Review
New expectations in the treatment of anemia in chronic kidney disease
Nuevas expectativas en el tratamiento de la anemia en la enfermedad renal crónica
Juan M. López-Gómez
, Soraya Abad, Almudena Vega
Corresponding author
Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, Spain
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To create a hypertonic medullary interstitium, adequate function of all the tubular sodium transporters is necessary, for example, NHE3 (<span class="elsevierStyleItalic">type 3 Na<span class="elsevierStyleSup">+</span>/H<span class="elsevierStyleSup">+</span> exchanger</span>), NaPi-2, (<span class="elsevierStyleItalic">type 2 Na-Pi cotransporter</span>), BSC-1 (<span class="elsevierStyleItalic">type 1 bumetanide-sensitive Na-K-2Cl cotransporter</span>), or TSC (<span class="elsevierStyleItalic">thiazide-sensitive cotransporter</span>) in the lumen side of the tubule (mechanism 1). A defect in its function would cause a loss of saline with an accompanied loss of water that would cause a less hypertonic medullary interstitium. Furthermore, adequate function of the urea transporters (UT-A1, UT-A2, UT-A3) is necessary to increase the medullary interstitium osmolality (mechanism 2). 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López-Gómez, Soraya Abad, Almudena Vega" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juan M." "apellidos" => "López-Gómez" "email" => array:1 [ 0 => "juanmlopez@senefro.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Soraya" "apellidos" => "Abad" ] 2 => array:2 [ "nombre" => "Almudena" "apellidos" => "Vega" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevas expectativas en el tratamiento de la anemia en la enfermedad renal crónica" ] ] "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" => 997 "Ancho" => 1460 "Tamanyo" => 56225 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of GATA inhibitors.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anaemia is a common complication in advanced chronic kidney disease (ACKD) and its severity increases as kidney function decreases. The introduction of treatment with recombinant human erythropoietin (EPO) (epoetin) three decades ago entirely changed the magnitude of the problem.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the most important events in the treatment of this condition to date.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">1–7</span></a> Throughout this time, the treatment of anaemia has been based on the use of erythropoiesis-stimulating agents (ESAs), which included epoetin and its analogues, together with the administration of iron by oral or parenteral route.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> The analogues of erythropoietin include darbepoetin and CERA (continuous erythropoietin receptor activator). Darbepoetin is composed of an EPO that includes two sialic acid molecules, giving it a longer half-life, while CERA is a pegylated EPOβ, with an even greater half-life. In recent years, agents that are biosimilar to epoetin have been incorporated into the therapeutic arsenal, as they are less expensive.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The objective of this review is to raise awareness of the drugs that are currently in different clinical trial phases and that may constitute the basis of treatment for renal anaemia in the coming years. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows a simple classification of the different ESAs that we will review.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">EPO-mimetic agents</span><p id="par0015" class="elsevierStylePara elsevierViewall">This group includes the peptide molecules that act on EPO receptors in a similar way to endogenous EPO. The first EPO-mimetic on the market is peginesatide (Hematide<span class="elsevierStyleSup">®</span>), composed of 2 peptide chains of 21 amino acids each, bound to a polyethylene glycol group. Its half-life is estimated at 80<span class="elsevierStyleHsp" style=""></span>h and it may be administered as a monthly injection; there are no differences between intravenous or subcutaneous routes. This drug was approved by the FDA in 2012, only for use in haemodialysis patients. As it does not require genetic technology for its manufacture, it is a less expensive product than epoetin. Preliminary studies demonstrated other potential advantages such as the absence of immunogenicity, and it may therefore be used in cases of pure red cell aplasia; its greatest efficacy is in patients who are more resistant to other ESAs.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In January 2013, 2 prospective, controlled and randomised studies were simultaneously published for peginesatide in patients with ACKD. The first (EMERALD <span class="elsevierStyleItalic">Study</span>) was carried out in the U.S.A. and in Europe. It included patients on haemodialysis and was compared to EPO-α administered 1–3 times/week. The main conclusion was that peginesatide, administered once a month, resulted in haemoglobin levels equivalent to those obtained with epoetin.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The second study (PEARL <span class="elsevierStyleItalic">Study</span>) was also developed in the same countries and it compared the efficacy of monthly peginesatide to darbepoetin every two weeks in patients with ACKD without dialysis. The results showed a similar efficacy between the 2 drugs at the end of 52 weeks. However, sudden death was 7 times greater in the peginesatide group, and the mortality rate due to unknown causes was twice as high.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> Post-marketing data have shown serious hypersensitivity reactions with several deaths,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> which lead the FDA to withdraw its approval. Therefore, it seems reasonable to assume that in a market as highly competitive as ESAs, the future of peginesatide is poor.</p><p id="par0030" class="elsevierStylePara elsevierViewall">There are other fusion proteins with EPO-mimetic properties currently in the initial study phases.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Agents that stimulate endogenous erythropoietin</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prolyl-hydroxylase inhibitors (PHIs)</span><p id="par0035" class="elsevierStylePara elsevierViewall">Patients with ACKD have a relative EPO deficiency, and although serum levels may be normal, they are inappropriate for the haemoglobin concentrations they present.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> Furthermore, there may be hepatic production of EPO, which may be stimulated during episodes of liver disease, as it was demonstrated in patients on haemodialysis many years ago.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> Moreover, there are EPO-producing cells that remain in the kidneys and other tissues, with a yield sufficient to maintain patients on haemodialysis without anaemia and no need for ESAs. This situation is more common in cases on a long period of renal replacement therapy, in patients with polycystic disease and in cases of liver disease due to hepatitis virus C.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">It has been known for many years that the inhabitants of the Andean altiplano have adapted to the state of hypoxia in which they live; in the same way that high altitude affects patients on haemodialysis.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> Low oxygen pressure induces the expression of the hypoxia-inducible factor (HIF), a transcription factor that regulates the expression of genes involved in erythropoiesis in response to changes in partial oxygen pressure. It is a heterodimeric protein with 2 components: hypoxia-sensitive HIF-α and HIF-β, which is an inactive component of the same molecule. The former has 3 subunits, which are called HIF-1α, HIF-2α and HIF-3α. HIF-1α is involved in the synthesis of EPO in embryonic states, losing its relevance after birth. It is also involved in processes of angiogenesis, mediated by VEGF, as well as in the anaerobic metabolism of glucose. Recently, it has been observed that this factor is also capable of contributing to the growth of renal cysts.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">HIF-2α is the most important subunit and is responsible for the changes in height and the genetic changes in the population that lives with these conditions. It is expressed in a large number of cells in the body, including the endothelial cells, hepatocytes, cardiomyocytes, glial cells, pneumocytes and renal peritubular interstitial cells. It is responsible for controlling EPO synthesis in adults and iron metabolism. Experimentally, it is known that HIF-2α inactivation followed by phlebotomy produces anaemia that cannot be recovered from, despite normal renal function, which gives an idea of how relevant a role it plays. For these reasons, HIF-2α becomes an important objective for pharmacological treatment. HIF-3α is the least important subunit and seems to play an inhibitory role.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In situations of normoxia, the participation of HIF-2α is not necessary, and it is therefore inactivated by hydroxylation through a proteosomal degradation process induced by prolyl-hydroxylase (PH). At least three PH subtypes are known, called PHD1, PHD2 and PHD3. In contrast, in situations of hypoxia, where an increase in the number of RBCs is needed to improve oxygen transport, HIF-2α stabilisation is produced by inhibition of the PH family. Therefore, HIF-2α becomes the main regulator of hypoxia-induced erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Currently, a family of drugs that act as PH inhibitors (PHIs) is being developed for clinical use. These new molecules are capable of increasing erythropoiesis by 2 mechanisms: first by stabilising HIF-2α levels, which likewise stimulates the synthesis of renal and hepatic EPO; second, through an improvement in iron metabolism, blocking the effect of hepcidin. Therefore, PHIs act physiologically, using the same mechanisms of action the body uses to adapt to less oxygen pressure in high altitudes.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Hepcidin, synthesised by the liver, plays an important role in anaemia associated with inflammation, as it contributes to decreasing iron bioavailability. It acts through ferroportin degradation, which is a protein that acts as the principle exporter of iron from all cells. It must be recalled that iron from food is absorbed in the duodenum and subsequently passes through blood circulation, where it is bound to transferrin. From there, it is deposited in the liver cells and the reticuloendothelial system. Subsequently, in those cases in which erythropoiesis needs to be activated, it will again enter the circulation and be incorporated into the bone marrow. Therefore, the absence of ferroportin induced by hepcidin prevents iron from exiting the cells, which gives rise to iron sequestration in duodenal enterocytes, hepatocytes and macrophages. Physiologically, hepcidin inhibition occurs in cases of anaemia, iron deficiency, hypoxia (induced by HIF-2α) or due to genetic alterations, such as in the case of haemochromatosis. In contrast, hepcidin stimulation mainly occurs in cases of inflammation, which contributes to the development of anaemia in these cases.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Preliminary phase 1 data have already shown the increase in haemoglobin after treatment with FG-2216 in 12 patients on haemodialysis and in 6 healthy controls.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> includes some of the PHIs recently evaluated in phase 2 clinical studies. The initial results from clinical trials have now become available. Thus, experimentally, Molidustat is capable of stimulating EPO and reticulocyte production, without increasing blood pressure. Its effect is dose-dependent and it is administered by oral route. A daily dose of 2.5<span class="elsevierStyleHsp" style=""></span>mg/kg obtains an effect equivalent to the administration of 100<span class="elsevierStyleHsp" style=""></span>IU/kg epoetin.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a> Roxadustat was compared to placebo in a controlled and randomised study. It was observed that a dose of 1<span class="elsevierStyleHsp" style=""></span>mg/kg administered 2 times a week obtains a similar response on days 1 and 29, and on both days peak plasma levels of endogenous EPO were reached around 8<span class="elsevierStyleHsp" style=""></span>h after administration. The effect on haemoglobin levels is also dose-dependent, with optimal doses at 1.5<span class="elsevierStyleHsp" style=""></span>mg/kg. No advantages were found at greater doses, and administration 3 times a week is preferable to 2. In contrast, there is a significantly greater reduction of hepcidin levels if it is administered in doses of 2<span class="elsevierStyleHsp" style=""></span>mg/kg 3 times per week.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> Similar results have recently been described with Daprodustat in stage 3–5 ACKD patients regarding the increase of haemoglobin and reticulocytes number, as well as in the decrease of hepcidin.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> Roxadustat maintain haemoglobin levels in patients on haemodialysis previously treated with epoetin, and also decrease hepcidin levels.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Therefore, PHIs constitute a new therapeutic group for the treatment of renal anaemia with a series of advantages such as the capacity to increase haemoglobin levels through HIF stabilisation, thereby preventing fluctuations. They can be administered orally, enable improvement of iron mobilisation and present a good safety profile. As such, this may be a good alternative in the future for the management of anaemia in patients with ACKD, especially if the price is competitive as compared to ESAs, which require recombinant engineering processes for their manufacture. Nevertheless, more long-terms studies are needed to ensure that the potential effect of HIF on angiogenesis does not present adverse effects.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">GATA inhibitors</span><p id="par0075" class="elsevierStylePara elsevierViewall">Erythropoiesis control by HIF-2α is negatively regulated by GATA, which is a transcription factor that inhibits EPO expression in the liver and kidneys. The main stimuli of this system are some of the known proinflammatory cytokines, such as IL-1, IL-6 or TNFα (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). There are 4 subtypes of GATA and it seems that GATA-2 is the one that acts most potently on the regulation EPO synthesis. Thus, just as drugs that stabilise HIF-2α cause an increase in EPO synthesis, drugs that are capable of blocking the GATA system can act in a similar way.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Currently, at least 2 specific GATA inhibitors are known. Animal studies have shown that K7174, which suppresses the activity of GATA-1, -2 and -3, is capable of increasing the synthesis of EPO previously inhibited by inflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> K11706 is a much more potent inhibitory factor of GATA-2 and -3. In vitro experience has shown that its oral administration reverses the decrease in haemoglobin, reticulocytes and colony forming units-erythroid (CFU-E) induced by cytokines such as IL-1β, or TNF-α.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> Therefore, this group of inhibitors may improve inflammation-induced erythropoiesis. Nevertheless, more advanced-phase clinical studies are needed to be able to show that they may have a role in human clinical practice.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Agents with other mechanisms of action</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Anti-hepcidin agents</span><p id="par0085" class="elsevierStylePara elsevierViewall">In addition to the inhibitory effect of hepcidin produced by PHIs that was described above, a specific anti-hepcidin drug has recently been developed. It was initially tested in monkeys,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> but the first publication in humans is now available. This drug, known as Lexaptepid, is capable of increasing serum iron levels and transferrin saturation in subjects who have previously developed an increase in hepcidin induced by endotoxaemia. The treatment was well tolerated.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> Therefore, treatment with anti-hepcidin drugs represents another new path for the management of anaemia associated with inflammation.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Anti-activin agents</span><p id="par0090" class="elsevierStylePara elsevierViewall">Activin is a protein formed by 2 similar monomers bound by disulphide bonds, which belongs to the TGF-β superfamily. It is mainly produced in the ovarian follicles and gonads, and its most important function is to regulate the menstrual cycle by controlling FSH secretion. It also controls spermatogenesis and participates in healing processes and in the regulation of insulin secretion. In the bones, it acts as an inhibitor of bone growth by stimulating osteoclasts and inhibiting osteoblasts. It has 2 types of receptors, type I and type II.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Recently, an activin receptor type IIA antagonist called Sotatercept was developed. In a phase 1 trial for the treatment of osteoporosis in postmenopausal women it demonstrated an improvement in bone formation markers and a decrease in bone resorption, but as a side effect there was an increase in haemoglobin levels and in reticulocyte count.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> Following these findings, a large number of clinical trials have been started for the treatment of anaemia associated with neoplastic processes, metastasis or ACKD.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Preliminary (unpublished) data have shown in a small sample of patients on haemodialysis that Sotatercept produces a dose-dependent improvement in haemoglobin levels; the best response is attained with 0.7<span class="elsevierStyleHsp" style=""></span>mg/kg. An added effect was bone formation stimulation, with an improvement in structure and density, assessed by quantitative computed tomography, together with an improvement in progression of vascular calcification assessed by the Agatston score. These findings make Sotatercept a promising molecule with the capacity to favourably treat the standard complications of ACKD patients, such as anaemia, vascular calcification and bone alterations.</p><p id="par0105" class="elsevierStylePara elsevierViewall">In sum, new molecules have been developed with the capacity to stimulate erythropoiesis by mechanisms different to current ESAs. Some of them can be administered orally and they have shown good tolerance to date. In addition to the possibility of reducing treatment costs, these molecules mark the start of a new encouraging era of anaemia management in patients with ACKD.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Key concepts</span><p id="par0110" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0115" class="elsevierStylePara elsevierViewall">New drugs for the treatment of renal anaemia, currently in advanced clinical trials, are showing very encouraging results for the coming years.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0120" class="elsevierStylePara elsevierViewall">PHIs stimulate erythropoiesis through HIF stabilisation and hepcidin inhibition.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0125" class="elsevierStylePara elsevierViewall">Activin inhibitors such as Sotatercept may act by improving anaemia, delaying vascular calcification and improving bone structure and density.</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare they received no funding of any type for this review.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest regarding the content of this review.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres828197" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec824429" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres828198" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec824430" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "EPO-mimetic agents" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Agents that stimulate endogenous erythropoietin" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Prolyl-hydroxylase inhibitors (PHIs)" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "GATA inhibitors" ] ] ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Agents with other mechanisms of action" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Anti-hepcidin agents" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Anti-activin agents" ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Key concepts" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-02-10" "fechaAceptado" => "2016-03-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec824429" "palabras" => array:5 [ 0 => "Chronic kidney disease" 1 => "Anemia" 2 => "Prolyl-hydroxylase inhibitors" 3 => "Sotatercept" 4 => "Hepcidin" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec824430" "palabras" => array:5 [ 0 => "Enfermedad renal crónica" 1 => "Anemia" 2 => "Inhibidores de prolil-hidroxilasa" 3 => "Sotatercept" 4 => "Hepcidina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The new drugs developed for the treatment of anemia in chronic kidney disease patients, together with their mechanisms of action are reviewed. At present, many of them are already in advanced stages of clinical trials and is expected to be incorporated into the therapeutic arsenal in the coming years. The potential benefits and possible limitations are also described.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se revisan los nuevos fármacos desarrollados para el tratamiento de la anemia en la enfermedad renal crónica, junto con sus mecanismos de acción. En la actualidad, muchos de ellos se encuentran ya en fases avanzadas de ensayos clínicos y es de esperar que se incorporen al arsenal terapéutico en los próximos años. Se describen las potenciales ventajas y sus posibles limitaciones.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: López-Gómez JM, Abad S, Vega A. Nuevas expectativas en el tratamiento de la anemia en la enfermedad renal crónica. Nefrologia. 2016;36:232–236.</p>" ] ] "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" => 997 "Ancho" => 1460 "Tamanyo" => 56225 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of GATA inhibitors.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1986 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">First publication with rH-EPO<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1990 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">rH-EPO approved by the EMEA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1998 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">“Hb normalisation” study<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Darbepoetin-¿ introduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CREATE and CHOIR studies<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">3,4</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pegylated rH-EPOβ approved \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TREAT study<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">“Biosimilars” introduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">First clinical trials with EPO-mimetics<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">6,7</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1393508.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Most noteworthy events in the treatment of renal anaemia.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Exogenous EPO</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Epoetin and analogues \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>EPO-mimetic agents \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Agents that stimulate endogenous EPO</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Prolyl-hydroxylase inhibitors (PHIs) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GATA inhibitors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Agents with other mechanisms of action</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anti-hepcidin agents \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anti-activin agents \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1393507.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Classification of erythropoiesis stimulating agents.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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="left" valign="top" scope="col" style="border-bottom: 2px solid black">PHI \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">Pharmaceutical company \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">Name \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 " align="left" valign="top">AKB6548 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Akebia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vadadustat \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GSK1278863 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GSK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Daprodustat \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BAY 85-3934 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bayer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Molidustat \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FG4592 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FibroGen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Roxadustat \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1393509.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Prolyl-hydroxylase inhibitors (PHIs).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.G. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 1 | 3 |
| 2024 October | 56 | 42 | 98 |
| 2024 September | 50 | 27 | 77 |
| 2024 August | 74 | 66 | 140 |
| 2024 July | 47 | 33 | 80 |
| 2024 June | 82 | 45 | 127 |
| 2024 May | 69 | 38 | 107 |
| 2024 April | 53 | 31 | 84 |
| 2024 March | 60 | 29 | 89 |
| 2024 February | 45 | 37 | 82 |
| 2024 January | 32 | 32 | 64 |
| 2023 December | 35 | 20 | 55 |
| 2023 November | 45 | 24 | 69 |
| 2023 October | 55 | 35 | 90 |
| 2023 September | 38 | 25 | 63 |
| 2023 August | 50 | 28 | 78 |
| 2023 July | 59 | 19 | 78 |
| 2023 June | 46 | 23 | 69 |
| 2023 May | 61 | 36 | 97 |
| 2023 April | 39 | 20 | 59 |
| 2023 March | 56 | 23 | 79 |
| 2023 February | 44 | 29 | 73 |
| 2023 January | 42 | 20 | 62 |
| 2022 December | 87 | 39 | 126 |
| 2022 November | 68 | 35 | 103 |
| 2022 October | 66 | 43 | 109 |
| 2022 September | 54 | 27 | 81 |
| 2022 August | 50 | 45 | 95 |
| 2022 July | 48 | 46 | 94 |
| 2022 June | 57 | 38 | 95 |
| 2022 May | 80 | 29 | 109 |
| 2022 April | 52 | 48 | 100 |
| 2022 March | 76 | 58 | 134 |
| 2022 February | 70 | 45 | 115 |
| 2022 January | 112 | 42 | 154 |
| 2021 December | 77 | 41 | 118 |
| 2021 November | 57 | 28 | 85 |
| 2021 October | 72 | 36 | 108 |
| 2021 September | 59 | 36 | 95 |
| 2021 August | 67 | 47 | 114 |
| 2021 July | 43 | 36 | 79 |
| 2021 June | 33 | 26 | 59 |
| 2021 May | 51 | 43 | 94 |
| 2021 April | 95 | 89 | 184 |
| 2021 March | 72 | 47 | 119 |
| 2021 February | 48 | 24 | 72 |
| 2021 January | 48 | 23 | 71 |
| 2020 December | 37 | 16 | 53 |
| 2020 November | 47 | 21 | 68 |
| 2020 October | 38 | 26 | 64 |
| 2020 September | 46 | 19 | 65 |
| 2020 August | 50 | 28 | 78 |
| 2020 July | 47 | 12 | 59 |
| 2020 June | 35 | 26 | 61 |
| 2020 May | 74 | 10 | 84 |
| 2020 April | 44 | 22 | 66 |
| 2020 March | 35 | 19 | 54 |
| 2020 February | 50 | 16 | 66 |
| 2020 January | 71 | 31 | 102 |
| 2019 December | 58 | 30 | 88 |
| 2019 November | 65 | 14 | 79 |
| 2019 October | 53 | 17 | 70 |
| 2019 September | 57 | 13 | 70 |
| 2019 August | 47 | 21 | 68 |
| 2019 July | 37 | 28 | 65 |
| 2019 June | 41 | 21 | 62 |
| 2019 May | 45 | 22 | 67 |
| 2019 April | 107 | 19 | 126 |
| 2019 March | 70 | 26 | 96 |
| 2019 February | 48 | 22 | 70 |
| 2019 January | 52 | 25 | 77 |
| 2018 December | 191 | 47 | 238 |
| 2018 November | 348 | 23 | 371 |
| 2018 October | 183 | 25 | 208 |
| 2018 September | 66 | 15 | 81 |
| 2018 August | 80 | 20 | 100 |
| 2018 July | 66 | 18 | 84 |
| 2018 June | 61 | 18 | 79 |
| 2018 May | 90 | 21 | 111 |
| 2018 April | 80 | 7 | 87 |
| 2018 March | 97 | 9 | 106 |
| 2018 February | 54 | 8 | 62 |
| 2018 January | 62 | 6 | 68 |
| 2017 December | 65 | 11 | 76 |
| 2017 November | 87 | 20 | 107 |
| 2017 October | 48 | 15 | 63 |
| 2017 September | 76 | 15 | 91 |
| 2017 August | 89 | 25 | 114 |
| 2017 July | 69 | 17 | 86 |
| 2017 June | 46 | 9 | 55 |
| 2017 May | 56 | 10 | 66 |
| 2017 April | 50 | 20 | 70 |
| 2017 March | 50 | 18 | 68 |
| 2017 February | 30 | 17 | 47 |
| 2017 January | 29 | 41 | 70 |
| 2016 December | 38 | 27 | 65 |
| 2016 November | 74 | 45 | 119 |
| 2016 October | 87 | 30 | 117 |
| 2016 September | 109 | 12 | 121 |
| 2016 August | 120 | 11 | 131 |
| 2016 July | 21 | 1 | 22 |
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