Printer Friendly

Erythropoiesis-stimulating agents for the management of anemia of chronic kidney disease: past advancements and current innovations.

The 20th century witnessed remarkable discoveries and advances in the treatment of patients with end stage renal disease (ESRD). Whereas previously there had been little hope of living more than a few weeks or months after a diagnosis of ESRD, developments in dialysis and kidney transplantation through the middle of the century enabled patients to survive for many years. However, for decades, the increased survival was not necessarily accompanied by improved quality of life (Evans et al., 1985; Levy & Wynbrandt, 1975). Per reflections of a patient with long-term kidney disease, "Survival alone has never been enough. What is the point of staying alive ? It is living a fulfilling life that really seems to make the difference" (Eady, 2008, p. S5). Although dialysis extended their lives, many patients failed to return to pre-disease levels of functioning; they experienced loss of income and high levels of emotional stress (Levy & Wynbrandt, 1975). Patients who were unable to return to work and those with greater physical impairment generally had worse subjective quality of life than those patients with minimal functional impairment (Evans et al., 1985). More recent studies have indicated that poor physical and mental health function are independent predictors of mortality in patients receiving dialysis (Knight, Ofsthun, Teng, Lazarus, & Curhan, 2003; Kusleikaite, Bumblyte, Kuzminskis, & Vaiciuniene, 2010).

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).


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).


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).


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.

Endogenous Erythropoietin

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).


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).



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.

Managing Anemia

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.


Affymax, Inc. (2012a). Affymax and Takeda announce FDA approval of Omontys (peginesatide) injection for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. Palo Alto, CA: Author.

Affymax, Inc. (2012b). Omontys[R] (peginesatide) Injection, for intravenous or subcutaneous use. Palo Alto, CA: Author.

Amgen, Inc. (2008). Aranesp[R] (darbepoetin alfa) for injection. Thousand Oaks, CA: Author.

Amgen Inc. (2010a). Amgen resolves EPO patent dispute with Roche. Thousand Oaks, CA: Author.

Amgen, Inc (2010b). Epogen[R] (epoetin alfa) for injection. Thousand Oaks, CA: Author.

Anonymous. (2004). History of nephrology and the American Nurses Assocation: A timeline. Nephrology Nursing Journal, 31, 133-135.

Basile, J.N. (2007). Clinical considerations and practical recommendations for the primary care practitioner in the management of anemia of chronic kidney disease. Southern Medical Journal, 100(12), 1200-1207.

Besarab, A., Locatelli, E, Covic, A., Martin, E., Bemardo, M., Macdougall, I., ... Duliege, A.M. (2011, April). Safety and efficacy of peginesatide for treatment of anemia in hemodialysis patients previously on epoetin alfa or beta (EMERALD 2). Poster presented at the National Kidney Foundation Spring Clinical Meetings, Las Vegas, NV.

Birkett, DJ. (1988). Half life. Australian Prescriber, 11(31988), 57-59.

Blagg, C.R. (2007). The early history of dialysis for chronic renal failure in the United States: A view from Seattle. American Journal of Kidney Diseases, 49(3), 482-496.

Bonsdorff, E., & Jalavisto, E. (1948). A humoral mechanism in anoxic erythrocytosis. Acta Physiologica Scandinavica, 16, 150-170.

Brines, M. (2010). The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: A tale of two receptors. Blood Purification, 29(2), 86-92.

Bunn, H.E (2007). New agents that stimulate erythropoiesis. Blood, 109(3), 868-873.

Byts, N., & Siren, A.L. (2009). Erythropoietin: A multimodal neuroprotective agent. Experimental and Translational Stroke Medicine, 1, 4.

Camot, E, & DeFlandre, C. (1906). On the hemopoietic activity of serum during the regeneration of blood. [Sur l'activite hemopoietique de serum au cours de la regeneration du sang]. Comptes Rendus del Academie des Sciences. Serie III, Sciences de la Vie, 143, 384-386.

Curran, M.E, & McCormack, P.L. (2008). Methoxy polyethylene glycol-epoetin beta: A review of its use in the management of anaemia associated with chronic kidney disease. Drugs, 68(8), 1139-1156.

D'Andrea, A.D., Lodish, H.F., & Wong, G.G. (1989). Expression cloning of the routine erythropoietin receptor. Cell, 57(2), 277-285.

Del Vecchio, L., Cavalli, A., & Locatelli, E (2008). Methoxypolyethylene glycolepoetin beta for the treatment of anemia associated with chronic kidney disease. Drugs of Today, 44(8), 577-584.

Demirjian, S.G., & Nurko, S. (2008). Anemia of chronic kidney disease: When normalcy becomes undesirable. Cleveland Clinic Journal of Medicine, 75(5), 353-356.

Diaz-Buxo, J.A. (2001). Evolution of continuous flow peritoneal dialysis and the current state of the art. Seminars in Dialysis, 14(5). 373-377.

Diskin, C.J., Stokes, T.J., Dansby, L.M., Radcliff, L., & Carter, T.B. (2008). Beyond anemia: the clinical impact of the physiologic effects of erythropoietin. Seminars in Dialysis, 21(5), 447-454.

Doss, S., & Schiller, B. (2011). Peginesatide: A potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure. Nephrology Nursing Journal, 37(6), 617-626.

Eady, R.A. (2008). Survival is not enough: Reflections of a long-term renal patient.J0urnal of Nephrology, 21(Suppl. 13), $3-$6.

Egrie, J.C., Dwyer, E., Browne, J.K., Hitz, A., & Lykos, M.A. (2003). Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Experimental Hematology, 31(4), 290-299.

Engert, A. (2005). Recombinant human erythropoietin in oncology: Current status and further developments. Annals of Oncology, 16(10), 1584-1595.

Erslev, A. (1953). Humoral regulation of red cell production. Blood, 8(4), 349-357.

Eschbach, J.W., Egrie, J.C., Downing, M.R., Browne, J.K., & Adamson, J.W. (1987). Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. New England Journal of Medicine, 316(2), 73-78.

Evans, R.W., Manninen, D.L., Garrison, L.R, Jr., Hart, L.G., Blagg, C.R., Gutman, R.A., ... Lowrie, E.G. (1985). The quality of life of patients with end-stage renal disease. New England Journal of Medicine, 312(9), 553-559.

Fan, Q., Leuther, K.K., Holmes, C.E, Fong, K.L., Zhang, J., Velkovska, S., ... Woodburn, K.W. (2006). Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Experimental Hematology, 34(10), 1303-1311.

Fisher, J.W. (2003). Erythropoietin: physiology and pharmacology update. Experimental Biology and Medicine, 228(1), 1-14.

Fisher, J.W. (2010). Landmark advances in the development of erythropoietin. Experimental Biology and Medicine, 235(12), 1398-1411.

Ginsburg, J., & White, M.C. (1980). Hirsutism and virilisation. British Medical Journal, 280(6211), 369-371.

Goldsmith, D. (2010). 2009: A requiem for rHuEPOs--But should we nail down the coffin in 2010? Clinical Journal of the American Society of Nephrology, 5(5), 929-935.

Gottchalk, C.W., & Fellner, S.K. (1997). History of the science of dialysis. American Journal of Nephrology, 77, 289-298.

Gross, A.W., & Lodish, H.F. (2006). Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP).

Journal of Biological Chemistry, 281(4), 2024-2032.

Hayat, A. (2008). Safety issues with intravenous iron products in the management of anemia in chronic kidney disease. Clinical Medicine and Research, 6(3-4), 93-102.

Hayat, A., Haria, D., & Salifu, M.O. (2008). Erythropoietin stimulating agents in the management of anemia of chronic kidney disease. Patient Preference and Adherence, 2, 195-200.

Higo, T., Ueda, Y., Oyabu, J., Okada, K., Nishio, M., Hiram, A., ... Kodama, K. (2009). Atherosclerotic and thrombogenic neointima formed over sirolimus drug-eluting stent: An angioscopic study. Journal of the American College of Cardiology: Cardiovascular Interventions, 2(5), 616-624.

Hillman, R.S., & Finch, C.A. (1996). General characteristics of the erythron. In R.S. Hillman & C.A. Finch (Eds.), Red cell manual (7th ed., pp. 138). Philadelphia, PA: F.A. Davis Company.

Jacobson, L.O., Goldwasser, E., Fried, W., & Plzak, L. (1957). Role of the kidney in erythropoiesis. Nature, 179(4560), 633-634.

Jelkmann, W. (1992). Erythropoietin: Structure, control of production, and function. Physiological Reviews, 72(2), 449-489.

Jelkmann, W. (2009). Erythropoiesis stimulating agents and techniques: A challenge for doping analysts. Current Medicinal Chemistry, 16(10), 1236-1247.

Jelkmann, W., Bohlius, J., Hallek, M., & Sytkowski, AJ. (2008). The erythropoietin receptor in normal and cancer tissues. Critical Reviews in Oncology/Hematology, 67(1), 39-61.

Jones, S.S., D'Andrea, A.D., Haines, L.L., & Wong, G.G. (1990). Human erythropoietin receptor: Cloning, expression, and biologic characterization. Blood, 76(1), 31-35.

Knight, E.L., Ofsthun, N., Teng, M., Lazarus, J.M., & Curhan, G.C. (2003). The association between mental health, physical function, and hemodialysis mortality. Kidney International, 63(5), 1843-1851.

Koury, MJ., Sawyer, S.T., & Brandt, S.J. (2002). New insights into erythropoiesis. Current Opinion in Hematology, 9(2), 93-100.

Kusleikaite, N., Bumblyte, I.A., Kuzminskis, V., & Vaiciuniene, R. (2010). The association between health-related quality of life and mortality among hemodialysis patients. Medicina, 46(8), 531-537.

Lacombe, C., & Mayeux, P. (1999). The molecular biology of erythropoietin. Nephrology Dialysis Transplantation, 14(Suppl. 2), 22-28.

Lai, P.H., Everett, R., Wang, F.F., Arakawa, T., & Goldwasser, E. (1986). Structural characterization of human erythropoietin. Journal of Biological Chemistry, 261(7), 3116-3121.

Lankhorst, C.E., & Wish, J.B. (2010). Anemia in renal disease: Diagnosis and management. Blood Reviews, 24(1), 39-47.

Levy, N.B., & Wynbrandt, G.D. (1975). The quality of life on maintenance haemodialysis. Lancet, 1(7920), 1328.

Lin, F.K., Suggs, S., Lin, C.H., Browne, J.K., Smalling, R., Egrie, J.C., ... Goldwasser, E. (1985). Cloning and expression of the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America, 82(22), 7580-7584.

Livnah, O., Stura, E.A., Johnson, D.L., Middleton, S.A., Mulcahy, L.S., Wrighton, N.C., ... Wilson, I.A. (1996). Functional mimicry of a protein hormone by a peptide agonist: The EPO receptor complex at 2.8 A. Science, 273(5274), 464-471.

Locatelli, E, Fishbane, S., Macdougall, I., Wiecek, A., Covic, A., Patel, H., ... Polu, K.R. (2011, November). Safety results from two phase 3 studies of peginesatide treatment for anemia in hemodialysis (HD) patients. Poster presented at the American Society of Nephrology Kidney Week, Philadelphia, PA.

Macdougall, I.C. (2000). Novel erythropoiesis stimulating protein. Seminars in Nephrology, 20(4), 375-381.

Macdougall, I.C. (2002). Optimizing the use of erythropoietic agents--Pharmacokinetic and pharmacodynamic considerations. Nephrology Dialysis Transplantation, 17(Suppl. 5), 66-70.

Macdougall, I.C. (2008). Novel erythropoiesis-stimulating agents: A new era in anemia management. Clinical Journal of the American Society of Nephrology, 3(1), 200-207.

Macdougall, I.C., & Ashenden, M. (2009). Current and upcoming erythropoiesis-stimulating agents, iron products, and other novel anemia medications. Advances in Chronic Kidney Disease, 16(2), 117-130.

Macdougall, I.C., Padhi, D., & Jang, G. (2007). Pharmacology of darbepoetin alfa. Nephrology, Dialysis, Transplantation, 22(Suppl. 4), iv2-iv9.

Macdougall, I.C., Casadevall, A., Stead, R., Taal, M., Faller, B., Karras, A., ... Eckardt, K.-U. (2012, May). Long-term results from a study of peginesatide in patients with antibody-mediated pure red cell aplasia (AB+PRCA). Poster presented at 49th ERA/EDTA Congress, Paris, France.

McBride, E (1989). Industry's contribution to the development of renal care. ANNA Journal, 16(3), 217-226.

McClellan, W., Aronoff, S.L., Bolton, W.K., Hood, S., Lorber, D.L., Tang, K.L., ... Leiserowitz, M. (2004). The prevalence of anemia in patients with chronic kidney disease. Current Medical Research and Opinion, 20(9), 1501-1510.

McKoy, J.M., Stonecash, R.E., Cournoyer, D., Rossert, J., Nissenson, A.R., Raisch, D.W., ... Bennett, C. L. (2008). Epoetin-associated pure red cell aplasia: Past, present, and future considerations. Transfusion, 48(8), 1754-1762.

Miyake, T., Kung, C.K., & Goldwasser, E. (1977). Purification of human erythropoietin. Journal of Biological Chemistry, 252(15), 5558-5564.

National Kidney Foundation (NKF) (2006). KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. American Journal of Kidney Diseases, 47(5, Suppl. 3), S11-145.

Neff, M.S., Goldberg, J., Slifkin, R.E, Eiser, A.R., Calamia, V., Kaplan, M., ... Mattoo, N. (1981). A comparison of androgens for anemia in patients on hemodialysis. New England Journal of Medicine, 304(15), 871-875.

Nurko, S. (2006). Anemia in chronic kidney disease: Causes, diagnosis, treatment. Cleveland Clinic Journal of Medicine, 73(3), 289-297.

Papayannopoulou, T., D'Andrea, A.D., Abkowitz, J.L., & Migliaccio, A.R. (2005). Biology of erythropoiesis, erythroid differentiation, and maturation.

In R. Hoffman et al. (Eds.), Hematology: Basic principles and practice (4th ed., pp. 267-288). Philadelphia, PA: Elsevier Churchill Livingstone.

Popovich, R.E, Moncrief, J.W., Nolph, K.D., Ghods, AJ., Twardowski, Z.J., & Pyle, W.K. (1978). Continuous ambulatory peritoneal dialysis. Annals of Internal Medicine, 88, 449-456.

Porter, J. (2005). Pathophysiology of iron overload. Hematology/Oncology Clinics of North America, 19 (Suppl.), 7-12.

Regan, E, & Taylor, C. (2002). Blood transfusion medicine. British Medical Journal, 325(7356), 143-147.

Reichel, C., & Gmeiner, G. (2010). Erythropoietin and analogs. Handbook of Experimental Pharmacology, 195, 251-294.

Rossert, J., Casadevall, N., & Eckardt, K.U. (2004). Anti-erythropoietin antibodies and pure red cell aplasia. Journal of the American Society of Nephrology, 15(2), 398-406.

Rossert, J., & Eckardt, K.U. (2005). Erythropoietin receptors: Their role beyond erythropoiesis. Nephrology, Dialysis, Transplantation, 20(6), 1025-1028.

Sargent, J.A., & Acchiardo, S.R. (2004). Iron requirements in hemodialysis. Blood Purification, 22(1), 112-123.

Schiller, B., Zeig, S., Hura, C., Levin, N., Kaplan, M., Tang, H., ... Duliege, A. M. (2011, April). Safety and efficacy of peginesatide for treatment of anemia in hemodialysis patients previously on epoetin alfa (EMERALD 1). Poster presented at the National Kidney Foundation Spring Clinical Meetings, Las Vegas, NV.

Schmid, H., & Schiffl, H. (2010). Erythropoiesis stimulating agents and anaemia of end-stage renal disease. Cardiovascular and Hematological Agents in Medical Chemistry, 8(3), 164-172.

Schreiner, G.E. (2000). How end-stage renal disease (ESRD)-Medicare developed. American Journal of Kidney Diseases, 35(4, Suppl. 1), S37-S44.

Thomas, R., Kanso, A., & Sedor, J.R. (2008). Chronic kidney disease and its complications. Primary Care, 35(2), 329-344.

U.S. Renal Data System (USRDS). (2012). United States Renal Data System 2012 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Division of Kidney, Urologic, and Hematologic Diseases.

Verdier, E, Walrafen, E, Hubert, N., Chretien, S., Gisselbrecht, S., Lacombe, C., & Mayeux, P. (2000). Proteasomes regulate the duration of erythropoietin receptor activation by controlling down-regulation of cell surface receptors. Journal of Biological Chemistry, 275(24), 18375-18381.

Walrafen, P., Verdier, F., Kadri, Z., Chretien, S., Lacombe, C., & Mayeux, P. (2005). Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood, 705(2), 600-608.

Winearls, C.G., Oliver, D.O., Pippard, M.J., Reid, C., Downing, M.R., & Cotes, EM. (1986). Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet, 2(8517), 1175-1178.

Woodburn, K.W., Holmes, C.R, Wilson, S.D., Fong, K.L., Press, R.J., Moriya, Y., & Tagawa, Y. (2011). Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats. Xenobiotica, 42(7), 660-670. /doi/ abs/10.3109/00498254.2011.649310

Youssoufian, H., Longmore, G., Neumann, D., Yoshimura, A., & Lodish, H.F. (1993). Structure, function, and activation of the erythropoietin receptor. Blood, 81(9), 2223-2236.

Zhang, Y.L., Radhakrishnan, M.L., Lu, X., Gross, A.W., Tidor, B., & Lodish, H.E (2009). Symmetric signaling by an asymmetric 1 erythropoietin: 2 erythropoietin receptor complex. Molecular Cell, 33(2), 266-274.

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

                   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

                  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.,

                                                        SC: 53.0 [+ or
                                                        -] 17.7 hours
                                                        (Affymax Inc.,

                                                        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-
                                                        is low. An
                                                        ongoing study
                                                        is evaluating
                                                        the efficacy of
                                                        for the
                                                        treatment of
                                                        patients with
                                                        PRCA; results
                                                        (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).
COPYRIGHT 2012 Jannetti Publications, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Dutka, Paula
Publication:Nephrology Nursing Journal
Article Type:Report
Date:Nov 1, 2012
Previous Article:Venous needle dislodgement in patients on hemodialysis.
Next Article:Deadly diarrhea: Clostridium difficile infection.

Terms of use | Privacy policy | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters