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 ( RBC s) 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 RBC s in patients with ESRD receiving standard or high doses of recombinant human erythropoietin (rh EPO ). Method Blood samples from twenty‐eight patients under sustained hemodialysis, responsive, or not to standard rh EPO 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 RBC s were characterized by pathological levels of shape distortions, surface removal signaling, and membrane exovesiculation, but reduced fragility compared to healthy RBC s. Irreversible transformation of RBC s was found to be a function of baseline Hb concentration. The more toxic uremic context in non‐responsive patients compared to rh EPO responders was blunted in part by the antioxidant, antihemolytic, and anti‐apoptotic effects of high rh EPO doses, and probably, of serum uric acid. A selective lower expression of RBC membrane in complement regulators ( CD 59, clusterin) and of CD 47 “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 rh EPO responsive compared to non‐responsive patients was also revealed. Conclusion Deregulation of RBC homeostasis might involve diverse molecular pathways driving erythrocyte signaling and removal in rh EPO non‐responders compared to responsive patients.