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Pure red cell aplasia due to follow-on epoetin

2008; Elsevier BV; Volume: 74; Issue: 12 Linguagem: Inglês

10.1038/ki.2008.230

1523-1755

Sai Ram Keithi-Reddy, Sadayandi Kandasamy, Ajay Singh,

Erythropoietin and Anemia Treatment

A 57-year-old man with end-stage renal disease secondary to chronic interstitial nephritis was initiated on hemodialysis in February 2006 for uremic symptoms. In April 2006, his hemoglobin (Hgb) was 10.7 g/dl and transferrin saturation was 12.7%. He was started on subcutaneous follow-on epoetin-alfa, Wepox (Wockhardt Limited India, Mumbai, India) and 10 weekly doses of 100 mg each of iron sucrose administered intravenously. His Hgb increased to 12.3 g/dl within 2 months after the initiation of epoetin. He then underwent coronary artery bypass graft surgery for triple vessel coronary artery disease. He received two units of packed cells during the post-operative period because of a decrease in the Hgb level to 8.2 g/dl. He was continued on epoetin at the same dose. Three months later the Hgb level later was 6.6 g/dl (Figure 1). Two units of red blood cell transfusion and intravenous iron were administered, and Wepox was continued. In December 2006, his Hgb decreased further to 4.9 g/dl. Further work up of his anemia revealed that a stool sample for occult blood was negative, an upper gastrointestinal endoscopy showed an antral ulcer, and gastric biopsy for Helicobacter pylori was positive. He was treated with ampicillin, tinidazole, and omeprazole for 10 days. A repeat endoscopy, 1 month later, revealed a healed duodenal ulcer. A peripheral smear showed reduced reticulocytes (0.8%) with normal platelet and myelocyte series. His serum transferrin saturation was 97.8%. lactate dehydrogenase was 385 U/l. Parvovirus B19 serology was negative (IgM level was 9.3 U/ml (negative if less than 17 U/ml)). He received, on an average, 4 units of packed red cells per month. A bone marrow trephine (Figure 2a) and aspirate (Figure 2b) showed a selective depletion of erythroblast precursors with normal granulopoiesis and megakaryopoiesis suggestive of pure red cell aplasia (PRCA). Wepox was withheld. His serum erythropoietin level was 558 mU/ml (normal range 10–30 mU/ml). The serum anti-erythropoietin antibody assay was positive (0.9% c.p.m. at 1:100 dilution and 4.3% c.p.m. at 1:20 dilution by radioimmunoprecipitation assay (RIPA)). Pure red cell aplasia due to Wepox. After discontinuation of Wepox, he received 6 units of blood transfusion and azathioprine at a dose of 300 mg per day, after which his hemoglobin (Hgb) increased to 9.3 g/dl within 2 weeks. He then underwent live unrelated renal transplantation in January 2007, 2 weeks after stopping Wepox. Since then, he has been managed on triple drug immunosuppression comprising of tacrolimus, mycophenolate mofetil, and prednisolone. The post-transplant course has been notable for two episodes of acute rejection, which responded to methylprednisolone. After his kidney transplant, he is not anemic. His Hgb and serum creatinine at 5 months post-transplant were 12.7 g/dl and 0.9 mg/dl, respectively. This presentation highlights the occurrence of PRCA with follow-on epoetins (FOEs). In Europe, FOEs are also referred to as biosimilar epoetins. In our patient, PRCA developed because of neutralizing IgG antibodies to the protein component of administered FOE, Wepox, that cross-reacted with endogenous epoetin. The precise mechanism for PRCA in patients treated with FOEs has not been elucidated. However, because PRCA from innovator epoetin appears to have resulted from problems in the manufacturing and storage of epoetin that have since been addressed, it is likely that this could also be the case with FOE, such as Wepox. Additionally, because FOEs are largely marketed in emerging countries where there is limited pharmacovigilance, surveillance for cases of FOEs-induced PRCA takes on even greater significance. Pure red cell aplasia (PRCA) is syndrome of marrow failure characterized by the selective reduction or absence of erythroid precursors. There is maturation arrest at the basophilic pronormoblastic phase in the bone marrow that is associated with reticulocytopenia and anemia. PRCA was originally described by Kaznelson1.Kaznelson P. Zur Enstehung der Blut Plattchen.Verh Dtsch Ges Inn Med. 1922; 34: 557Google Scholar in 1922 as an entity distinct from aplastic anemia. In the 1930s, Krantz et al.2.Young N.S. Pure red cell aplasia.in: Lichtman M.A.B. Kipps Ernest Seligsohn Thomas J. Kaushansky Uri Prchal Kenneth Josef T. 7th edn. Williams Hematology. 34. McGraw-Hill Health Professions Division, New York, NY2006: 437-447Google Scholar, characterized the immune mechanisms for the PRCA by identifying anti-erythroid precursor cell antibodies and T-cell-mediated inhibition of erythropoiesis. Two forms of PRCA have been reported: acquired and congenital. The congenital form of PRCA, also termed Diamond–Blackfan anemia, is sporadic in onset and presents in childhood with severe anemia. It is hypothesized that these patients have poor differentiation of red cell precursors. More than 50% of these patients demonstrate craniofacial, thumb, or neck anomalies and genitourinary malformations.3.Halperin D.S. Freedman M.H. Diamond-blackfan anemia: etiology, pathophysiology, and treatment.Am J Pediatr Hematol/Oncol. 1989; 11: 380-394PubMed Google Scholar Many of these patients respond to corticosteroids. The acquired form of PRCA may result from various etiologies (Table 1). Although most cases are considered idiopathic, in a series by Lacy et al.4.Lacy M.Q. Kurtin P.J. Tefferi A. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities.Blood. 1996; 87: 3000-3006PubMed Google Scholar, T-cell large granular lymphocytic leukemia, thymoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma were among the commonest causes in 47 adult patients with acquired PRCA. The pathogenesis of PRCA in these patients is not clear. Some of the suppressive effects on erythroid progenitors in PRCA are mediated by IgG autoantibodies or cytotoxic T lymphocytes.4.Lacy M.Q. Kurtin P.J. Tefferi A. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities.Blood. 1996; 87: 3000-3006PubMed Google Scholar Among the drug-related causes, PRCA is most frequently the result of an idiosyncratic reaction with phenytoin.Table 1Causes of PRCA in adults24.Verhelst D. Rossert J. Casadevall N. et al.Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study.Lancet. 2004; 363: 1768-1771Abstract Full Text Full Text PDF PubMed Scopus (113) Google ScholarDrugsHematological conditions/ malignancyPhenytoin/valproic acidLarge granular lymphocyte leukemiaaImportant causes of PRCA.Trimethoprim-sulfomethoxazoleLymphoreticular malignancyChloramphenicolMyelodysplastic syndromeaImportant causes of PRCA.IsoniazidMetastatic carcinomaZiduvudineThymomaaImportant causes of PRCA.ChlorpropamideSystemic lupus erythematosusaImportant causes of PRCA.,bAutoimmune diseases.AzathioprineRheumatoid arthritisaImportant causes of PRCA.,bAutoimmune diseases.ProcainamideJuvenile rheumatoid arthritisaImportant causes of PRCA.,bAutoimmune diseases.Recombinant human erythropoietinMultiple endocrine insufficiency syndromesaImportant causes of PRCA.,bAutoimmune diseases.Infections Parvovirus B19 infection Hepatitis (pregnancy) Adult T-cell leukemia virus (idiopathicaImportant causes of PRCA.) Epstein–Barr virus (idiopathicaImportant causes of PRCA.)PRCA, pure red cell aplasia.a Important causes of PRCA.b Autoimmune diseases. Open table in a new tab PRCA, pure red cell aplasia. Innovator epoetin (Epoetin-alfa; Epogen) was introduced by Amgen (Amagen Inc., thousand oaks, CA, USA) in 1989 for the treatment of chronic kidney disease anemia. Initially, cases of PRCA were anecdotally reported.5.Montagnac R. Boffa G.A. Schillinger F. et al.Sensitization to recombinant human erythropoietin in a woman under hemodialysis.Presse Med. 1992; 21: 84-85PubMed Google Scholar Subsequently, Casadevall et al.6.Casadevall N. Nataf J. Viron B. et al.Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin.N Engl J Med. 2002; 346: 469-475Crossref PubMed Scopus (1065) Google Scholar, published the Food and Drug Administration (FDA) Med Watch data on a series of patients with epoetin-related PRCA. Most cases of PRCA have been reported from outside the United States with epoetin-alfa and have been attributed to the substitution of Tween in place of human serum albumin as a stabilizer for epoetin (of note, Tween 80 is still used as a stabilizer for non-US epoetin-alfa and Tween-20 for epoetin-beta). Although epoetin-related PRCA has been reported in patients treated with other innovator epoetin molecules, including darbepoetin alfa and epoetin-beta, the frequency was much lower than epoetin-alfa, and remained constant through the years. The interaction of Tween and the uncoated rubber in pre-filled syringes appears to cause leachates. These leachates have been implicated in causing aggregation of epoetin molecules that then enhance their antigencity.7.Ryan M.H. Heavner G.A. Brigham-Burke M. et al.An in vivo model to assess factors that may stimulate the generation of an immune reaction to erythropoietin.Int Immunopharmacol. 2006; 6: 647-655Crossref PubMed Scopus (35) Google Scholar,8.Sharma B. Bader F. Templeman T. et al.Technical investigations into the cause of the increased incidence of antibody-mediated pure red cell aplasia associated with EPREX.Eur J Hosp Pharm. 2004; 5: 86-91Google Scholar Although these patients develop antibodies to the exogenously administered epoetin that cross-react with the endogenous epoetin, they also have factors that inhibit erythroid precursors.6.Casadevall N. Nataf J. Viron B. et al.Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin.N Engl J Med. 2002; 346: 469-475Crossref PubMed Scopus (1065) Google Scholar It is hypothesized that neutralizing anti-erythropoietin antibodies block the interaction between erythropoietin and its receptor, leading to ineffectiveness of the circulating erythropoietin. Furthermore, it is postulated that the production of anti-erythropoietin antibodies against endogenous epoetin occurs more frequently in patients administered exogenous epoetin. It is postulated that anti-erythropoietin antibodies cross-react against the protein component of the exogenous recombinant epoetin. Other possible mechanisms that have been raised include interruption of the cold chain, presumably resulting in modification in the folding of the epoetin molecule, and the use of the subcutaneous route of administration. Subcutaneous administration of epoetin also appears to contribute to the development of PRCA.6.Casadevall N. Nataf J. Viron B. et al.Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin.N Engl J Med. 2002; 346: 469-475Crossref PubMed Scopus (1065) Google Scholar Nevertheless, following modifications in the manufacturing process, reinforcement of cold chain, and decrease in the subcutaneous administration, there has been a dramatic reduction (>80%) in PRCA.9.Bennett C.L. Luminari S. Nissenson A.R. et al.Pure red-cell aplasia and epoetin therapy.N Engl J Med. 2004; 351: 1403-1408Crossref PubMed Scopus (368) Google Scholar It is intriguing that most epoetin-associated PRCA cases are reported in patients with chronic kidney disease and not those treated for anemia of chronic disease of other etiologies. In addition, not all patients with chronic kidney disease develop PRCA, suggesting that there may be some genetic predisposition to the susceptibility to PRCA. Alternatively, epoetin aggregation from leachates may not represent the complete explanation for the mechanism of PRCA and additional pathways for PRCA will need to be sought out. The 2006 Kidney/Dialysis Outcome Quality Initiative (K/DOQI) guidelines, which are similar to the European Best Practice Guidelines published in 2004, suggest that PRCA should be suspected in patients receiving erythropoiesis stimulating agents therapy for more than 4 weeks who develop a sudden rapid decline in Hgb level (at the rate of 0.5–1.0 g per 100 ml per week), or require red blood cell transfusions at a rate of approximately 1–2 per week in the context of normal platelet and white blood cell counts and an absolute reticulocyte count less than 10,000/μl.10.K/DOQI KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease.Am J Kidney Dis. 2006; 47: S11-S145Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,11.Locatelli F. Aljama P. Barany P. et al.Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure.Nephrol Dial Transplant. 2004; 19: ii32-ii36Google Scholar The diagnosis of PRCA is usually made from the examination of the peripheral smear and the bone marrow aspirate. The peripheral smear shows normocytic anemia and the absence of polychromasia with a reticulocyte count of <3% or 10,000/μl. Monitoring of serial reticulocyte counts in patients suspected of PRCA is helpful in early diagnosis of PRCA. The bone marrow aspirate demonstrates the presence of maturation arrest of the erythroid series at the level of basophilic pronormoblast phase with preserved myelopoiesis and megakaryopoiesis. Bone marrow trephine has a higher yield than the bone marrow aspirate, and is also helpful in diagnosing secondary causes of PRCA, such as Parvovirus B19 infection (giant pronormoblast), lymphomas and metastatic carcinomas, and myelodysplastic syndromes. As there is inadequate utilization of iron, serum ferritin and transferrin saturation are frequently very high and are characteristic of this condition. In patients on epoetin, the presence of anti-erythropoietin antibodies coupled with the presence of typical bone marrow findings is usually sufficient to make the diagnosis of epoetin-related PRCA. The assays used for the detection of anti-erythropoietin antibodies can be broadly divided into in vitro assays, such as antibody detection and functional assays, and in vivo assays. The following three assays: RIPA, the enzyme-linked immunosorbent assays, and the biosensor immunoassay are the most commonly used in vitro-neutralizing antibody detection assays. RIPA is considered the most specific and sensitive, and most commonly recommended test for detection of anti-erythropoietin antibodies. RIPA is based on competitive inhibition. The results for this assay are given for three individual determinations of anti-EPO antibody levels. A positive antibody is ≥0.9% c.p.m. bound in the above assay. A negative antibody is ≤0.6% c.p.m. bound in the above assay. Results that are between positive and negative are considered borderline. This test is not only specific but also very sensitive, as it can detect the presence of high-affinity anti-EPO IgG at a concentration as low as 10 ng/ml. Enzyme-linked immunosorbant assays is a quantitative method with easy implementation due to the simplicity of the procedure. However, high interassay variability and dependence on the laboratory conditions make it less sensitive than RIPA. The introduction of the 'bridging ELISA' has only modestly increased the specificity of the test. A biosensor immunoassay has recently been used for the detection of EPO antibodies. It is useful for characterization of the antibodies such as affinity and isotype. The major disadvantages are that it is expensive and its specificity (may detect non-pathogenic antibodies). The neutralizing capacity of anti-erythropoietin antibodies is best assessed by the cell proliferation assays. In the developing world and more recently in Europe, follow-on biologics are available for the treatment of anemia of kidney disease. These follow-on biologics are proteins that are similar but not identical to an already licensed or approved innovator biologic (the innovator biologic) with respect to bioequivalence and/or therapeutic equivalence. Innovator biologics are developed through biotechnology practices, including recombinant human technology, gene technology, or antibody methods. Each area of the manufacturing process of a biopharmaceutical, such as choice of the expression vector, cell fermentation, host cell line, protein purification protocols, sterile filling, and drug product formulation, is a determining factor.12.Covic A. Kuhlmann M.K. Biosimilars: recent developments.Int Urol Nephrol. 2007; 39: 261-266Crossref PubMed Scopus (28) Google Scholar Subtle variations in temperature, cell culture conditions, or even transport or storage conditions may result in significant changes in the clinical efficacy, biological activity, or immunogenicity of the product in some cases.13.Dove A. Uncorking the biomanufacturing bottleneck.Nat Biotechnol. 2002; 20: 777-779Crossref PubMed Scopus (63) Google Scholar,14.Restelli V. Wang M.D. Huzel N. et al.The effect of dissolved oxygen on the production and the glycosylation profile of recombinant human erythropoietin produced from CHO cells.Biotechnol Bioeng. 2006; 94: 481-494Crossref PubMed Scopus (65) Google Scholar,15.Misaizu T. Matsuki S. Strickland T.W. et al.Role of antennary structure of N-linked sugar chains in renal handling of recombinant human erythropoietin.Blood. 1995; 86: 4097-4104Crossref PubMed Google Scholar Thus, follow-on biologics, such as FOEs, originating from different manufacturers may be associated with subtle differences in their biochemical composition, which could translate into therapeutic differences.16.Schellekens H. How similar do 'biosimilars' need to be?.Nat Biotechnol. 2004; 22: 1357-1359Crossref PubMed Scopus (78) Google Scholar,17.Schellekens H. When biotech proteins go off-patent.Trends Biotechnol. 2004; 22: 406-410Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In addition, the differences in conformation of the biologic could potentially impact on their immunogenicity. FOEs are targeted to mimic the action of the original innovator epoetins. FOEs are frequently produced by local biotechnology companies and licensed by the local country's FDA or equivalent drug regulatory agency. In developing countries, FOEs are an inexpensive substitute for innovator epoetins. Indeed, the price may be discounted as much as 60% over the cost of the innovator epoetin. On the other hand, in Europe, FOEs are likely to be priced more closely to the innovator epoetin. Hitherto, prior to the patient described here, PRCA had not been reported with FOEs. However, FOEs may differ from the innovator biologic with respect to tertiary or quaternary folding, the cell lines used to express the protein, glycosylation content, and the degree of aggregation and isomer content. Others have also documented variable physical characteristics, such as pH, osmolality, and isoelectric charge, with FOE18.Singh A. Gaps in the quality and potential safety of biosimilar epoetins in the developing world: an international survey. American Society of Nephrology, Renal Week2006Google Scholar,19.Combe C. Tredree R.L. Schellekens H. Biosimilar epoetins: an analysis based on recently implemented European medicines evaluation agency guidelines on comparability of biopharmaceutical proteins.Pharmacotherapy. 2005; 25: 954-962Crossref PubMed Scopus (73) Google Scholar. These subtle differences could provide plausible explanations for potential immunogenicity for FOEs. Indeed, it is most likely that the same mechanisms that accounted for the immunogenicity of innovator epoetin could also explain the immunogenicity of FOEs. Each manufacturer of a FOE develops their own manufacturing processes and has their own quality surveillance protocols; this has the potential to generate subtle differences that could impact on the content and activity of the biologic. With the inability to reproduce identical molecule, efficacy measures and standardized analytical and pre-clinical tests for FOEs have been insufficient to demonstrate the comparability of two biological products.19.Combe C. Tredree R.L. Schellekens H. Biosimilar epoetins: an analysis based on recently implemented European medicines evaluation agency guidelines on comparability of biopharmaceutical proteins.Pharmacotherapy. 2005; 25: 954-962Crossref PubMed Scopus (73) Google Scholar,20.Ramos A.S. Schmidt C.A. Andrade S.S. et al.Biological evaluation of recombinant human erythropoietin in pharmaceutical products.Braz J Med Biol Res. 2003; 36: 1561-1569Crossref PubMed Scopus (24) Google Scholar In a study that we have conducted, FOE samples procured from pharmacies in Korea, Thailand, Vietnam, India, Philippines, Indonesia, Iran, Yemen, Jordan, Lebanon, and Columbia revealed variable physical characteristics with respect to pH, osmolality, and isoelectric charge. Some of these FOEs revealed varying potencies, higher endotoxins, and aggregates compared with epoetin-alfa.18.Singh A. Gaps in the quality and potential safety of biosimilar epoetins in the developing world: an international survey. American Society of Nephrology, Renal Week2006Google Scholar Since the European Union (EU) has developed more stringent standards for the monitoring of quality, it is unlikely that this variability in quality and problems with endotoxin contamination will be observed with FOEs that are marketed in Europe, although pharmacovigilance is still warranted. An inherent risk involved in the use of any biologic is its immunogenic potential. Immunogenicity can be due to many factors, such as altered chemical structure of the molecule, physical degradation, and chemical decomposition, apart from an effect of protein purification and product formulation.21.Hermeling S. Aranha L. Damen J.M. et al.Structural characterization and immunogenicity in wild-type and immune tolerant mice of degraded recombinant human interferon alpha2b.Pharm Res. 2005; 22: 1997-2006Crossref PubMed Scopus (126) Google Scholar The role of epoetin aggregates, leachates from rubber lined pre-filled syringes, and the subcutaneous route of administration have all been implicated in the etiology of PRCA secondary to innovator epoetins. Although FOEs are often used by practitioners for economic reasons, the varying potency observed in tested lots of the FOE raises questions about whether there is sufficient scrutiny of FOEs that are currently being marketed, especially in developing nations. There is no consensus on optimal therapy for PRCA. As in our patient, withdrawal of all kinds of erythropoiesis-stimulating agents was the critical step because prior observations demonstrate that the cross-reacting antibodies bind the diverse range of epoetin molecules, including darbepoetin alfa.22.Rossert J. Macdougall I. Casadevall N. Antibody-mediated pure red cell aplasia (PRCA) treatment and re-treatment: multiple options.Nephrol Dial Transplant. 2005; 20: iv23-iv26PubMed Google Scholar Despite reports of allergic reactions after re-introduction of erythropoietin, studies suggested success with reintroduction of epoetin after complete disappearance of anti-erythropoietin antibodies.23.Bennett C.L. Cournoyer D. Carson K.R. et al.Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project.Blood. 2005; 106: 3343-3347Crossref PubMed Scopus (72) Google Scholar The ESRD patient in whom kidney transplantation is not feasible is especially challenging from a management standpoint. Although spontaneous remissions are rare, immunosuppressive treatment accelerates recovery from erythropoietin-induced PRCA.23.Bennett C.L. Cournoyer D. Carson K.R. et al.Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project.Blood. 2005; 106: 3343-3347Crossref PubMed Scopus (72) Google Scholar,24.Verhelst D. Rossert J. Casadevall N. et al.Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study.Lancet. 2004; 363: 1768-1771Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar In these patients, there is an agreement that long-term treatment with steroids and cyclophosphamide is warranted. Other treatment modalities include plasmapheresis, cyclosporine, intravenous gamma globulins, and rituximab. Hematide is a pegylated synthetic peptide, which has been developed as an erythropoiesis-stimulating agent. No reports of PRCA have appeared in the literature, perhaps because hematide has novel amino acid sequences that are not related to endogenous erythropoietin. Although preliminary studies in rat models with hematide were promising with the correction of antibody-induced anemia (rat PRCA model), studies with long-term follow-up, especially in patients with chronic kidney disease, are not available.25.Stead R.B. Lambert J. Wessels D. et al.Evaluation of the safety and pharmacodynamics of hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers.Blood. 2006; 108: 1830-1834Crossref PubMed Scopus (99) Google Scholar,26.Woodburn K.W. Fan Q. Winslow S. et al.Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model.Exp Hematol. 2007; 35: 1201-1208Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar An algorithm based on the recommendation of the 2004 Revised European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure is described in Table 2 (specific hematologic and/or bone marrow criteria are detailed in the original guideline document).10.K/DOQI KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease.Am J Kidney Dis. 2006; 47: S11-S145Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,11.Locatelli F. Aljama P. Barany P. et al.Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure.Nephrol Dial Transplant. 2004; 19: ii32-ii36Google ScholarTable 2Algorithm for PRCA due to innovator/follow-on epoetinI. Suspect a case Patient on epoetin for ≥4 weeks Severe or progressively worsening anemia Reticulocytopenia Normal platelet and leukocyte counts Requirement for frequent blood transfusionsII. Diagnosis Bone marrow biopsy Anti-erythropoietin antibodies by RIPA Increased transferrin saturation or ferritinIII. Treatment Withdrawal of erythropoietin Renal transplantation Prednisone±cyclophosphamidePRCA, pure red cell aplasia; RIPA, radioimmunoprecipitation assay. Open table in a new tab PRCA, pure red cell aplasia; RIPA, radioimmunoprecipitation assay. In summary, with the patent expiry of innovator epoetins, FOEs will be an important option for the treatment of chronic kidney disease anemia. Physicians must be vigilant because FOEs may result in PRCA. Furthermore, although pharmacovigilance is a daunting and potentially expensive task for drug regulatory authorities, especially for countries in the developing world, scrutiny of the manufacturing and storage processes for epoetin is essential. Perhaps even more important in ensuring the long-term safety of biologic products, especially FOEs, is the development of a post-marketing surveillance infrastructure that allows for pharmacovigilance. It seems a price worth paying.