Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial

Abstract

BackgroundIn a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients.MethodsThe study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference.ResultsNo difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa.ConclusionsThe reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov: NCT01666301

Influence of continuous erythropoietin receptor activator (CERA) administration intervals on erythropoietic effect in hemodialysis patients

“…Although this is just a single observational datum, this example suggests that the erythropoietic effect of CERA is not sustained for more than 4 weeks. This is in accordance with the reports of reticulocyte dynamics in hemodialysis patients treated with CERA [15,19].…”

“…Reticulocyte counts were maximal at 7-10 days of CERA administration and returned to the same levels by the next monthly CERA administration [15,19], which influenced Hb levels. As a result, not only reticulocyte counts but also Hb levels differ according to the timing of the CERA administration and bloodwork, with the timing effect more prominent when CERA administration intervals are longer.…”

“…As a result, not only reticulocyte counts but also Hb levels differ according to the timing of the CERA administration and bloodwork, with the timing effect more prominent when CERA administration intervals are longer. This is also the case when we evaluate the serum iron, ferritin, or hepcidin levels which change in a mirror-image manner to the reticulocyte counts [7,9,15,19].…”

“…Although the influence of RBC lifespan on Hb levels in hemodialysis patients is substantial, this factor has been largely neglected [20]. In hemodialysis patients, RBC lifespan is influenced by the uremic state [21,22], ESA administration [19,23], and/or inflammation. The higher levels of CRP and hepcidin and lower levels of iron in patients receiving CERA 150 μg/4W than in those receiving 100 or 50 μg/4W may indicate the bluntness of iron recruitment for erythropoiesis but may also indicate a shorter RBC lifespan in patients requiring higher doses of CERA.…”

Fixed dose of long‐acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis

“…The dosing strategy used in this study resulted in significant increases in overall RBC count, Hb, Hct and MCHC and a significant decrease in MCV. Mature RBCs are smaller than immature ones . The inflammatory markers TNF, IL‐6, and hepcidin also decreased significantly after treatment.…”