title: Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease.
abstract: BACKGROUND
  Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR) found in human blood, however its role in anemia is not known.
  
  
  RESULTS
  Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5) phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance.
  
  
  CONCLUSIONS
  These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro-inflammatory cytokines.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Eliyahu V
authors.initials: EV
authors.lastname: Khankin
authors.forename: Walter P
authors.initials: WP
authors.lastname: Mutter
authors.forename: Hector
authors.initials: H
authors.lastname: Tamez
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Yuan
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Ravi
authors.initials: R
authors.lastname: Thadhani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D020014:K562 Cells; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy* / Q000628:therapy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D017467:Receptors, Erythropoietin / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D006435:Renal Dialysis; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin