Factors Influencing Response to ESAs
A large body of epidemiologic data suggests that treating anemia of CKD with erythropoiesis-stimulating agents (ESAs) results in better clinical outcomes. Although randomized, controlled trials have shown an improved quality of life for most patients, data have failed to show unequivocally better survival or morbidity rates.
The response to ESAs is variable, and some patients are completely hyporesponsive or respond only to very high doses. True hyporesponsiveness to ESAs is hard to define, but it has been associated with poor clinical outcomes and estimated to occur in 4%-10% of the dialysis population.
The factors involved in ESA hyporesponsiveness remain undefined in CKD patients, but iron homeostasis appears to be altered. Some of the observed alterations implicate a diminished release of recycled iron from the reticuloendothelial system (RE), decreased enteral absorption, and a diminished capacity to transport iron to the developing erythrocytes due to a lower serum transferrin.
This decreased capacity to release and deliver iron to the bone marrow forces ESA-induced erythropoiesis to be dependent on external iron, usually delivered as parenteral iron. This dependence on parenteral iron has resulted in a higher-than-normal percentage transferrin saturation (TSAT) and serum ferritin (SF). We have come to tolerate levels of 50% TSAT and SF up to 500 ng/mL.
The long-term clinical and molecular consequences of this practice are not well known and are highly debated. Hepcidin, a 25-amino-acid defensinlike peptide produced by the liver, profoundly influences iron metabolism in vivo by binding and internalizing ferroportin, the only known iron extruder transporter. This effect of hepcidin on ferroportin blocks iron release from enterocytes and macrophages of the RE, ultimately resulting in a lower serum iron.
Therefore, a low hepcidin level would be expected in physiologic states requiring iron, and a high hepcidin would be expected if iron needs to be limited and/or is in excess, as happens in infection and hemochromatosis, respectively. Indeed hepcidin expression is downregulated by anemia/hypoxia, i.e., a situation in which iron is required, and upregulated by iron overload and inflammation, i.e., iron is not needed.
Researchers have speculated that diminished iron absorption and blocked iron release from the RE seen in CKD could be mediated by an elevated hepcidin as a result of inflammation and or a lower clearance. However, hepcidin levels and the role and/or function of hepcidin in CKD are not known.