Role of circulating endothelial progenitors in responsiveness to erythropoiesis-stimulating agents in hemodialysis patients

Though treatment of anemia in chronic kidney disease (CKD) patients has been improved remarkably by erythropoiesis-stimulating agents (ESA), hypo-responsiveness to ESA poses a persistent problem in a subgroup of CKD patients, especially those on dialysis, with deteriorated mortality or cardiovascular risks. Pathomechanism of this condition including cardiovascular implications has not been sufficiently investigated. Clinical parameters of 101 chronic hemodialysis patients which included those hospitalized in our university hospital were examined cross-sectionally. As a marker estimating ESA hypo-responsiveness, erythropoietin resistance index (ERI) was calculated. Numbers of circulating endothelial progenitor cells (EPC) were measured by flow cytometry. Associations among values were analyzed by methods including multiple linear regression. Majority (93%) of the subjects were hospitalized patients with various comorbidities. ERI (18.4 [7.2–33.0] IU/week/kg/g/dL) and ESA dose (161.6 [75.0–320.9] IU/week/kg) of all the subjects were relatively high. Factors negatively correlated with EPC included age, HD vintage, CRP, pulse rate, ESA dose and ERI, while male sex and systolic blood pressure were positively correlated. By multiple linear regression analysis, age, sex and ERI (standardized coefficient beta − 0.202, p = 0.039) remained as the independently predicting factors of EPC (log CD133/Flk1+ EPC). Darbepoetin alpha was used in 65 patients, especially predominant when requiring higher ESA doses, but by correlation or multivariable analyses, this did not substantially modify the negative association between ERI and EPC. ERI was independently associated with EPC paucity in a cohort with various comorbidities. This may suggest a link which connects ESA hypo-responsiveness to compromised cardiovascular prognosis of dialysis patients.