title: Pathophysiological aspects of red blood cells in end-stage renal disease patients resistant to recombinant human erythropoietin therapy.
abstract: OBJECTIVE
  Modified, bioreactive red blood cells (RBCs) and RBC-derived microvesicles (MVs) likely contribute to the hematological and cardiovascular complications in end-stage renal disease (ESRD). This study assesses the physiological profile of RBCs in patients with ESRD receiving standard or high doses of recombinant human erythropoietin (rhEPO).
  
  
  METHODS
  Blood samples from twenty-eight patients under sustained hemodialysis, responsive, or not to standard rhEPO administration were examined for RBC morphology, fragility, hemolysis, redox status, removal signaling, membrane protein composition, and microvesiculation before and after dialysis. Acute effects of uremic plasma on RBC features were examined in vitro through reconstitution experiments.
  
  
  RESULTS
  Overall, the ESRD RBCs were characterized by pathological levels of shape distortions, surface removal signaling, and membrane exovesiculation, but reduced fragility compared to healthy RBCs. Irreversible transformation of RBCs was found to be a function of baseline Hb concentration. The more toxic uremic context in non-responsive patients compared to rhEPO responders was blunted in part by the antioxidant, antihemolytic, and anti-apoptotic effects of high rhEPO doses, and probably, of serum uric acid. A selective lower expression of RBC membrane in complement regulators (CD59, clusterin) and of CD47 "marker-of-self" was detected in non-responders and responders, respectively. Evidence for different short-term dialysis effects and probably for a different erythrocyte vesiculation mechanism in rhEPO responsive compared to non-responsive patients was also revealed.
  
  
  CONCLUSIONS
  Deregulation of RBC homeostasis might involve diverse molecular pathways driving erythrocyte signaling and removal in rhEPO non-responders compared to responsive patients.
authors.affiliation: Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
authors.forename: Hara T
authors.initials: HT
authors.lastname: Georgatzakou
authors.affiliation: Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
authors.forename: Vassilis L
authors.initials: VL
authors.lastname: Tzounakas
authors.affiliation: Department of Medical Laboratories, Faculty of Health and Caring Professions, Technological and Educational Institute (TEI) of Athens, Athens, Greece.
authors.forename: Anastasios G
authors.initials: AG
authors.lastname: Kriebardis
authors.affiliation: Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
authors.forename: Athanassios D
authors.initials: AD
authors.lastname: Velentzas
authors.affiliation: Department of Medical Laboratories, Faculty of Health and Caring Professions, Technological and Educational Institute (TEI) of Athens, Athens, Greece.
authors.forename: Effie G
authors.initials: EG
authors.lastname: Papageorgiou
authors.affiliation: "Apostle Paul" Educational Institution, Thessaloniki, Greece.
authors.forename: Artemis I
authors.initials: AI
authors.lastname: Voulgaridou
authors.affiliation: Chronic Hemodialysis Centre "Ionion", Piraeus, Greece.
authors.forename: Apostolos C
authors.initials: AC
authors.lastname: Kokkalis
authors.affiliation: Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
authors.forename: Marianna H
authors.identifier: http://orcid.org/0000-0003-3787-3596
authors.initials: MH
authors.lastname: Antonelou
authors.affiliation: Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
authors.forename: Issidora S
authors.initials: IS
authors.lastname: Papassideri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051928:CD47 Antigen / Q000097:blood / Q000235:genetics; D018957:CD59 Antigens / Q000097:blood / Q000235:genetics; D016022:Case-Control Studies; D048430:Cell Shape / Q000187:drug effects; D051152:Clusterin / Q000097:blood / Q000235:genetics; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000627:therapeutic use*; D000067128:Extracellular Vesicles / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000473:pathology / Q000628:therapy*; D008297:Male; D009996:Osmotic Fragility / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use*; D006435:Renal Dialysis; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D018957:CD59 Antigens; C495242:CLU protein, human; D051152:Clusterin; D006454:Hemoglobins; D011994:Recombinant Proteins; C051590:CD59 protein, human; D004921:Erythropoietin; D014527:Uric Acid
keywords: end-stage renal disease; hemodialysis; recombinant human erythropoietin; red blood cells; rhEPO resistance