Continuing Education Activity

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. PO2 directly regulates EPO production. The lower the pO2, the greater the production of EPO. Erythropoietin stimulating agents (ESAs) 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. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of ESAs in light of the natural physiology of erythropoietin, pertinent for members of the interprofessional team in the treatment of patients with conditions where these agents are indicated.

Objectives:

• Describe the physiology of erythropoietin.
• Review the indications for using erythropoietin stimulating agent therapy.
• Identify the contraindications and adverse events associated with erythropoietin stimulating agents.
• Outline interprofessional team strategies for improving care coordination and communication to advance and improve outcomes using erythropoietin stimulating agents to stimulate erythropoietin.

Indications

Endogenous 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, although in a fetus, the liver is the primary site of production.[1] EPO production also occurs in the spleen, liver, bone marrow, lung, and brain in small quantities. The partial pressure of oxygen (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 (ESAs) are recombinant versions of EPO produced pharmacologically via recombinant DNA technology in cell cultures. Examples of erythropoietin stimulating agents include epoetin alfa, darbepoetin, and methoxy polyethylene glycol-epoetin beta.[1]

ESAs are generally indicated in conditions where there is impaired red blood cell production. The two primary FDA-approved indications for ESAs are anemia secondary to chronic kidney disease and chemotherapy-induced anemia in patients with cancer.[2] 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) anemia in preterm infants.

In CKD, where there is damage to the kidneys and limited EPO production by the peritubular cells, ESAs are beneficial.[3] In CKD, ESAs are useful in patients who are receiving dialysis as well as 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 hemoglobin less than 10g/dL due to the risk of adverse effects.[2]

Mechanism of Action

Endogenous erythropoietin and erythropoietin stimulating agents stimulate the division and differentiation of erythroid progenitor cells.[3] The surface of CD34+ hematopoietic stem cells, very early developing erythrocytes, contains EPO receptors. The 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.

Administration

Transfected Chinese hamster ovary cells (CHOs) are the usual source for large-scale manufacturing of erythropoietin stimulating agents.[3] An isotonic solution buffers the ESA powder, which the provider can administer intravenously or subcutaneously.

Standard dosing for epoetin alfa by indication follows. Dosing and frequency can be adjusted based on response to treatment. Chronic kidney disease-associated anemia: Start with 50 to 100 units/kg IV or subcutaneously three times per week. (Specific dosing protocols and alternate dosing regimens should be verified via manufacturer information or facility protocols.)

• HIV-associated anemia: Start with 100 units/kg/dose IV or subcutaneously three times per week; max 300 units/kg/dose three times weekly.
• Chemo-related anemia: Start with 40,000 units subcutaneously every week or 150 units/kg/dose subcutaneously three times weekly.
• Surgery-associated transfusion reduction: 300 units/kg/dose subcutaneously daily for 15 days.

Darbepoetin alfa dosing for specific indications is as follows: (Specific dosing protocols and alternate dosing regimens should be verified via manufacturer information or facility protocols.)

• Chronic kidney disease-associated anemia: Start with 0.45 mcg/kg IV or subcutaneously weekly.
• Chemo-related anemia: Start with 2.25 mcg/kg/dose subcutaneously every week or 500 mcg subcutaneously every three weeks.

Adverse Effects

The most severe adverse effects of EPO are related to a significant risk of thrombotic events, particularly in surgical patients.[3] Supplemental use of erythropoietin stimulating agents leads to an increase in blood viscosity because of a higher rate of erythrocyte production. Given this, as well as the reduced vasodilatory effect due to a low baseline pO2, there is an associated increased risk of ischemic stroke and myocardial infarction.[4] There is also an increased risk of venous thromboembolism, and some have proposed the use of antithrombotic prophylaxis in patients receiving ESA therapy.[3]

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.[5] The mechanism is through increased cell signaling and tumor angiogenesis.

Researchers reported nausea, vomiting, diarrhea, fatigue, insomnia, peripheral edema, thrombocytopenia, myalgias, arthralgias, rashes, abdominal pain, headache, and paresthesias as common adverse effects experienced by patients undergoing chemotherapy who received epoetin alfa in a multicenter study.[6]

Contraindications

Erythropoietin stimulating agents are contraindicated in patients with hypersensitivity to non-human mammal-derived products because of ESA production methods.[3]

Because of increased blood viscosity when using ESA, physicians should exercise caution in patients with a history of DVT, pulmonary embolism, or hypercoagulability disorder. Likewise, caution is necessary for patients with a history of ischemic stroke or cardiovascular disease.[4]

ESAs containing benzyl alcohol are contraindicated in neonates, peripartum mothers, and breastfeeding mothers due to the risk for gasping syndrome. This syndrome causes gasping respirations, renal failure, and neurological deterioration in neonates, resulting from severe metabolic acidosis.[7]

Monitoring

Patients receiving erythropoietin stimulating agent therapy should have baseline hemoglobin and transferrin checked before administration.[3] 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 clinician should withhold the ESA.[8] Consider iron supplementation in patients with poor response to therapy as iron availability may be inadequate.[3]

Toxicity

Most erythropoietin stimulating agent toxicity cases 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.[9] He received treatment with IV fluids, serial phlebotomy, and mechanical ventilation.

Enhancing Healthcare Team Outcomes

Treating anemia in patients using erythropoietin stimulating agents (ESA) requires an interprofessional team of medical providers. This team 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.

The healthcare team should arrange appropriate follow-up appointments to reassess the patient’s health status and any adverse effects of the ESA; this is where specialty-trained nurses and pharmacists can play a significant role. Nursing will have the most frequent and ongoing contact with the patient, so they can provide education and monitor for adverse effects and administer the medication. Pharmacists with specialty oncology certification should monitor dosing, interactions, and lab values that may alter or stop the dosing of the ESA. Both nurses and pharmacists must chart and inform the treating physician of any findings, changes, or concerns.

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 ESA.

Only through the coordinated effort of an interprofessional healthcare team can ESA therapy be administered safely and effectively, with minimal adverse events and optimal patient results. [Level 5]

Monitoring 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 ESA. 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.[10] In this pooled analysis, there was no benefit in survival in patients treated with ESA 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]