anaemia is a serious complication of chronic kidney disease ( ckd ) and cancer therapy . erythropoiesis - stimulating agents ( esas ) , based on recombinant human erythropoietin ( rhuepo ) , are used to treat anaemia by raising haemoglobin ( hb ) levels , alleviating its effects and reducing the need for blood transfusions . available esas include epoetin alfa ( epogen , eprex or procrit ; amgen , johnson & johnson and ortho biotech , respectively ) , epoetin beta ( neorecormon , roche ) and darbepoetin alfa ( aranesp , amgen ) , a super - sialylated analogue of epoetin alfa with a longer circulating half - life that can be administered less frequently than epoetin alfa ( neorecormon , roche , manufactured in mannheim , germany aranesp , amgen , manufactured in thousand oaks , usa ) . esa use is associated with a risk of auto - antibody production   directed against rhuepo and the native epo molecule . this can cause development of a rare condition known as antibody - mediated pure red cell aplasia ( prca ) . patients with prca have erythroid precursor deficiency in the bone marrow and thus become resistant to rhuepo treatment and dependent on blood transfusions for hb maintenance . we report the development and management of prca in a patient with ckd following a switch from darbepoetin alfa to epoetin beta . a 63-year - old man with end - stage renal disease was started on intravenous ( i.v . ) darbepoetin alfa ( 20 g q2w ) for anaemia in january 2005 after transfer from another haemodialysis unit , where he had received this medication for at least 1 year . the patient had been receiving haemodialysis since 1999 and in december 2001 received a renal transplant , but hyperacute rejection caused immediate renal vein thrombosis . during i.v . darbepoetin alfa treatment between january 2005 and february 2006 , hb levels varied between 10.9 g/ dl and 12.5 g / dl ( figure 1 ) . esa doses were adjusted as necessary and ranged from 25 g q2w to 10 g qw . hb remained stable , varying between 12.2 g / dl and 12.9 g/ dl for 6 months , but then began to fall ( figure 1 ) . the epoetin beta dose was progressively increased to 24  000 u / week , but the patient was unresponsive . by january 2007 , hb level was 7.1 g / dl and reticulocyte count 0.0  10/l , with normal white blood cell and platelet counts . a test for anti - epo antibody in january 2007 was positive ( 964 ng / ml ) and a bone marrow examination revealed the absence of erythroid precursors , confirming the suspected prca . in addition , prostate - specific antigen , immunoglobulins igg , iga and igm , complement proteins c3 and c4 , anti - nuclear antibody , anti - dna antibody , anti - neutrophil cytoplasmic antibodies and serum protein electrophoresis results were all normal . laboratory parameters on diagnosis of pure red cell aplasia crp , c - reactive protein ; pthi , parathyroid hormone ; ldh , lactate dehydrogenase . epoetin beta was discontinued at the end of january 2007 ; prednisone ( 1 mg / kg / day to 60 mg / day ) and cyclophosphamide ( 50 mg / day ) treatment was started to repress antibody formation . hb values were variable but slowly increased in response to immunosuppressive therapy ( figure 1 ) . by may 2007 reticulocyte count on follow - up in february 2007 had increased to 4.0  10/l , but was still below the normal range . we report the development of prca in a patient with ckd 6 months after a switch from i.v . the national kidney foundation kidney disease outcomes quality initiative anaemia guidelines   suggest that anti - epo antibody - induced prca should be considered and further evaluated in a previously responsive patient who , after at least 4 weeks of esa therapy , displays a rapid decline in hb level ( > 0.5 1 g / dl per week ) or a transfusion requirement of 12 units per week in order to maintain adequate hb . other signs are a reticulocyte count < 10  000/l with normal white blood cell and platelet counts and severe erythroid hypoplasia , with < 5% red blood cell precursors in the bone marrow aspirate . radio - immunoprecipitation assays or enzyme - linked immunosorbent assays are used to determine the presence of epo - binding antibodies . bioassays , in which patient serum or immunoglobulin inhibits red blood cell precursor growth in bone marrow or cell line cultures , are used to determine the presence of epo - neutralizing antibodies . in suspected or confirmed prca cases , esas should be discontinued and immunosuppressive therapy , for example cyclophosphamide combined with prednisone , should be initiated . there are more reported prca cases following s.c . , compared with i.v . , esa administration . whereas the vast majority of reports of recombinant epo - related prca have been attributable to treatment with eprex , cases attributable to other recombinant epos have been reported [ 46 ] . the number of antibody - mediated prca cases in ckd patients treated with s.c . this coincided with changes in the formulation and packaging of eprex. human serum albumin stabilizer was replaced with glycine and polysorbate 80 in 1998 , due to concerns over creutzfeld formation of micelles between polysorbate 80 and epoetin alfa   has been proposed as a possible cause of increased immunogenicity . neorecormon is stabilized by polysorbate 80 and aranesp by polysorbate 20 , glycine , a 5-amino - acid complex , calcium chloride and urea . another suggested cause is leaching of organic compounds by polysorbate 80 from the uncoated rubber stoppers used in eprex syringes . the variation in post - translational modifications , aggregation , dose , treatment duration and patient genetic characteristics may also influence immunogenicity . physicians should be aware of the characteristics indicative of prca development , and the potential impact of switching between similar biopharmaceuticals . it is important to note that switching a patient between available esas may lead to difficulties in attributing the development of prca to one particular esa . to monitor potential esa immunogenicity and achieve the highest levels of patient safety concerns over prca will become more prominent given the imminent market introduction of biosimilar recombinant epos . the routine practice , in some countries , of switching biopharmaceuticals for similar products does not allow pharmacovigilance and may delay diagnosis of complications such as prca in ckd patients .
we report the development of antibody - mediated pure red cell aplasia ( prca ) in a 63-year - old man with end - stage renal disease following a switch from darbepoetin alfa to epoetin beta . 
 haemoglobin levels began to decrease 6 months after the switch . increasing 
 the epoetin beta dose produced no response and regular blood transfusions were required ; prca was confirmed and epoetin beta was discontinued . 
 the patient responded positively to immunosuppression ; after 2 months on prednisone and cyclophosphamide , haemoglobin levels stabilized and no further transfusions were required . 
 this case highlights the difficulty in establishing a cause - effect relationship where more than one erythropoiesis - stimulating agent is involved .