Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease.
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.
Khankin
Eliyahu V
EV
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
Mutter
Walter P
WP
Tamez
Hector
H
Yuan
Hai-Tao
HT
Karumanchi
S Ananth
SA
Thadhani
Ravi
R
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
D015850:Interleukin-6; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin