Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations

Routine clinical and laboratory assessments facilitate diagnosis of erythropoietin (EPO) resistant anemia by allowing early identification of patients with non-adherence. Any new event that impairs response to EPO (e.g., catheter sepsis) must be promptly controlled. Because of the confounding interaction of its risk factors, initial evaluation should include nutrition, dialysis adequacy, hemorrhage, bone mineral metabolism, and inflammation. Prevention of EPO resistance is more cost effective and should include adequate dialysis and nutritional supplements. Blood loss during hemodialysis (HD) procedures should be minimized. If there is laboratory proof of iron deficit intravenous repletion is most effective. Oxidative stress may be attenuated by vitamins E and C, while optimal control of hyperparathyroidism will enhance EPO stimulation. Contaminated dialysates should be suspected if there is EPO-stimulating agents (ESA) resistance at the same time among most members of a dialysis program. Heavy metal toxicity should be suspected in high-risk patients. The impact of co-morbidities such as hemoglobinopathy, glucose 6 phosphate dehydrogenase (G6PD) deficiency and connective tissue diseases must be excluded in an appropriate setting. In conclusion, given the multiple risk factors of EPO resistance promotion of the overall health status will most likely yield an enduring benefit. Finally, there are experimental trials of gene-based (therapy) to stimulate endogenous EPO synthesis with the goal of avoiding the off-target effect of excessive dosing.