epoetin-alfa and Iron-Overload

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800 ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

Topics: Anemia, Iron-Deficiency; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Iron Overload; Kidney; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Survival Analysis; Transferrin

Stimulation of red blood cell precursors by Epoetin alfa results in a predictable, dose-dependent increase in red blood cell mass. Iron is an important substrate that supports red blood cell and hemoglobin development. Patients who receive Epoetin alfa therapy typically require intravenous iron supplementation to ensure proper red cell formation. Target and ceiling iron levels should be determined on the basis of safety considerations, the predicted clinical response, and individual patient replacement needs. Nurses can use clinical parameters such as body weight, baseline and target hemoglobin values, and iron losses from blood and other sources to estimate iron replacement doses, thereby providing a guide for appropriate iron replacement.

Topics: Anemia, Iron-Deficiency; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epoetin Alfa; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron Compounds; Iron Overload; Kidney Failure, Chronic; Nurse's Role; Nursing Assessment; Recombinant Proteins; Renal Dialysis; Safety Management; Transferrin

Erythropoietin (EPO) plays a central role in the regulation of red blood cell (RBC) production. Since iron is an essential element for erythropoiesis and hemoglobin (Hb) synthesis, its importance is heightened in patients treated with epoetin alfa. Stimulation of erythropoiesis following the administration of epoetin alfa is associated with several changes in iron metabolism; indeed, plasma ferritin levels fall as a result of increased utilization of iron by the expanding erythroid marrow. The administration of epoetin alfa can therefore lead to a state of relative iron deficiency. Thus, iron supplementation is essential to maximize the effect of epoetin alfa-induced erythropoiesis.

Topics: Adult; Anemia, Hypochromic; Bone Marrow; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Iron Deficiencies; Iron Overload; Male; Middle Aged; Recombinant Proteins

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Ferroptosis; Iron Overload; Mice

Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in Hbb(th3/+) mice with thalassemia intermedia, where it contributes to the suppression of hepcidin and the systemic iron overload characteristic of this disease.

Topics: Anemia; Animals; beta-Thalassemia; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gene Expression Profiling; Hemoglobins; Hemorrhage; Hepcidins; Hormones; Iron; Iron Overload; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 mug/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.

Topics: Adult; Biopsy; Bone Marrow Transplantation; Combined Modality Therapy; Darbepoetin alfa; Diagnosis, Differential; Disease Progression; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Ferritins; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Iron Overload; Liver Diseases; Male; Middle Aged; Pancreatic Diseases; Phlebotomy; Prospective Studies; Recombinant Proteins; Skin Diseases; Transferrin; Transplantation Conditioning; Transplantation, Homologous