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Update on Anemia Management in Nephrology, Including Current Guidelines on the Use of Erythropoiesis-Stimulating Agents and Implications of the Introduction of "Biosimilars"

^aDepartment of Nephrology, Dialysis and Renal Transplantation, A. Manzoni Hospital, Lecco, Italy; ^bPrivate Consultant, Zwingenberg, Germany

Key Words. Erythropoiesis-stimulating agents • Nephrology • Chronic kidney disease • Quality of life • Hemoglobin levels • Biosimilars

Correspondence: Francesco Locatelli, M.D., F.R.C.P., Department of Nephrology and Dialysis, A. Manzoni Hospital, Via dell'Eremo 9/11, IT-23900 Lecco, Italy. Telephone: 39-0341-489-850; Fax: 39-0341-489-860; e-mail: f.locatelli{at}ospedale.lecco.it

Received February 6, 2009; accepted for publication April 29, 2009.

Disclosures: Francesco Locatelli: Consultant/advisory role: Amgen, Roche, Affimax; Harald Becker: Consultant/advisory role: Ortho Biotech International; Ownership interest: Johnson & Johnson.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

	ABSTRACT

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Several million patients with chronic kidney disease (CKD) have benefited from the use of erythropoiesis-stimulating agents (ESAs) to correct severe anemia. However, mortality data now suggest that treating CKD patients to achieve a hemoglobin (Hb) level >13 g/dl can be harmful. For levels of 11.5–13 g/dl, there is no evidence of either harm or benefit compared with a lower Hb level. Quality of life studies are variable in quality but do suggest superior outcomes and functional status. In the 9 years following 1997, the target Hb level recommended by international guidelines tended to increase, especially for patients without accompanying cardiovascular disease. However, strangely enough, the most recent target level of the Kidney Disease Outcomes Quality Initiative is 11–12 g/dl, which is exactly the range advocated by the same group a decade earlier. The relative importance of quality of life compared with other outcomes, the use of iron, and the impact of venous thrombotic events continue to be debated. In addition, new issues have arisen from the introduction of "biosimilar" erythropoietins, biopharmaceuticals that refer to the existing agents and are submitted for marketing authorization after the existing agents' protection expires. Biosimilars can resemble the agents on which they are modeled but cannot fully copy their properties. The complexity in molecular structure, the possible presence of impurities (which may include bacterial endotoxins), and the inherent immunogenicity of such agents have required authorities to develop a sophisticated regulatory framework.

	INTRODUCTION

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Erythropoietin is needed for erythroid proliferation and differentiation. It acts synergistically with other cytokines on bone marrow colony-forming unit–erythroid cells to cause maturation and proliferation at the normoblast stage of erythroid cell development [1]. Its absence results in a higher rate of apoptosis of cells committed to the erythroid line. Anemia resulting from various conditions in which there is impaired physiological regulation of RBC production by erythropoietin can be successfully treated with recombinant human erythropoietin (rHuEPO). The use of rHuEPO raises levels of hemoglobin (Hb), reducing transfusion requirements and improving quality of life. It was suggested that early correction of anemia with rHuEPO may result in a more benign progression of chronic kidney disease (CKD), although recent data from randomized controlled trials seem to not support this view. The considerable potency and high degree of regulation of the erythropoietin system suggests that replacement therapy should be aimed at reproducing as closely as possible the physiological profile of the cytokine.

Anemia is a severe complication of CKD and is seen in the majority of stage 3–5 patients. The primary cause is inadequate production of erythropoietin by the damaged kidneys. CKD-related severe anemia has many adverse effects, including reduced quality of life, cognitive function, cardiac function, and immune response. It results in a higher risk for left ventricular hypertrophy, myocardial infarction, stroke, and death. This is the context in which the effects of erythropoiesis-stimulating agents (ESAs) must be assessed.

	THE CONSEQUENCES OF REDUCED HB

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In 2004, the report of the Dialysis Outcomes and Practice Patterns Study, which used data from >11,000 patients in 12 countries, showed an association with a significantly higher mortality when patients with an Hb level <8 g/dl were compared with those with higher levels (relative risk [RR], 1.26; p = .04) [2]. This finding was reflected in the European experience. Compared with reference values of 11–11.9 g/dl, lower levels of Hb (<10 g/dl) in CKD patients were associated with a markedly higher risk for death (Fig. 1) [3]. In dialyzed patients aged 18–65 years, the RR was 1.51 (p = .02), and in patients aged >65 years it was 1.11 (p = .46). In older patients, but not in their younger counterparts, Hb levels in the range of 10–10.9 g/dl were also associated with a significantly higher RR for death. In a study of 41,919 dialysis patients followed over 2 years, the association RR for mortality rose sharply in patients who spent >40% of the time with Hb levels <11 g/dl [4]. This relationship was found both in patients with cardiovascular disease and in those without it. The associated proportion of hemodialyzed patients surviving for >180 days was 84% in those with an Hb level <9 g/dl but remained close to 100% in those with an Hb level 13 g/dl [5].

View larger version (20K): [in this window] [in a new window]   Figure 1. Relationship between different categories of hemoglobin concentration and mortality risk in hemodialysis patients 65 and >65 years old. Abbreviation: RR, relative risk. Adapted from Locatelli F, Pisoni R, Combe C et al. Anaemia in haemodialysis patients of five European countries: Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004;19:121–132, by permission of Oxford University Press.

	TREATMENT WITH ESAS

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Following cloning of the erythropoietin gene and subsequent genetic engineering, the first study of rHuEPO in renal anemia was reported in 1986. Until this point, the only available therapy for severe anemia had been RBC transfusion. After studies showed consistent evidence of benefit (including a reduction in the risks associated with the repeated need for transfusion), epoetin alfa was approved by the European Medicines Agency (EMEA) in 1988 and by the U.S. Food and Drug Administration in 1989 for the treatment of anemia related to chronic renal failure. The studies conducted in this early period generally involved raising Hb levels from the severely anemic, that is, anywhere in the range of 6–9.5 g/dl, to >10.5 g/dl [7]. In the decade since 1998 [8], the emphasis has been on improving quality of life through designing trial comparison mild-to-moderately anemic levels of Hb to values >13g/dl. Thus the Hb values achieved by the intervention arms in the early studies became the control values in the later studies [7–9].

A recent meta-analysis including nine randomized clinical trials (involving a total of >5,000 patients) showed a significantly greater risk for mortality in patients assigned to higher Hb values (RR, 1.17; confidence interval [CI], 1.01–1.35) [10]. There was also a significantly higher risk for vascular access thrombosis. Among the major studies contributing to the meta-analysis were the Besarab et al. [8] trial of normalization of hematocrit (Hct) and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) studies.

Among hemodialysis patients with clinically evident congestive heart failure or ischemic heart disease, the use of epoetin with the aim of raising the Hct to 42% (rather than 30%) was associated with a higher risk for death or first nonfatal myocardial infarction [8]. The CHOIR study assessed the probability of a cardiovascular event (death, myocardial infarction, hospitalization for congestive heart failure, or stroke) in patients assigned to achieve a target Hb level of either 13.5 g/dl or 11.3 g/dl [11]. The risk for an event occurring over a median follow-up of 16 months was significantly greater in the high than in the low Hb group (hazard ratio, 1.34; 95% CI, 1.03–1.74; p = .03). The outcome of the CREATE study, in which the primary endpoint was made up of eight cardiovascular events, was less clear-cut. Although in the same trial patients randomized to complete anemia correction experienced a shorter time to dialysis, no differences were found in terms of disease progression, as indicated by the glomerular filtration rate estimated by the Cockcroft-Gault method [12].

Based on mortality data, evidence from nephrology patients treated with ESAs suggests that aiming at Hb levels 13 g/dl can be harmful [13]. This situation was acknowledged in the 2007 Kidney Disease: Improving Global Outcomes anemia management position statement, in which the suggested range to aim for is 11–12 g/dl [7]. The European Best Practice Guideline (issued in 2004) cited a maximum of 14 g/dl in hemodialysis patients (and 12 g/dl in patients with congestive cardiac failure or diabetes) [14], whereas the position statement from the new group, the European Renal Best Practice Work Group, recommends that ESA therapy be cautiously used in patients with CKD, targeting Hb values of 11–12 g/dl without intentionally exceeding 13 g/dl [15].

	QUALITY OF LIFE

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Although evidence for longer survival and fewer cardiovascular complications in targeting higher Hb levels is generally negative, there are indications that achieving an Hb level >13 g/dl improves quality of life. Relatively early evidence of this came from the Spanish cooperative groups, who showed that a higher Hb level (in patients aged 65 years without existing cardiovascular disease) was associated with reductions in the physical, psychosocial, and global impact of sickness [16]. In the larger CREATE study, anemic patients with a target Hb level of 13–15 g/dl enjoyed improved SF-36 scores for general and mental health, physical function and role, social function, and vitality when compared with baseline [12]. Patients assigned to a lower Hb target did not. However, the anemia management position statement from Kidney Disease: Improving Global Outcomes [13] clearly underlines that the quality of papers in this field is rather poor.

	HB CYCLING

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Hb cycling is common in ESA-treated patients on hemodialysis and has implications for management [17, 18]. Cyclic fluctuations, defined as having an amplitude of >1.5 g/dl Hb and a duration >8 weeks, were seen in >90% of patients, and the mean number of excursions per year was 3.1. The causes are not completely understood, but many factors are involved, including the underlying disease and comorbidities, variations in the dose of erythropoietin, fluid balance, and the nature and continuation or discontinuation of iron therapy.

	OTHER ISSUES

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Among topics of interest in anemia management are the relatively low importance given to quality of life compared with other outcomes, the impact of venous thrombotic events, thrombosis of vascular access for hemodialysis patients, and the balance between ESAs and the use of iron. Studies that have investigated the merits of i.v. versus oral iron have differed in experimental design, severity of anemia, the use and timing of rHuEPO therapy, and the dose and timing of i.v. iron. These and other abiding issues are discussed at length elsewhere in this supplement in articles by Aapro and Spivak [19]; Besarab, Hörl, and Silverberg [20]; Fandrey and Dicato [21]; and Spivak, Gascón, and Ludwig [22]. However, the nephrology community is also now faced with the role of "biosimilars" in anemia management.

	HOW SIMILAR IS BIOSIMILAR, AND WHAT ARE THE IMPLICATIONS?

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Consistency and clarity in the use of definitions is an essential starting point (Table 1). The EMEA distinguishes between the low-molecular-weight drugs that are the classic medicinal products and a newer group of "biopharmaceuticals" [23]. The latter are defined as medicinal products "developed by one or more of the following biotechnology practices: recombinant DNA, controlled gene expression, antibody methods." Corresponding to the classical generic drug, it recognizes a new class of "biosimilars," which are defined as "a biological medicinal product referring to an existing one and submitted to regulatory authorities for marketing authorization by an independent applicant after the time the original product expired."

Although mass spectrometry and chromatography can elucidate their primary structure, no analytic technique or combination of techniques can fully capture the complex secondary to quaternary structures of these molecules [26]. Impurities derived from the host cell line, from the complex growth media required, and from purification processes themselves are inevitable. Schellekens and colleagues investigated 11 epoetin alfa copies from three manufacturers available in Argentina, China, and India [27]. Isoform patterns varied even between samples from the same manufacturer, and in vivo bioactivities ranged from 71% of the Eprex® (Janssen-Cilag, Baar, Switzerland) standard to 226%. Most worryingly, three samples contained unacceptable levels of bacterial endotoxins (which, in one instance, were 25 times higher than that allowable in Europe). In its role of detecting "nonself," our immune system is exquisitely sensitive to differences between exogenous proteins and their endogenous equivalents. Although the incidence of antibody formation with erythropoietins is rare in comparison, for example, with recombinant interferons, such antibodies may result in neutralization not only of the therapeutic product but also the native protein [28].

In response to these challenges, the European Union (EU) has developed a regulatory framework specific to biosimilars [29]. The precise requirements vary from case to case, but certain general principles apply. These include the fact that the biosimilar must be evaluated in the same form, strength, and route of administration as the reference product (with no extrapolation allowed) and that the same reference product (which must be licensed in the EU) must be used during the entire process of product development [30]. Assessment of immunogenicity must be rigorous, with both radioimmunoprecipitation screening and a cell-based bioassay required [31]. Antibodies must be monitored long term at predetermined intervals. Annexes specific to classes of biosimilar products have been issued, of which epoetin is one. In addition to pharmacodynamic activity and toxicology, this requires that clinical efficacy be demonstrated in two randomized, parallel-group trials, preferably in chronic renal failure patients with anemia, in which a 6-month correction phase is followed by at least 3 months of maintenance therapy. Comparable efficacy will preferably have to be shown separately for i.v. and s.c. administration. Demonstration of safety requires data on immunogenicity over at least 1 year of treatment, using a highly sensitive assay for antierythropoietin antibodies. This will not, in itself, be sufficient to detect rare adverse events such as pure red cell aplasia. For this reason, a pharmacovigilance plan must be put into effect after licensing. This will collect safety data in all approved indications and clearly identify exposure to specific biosimilars.

	AUTHOR CONTRIBUTIONS

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Data analysis and interpretation: Francesco Locatelli, Harald Becker

Manuscript writing: Francesco Locatelli

Final approval of manuscript: Francesco Locatelli, Harald Becker

The authors take full responsibility for the content of this article and thank Rob Stepney, medical writer, and Julia O'Regan, Bingham Mayne and Smith, Edinburgh, supported by an educational grant from Ortho Biotech, a division of Janssen-Cilag Europe, for their assistance in preparing a first draft of the manuscript based on an oral presentation at a meeting held on November 20, 2008 in Sitges, Spain, organized by a Scientific Committee of Matti Aapro, Mario Dicato, Pere Gascón, Francesco Locatelli, Jerry Spivak, and Jay Wish.

	REFERENCES

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Locatelli, F. Articles by Becker, H. PubMed PubMed Citation Articles by Locatelli, F. Articles by Becker, H.