[Erythropoiesis-stimulating agents: from the origins to new challenges]

The structure, pharmacodynamics and pharmacokinetics of erythropoiesis-stimulating agents (ESAs) have changed from the first (rHuEPO) to the second (darbepoetin) and third generations (CERA), with an increase in glycosylated groups accompanied by a reduction of the affinity for the receptor and an increased half-life. After the initial success resulting from the correction of anemia, large observational trials have shown an increase in mortality related to higher hemoglobin values in kidney patients. Subsequent analysis of the trial results revealed that the cause of the worse outcomes was not the hemoglobin level but the high ESA dose. Resistance to ESAs resulting in their increased consumption is hepcidin mediated, as the hormone is upregulated by inflammatory factors and by a drop in the ESA level below the physiological erythropoietic threshold. This is where the ESA kinetics comes into play. Analysis of different databases has shown that the variability of hemoglobin levels over time caused outcomes to worsen and was correlated with frequent changes in the ESA dose. Many studies have demonstrated that third-generation ESAs ensure greater stability and physiological action, allowing to reduce dose changes and overshooting to a minimum.