Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease

• Published in: PloS one Vol. 5; no. 2; p. e9246
• Main Authors: Khankin, Eliyahu V., Mutter, Walter P., Tamez, Hector, Yuan, Hai-Tao, Karumanchi, S. Ananth, Thadhani, Ravi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.02.2010; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; Alternative splicing; Anemia; Animals; Blotting, Western; Bone marrow; Cancer; Cell Line; Chronic illnesses; Chronic kidney failure; Combined Modality Therapy; Cytokines; Dialysis; Disease control; Disease resistance; Dose-Response Relationship, Drug; Drug dosages; Drug Resistance; End-stage renal disease; Erythroblasts; Erythropoietin; Erythropoietin - administration & dosage; Erythropoietin - therapeutic use; Female; Glycosylated hemoglobin; Growth factors; Hematology/Anemias; Hemodialysis; Hemoglobin; Humans; Hypoxia; Inflammation; Interleukin 6; Interleukin-6 - pharmacology; Iron; K562 Cells; Kidney diseases; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - therapy; Kidney transplantation; Kidneys; Kinases; Ligands; Logistic Models; Male; Medical schools; Medicine; Middle Aged; Molecular Weight; Mortality; Nephrology/Chronic Kidney Disease; Nephrology/Dialysis and Renal Transplantation; Patients; Phosphorylation; Phosphorylation - drug effects; Proteins; Receptors, Erythropoietin - blood; Receptors, Erythropoietin - chemistry; Receptors, Erythropoietin - metabolism; Renal Dialysis; RNA; Stat5 protein; STAT5 Transcription Factor - metabolism; Thromboembolism; Transcription; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; United States > US; Massachusetts
• DOI: 10.1371/journal.pone.0009246
• ISSN: 1932-6203

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. 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. 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.