Resistance to recombinant human erythropoietin therapy in haemodialysis patients

The involvement of a humoral factor (named as haemopoietin) in the regulation of haematopoiesis, was firstly described in literature in 1906 (Carnot  Deflandre, 1906). However, only 40 years later a linkage between erythropoietin (EPO) and erythropoiesis was described (Bondsdorff  Jalavisto, 1948), and only in the 1950s was established that the kidney is the main site of production of EPO (Jacobson, 1957). In 1977, EPO was purified from urine collected from patients suffering from aplastic anaemia (Miyake, 1977). The nucleotide sequence of human EPO gene was determined in 1985 and the cloning and expression of the gene led to the production of recombinant human EPO (rhEPO) (Lin, 1985; Jacobs, 1985). EPO is an endogenous cytokine that is essential in erythropoiesis regulation. This glycoprotein has a molecular mass of 30-35 kDa, 165 amino acids and is heavily glycosylated, with the carbohydrate moiety comprising approximately 40% of its weight. There are three N-terminal glycosylation sites at aspartate residues 24, 38 and 83, and one Olinked acidic oligonucleotide side-chain at serine 126. Human EPO has two disulphide bridges, between cysteines 7 and 161, and between cysteines 29 and 33, which are important in maintaining its in vivo bioactivity and the correct shape for binding to the EPO receptor (EPOR) (Lai, 1986). The regulation of EPO gene expression occurs essentially at the transcriptional level by DNA-dependent mRNA synthesis and gene activation. In kidneys, hypoxia gives rise to increased EPO expression, stimulated by the DNA binding protein, hypoxia inducible factor, which binds to the 3 ́ flanking region of EPO gene (Wang  Semenza, 1993). EPO is secreted into the plasma and, within the bone marrow, binds to EPOR in the surface of erythroid progenitor cells. EPOR activation follows a sequential dimerization activation mechanism involving the Janus kinase 2 (JAK2), and phosphorylation and nuclear translocation of signal transducer and activator of transcription 5 (STAT5) pathways (Fig. 1). The first clinical trial using rhEPO in the treatment of the anaemia of end-stage renal failure was published in 1987 (Eschbach, 1987), and, nowadays, rhEPO is currently used for the treatment of that anaemia in haemodialysis (HD) patients (Kimel, 2008; Obladen, 2000), as well as for a variety of other clinical situations associated with anaemia.