Review
Renal anemia: current treatments and emerging molecules
Anemia renal: tratamientos actuales y moléculas emergentes
M. Heras-Benito
Nephrology Service, Hospital Universitario de Salamanca, Salamanca, Spain
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"apellidos" => "Heras-Benito" "email" => array:1 [ 0 => "mherasb@saludcastillayleon.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Nephrology Service, Hospital Universitario de Salamanca, Salamanca, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anemia renal: tratamientos actuales y moléculas emergentes" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1608 "Ancho" => 3008 "Tamanyo" => 214497 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Action of the hypoxia-inducible factor in conditions of normoxia (A), in conditions of hypoxia (B), and mechanism of action of hypoxia-inducible factor prolyl hydroxylase inhibitors.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">HIF: hypoxia-inducible factor; PH: prolyl hydroxylase.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Definition</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anemia is defined as a hemoglobin value <13 g/dl in men and <12 g/dl in nonpregnant women.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The first association between anemia and kidney disease was established by the British physician Richard Bright in 1836.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Renal anemia is a form of normocytic, normochromic, hypoproliferative anemia.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It usually presents when the glomerular filtration rate (GFR) is less than 50 ml/min/1.73 m<span class="elsevierStyleSup">2</span>.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> especially in diabetic patients, in whom it has an earlier onset,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a> and in older adults, in whom it may be detected later with a GFR < 30 ml/min/1.73 m<span class="elsevierStyleSup">2</span>.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The onset of anemia in patients with chronic kidney disease (CKD) with a GFR greater than 60 ml/min/1.73 m<span class="elsevierStyleSup">2</span> would make it necessary to rule out other types of anemias such as iron deficiency or deficiency anemias (vitamin B12-folate), though renal and iron deficiency anemia can coexist.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The prevalence of anemia in patients with CKD is nearly double than in the general population and it is more common in stage 5 of the disease.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In Spain, a study conducted on 504 patients with stage 3–5 CKD who were not on dialysis showed a prevalence of anemia of 58.5%. However, only 15% had hemoglobin values less than 11 g/dl.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In addition, the prevalence is much higher in the older population compared to the younger population and in patients with diabetes versus those who do not have diabetes.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,4,8</span></a> On the other hand, other diseases that may progress to end-stage renal disease, such as hepatorenal polycystosis, tend to have a lower frequency of anemia due to the presence of renal cysts and an increase in endogenous erythropoietin production.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As a consequence of anemia, renal patients have worse quality of life, greater in-hospital morbidity, a higher rate of hospitalizations, and higher mortality.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,10</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathogenesis of renal anemia</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Erythropoietin</span><p id="par0020" class="elsevierStylePara elsevierViewall">It has been known since the 1950s that the kidney plays a crucial role in erythropoiesis through the amount of circulating erythropoietin, whose production is regulated by the body’s oxygen supply and demand.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Erythropoietin is a regulating hormone synthesized in the cells of the renal interstitium in response to tissue hypoxia.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Its binding to specific receptors in erythroid progenitor cells in the bone marrow leads to an increase in circulating erythrocytes and an increase in hemoglobin values.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Iron</span><p id="par0025" class="elsevierStylePara elsevierViewall">Iron, which is essential for hemoglobin synthesis, plays an important role in biological reactions, including oxygen transport, cellular respiration, and DNA synthesis; in excess, it is potentially toxic.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,14</span></a> Its poor bioavailability make it so that most organisms have a conservation and internal recycling system for it.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Causes of renal anemia</span><p id="par0030" class="elsevierStylePara elsevierViewall">The relative deficiency of erythropoietin is not the only cause of renal anemia.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In addition to this, other causes have been linked to the pathogenesis of renal anemia, including absolute iron deficiency (transferrin saturation index (TSI) <20% and ferritin <100 ng/ml or functional iron deficiency (TSI <20% and normal or high ferritin concentration)<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>; circulating uremic-induced inhibitors of erythropoiesis; nutritional deficiencies, such as vitamin B12 and folate deficiency; blood loss due to hemodialysis; and inflammation.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Regarding treatment, untreated iron deficiency in patients with CKD can cause anemia and, in addition, contribute to resistance to the action of erythropoiesis-stimulating agents (ESA).<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Evolution of renal anemia treatment</span><p id="par0035" class="elsevierStylePara elsevierViewall">Periodic red blood cell transfusions were an effective way to address hemoglobin values of 5–6 g/dl which renal patients presented with before the discovery of recombinant human erythropoietin in 1989.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Blood transfusions had the beneficial effects of improving quality of life and the lethargy these patients presented with, but they entailed other side effects, such as iron overload and organ dysfunction due to deposits, the possibility of infection transmission, and sensitization to HLA antigens in dialysis patients who may require a renal transplant.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The discovery of recombinant human erythropoietin and the development of ESA represented a change in the approach to anemia in renal disease.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,18</span></a> First-generation ESAs (epoetin alfa and beta) were effective, but needed to be administered three times per week. Their pharmacological modification allowed for extending their half-life, giving rise to second-generation ESAs (darbepoetin alfa and continuous erythropoietin receptor activator (CERA)).<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Hemoglobin targets in the treatment of renal anemia</span><p id="par0045" class="elsevierStylePara elsevierViewall">The hemoglobin values used to define renal anemia (hemoglobin <13 g/dl in men and <12 g/dl in women) are not the same as those used for indicating treatment.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In fact, the recommendations of anemia working groups indicate the benefit of maintaining hemoglobin levels of around <11 g/dl and, in any case, not exceeding 13 g/dl, especially in ESA treatment.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In Spain, a multicentric study demonstrated that in most nephrology units, patients with CKD who were not on dialysis and who received ESA treatment, the focus was on maintaining a target hemoglobin level of <11 g/dl.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> On the other hand, certain groups, such as patients with diabetes, cerebrovascular disease, or cancer must take special precautions during ESA treatment and a hemoglobin target of less than 10 g/dl can be considered.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Regarding the recommendation to start iron supplement treatment, it would be indicated in patients with CKD and anemia with hemoglobin <12 g/dl whereas there is no consensus on patients with hemoglobin >12 g/dl except when they have an absolute or functional iron deficiency.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Current renal anemia treatments</span><p id="par0055" class="elsevierStylePara elsevierViewall">At present, the pillars of treatment for CKD-related anemia are based on the use of ESAs, iron supplementation (oral or IV), and, to a lesser extent, the use of periodic transfusions.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,20</span></a> The latter may only be the consequence of ESA treatment failure due to resistance to its action and/or absence of iron deficiency.</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment with erythropoiesis-stimulating agents</span><p id="par0060" class="elsevierStylePara elsevierViewall">ESAs have beneficial effects for patients, improve their symptoms, and, in the absence of resistance to their action, prevent dependence on periodic transfusions and the negative consequences they entail.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> On the other hand, side effects of ESAs have been described. They are possibly related to reaching a high hemoglobin target or the use of high doses of ESAs (supraphysiological doses) due to erythropoietin resistance.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a> These side effects include an increase in cardiovascular risk, worsening of hypertension, and vascular access thrombosis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The need for a parenteral route of administration and cold storage as well as the generation of anti-erythropoietin antibodies, which may cause pure red cell aplasia, are other negative factors of ESAs.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,21</span></a> In certain countries with funding problems, their high cost may limit access and therefore the need to resort to periodic transfusions.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> The loss of the European patent on recombinant human erythropoietin and the development of erythropoietin biosimilars with a similar efficacy and safety to the original medicine has led to a greater number of patients having access to these molecules with a lower cost to countries’ healthcare budgets.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Iron supplementation</span><p id="par0070" class="elsevierStylePara elsevierViewall">The use of ESAs entails an increase in iron demand to achieve effectiveness, with absolute or functional iron deficiency a factor to consider in the case of a poor response to ESA.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In addition, an increase in iron losses has been described in patients with CKD. Losses are estimated to be around 1–3 g per year in hemodialysis patients and are associated with bleeding due to uremia-associated platelet dysfunction or blood becoming entrapped in capillary dialyzers.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,21</span></a> Worse oral iron absorption makes it necessary to resort to parenteral administration of iron preparations,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> which increase hemoglobin levels more quickly and efficiently and reduce ESA doses.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Among the strategies for using intravenous iron preparations in patients with CKD who are not on dialysis include using a high dose and a low frequency of administration with the goal of preserving venous access for patients who may later begin hemodialysis. What’s more, this is a safe and cost-effective approach.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Among the beneficial effects of iron supplementation are an improvement in physical, cognitive, and immune function.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Its negative effects are linked to an increase in iron deposits in tissues and increase in the risk of infection and oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,24</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">New targets in the treatment of renal anemia</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Hypoxia-inducible factor</span><p id="par0075" class="elsevierStylePara elsevierViewall">Hypoxia-inducible factor (HIF) is a key transcription factor that produces a physiological response to reduced tissue oxygen levels through the expression of certain genes, including those involved in erythropoiesis, whose purpose is to restore the oxygen balance and protect against cellular damage.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> In addition to erythropoiesis, HIF is involved in the control of genes involved in angiogenesis, metabolism, apoptosis, and cell migration.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> It is a heterodimer composed of two subunits (α and β). The α subunit contains three isoforms (HIF-1α, HIF-2α, HIF-3α) and any of them can join with the β subunit in the nucleus, giving rise to the expression of different genes.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The HIF-2α isoform is expressed in peritubular fibroblasts, which is the main site of renal erythropoietin production.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,27</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">HIF activity is regulated by hydroxylation at two proline residues by a family of prolyl hydroxylase enzymes (so called prolyl-hydroxylase, which in turn has three members: PHD1, PHD2, PHD3).<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In normal oxygen conditions, the α subunits of HIF are degraded by prolyl hydroxylase action. In conditions of hypoxia, prolyl hydroxylase decreases its activity, allowing for HIFα stabilization and its heterodimerization by binding to the β subunit; by accumulating in the nucleus, it allows the expression of HIF target genes.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,25,28</span></a><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> summarizes HIF action in conditions of normoxia (A), in conditions of hypoxia (B), and the mechanism of action of HIF prolyl hydroxylase inhibitors.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Hepcidin-ferroportin axis</span><p id="par0085" class="elsevierStylePara elsevierViewall">Hepcidin, a peptide hormone composed of 25 amino acids that is synthesized in the liver, plays a fundamental role in iron homeostasis regulation in order to maintain a constant supply of red blood cells and prevent high iron levels becoming harmful to tissues.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15,29</span></a> It is regulated according to iron supply, the need for erythropoiesis, and the state of inflammation.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Its effect on the cellular level is related to binding with ferroportin, the main iron exporting protein. Thus, in conditions of iron deficiency or after an episode of bleeding, hepcidin levels decrease and the iron taken up by the cells is released into the plasma through ferroportin, promoting erythropoiesis. On the contrary, in conditions of inflammation or infection, hepcidin levels increase and iron sequestration occurs in the cells that express ferroportin, limiting the availability of iron and, in turn, erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">New emerging molecules for the treatment of renal anemia: hypoxia-inducible factor prolyl hydroxylase inhibitors</span><p id="par0095" class="elsevierStylePara elsevierViewall">In CKD, the increase in hepcidin—due to its decreased clearance and inflammation—is a cause of ESA hyporesponsiveness, as iron deposits are not available for erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The development of molecules that inhibit the HIF prolyl hydroxylase enzyme are an emerging therapy for the treatment of CKD anemia through their stimulation of endogenous erythropoietin synthesis and by improving iron availability (decline in hepcidin and ferritin).<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,25</span></a> Based on this mechanism of action, patients who may benefit from its use are those with CKD anemia with resistance to ESA action who require high doses, with the consequent increased risk of side effects.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Several molecules have been developed as HIF prolyl hydroxylase inhibitors. Their route of administration is oral and they are primarily eliminated from the body through renal clearance. Their plasma concentrations can be increased through interactions with other drugs that inhibit enzymes and specific transporters.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> There is diversity in prolyl-hydroxylase selectivity according to the domain: molidustat inhibits PHD2 and roxadustat inhibits the three PHD domains.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The main HIF prolyl hydroxylase inhibitors that have been studied in clinical trials are roxadustat,<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31–41</span></a> daprodustat,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> vadadustat,<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> desidustat,<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> enarodustat,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and molidustat.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the main clinical trials conducted with roxadustat.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">A recent meta-analysis by Chen et al. that included more than 13,000 patients from 30 studies (including roxadustat, daprodustat, vadadustat, molidustat, desidustat, and enarodustat) and analyzed the long-term safety and efficacy of HIF prolyl hydroxylase inhibitors for the treatment of renal anemia concluded that these drugs increase hemoglobin levels and promote iron use; they are also well-tolerated.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In this meta-analysis, in regard to side effects, both hyperkalemia (especially with roxadustat) and hypertension were more frequent than in the placebo group.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> The cause for the increase in thrombotic events is not clear, although it could be related to the increase in hemoglobin due to the change from an ESA dose to HIF prolyl hydroxylase inhibitors.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Use of hypoxia-inducible factor prolyl hydroxylase inhibitors in clinical practice</span><p id="par0115" class="elsevierStylePara elsevierViewall">Most experience with this new drug class comes from Asian countries, where they are already in use. The Asian Pacific Society of Nephrology (APSN), which has a HIF prolyl hydroxylase inhibitor Expert Committee comprising 11 nephrologists with clinical experience or researchers who work with these drugs, has created a document with recommendations on the use of these molecules. Among these recommendations, it is indicated to consider these agents as an alternative to ESAs for correcting and maintaining the target hemoglobin level in order to prevent renal anemia in patients with CKD who are or are not on dialysis.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Likewise, for these agents to be effective, it is recommended to evaluate iron status before their administration and correct iron deficiency in the event it is detected (ferritin <100 ng/dl when not on dialysis and <200 ng/ml on dialysis or transferrin saturation index <20%).<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In Europe, roxadustat is the only approved HIF prolyl hydroxylase inhibitor. In Spain, where it is about to be marketed, there is a therapeutic positioning report on its use from the Ministry of Health.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">On the other hand, although the efficacy of these drugs in controlling renal anemia has been demonstrated in clinical trials, the concerning safety aspects and possible severe long-term side effects are issues that generate uncertainty and remain to be clarified.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Some of these safety aspects may arise from an exaggerated pharmacological response or due to the effects of these agents in transcription beyond the genes involved in erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Therefore, among its recommendations, the Asian Pacific Society of Nephrology also includes a section on potential concerns, including malignancy, retinopathy, liver dysfunction, hyperkalemia, hypertension, pulmonary hypertension and heart failure, thrombotic events, and vascular calcification. They urge close monitoring of patients on these drugs.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion, advances in the pathogenesis of renal anemia have allowed for developing effective treatments for treating renal anemia based on the use of erythropoiesis-stimulating agents, iron supplementation, and, to a lesser extent, blood transfusions. The development of new molecules that allow for endogenously stimulating erythropoietin synthesis and improving iron availability are an emerging therapeutic alternative for renal anemia, especially in patients with hyporesponsiveness to erythropoiesis-stimulating agents.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Key points</span><p id="par0130" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1.</span><p id="par0135" class="elsevierStylePara elsevierViewall">Anemia is a complication of chronic kidney disease with a greater prevalence and severity as the disease progresses. It entails an increase in morbidity and mortality and worse quality of life in renal patients.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2.</span><p id="par0140" class="elsevierStylePara elsevierViewall">Erythropoietin deficiency, absolute or functional iron deficiency, nutritional deficiencies, uremic erythropoiesis inhibitors, blood loss related to the hemodialysis process, and inflammation contribute to the onset of renal anemia.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3.</span><p id="par0145" class="elsevierStylePara elsevierViewall">The current treatment for renal anemia is based on the use of erythropoiesis-stimulating agents through a parenteral route of administration and iron supplementation (oral or intravenous) and, in cases that do not respond to these measures, on periodic blood transfusions.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4.</span><p id="par0150" class="elsevierStylePara elsevierViewall">The discovery of hypoxia-inducible factor and the hepcidin-ferroportin axis is an alternative pathway for the treatment of renal anemia, especially in patients who are resistant to erythropoiesis-stimulating agents with a need for high doses and, thus, greater risk of side effects.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5.</span><p id="par0155" class="elsevierStylePara elsevierViewall">Phase III clinical trials on hypoxia-inducible factor prolyl hydroxylase inhibitors have demonstrated the efficacy of these agents in the control of renal anemia through an oral route of administration. However, concerning long-term safety aspects remain to be clarified.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">6.</span><p id="par0160" class="elsevierStylePara elsevierViewall">Asian countries have more experience with the use of hypoxia-inducible factor prolyl hydroxylase inhibitors and a document with recommendations has been created by the Asian Pacific Society of Nephrology (APSN). Roxadustat is the only agent from this drug class approved in Europe.</p></li></ul></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0165" class="elsevierStylePara elsevierViewall">The author declares that he has not received funding for conducting this study.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The author declares no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres2050074" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1750881" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2050075" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1750882" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Definition" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Pathogenesis of renal anemia" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Erythropoietin" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Iron" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Causes of renal anemia" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Evolution of renal anemia treatment" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Hemoglobin targets in the treatment of renal anemia" ] 8 => array:3 [ "identificador" => "sec0040" "titulo" => "Current renal anemia treatments" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Treatment with erythropoiesis-stimulating agents" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Iron supplementation" ] ] ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "New targets in the treatment of renal anemia" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Hypoxia-inducible factor" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Hepcidin-ferroportin axis" ] ] ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "New emerging molecules for the treatment of renal anemia: hypoxia-inducible factor prolyl hydroxylase inhibitors" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Use of hypoxia-inducible factor prolyl hydroxylase inhibitors in clinical practice" ] 12 => array:2 [ "identificador" => "sec0080" "titulo" => "Key points" ] 13 => array:2 [ "identificador" => "sec0085" "titulo" => "Funding" ] 14 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflicts of interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-01-16" "fechaAceptado" => "2023-04-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1750881" "palabras" => array:5 [ 0 => "Anemia" 1 => "Chronic kidney disease" 2 => "Erythropoiesis" 3 => "Erythropoiesis-stimulating agents" 4 => "Hypoxia-inducible factor prolyl-hydroxylase inhibitors" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1750882" "palabras" => array:5 [ 0 => "Anemia" 1 => "Enfermedad renal crónica" 2 => "Eritropoyesis" 3 => "Agentes estimuladores de eritropoyesis" 4 => "Inhibidores de prolil-hidroxilasa de factor inducible por hipoxia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Anemia is a common complication of kidney disease and the prevalence increases as the disease progresses. It worsens the quality of life of patients and increases morbidity and mortality. The current rationale for treating renal anemia is based on the use of erythropoiesis-stimulating agents, iron supplementation and, to a lesser extent, the use of transfusions. Stimulation of endogenous erythropoietin synthesis and improvement of iron availability, through inhibition of prolil-hydroxilase-hypoxia-inducible factor (PH-HIF), represents a new oral alternative for renal anemia treatment. Clinical trials with PH-HIF inhibitors have demonstrated their efficacy in maintaining target hemoglobin levels. However, aspects concerning long-term safety are pending a clarification. In conclusion, advances in the pathogenesis of renal anemia make it possible to have current treatments to treat renal anemia. The development of new molecules, based on the inhibition of PH-HIF, represents a new effective alternative for anemia associated with kidney disease, especially in patients with resistance to erythropoiesis-stimulating agents.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La anemia es una complicación frecuente de la enfermedad renal cuya prevalencia aumenta a medida que progresa la enfermedad, empeora la calidad de vida de pacientes y aumenta la morbimortalidad. El fundamento actual para tratar la anemia renal se basa en empleo de agentes estimuladores de eritropoyesis, la suplementación con hierro y en menor medida, el uso de trasfusiones. La estimulación de la síntesis endógena de eritropoyetina y la mejora de la disponibilidad del hierro, a través de la inhibición de prolil-hidroxilasa del factor inducible por la hipoxia (PH-HIF), representa una nueva alternativa oral de tratamiento de la anemia renal. Los ensayos clínicos con inhibidores PH-HIF han demostrado su eficacia en mantener niveles de hemoglobina objetivo. Sin embargo, aspectos concernientes a la seguridad a largo plazo se encuentran pendientes de clarificar. En conclusión, los avances en la patogenia de anemia renal permiten disponer de tratamientos actuales para tratar la anemia renal y el desarrollo de nuevas moléculas, basadas en la inhibición de PH-HIF, representa una nueva alternativa eficaz para anemia asociada con enfermedad renal, especialmente en pacientes con resistencia a agentes estimuladores de eritropoyesis.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1608 "Ancho" => 3008 "Tamanyo" => 214497 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Action of the hypoxia-inducible factor in conditions of normoxia (A), in conditions of hypoxia (B), and mechanism of action of hypoxia-inducible factor prolyl hydroxylase inhibitors.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">HIF: hypoxia-inducible factor; PH: prolyl hydroxylase.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">HD: hemodialysis; PD: peritoneal dialysis.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author, publication/reference \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study phase, location \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Roxadustat vs comparator \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Result \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chen, NEJM 2019<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02652819 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No dialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superior; hyperkalemia and metabolic acidosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shutot, NDT 2021<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT01887600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, European \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No dialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superior and good tolerance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fishbane, JASN 2021<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02174627 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, International \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No dialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increase in hemoglobin; similar side effects \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Barrat, NDT 2021<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DOLOMITES \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, European \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No dialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Darbepoetin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not inferior \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chen, NEJM 2019<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02652806 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not inferior; hyperkalemia, upper respiratory infection \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Csiky, Adv Ther 2021<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PYRENEES \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, European \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alfa/darbepoetin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not inferior \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Charytan, KI rep, 2021<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SIERRAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, United States of America \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not inferior \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Akizawa, JASN 20<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02952092 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Darbepoetin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not inferior \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fishbane, JASN 2022<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ROCKIES NCT02174731 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, International \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dialysis (HD/PD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increase in hemoglobin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Akizawa, Ther Apher Dial 2020<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02780726 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment with previous ESAs or not \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Safe and effective \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Provenzano, NDT 2021<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HIMALAYAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, International \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Incidents of dialysis (HD or PD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Corrects and maintains hemoglobin. 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