KIM-1 (<span class="elsevierStyleItalic">kidney injury molecule-1</span>) are useful in detecting early tubular damage.<span class="elsevierStyleSup">26</span></p><p class="elsevierStylePara">People with incipient renal injury are more susceptible to the nephrotoxic effects of Cd.<span class="elsevierStyleSup">27</span> In patients with diabetic nephropathy, urinary excretion of CD is directly related to increased urinary excretion of beta-2-microglobulin and albuminuria.<span class="elsevierStyleSup">28</span></p><p class="elsevierStylePara">Determining Cd levels in the bloodstream is used to diagnose acute exposure, whilst urinary excretion of Cd is used to assess Cd body burden and is useful for evaluating chronic exposure.<span class="elsevierStyleSup">29</span></p><p class="elsevierStylePara">Prevention is the most important factor in the management of exposure to this metal, since there is no effective means of treating Cd toxicity.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">LEAD NEPHROTOXICITY</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The toxic effects of Pb have been known for more than 2000 years, since lead intake was a common problem among the Romans. At present, exposure to high concentrations of Pb is less common, due to better industrial management and the fact that Pb is no longer added to paint and petrol. However, Pb contamination is still a public health problem in many countries in Africa, Asia and Latin America due to domestic exposure through contaminated water and soil.<span class="elsevierStyleSup">30</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Epidemiology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The first reported case of nephrotoxicity associated with Pb was described in the 19<span class="elsevierStyleSup">th</span> century. Since then, exposure to high concentrations of Pb has been considered a risk factor for developing high blood pressure and kidney injury. However, it was not until recent times that studies recognised that exposure to “normal” levels had a direct effect on kidney function and increased the risk of cardiovascular morbidity.<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">Based on results from the NHANES III study, Menke et al<span class="elsevierStyleSup">32</span> monitored a population over 12 years and demonstrated that the higher the Pb levels, the higher the mortality rates (mainly due to cardiovascular problems).<span class="elsevierStyleSup"> </span></p><p class="elsevierStylePara">In a population of 4813 patients with high blood pressure, Muntner et al<span class="elsevierStyleSup">33</span> found increased risk of chronic renal failure (OR: 2.6, 95% CI: 1.5-4.45) in those with higher serum Pb levels. Follow-up studies carried out in Taiwan by Lin et al<span class="elsevierStyleSup">34,35</span> found that individuals with chronic nephritis (glomerular filtration rate [GFR]<60ml/min) and high levels of Pb in the body experienced faster deterioration of renal function, and also that chelation therapy with ethylenediaminetetraacetic acid (EDTA) decreased kidney injury progression.</p><p class="elsevierStylePara">Establishing the maximum non-toxic levels of Pb in blood and urine remains a matter for debate, since there is increasing evidence suggesting that levels previously considered to be non-toxic are associated with higher morbidity and mortality rates in the general population.<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Physiopathology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Pb is mainly absorbed by the intestine and the respiratory system and, to a lesser extent, through the skin. Intestinal absorption is mediated by DMT-1 and increases with deficient intake of Fe and Zn. The respiratory system is a highly efficient route of absorption, with an uptake rate of more than 40% of inhaled Pb; however, the molecular mechanism by which Pb is absorbed is unknown.</p><p class="elsevierStylePara">Once in the blood, 99% of Pb binds to proteins in the erythrocytes and it is distributed to soft tissue and bone. Bone is the main reservoir for lead in the body and Pb transport to the bloodstream increases during times with the highest bone turnover, such as adolescence and pregnancy.<span class="elsevierStyleSup">31</span> Urinary excretion is the main route of Pb elimination from the body.</p><p class="elsevierStylePara">Pb bound to low molecular weight proteins (<1% of the total) is filtered freely at the glomerulus and is reabsorbed by PCT cells by endocytosis. Within the cell, Pb causes mitochondrial damage, formation of free radicals, intracellular depletion of GSH and apoptosis (Figure 2).<span class="elsevierStyleSup">36</span> Pb also affects enzymatic reactions in which calcium plays a role, and the calcium-sensing receptor can also be activated by Pb, which suggests that there may be other mechanisms for lead nephrotoxicity.<span class="elsevierStyleSup">37,38</span></p><p class="elsevierStylePara">Pb induces activation of transcription nuclear factor kappa B, activation of the intrarenal renin-angiotensin system and attraction of macrophages, which generates an inflammatory process in the renal interstitium that may be involved in the development of tubulointerstitial damage and high blood pressure.<span class="elsevierStyleSup">39 </span></p><p class="elsevierStylePara">In endothelial cells, it has been shown that increased formation of free radicals induced by Pb decreases nitric oxide production and the expression of the enzyme guanylate cyclase. These effects explain how high blood pressure can develop as a result of exposure to this metal.<span class="elsevierStyleSup">36-41</span> In addition, it stimulates the activity of NADP(H) oxidase by increasing production of hydrogen superoxide and hydrogen peroxide, thus affecting oxidative stress and the intracellular redox potential.<span class="elsevierStyleSup">42</span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Clinical manifestations</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Acute exposure to high doses of Pb can cause PCT lesions, which manifest clinically as aminoaciduria, glycosuria or hyperphosphatemia. Other clinical manifestations include haemolytic anaemia, acute attacks of gout, intense abdominal pain (“painter’s colic”) and encephalopathy.<span class="elsevierStyleSup">43</span></p><p class="elsevierStylePara">Diagnosing chronic nephritis due to Pb is difficult, since urinary symptoms and findings are variable and lack specificity. Diagnosis is therefore based largely on a clinical history of exposure. Chronic exposure is associated with tubulointerstitial nephritis and progressive deterioration of renal function. Urinary excretion of urates decreases due to the effect of Pb on the PCT and renal blood flow decreases as well, resulting in increased urate levels in the bloodstream.<span class="elsevierStyleSup">44</span></p><p class="elsevierStylePara">In bone, chronic exposure is related to the pathogenesis and progression of osteoporosis, since Pb has adverse effects on osteoblasts and osteoclasts that affect bone formation and reabsorption.<span class="elsevierStyleSup">45</span></p><p class="elsevierStylePara">There is no adequate treatment for decreasing high Pb levels in the blood, but EDTA chelation therapy (1g in 200ml saline at 0.9%, administered weekly during 3 months) helps decrease Pb toxicity. Preventing exposure to this metal is the best means of reducing high levels in the bloodstream.<span class="elsevierStyleSup">35</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">ARSENIC NEPHROTOXICITY </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Arsenic is one of the most widespread environmental pollutants and millions of people (mostly in Asia and Latin America) suffer from exposure to As, since it is a common pollutant in drinking water. Another less common form of exposure is through medications containing As, such as arsenic trioxide used in the treatment of acute promyelocytic leukaemia, and other drugs used to treat sleeping sickness and leishmaniasis.<span class="elsevierStyleSup">46</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Epidemiology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The causal association between As and the formation of tumours in the skin, lungs, bladder, liver and kidneys has been exhaustively described. Some epidemiological studies have shown an association between exposure to high levels of As and increased risk of cardiovascular disease and diabetes mellitus. However, studies conducted in areas with low to moderate exposure have not yet demonstrated this association conclusively.</p><p class="elsevierStylePara">Until now, there have been few reports in the literature on the effects of As on the renal function of the general population. Hsueh et al<span class="elsevierStyleSup">47</span> studied 125 people with GFR<60ml/min and 229 people with normal renal function and found a weak association between urinary levels of As and decreased renal function (r<span class="elsevierStyleSup">2</span>=0.04, <span class="elsevierStyleItalic">P</span>≤.001). Meliker et al<span class="elsevierStyleSup">48</span> showed that in patients with decreased renal function, higher As levels were associated with higher mortality rates (OR: 1.11, 95% CI: 1.09-1.13).</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Physiopathology</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">As is absorbed by the intestine, lungs (inhalation) and, to a lesser extent, through the skin. Once it has been absorbed, it is transported to all tissues in the body. The intake of selenium and vitamin B decrease intestinal absorption of As. Arsenic is methylated in the liver in a GSH-mediated process which decreases its toxicity and facilitates its biliary and urinary excretion.<span class="elsevierStyleSup">49</span> Arsenic enters the intracellular medium through the aquaglyceroporins AQ3 and AQ9 and studies in cell cultures have shown that the increase in AQ3 and AQ9 cellular expression increases intracellular accumulation of As. In the liver, AQ9 is important for biliary excretion of As.<span class="elsevierStyleSup">50 </span></p><p class="elsevierStylePara">Another group of As transport proteins includes MRP-1 and 2 (ATP binding cassette-multidrug resistance protein) which were first described in the liver, where they transport As bound to GSH to the bile. The MRP-2 transporter is also located in proximal tubule cells, which favours entry of As into these cells.<span class="elsevierStyleSup">51</span> Arsenic toxicity in PCT cells is due to GSH depletion and an increase in oxidative activity by free radicals (Figure 3).</p><p class="elsevierStylePara">The literature does not currently offers sufficient information on clinical manifestations of As toxicity in the kidneys, but it is likely to manifest as data indicating tubular damage, such as low molecular weight proteinuria, aminoaciduria, glycosuria and phosphaturia, as well as progressive deterioration of renal function.<span class="elsevierStyleSup">52</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In conclusion, there is ample evidence of the renal damage associated with these heavy metals. In addition, the combination of different metals has been shown to have a cumulative nephrotoxic effect. Since these metals are commonly found in the environment and there are no treatment options that decrease their systemic effects, increased vigilance is needed in order to decrease environmental levels of Pb, Cd and As.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">The authors declare potential conflicts of interest:</p><p class="elsevierStylePara">- Grants awarded: mixed funding from the State of Querétaro (<span class="elsevierStyleItalic">Fondos Mixtos del Estado de Querétaro</span>). Mexican National Council for Science and Technology.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS</span></p><li>The nephrotoxic action of metals such as Cd, Pb and As mainly affects the proximal convoluted tubule cells. </li><li>The initial clinical manifestations of kidney damage are subtle and include low molecular weight proteinuria, aminoaciduria, phosphaturia and glycosuria. </li><li>Biomarkers such as alpha 1-microglobulin, NGAL and KIM-1 are useful for detecting early renal injury. </li><p class="elsevierStylePara"><a href="grande/10928_16025_28802_en_f1_10928.jpg" class="elsevierStyleCrossRefs"><img src="10928_16025_28802_en_f1_10928.jpg" alt="Physiopathological mechanisms of cadmium-induced kidney injury"></img></a></p><p class="elsevierStylePara">Figure 1. Physiopathological mechanisms of cadmium-induced kidney injury</p><p class="elsevierStylePara"><a href="grande/10928_16025_28803_en_f2_10928.jpg" class="elsevierStyleCrossRefs"><img src="10928_16025_28803_en_f2_10928.jpg" alt="Physiopathological mechanisms of lead-induced kidney injury"></img></a></p><p class="elsevierStylePara">Figure 2. Physiopathological mechanisms of lead-induced kidney injury</p><p class="elsevierStylePara"><a href="grande/10928_16025_28804_en_f3_10928.jpg" class="elsevierStyleCrossRefs"><img src="10928_16025_28804_en_f3_10928.jpg" alt="Physiopathological mechanisms of arsenic-induced kidney injury"></img></a></p><p class="elsevierStylePara">Figure 3. Physiopathological mechanisms of arsenic-induced kidney injury</p>" "pdfFichero" => "P1-E536-S3496-A10928-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438235" "palabras" => array:1 [ 0 => "Cadmio" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438237" "palabras" => array:1 [ 0 => "Arsénico" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438239" "palabras" => array:1 [ 0 => "Plomo" ] ] ] "en" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438236" "palabras" => array:1 [ 0 => "Cadmium" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438238" "palabras" => array:1 [ 0 => "Arsenic" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438240" "palabras" => array:1 [ 0 => "Lead" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">En la actualidad se reconoce que contaminantes ambientales como el cadmio, el plomo y el arsénico tienen un papel importante en la génesis de la insuficiencia renal crónica. Estudios epidemiológicos han demostrado la fuerte asociación entre exposición a estos metales y la presencia de daño renal crónico. Los mecanismos fisiopatológicos de daño renal por metales son complejos y aún se desconocen varios aspectos de su metabolismo y mecanismos de daño en el organismo. Es objetivo de esta revisión analizar dichos mecanismos fisiopatológicos de daño renal por cadmio, plomo y arsénico. </p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">We currently recognise that environmental toxins such as cadmium, lead, and arsenic play a significant role in the development of chronic renal failure. Epidemiological studies have shown a strong association between exposure to these metals and the presence of chronic kidney injury. The physiopathological mechanisms behind metal-induced kidney injury are complex, and some aspects of their metabolism and damage mechanisms remain unknown. This review aims to analyse the physiopathological mechanisms of kidney injury due to cadmium, lead and arsenic.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10928_16025_28802_en_f1_10928.jpg" "Alto" => 1208 "Ancho" => 2112 "Tamanyo" => 440441 ] ] "descripcion" => array:1 [ "en" => "Physiopathological mechanisms of cadmium-induced kidney injury" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10928_16025_28803_en_f2_10928.jpg" "Alto" => 1185 "Ancho" => 2102 "Tamanyo" => 432324 ] ] "descripcion" => array:1 [ "en" => "Physiopathological mechanisms of lead-induced kidney injury" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10928_16025_28804_en_f3_10928.jpg" "Alto" => 713 "Ancho" => 1010 "Tamanyo" => 155568 ] ] "descripcion" => array:1 [ "en" => "Physiopathological mechanisms of arsenic-induced kidney injury" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:52 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Edwards JR, Prozialeck. Cadmium, diabetes and chronic kidney disease. Toxicol Appl Pharmacol 2009;238:289-93. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19327375" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Garrick MD, Dolan KG, Horbinsky C, Ghio AJ, Higgins D, Porubcin M, et al. DMT1: A mammalian transporter for multiple metals. Biometals 2003;16:41-54. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12572663" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bradmann A, Eskenazi B, Sutton P. Iron deficiency associated with higher blood lead in children living in contaminated environments. Environ Health Perspect 2001;109:1079-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11675273" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bannon DI, Abounader R, Lees PS, Bressler JP. Effect of DMT1 knockdown on iron, cadmium, and lead uptake in Caco-2 cells. Am J Physiol Cell Physiol 2003;284:C44-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12388109" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Sabolic I, Breljak D, Karica MS, Herak-Kramberger. Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 2010;23:897-926. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20549307" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Liu Y, Liu J, Klaassen CD. Metallothionein-null and wild-type mice show similar cadmium absorption and tissue distribution following oral cadmium administration. Toxicol Appl Pharmacol 2001;175:253-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11559024" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tucker P. Agency for toxic substances and disease registry (ATSDR). Case studies in environmental medicine: cadmium toxicity 2008:10-44. Available at: www.atsdr.cdc.gov/csem/cadmium/ [Accesses: june 25, 2010*]" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Emmerson BT. ¿Ouch-Ouch¿ disease: the osteomalacia of cadmium nephropathy. Ann Intern Med 1970;73:854-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/5476215" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Adams RG, Harrison JF, Scott P. The development of cadmium-induced proteinuria, impaired renal function, and osteomalacia in alkaline battery workers. Q J Med 1969;38:425-43. <a href="http://www.ncbi.nlm.nih.gov/pubmed/5355536" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lauwerys RR, Bernard AM, Buchet JP, Roels HA. Assessment of the health impact of environmental exposure to cadmium: contribution of the epidemiologic studies carried out in Belgium. Environ Res 1993;62:200-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8344230" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Järup L, Hellström L, Alfvén T, Carlsson MD, Grubb A, Persson B, et al. Low level exposure to cadmium and early kidney damage: the OSCAR study. Occup Environ Med 2000;57:668-72. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10984338" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Noonan C, Sarasua S, Campagna D, Kathman SJ, Lybarger JA, Mueller PW. Effects of exposure to low levels of environmental cadmium on renal biomarkers. Environ Health Perspect 2002;110:151-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11836143" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hellström L, Elinder CG, Dahlberg B, Lundberg M, Järup L, Persson B, et al. Cadmium exposure and end-stage renal disease. Am J Kidney Dis 2001;38:1001-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11684553" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Schwartz GG, Yasova DI, Ivanova A. Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III. Diabetes Care 2003;26:468-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12547882" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Menke A, Muntner P, Silbergeld E, Platz E, Guallar E. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect 2009;117:190-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19270787" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Gallagher CM, Meliker JR. Blood and urine cadmium, blood pressure, and hypertension: A systematic review and mata-analysis. Environ Health Perspect 2010;118:1676-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20716508" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Fujishiro H, Okugaki S, Kubota K, Fujiyama T, Himeno S. The role of ZIP8 down-regulation in cadmium-resistant metallothionein-null cells. J Appl Toxicol 2009;29:367-73. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19194888" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Thévenod F. Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals 2010;23:857-75. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20204475" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Klassen RB, Crenshaw K, Kozyraki R, Verroust PJ, Tio L, Atrian S, et al. Megalin mediates renal uptake of heavy metal methallothionein complexes. Am J Physiol Renal Physiol 2004;287:F393-403. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15126248" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Olivi L, Sisk J, Bressler J. Involvement of DMT1 in uptake of Cd in MDCK cells: role of protein kinase C. Am J Physiol Cell Physiol 2001;281:C793-800. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11502556" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hirano S, Sun X, DeGuzman C, Ransom R, MacLeish K, Smoyer WE, et al. p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli. Am J Physiol Renal Physiol 2005;288:F1133-43. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15687248" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Gunawardana CG, Martínez RE, Xiao W, Templeton DM. Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells. Am J Physiol Renal Physiol 2006;290:F1074-82. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16263807" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Barbier O, Jacquillet M, Tauc M, Poujeol P, Cougnon M. Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo. Am J Physiol Renal Physiol 2004;287:F1067-75. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15280159" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Klaassen CD, Liu J, Diwan BA. Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 2009;238:215-20. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19362100" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Jacquillet G, Barbier O, Rubera I, Tauc M, Borderie A, Namorado MC, et al. Cadmium causes delayed effects on renal function in the offspring of cadmium-contaminated pregnant female rats. Am J Physiol Renal Physiol 2007;293:F1450-60. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17686954" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prozialeck WC, Vaidya VS, Liu J, Waalkes MP, Edwards JR, Lamar PC, et al. Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney Int 2007;72:985-93. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17687258" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hotz P, Buchet JP, Bernard A, Lison D, Lauwerys R. Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study. Lancet 1999;354:1508-13. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10551497" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Nordberg G, Chen L, Lei L, Jin T, Nordberg M. Plasma metallothionein antibody, urinary cadmium, and renal dysfunction in a Chinese type 2 diabetic population. Diabetes Care 2006;29:2682-87." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bernard A. Cadmium and its adverse effects on human health. Indian J Med Res 2008;128:557-64. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19106447" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Meyer P, Brown MJ, Falk H. Global approach to reducing lead exposure and poisoning. Mutat Res 2008;659:166-75. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18436472" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013001692" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity: A review of the epidemiologic evidence. Kidney Int 2006;70:2074-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17063179" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Menke A, Muntner P, Batuman V, Sibergeld E, Guallar E. Blood lead below 10µg/dl and mortality among US adults. Circulation 2006;114:1388-94. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16982939" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Muntner P, He J, Vupputuri S, Coresh J,\u{A0}Batuman V. Blood lead and chronic kidney disease in the general United States population: results from NHANES III. Kidney Int 2003;63:1044-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12631086" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med 2003;348:277-86. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12540640" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tan DT, Lin JL, Yen TH, Chen KH, Huang YL. Long-term outcome of repeated lead chelation therapy in progressive non-diabetic chronic kidney diseases. Nephrol Dial Transplant 2007;22:2924-31. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17556414" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Wang L, Wang H, Hu M, Cao J, Chen D, Liu Z. Oxidative stress and apoptotic changes in primary cultures of rat proximal tubular cells exposed to lead. Arch Toxicol 2009;83:417-27. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19347332" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Chiu TY, Teng HC, Huang PC, Kao FJ, Yang DM. Dominant role of Orai1 with STIM1 on the cytosolic entry and cytotoxicity of lead ions. Toxicol Lett 2009;110:353-62." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Handlogten M, Shiraishi N, Awata H, Huang C, Tyler-Miller R. Extracellular Ca2-sensing receptor is a promiscuous divalent cation sensor that responds to lead. Am J Physiol Renal Physiol 2000;279:F1083-91. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11097627" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bravo Y, Quiroz Y, Ferrebuz A, Vaziri N, Rodríguez-Iturbe B. Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension. Am J Physiol Renal Physiol 2007;293:F616-23. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17567935" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Vaziri N. Mechanisms of lead-induced hypertension and cardiovascular disease. Am J Physiol Heart Circ Physiol 2008;295:H454-65. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18567711" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Courtois E, Marques M, Barrientos A, Casado S, López-Farré A. Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2. J Am Soc Nephrol 2003;14:1464-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12761246" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ni Z, Hou S, Barton C, Vaziri N. Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells. Kidney Int 2004;66:2329-36. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15569323" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bennett W. Lead Nephropathy. Kidney Int 1985;28:212-20. <a href="http://www.ncbi.nlm.nih.gov/pubmed/3834232" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lin JL, Yu CC, Lin-Tan D, Ho HH. Lead chelation therapy and urate excretion in patients with chronic renal diseases and gout. Kidney Int 2001;60:266-71. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11422760" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Potula V, Henderson A, Kaye W. Calciotropic hormones, bone turnover, and lead exposure among female smelter workers.\u{A0}Arch Environ Occup Health 2005;60:195-204. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17214290" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Mahmudur-Rahman R, Ng JC, Naidu R. Chronic exposure of arsenic via drinking water and its adverse health impacts on humans. Environ Geochem Health 2009;31:189-200. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19190988" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hsueh YM, Chung CJ, Shiue HS, Chen JB, Chiang SS, Yang MH, et al. Urinary arsenic species and CKD in a Taiwanese population: A case-control study. Am J Kidney Dis 2009;54:859-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19682779" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Meliker JR, Wahl RL, Cameron LL. Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: A standardized mortality ratio analysis. Environ Health 2007;6:4-10." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Thomas D. Unraveling arsenic-glutathione connections. Toxicol Sci 2009;107:309-11. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19074764" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Carbrey JM, Song L, Zhou Y, Yoshinaga M, Rojek A. Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice. Proc Natl Acad Sci U S A 2009;106:15956-60. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19805235" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lee TC, Ho IC, Lu WJ, Huang JD. Enhanced expression of multidrug resistance-associated protein 2 and reduced expression of aquaglyceroporin-3 in an arsenic-resistant human cell line. J Biol Chem 2006;281:18401-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16672223" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Huang M, Choiu SJ, Kim DW, Kim NY, Park CH, Yu SD, et al. Risk assessment of low-level cadmium and arsenic on the kidney. J Toxicol Environ Health A 2009;72:1493-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20077223" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003200000003/v0_201502091613/X2013251412001356/v0_201502091613/en/main.assets" "Apartado" => array:4 [ "identificador" => "35445" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Short Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003200000003/v0_201502091613/X2013251412001356/v0_201502091613/en/P1-E536-S3496-A10928-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251412001356?idApp=UINPBA000064" ]
Year/Month | Html | Total | |
---|---|---|---|
2024 November | 42 | 12 | 54 |
2024 October | 243 | 106 | 349 |
2024 September | 220 | 81 | 301 |
2024 August | 202 | 98 | 300 |
2024 July | 210 | 122 | 332 |
2024 June | 263 | 117 | 380 |
2024 May | 241 | 99 | 340 |
2024 April | 188 | 100 | 288 |
2024 March | 235 | 84 | 319 |
2024 February | 153 | 96 | 249 |
2024 January | 151 | 66 | 217 |
2023 December | 152 | 75 | 227 |
2023 November | 182 | 96 | 278 |
2023 October | 177 | 96 | 273 |
2023 September | 136 | 94 | 230 |
2023 August | 177 | 56 | 233 |
2023 July | 197 | 95 | 292 |
2023 June | 218 | 82 | 300 |
2023 May | 215 | 95 | 310 |
2023 April | 176 | 97 | 273 |
2023 March | 172 | 70 | 242 |
2023 February | 139 | 39 | 178 |
2023 January | 144 | 58 | 202 |
2022 December | 154 | 59 | 213 |
2022 November | 177 | 82 | 259 |
2022 October | 179 | 84 | 263 |
2022 September | 151 | 80 | 231 |
2022 August | 137 | 106 | 243 |
2022 July | 99 | 84 | 183 |
2022 June | 163 | 75 | 238 |
2022 May | 147 | 79 | 226 |
2022 April | 150 | 98 | 248 |
2022 March | 174 | 73 | 247 |
2022 February | 128 | 98 | 226 |
2022 January | 205 | 80 | 285 |
2021 December | 124 | 86 | 210 |
2021 November | 178 | 81 | 259 |
2021 October | 187 | 74 | 261 |
2021 September | 132 | 81 | 213 |
2021 August | 152 | 84 | 236 |
2021 July | 112 | 71 | 183 |
2021 June | 146 | 70 | 216 |
2021 May | 193 | 90 | 283 |
2021 April | 415 | 80 | 495 |
2021 March | 220 | 110 | 330 |
2021 February | 191 | 69 | 260 |
2021 January | 151 | 51 | 202 |
2020 December | 166 | 52 | 218 |
2020 November | 152 | 29 | 181 |
2020 October | 132 | 23 | 155 |
2020 September | 175 | 29 | 204 |
2020 August | 162 | 39 | 201 |
2020 July | 195 | 60 | 255 |
2020 June | 184 | 43 | 227 |
2020 May | 201 | 55 | 256 |
2020 April | 141 | 63 | 204 |
2020 March | 182 | 54 | 236 |
2020 February | 226 | 56 | 282 |
2020 January | 156 | 56 | 212 |
2019 December | 195 | 100 | 295 |
2019 November | 150 | 44 | 194 |
2019 October | 188 | 58 | 246 |
2019 September | 184 | 66 | 250 |
2019 August | 169 | 58 | 227 |
2019 July | 194 | 51 | 245 |
2019 June | 149 | 51 | 200 |
2019 May | 229 | 55 | 284 |
2019 April | 309 | 68 | 377 |
2019 March | 213 | 71 | 284 |
2019 February | 144 | 69 | 213 |
2019 January | 130 | 51 | 181 |
2018 December | 272 | 72 | 344 |
2018 November | 369 | 56 | 425 |
2018 October | 373 | 39 | 412 |
2018 September | 461 | 32 | 493 |
2018 August | 242 | 24 | 266 |
2018 July | 334 | 31 | 365 |
2018 June | 313 | 33 | 346 |
2018 May | 444 | 23 | 467 |
2018 April | 364 | 20 | 384 |
2018 March | 375 | 20 | 395 |
2018 February | 337 | 28 | 365 |
2018 January | 286 | 22 | 308 |
2017 December | 364 | 30 | 394 |
2017 November | 335 | 29 | 364 |
2017 October | 260 | 27 | 287 |
2017 September | 318 | 21 | 339 |
2017 August | 307 | 29 | 336 |
2017 July | 367 | 24 | 391 |
2017 June | 387 | 21 | 408 |
2017 May | 402 | 25 | 427 |
2017 April | 309 | 23 | 332 |
2017 March | 393 | 39 | 432 |
2017 February | 444 | 41 | 485 |
2017 January | 164 | 53 | 217 |
2016 December | 285 | 29 | 314 |
2016 November | 504 | 58 | 562 |
2016 October | 673 | 51 | 724 |
2016 September | 716 | 45 | 761 |
2016 August | 869 | 37 | 906 |
2016 July | 566 | 47 | 613 |
2016 June | 420 | 0 | 420 |
2016 May | 341 | 0 | 341 |
2016 April | 309 | 0 | 309 |
2016 March | 284 | 0 | 284 |
2016 February | 289 | 0 | 289 |
2016 January | 236 | 0 | 236 |
2015 December | 215 | 0 | 215 |
2015 November | 200 | 0 | 200 |
2015 October | 190 | 0 | 190 |
2015 September | 157 | 0 | 157 |
2015 August | 143 | 0 | 143 |
2015 July | 152 | 0 | 152 |
2015 June | 98 | 0 | 98 |
2015 May | 122 | 0 | 122 |
2015 April | 36 | 0 | 36 |