Erythropoiesis-stimulating agents for the management of anemia of chronic kidney disease: past advancements and current innovations.
Anemia is a hallmark complication of ESRD that negatively impacts the daily lives of patients on dialysis (Nurko, 2006). Red blood cells (RBCs) play the essential role of transporting oxygen to tissues (Reichel & Gmeiner, 2010), and anemia is the "clinical manifestation of a decrease in circulating RBC mass" (National Kidney Foundation [NKF], 2006, p. S11). A highly prevalent complication in all stages of chronic kidney disease (CKD), anemia worsens as the glomerular filtration rate (GFR) decreases and kidney function declines (NKF, 2006). In one study, 27% of patients with Stage 5 CKD (GFR less than 15 mL/min/1.73 [m.sup.2])) were found to have hemoglobin (Hb) levels of 10 g/dL or less, and 76% had Hb of 12 g/dL or less (McClellan et at., 2004). Erythropoietin deficiency is a primary underlying cause of anemia of CKD. Reduced iron availability, chronic inflammation, and shortened RBC lifespan are among the other contributing factors (Schmid & Schiffl, 2010). Additionally, anemia in patients receiving hemodialysis may be confounded by the blood loss experienced at each dialysis session, estimated to be as high as 2 to 3 L over the course of a year (Sargent & Acchiardo, 2004).
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Until the latter part of the 20th century, clinicians had few options to offer for treatment of anemia. The development of erythropoiesis-stimulating agents (ESAs) in the 1980s revolutionized anemia management; it provided patients and clinicians with a much-needed treatment option and hope for improved quality of life. This article charts the history of anemia management in patients with ESRD, discusses the receptor science behind the discovery of erythropoietin and subsequent development of ESA therapy, and briefly reviews the mechanism of action and select attributes of ESAs.
A Century of Discoveries And Advances
A timeline of key research strides and advances in management of ESRD and anemia over the last 100 years is depicted in Figure 1, and a summary of these advancements follows.
Development of Dialysis
The relationship between the symptoms of kidney failure and its pathology were established as early as 1827, but it was not until nearly a century later (in 1924) that the first dialysis procedure was performed on a human (Gottschalk & Fellner, 1997). The next few decades witnessed the development of suitable dialysis machines, initially used to help patients recover from acute kidney failure; in the United States, the first dialysis treatment was recorded in 1947 at Mount Sinai Hospital in New York (McBride, 1989). In 1960, the first long-term dialysis treatment began for patients with chronic kidney failure, and in 1962, the first outpatient hemodialysis facility was established to treat these patients (Blagg, 2007). Also in the 1960s, home dialysis became possible, and dialysis systems (both hemodialysis and peritoneal dialysis) continued to be refined and automated to improve treatment outcomes (Blagg, 2007; McBride, 1989). In 1972, Congress passed Public Law 92-603, allowing for Medicare reimbursement for dialysis. This led to dramatically improved prognosis for many patients with ESRD (Schreiner, 2000). Continuous ambulatory peritoneal dialysis (CAPD) was developed in 1976 (Popovich et al., 1978), and continuous cyclic peritoneal dialysis (CCPD) was introduced in 1981 (Diaz-Buxo, 2001). By December 31, 2010, 383,992 patients in the United States were receiving hemodialysis, and 29,733 were receiving peritoneal dialysis, bringing the total dialysis population to 413,725 patients (U.S. Renal Data System [USRDS], 2012).
Discovery of Erythropoietin
In the late 1800s, a series of papers reported on the enhanced oxygen capacity of blood at higher altitudes and described the associated increase in red blood cells (RBCs) (Bert 1878, 1882; Viault, 1890; as cited in Jelkmann, 1992). This phenomenon has long been recognized by athletes and is the impetus for runners to train at high altitudes (Jelkmann, 1992). In the early part of the 20th century, Carnot and Deflandre (1906) conducted animal experiments to determine whether increased RBC production was directly controlled by blood oxygenation via an intermediary humoral factor, which they called "hemopoietine" (Carnot & DeFlandre, 1906; Higo et al., 2009). In 1948, "hemopoietine" was renamed "erythropoietin" to reflect its primary effect on RBC production (Bonsdorff & Jalavisto, 1948; Fisher, 2010).
Erslev (1953) was the first to conclusively demonstrate the existence of a plasma factor capable of stimulating RBC production (erythropoietin) through controlled experiments comparing the ability of plasma from anemic and normal rabbits to stimulate RBC production. The results showed increased hematocrit levels (in a dose-dependent manner) in response to repeated injections of plasma from the anemic rabbit donors only (Erslev, 1953). In 1957, a series of experiments by Jacobson and colleagues established that during hypoxia, there is an absence of erythropoietin activity in nephrectomized animals, thus establishing the role of the kidney in erythropoiesis (Jacobson, Goldwasser, Fried, & Plzak, 1957). Human erythropoietin was eventually isolated in 1977 by purifying small quantities of the protein from human urine (Miyake, Kung, & Goldwasser, 1977). This allowed reliable radioimmunoassays to be conducted for the hormone, eventually leading to the successful cloning of the human erythropoietin gene in 1985 (Lin et al., 1985).
Life Prior to the Availability Of ESAs
Prior to the availability of ESAs, dialysis was a life-saving modality, but CKD-associated anemia complicated patients' quality of life and contributed to their morbidity. The clinical picture for a patient in the pre-ESA era focused on symptoms indicative of reduced delivery of oxygen to tissues (see Figure 2), including weakness, fatigue, shortness of breath, reduced exercise capacity, and impairments in cognitive and immune function (Basile, 2007; Hayat, Haria, & Salifu, 2008). Recent data show that poorly controlled anemia also exacerbates other CKD-associated complications, such as cardiovascular disease (Thomas, Kanso, & Sedor, 2008).
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Historically, treatment options for managing anemia of ESRD were limited, and large numbers of patients on dialysis were transfusion-dependent. Even with repeated RBC transfusions, Hb typically only increased transiently (from 6 g/dL to 8 or 9 g/dL) (Macdougall, 2008). Aside from their modest efficacy in raising Hb levels, frequent blood transfusions carried the risk of iron overload (Porter, 2005). Other safety concerns included the potential for viral and bacterial infection from contaminated blood, acute hemolysis due to ABO incompatibility, chronic hemolysis, graft-versus-host reactions, immune suppression, and transfusion-related errors (Engert, 2005; Regan & Taylor, 2002). Additionally, frequent blood transfusions increased the patient's risk for allosensitization and decreased the chances for identifying a matched donor kidney (Eady, 2008).
Iron supplementation has historically played an important adjunct role in patients with functional iron deficiency. However, safety risks associated with intravenous iron are an important consideration, including increased potential for acute allergic and/or toxic reactions (particularly linked with high-molecular-weight iron dextran) and nephrotoxicity (particularly associated with iron sucrose and iron gluconate) (Hayat, 2008).
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Androgens, although potentially effective in increasing production of erythropoietin, historically played a small role in the management of anemia of ESRD prior to the introduction of ESAs. Their utilization was limited because of safety concerns, including liver impairment, and their potential to cause development of male secondary sexual characteristics in female patients (Ginsburg & White, 1980; Neff et al., 1981), an effect that is difficult for many women to accept.
Erythropoietin and Its Relationship With the Erythrpoietin Receptor
"Therapeutic breakthroughs over the last century reflect increasing understanding of the physiologic processes underlying erythropoiesis. This understanding, along with advances in technology, opened the door to production of the first recombinant ESA and the ability to treat the cause of anemia in patients with kidney disease. An overview of these concepts follows.
Erythropoietin is the key hormone responsible for governing RBC development. Its primary action is to stimulate erythropoiesis via promoting proliferation, differentiation, and maturation of erythroid progenitor cells in the bone marrow (pluripotent stem cells, burst-forming units [BFUs], and colony-forming units [CFUs]) into mature erythrocytes (see Figure 3) (Fisher, 2003). During fetal development, erythropoietin is produced primarily in the liver; however, soon after birth, the kidneys become the main production site (Jelkmann, 1992).
The erythropoietin gene is located on chromosome 7 in humans (Jelkmann, 1992). There is a high degree of similarity of the amino acid sequence (165-amino-acid protein) across species (for example, the human sequence shares 92% amino acid identity with monkey and 80o/0 with mouse) (Jelkmann, 1992), indicating the functional importance of this protein. From the cloned sequence and subsequent studies, the structure of endogenous erythropoietin was determined, which enabled further research and understanding of its functioning in humans (Jelkmann, 1992; Lai, Everett, Wang, Arakawa, & Goldwasser, 1986).
Physiologically, production of erythropoietin is regulated by the presence of hypoxia (it is the only hematopoietic growth factor for which this is the case) (Diskin, Stokes, Dansby, Radcliff, & Carter, 2008; Lacombe & Mayeux, 1999). In response to hypoxia, erythropoietin levels rise rapidly in circulation (a reflection of the finding that expression of the erythropoietin gene transcript increases in response to a decrease in tissue oxygen tension) (Jelkmann, 2009). This capacity of erythropoietin to increase oxygenation (and thereby enhance physical performance and stamina) has led to its abuse by athletes; accordingly, recombinant human erythropoietins (rHuEPO) are among the substances classified as "doping agents" and are prohibited by the World Anti-Doping Agency and other sports organizations (Jelkmann, 2009).
Erythropoietin Receptor and The Process of Erythropoiesis
The identification, isolation, and cloning of erythropoietin led researchers to search for the target receptor(s) to which it binds. Through the late 1980s, binding studies with radiolabeled erythropoietin in both mouse and human erythroid cell lines suggested that receptor sites were present on erythropoietin-responsive RBC precursor cells (Jones, D'Andrea, Haines, & Wong, 1990). Efforts to understand the receptor-binding properties of erythropoietin ultimately led to the isolation and sequencing of the mouse erythropoietin receptor in 1989 (D'Andrea, Lodish, & Wong, 1989) and the human erythropoietin receptor in 1990 (Jones et al., 1990).
The human erythropoietin receptor is a protein consisting of 508 amino acids that shares 80% similarity with the mouse receptor at both the cDNA and protein levels (jelkmann, 1992). It is a member of a large cytokine receptor family, including receptors that bind to (among many others) interleukins (IL 2-7), granulocyte colony-stimulating factor, thrombopoietin, and growth hormone (Youssoufian, Longmore, Neumann, Yoshimura, & Lodish, 1993). The erythropoietin receptor has three main domains: an extracellular region to which erythropoietin binds, a transmembrane region that anchors it in the cell membrane, and an intracellular (cytoplasmic) domain that interacts with cell signaling proteins within the erythroid precursor cell (Jelkmann, gohlius, Hallek, & Sytkowski, 2008).
The erythropoietin receptor is an essential member of the "erythropoiesis team." After binding erythropoietin, the receptor initiates the signal transduction cascade that ultimately leads to RBC development and subsequent tissue oxygenation. Stimulation of erythropoiesis depends on both the level of circulating erythropoietin (based on the level of hypoxia, as discussed previously) and erythropoietin-receptor interactions (Macdougall, 2002). The erythropoietin receptor is expressed primarily on CFU-Es, with small numbers expressed on BFU-Es (Fisher, 2003; Jelkmann et al., 2008). There are between 200 and 1000 receptors on each CFU-E (Macdougall, 2002). The mechanisms that govern the binding relationship between erythropoietin and its receptor continue to be elucidated, and it is still unclear how long erythropoietin remains bound to the receptor in vivo (Macdougall, 2002).
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Studies have shown that within erythroid precursor cells of the bone marrow, the erythropoietin receptors sit in the cell membrane as homo dimers (two identical receptor molecules associated together) (Koury, Sawyer, & Brandt, 2002). Erythropoietin, an asymmetric molecule (Zhang et al., 2009), binds to the erythropoietin receptor at two sites; the binding at one site has a higher affinity for the receptor (stronger binding) than the other. It was originally proposed that binding in this asymmetric fashion was necessary for receptor activation, but subsequent studies have shown that symmetric binding of novel ESAs can also induce receptor activation (Livnah et al., 1996). Binding of a single erythropoietin molecule to a receptor homodimer (Jelkmann et al., 2008) causes a conformational change of the receptor, thus activating the receptor and triggering the downstream, intracellular erythropoiesis signaling cascade (described in more detail below) that results in proliferation, differentiation, and maturation of RBCs (see Figure 4) (Brines, 2010; Bunn, 2007; Byts & Siren, 2009; Koury et al., 2002).
The intracellular signaling cascade consists of activation or inactivation of several pathways; a detailed description of the complex processes involved is beyond the scope of this article. As a brief overview, the first step in the cascade is phosphorylation of Janus family tyrosine protein kinase 2 (JAK2) (Rossert & Eckardt, 2005), defined as a chemical process of introducing a phosphate group into the JAK2 molecule resulting in its activation. This results in the phosphorylation of the erythropoietin receptor, initiating a signal transduction cascade through several different pathways, including STAT5, Ras-Raf-MAP kinase pathway, and the phosphatidylinositol 3-kinase (PI3K) pathway (Jelkmann et al., 2008). These pathways all work within the cell to control the differentiation and proliferation of the erythroid precursor cells into mature RBCs by reducing apoptosis and inducing the gene activation events that allow the precursor cells to mature (Fisher, 2003). The end result of the binding of erythropoietin to the erythropoietin receptor is the development and maturation of RBCs to bind and deliver oxygen to tissues.
Following receptor activation, the receptor-ligand complexes are internalized and subsequently degraded, thus stopping further signaling (Verdier et al., 2000). Down-regulation of the erythropoietin receptors is mediated via degradation by proteasomes and lysosomes (Verdier et al., 2000; Walrafen et al., 2005). However, approximately 60% of the internalized erythropoietin is recycled intact back onto the cell surface (Gross & Lodish, 2006), where it is hypothesized that it can act on erythropoietin receptors on additional cells.
ESAs: Key Attributes and Receptor Science
Erythropoiesis Stimulating Agents: Overview of Development Timeline
The cloning of the erythropoietin gene allowed large quantities of recombinant human erythropoietin (rHuEPO) to be produced commercially (Goldsmith, 2010). Results of the first human trials of rHuEPO were published in 1986-1987 (Eschbach, Egrie, Downing, Browne, & Adamson, 1987; Winearls et al., 1986), paving the way for the clinical introduction of the first rHuEPO, epoetin alfa (Epogen[R], Amgen; also marketed under the brand name Procrit[R] by Johnson & Johnson), in the United States in 1989 (Demirjian & Nurko, 2008; Goldsmith, 2010). Epoetin alfa has a short half-life and a frequent administration schedule in patients receiving dialysis (three times weekly) (Amgen, Inc., 2010b).
Over the 20 years that followed, greater understanding of erythropoietin receptor biology and clinical interest in overcoming the need for frequent dosing led to development of new ESAs with refined properties. Darbepoetin alfa (Aranesp[R]), a hyperglycosylated (contains additional carbohydrate groups) form of rHuEPO that has a longer half-life in vivo and requires less frequent dosing than epoetin (Amgen, Inc., 2008; Egrie, Dwyer, Browne, Hitz, & Lykos, 2003; Macdougall, 2000) was developed. Regarded as a "second-generation ESA," darbepoefin was approved by the U.S. Food and Drug Administration (FDA) in 2001 (Goldsmith, 2010).
A polyethylene glycol (PEG)linked epoetin variant, methoxy polyethylene glycol epoetin beta (Mircera[R]), was approved in 2007; however, it is currently only marketed in Europe (Macdougall & Ashenden, 2009). Pegylation results in a larger molecular weight, resulting in a longer half-life (Del Vecchio, Cavalli, & Locatelli, 2008; Goldsmith, 2010). Methoxy polyethylene glycol epoetin beta is dosed every two weeks or once monthly (Curran & McCormack, 2008). Due to the settlement of patent infringement claims, this agent will be unavailable in the United States until 2014 (Amgen, Inc., 2010a).
Recently, a new therapeutic alternative to treat anemia of CKD in adult patients on dialysis was approved by the FDA (Affymax, Inc., 2012a). OMONTYS[R] (peginesatide) is a PEGylated, synthetic peptide (not produced in cell culture, nonrecombinant) with an amino acid sequence unrelated to that of erythropoietin (Affymax Inc., 2012a; Woodburn et al., 2011). Phase 3 trials evaluating its efficacy and safety have been reported at scientific congresses (Besarab et al., 2011; Locatelli et al., 2011; Schiller et al., 2011).
Key Attributes of ESAs
Summaries of key attributes of epoetin, darbepoefin, and peginesatide are presented in Table 1 and are discussed below.
Although all ESAs have the same mechanism of action as endogenous erythropoietin (binding to the erythropoietin receptor to trigger signal transduction), substantial differences exist in their pharmacokinetic and pharmacodynamic profiles. Half-life, a pharmacokinetic parameter, is a measure of how long a molecule persists in the circulation. Specifically, the half-life reflects the time taken for the plasma concentration of a drug (the amount of drug in the body) to decline by half (Birkett, 1988). The pharmacodynamic properties of a drug, on the other hand, are reflective of its clinical activity (for example, the ability to reach and maintain target Hb levels) (Macdougall, Padhi, & Jang, 2007). As such, half-life alone does not predict duration of drug effect. Parameters such as affinity for the erythropoietin receptor (the strength with which the ESA binds), the rate of dissociation from the erythropoietin receptor (how quickly the ESA detaches from the receptor/ length of time for which the ESA remains bound to the receptor), how quickly the ESA is internalized and degraded, and rate of clearance from the body all play a role (Birkett, 1988; Egrie et al., 2003; Gross & Lodish, 2006). Differences in pharmacokinetic and pharmacodynamic parameters among ESAs lead to differing dosing frequency profiles (discussed below).
Epoetin alfa, darbepoetin, and peginesatide are the three ESAs currently available in the United States. Of these, epoetin alfa and darbepoetin are manufactured using recombinant cell expression systems, and both are structurally similar to endogenous erythropoietin (see Figure 5) (Egrie et al., 2003; Reichel & Gmeiner, 2010). Peginesatide, on the other hand, is not a recombinant protein and is manufactured using synthetic peptide chemistry techniques (Fan et al., 2006). It was designed and engineered to stimulate specifically the erythropoiefin receptor homodimer that governs erythropoiesis. However, the structure and amino acid sequence (building blocks) of peginesatide are unrelated to endogenous erythropoietin (Woodburn et al., 2011).
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Epoetin alfa has a short half-life; thus, it typically requires frequent administration (three times weekly) in patients on dialysis. Darbepoetin, on the other hand, has a longer half-life and can be administered once weekly or once every two weeks in patients on dialysis (Amgen, Inc., 2008, 2010b). Compared with epoetin alfa, darbepoetin has approximately a fourfold overall lower affinity for the erythropoietin receptor (binds to the erythropoietin receptor with less strength) (Egrie et al., 2003). Darbepoetin also dissociates from the erythropoietin receptor faster than epoetin alfa (Gross & Lodish, 2006). This property presumably allows for less darbepoetin to be internalized, and therefore, less is subjected to degradation in the lysosome, enabling it to signal more times in its lifetime than epoetin alfa (Gross & Lodish, 2006). Darbepoetin is also cleared from the body in vivo more slowly than epoetin alfa, thus further extending its duration of activity (Egrie et al., 2003; Macdougall, 2002).
As mentioned earlier, unlike the case with epoetin, darbepoetin, and methoxy polyethylene glycol epoetin beta, peginesatide is not a recombinant protein. Rather, it comprises a peptide sequence that is dimerized and linked to a two-branched 20-kDa PEG moiety (see Figure 6), thus prolonging systemic circulation and reducing degradation by enzymes (Woodburn et al., 2011). This permits a once-monthly dosing schedule. Currently, peginesatide is the only once-monthly ESA for anemia to be made available to the dialysis patient population in the United States.
When evaluating laboratory results (such as Hb levels), anemia managers need to take into consideration the principles of erythropoiesis, including length of time for maturity of RBCs, the pharmacokinetics of the ESA (for example, half-life), and the pharmacodynamics of the ESA (for example, residence time). When managing ESA therapy, decisions should be based on trends of Hb levels rather than just the actual number. Understanding the processes of erythrokinetics (including pharmaeokinetics and pharmacodynamics of ESAs) will assist nurses in better managing the anemia seen in our patients.
ESAs: The Future
The enhanced understanding of the processes involved in the interaction of erythropoietin with its receptor, along with the evolution of evidence-based treatment guidelines for anemia management throughout the years, has paved the way for the discovery and responsible use of ESAs in clinical practice. Research strides in developing novel ESAs with improved pharmacodynamics have helped to greatly improve the quality of life of patients with ESRD. It is hoped that continued research efforts in receptor-binding interactions will further expand the availability of safe, convenient, and cost-efficient treatment options (Bunn, 2007).
Acknowledgments/Sources of Support/.Disclaimers: Medical writing and editorial assistance provided by Norma Padilla, PhD, and Sophia Shumyatsky, PharmD, of ApotheCom Associates was supported by Affymax and Takeda Pharmaceuticals North America, Inc.
Statement of Disclosure: The author has disclosed that she is a contracted consultant (member and researcher) for Affymax/Takeda Advisory Board. Ms. Dutka has participated in the conduct of numerous clinical trials in the area of anemia management since 1988. The author also wishes to impart that the opinions in this article are her own and are not necessarily those of Winthrop University Hospital, where she is employed.
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Paula Dutka, MSN, RIg, CNN, is Director, Education/Research, Nephrology Network, Winthrop University Hospital, Mineola, NY, is a member of ANNA's Long Island Chapter, and is a member of the Nephrology Nursing Journal Editorial Board.
Table 1 Attributes of Select ESAs: Erythropoietin Alfa, Darbepoetin Alfa, and Peginesatide Epoetin Alfa Darbepoetin (Epogen[R], Alfa Procrit[R]) (Aranesp[R]) (First (Second Peginesatide Generation) Generation) (OMONTYS[R]) Structure Human Hyperglycosylated Peptide erythropoietin analog of sequence that analog (Reichel recombinant is dimerized & Gmeiner, human and PEGylated 2010) erythropoietin via a (Macdougall, 2000) Same amino acid Contains 2 chemical linker sequence as additional (Reichel & endogenous asparagine (N)- Gmeiner, 2010; erythropoietin linked Woodburn et (aside from oligosaccharide al., 2011) slight chains (Bunn, No sequence differences in 2007; homology to composition and Macdougall, endogenous arrangement of 2000; Reichel & human sugar moieties) Gmeiner, 2010) erythropoietin (Bunn, 2007) (Bunn, 2007; Woodburn et al., 2011) Synthesis Genetic Genetic Synthetic: No (Bunn, 2007; engineering: engineering: genetic Reichel & Chinese hamster Chinese hamster engineering Gmeiner, 2010) ovary cells ovary cells (Bunn, 2007; (Reichel & (Reichel & Woodburn et Gmeiner, 2010) Gmeiner, 2010) al., 2011) Half-life IV: 4 to 9 IV: 21 hours in Healthy (Fisher, 2003) hours (Fisher, CKD-HD (Amgen, volunteers 2003) SC: 19 to Inc., 2008) 25 hours IV: 25.0 [+ or (Reichel & -] 7.6 hours Gmeiner, 2010) (Affymax Inc., 2012b) SC: 53.0 [+ or -] 17.7 hours (Affymax Inc., 2012b) CKD-HD: 47.9 [+ or -] 16.5 hours (Affymax, Inc., 2012b) Dosing Schedule 3 times per SC: 46 hours in Once monthly week (Amgen, CKD-HD, 70 (Affymax Inc., Inc., 2010b) hours in CKD- 2012b) ND (Amgen, Inc., 2008) Once weekly (CKD-HD) or once every 2 weeks (CKD- nonHD) (Amgen, Inc., 2008) Immunogenicity Yes (McKoy et Yes (McKoy et Unlikely (cross- al., 2008) al., 2008) reactive with Because its endogenous amino acid erythropoietin; sequence is risk of pure unrelated to red cell endogenous aplasia *) erythropoietin, the likelihood of cross- reactive immunogenicity is low. An ongoing study is evaluating the efficacy of peginesatide for the treatment of patients with PRCA; results appear promising (Macdougall et al., 2012) Note: CKD, chronic kidney disease; HD, hemodialysis; IV, intravenous; ND, nondialysis; SC, subcutaneous. * The structural similarity of epoetin alfa and darbepoetin to endogenous erythropoietin increases the risk of pure red cell aplasia (PRCA), a rare but potentially life-threatening complication. Because they are structurally similar, antibodies formed in response to the recombinant ESA can neutralize endogenous erythropoietin, resulting in severe anemia and transfusion dependence (McKoy et al., 2008). PRCA has been reported mostly with epoetin alfa formulations available in Europe (Rossert, Casadevall, & Eckardt, 2004).
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|Publication:||Nephrology Nursing Journal|
|Date:||Nov 1, 2012|
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