Erythropoietin (EPO) is a glycoprotein hormone, naturally produced by the peritubular cells of the kidney, that stimulates red blood cell production. Renal cortex peritubular cells produce most EPO in the human body, though in a fetus, the liver is the primary site of production. EPO is also produced in the spleen, liver, bone marrow, lung, and brain in small quantities. PO2 directly regulates EPO production. The lower the pO2, the greater the production of EPO. Indirectly, low hemoglobin levels stimulate EPO production.
Erythropoietin Stimulating Agents (ESA) are recombinant versions of EPO produced pharmacologically. Examples of ESAs are epoetin, darbepoetin, and methoxy polyethylene glycol-epoetin beta.
ESAs are generally indicated in conditions where there is impaired red blood cell production. The two main FDA approved indications for the use of ESAs are anemia secondary to chronic kidney disease and chemotherapy-induced anemia in cancer patients. Other approved indications are anemia secondary to zidovudine treatment in HIV infection, support in patients receiving autologous blood transfusions, anemic patients undergoing elective surgery (both pre-op and post-op), and anemia in pre-term infants.
In CKD, where there is damage to the kidneys and limited EPO production by the peritubular cells, ESAs are beneficial. In CKD, ESAs are given in patients who are receiving dialysis and patients soon to need dialysis. The FDA approved the use of epoetin (1993) and darbepoetin (2002) for patients with chemotherapy-induced anemia. In patients with CKD and chemotherapy-induced anemia, ESAs are generally limited to patients with a hemoglobin less than 10g/dL due to the risk of adverse effects.
Endogenous erythropoietin and erythropoietin stimulating agents stimulate division and differentiation of erythroid progenitor cells. The surface of CD34+ hematopoietic stem cells, very early developing erythrocytes, contain EPO receptors. Binding of endogenous EPO or recombinant analogs creates a cellular signaling cascade, activating genes that promote cell proliferation and prevent apoptosis. The result is stimulating an increase in total body hemoglobin and hematocrit.
Transfected Chinese hamster ovary cells (CHO’s) are the usual source for large-scale manufacturing of ESAs. An isotonic solution buffers the ESA powder which can be administered intravenously or subcutaneously. Standard dosing for epoetin alfa in patients with anemia secondary to CKD or chemotherapy is 50 to 100 international units per kilogram. This dose is initially given three times weekly. Dosing and frequency can be adjusted based on response to treatment.
The most severe adverse effects of EPO are related to a significant risk of thrombotic events, particularly in surgical patients. Supplemental use of ESAs causes an increase in blood viscosity because of a higher rate of erythrocyte production. Given this and given less of a vasodilatory effect due to a low baseline pO2, there is an increased risk of ischemic stroke and myocardial infarction. There is also an increased risk of venous thromboembolism, and some have proposed the use of antithrombotic prophylaxis in patients receiving ESA.
There has been concern regarding the potential progression of tumorigenesis in patients with certain forms of cancer, particularly breast cancer, non-small cell lung cancer, head and neck cancer, lymphoid cancer, and cervical cancer. The mechanism is through increased cell signaling and tumor angiogenesis.
Nausea, vomiting, diarrhea, fatigue, insomnia, peripheral edema, thrombocytopenia, myalgias, arthralgias, rashes, abdominal pain, headache, and paresthesias were reported as common adverse effects experienced by patients undergoing chemotherapy who received epoetin alfa in a multicenter study.
ESAs are contraindicated in patients who have hypersensitivity to non-human mammal-derived products because of ESAs production methods.
Because of the increase in blood viscosity using ESAs, physicians should exercise caution in patients with a history of DVT, pulmonary embolism, or hypercoagulability disorder. Likewise, caution is recommended in patients with a history of ischemic stroke or cardiovascular disease.
ESAs containing benzyl alcohol are contraindicated in neonates, peripartum mothers, and mothers who are breastfeeding due to risk for Gasping Syndrome. This syndrome causes gasping respirations, renal failure, and neurological deterioration in neonates, resulting from severe metabolic acidosis.
Patients receiving ESAs should have baseline hemoglobin, and transferrin checked before administration. Hemoglobin should be checked frequently at the beginning of treatment weekly. The dosing and frequency of administration should be adjusted based on the response to treatment. If hemoglobin rises to a non-anemic level, the ESA should be withheld. Consider iron supplementation in patients with poor response to treatment as iron availability may be low.
Most cases of ESA toxicity are related to the adverse effects of chronic use. There are few case reports of acute toxicity. One study involves a man who intentionally injected himself with recombinant human erythropoietin, causing his hemoglobin to rise to a dangerously high level. He received treatment with IV fluids, serial phlebotomy, and mechanical ventilation.
Treatment of anemia in patients using erythropoietin stimulating agents (ESAs) requires an interdisciplinary team of medical providers. This should include a nephrologist in patients with chronic kidney disease, a hematologist/oncologist in patients undergoing chemotherapy, appropriate nursing staff, a pharmacist for ESA dosing, a phlebotomy lab/ technician for blood draws to monitor for improvement.
Appropriate follow-up appointments should be arranged to reassess the patient’s health status and any adverse effects of the ESA. Patients should receive counseling on the potential adverse effects and when to seek immediate medical care. Emergency medical providers should be aware of the adverse effects of ESAs to risk-stratify patients for venous thromboembolism, acute coronary syndrome, ischemic stroke, and other emergent conditions related to ESAs.
Monitoring of the hemoglobin level to optimize patient outcomes and minimize adverse effects is very important. A debate exists regarding the appropriate target hemoglobin in individuals treated with ESAs. A pooled analysis of nine randomized control trials on patients with chronic kidney disease indicates that patients have higher mortality and morbidity from cardiovascular-related events when the hemoglobin falls below 10 g/dL.In this pooled analysis, there was no benefit in survival in patients treated with ESAs when the hemoglobin exceeded 13 g/dL, yet there was a higher incidence of adverse events such as hypertension, vascular access thrombosis, and stroke. Therefore, current guidelines call for individual tailoring of target hemoglobin levels, but optimal levels generally fall between 11 and 12 g/dL with the knowledge that higher doses of ESAs may increase the risk for thrombotic events [level 1].