EPO (Erythropoietin)
Also known as: Erythropoietin, Epoetin alfa, Epoetin beta, Recombinant human erythropoietin (rHuEPO), Epogen, Procrit, Retacrit, Eprex
FDA-approved prescription ESA (epoetin alfa, 1989; biosimilar epoetin alfa-epbx); boxed warning for increased risk of death, MI, stroke, VTE and tumor progression; prohibited by WADA.
5 notable studies · 5 references
TLDR
Erythropoietin is the kidney hormone that drives red-blood-cell production; recombinant EPO has been FDA-approved since 1989 for anemia of kidney disease and other specific anemias, but large trials showed that pushing hemoglobin too high raises the risk of death, heart events and stroke, it carries a boxed warning, and it is banned in sport.
At a Glance
Classification: Endogenous 165-amino-acid glycoprotein hormone (cytokine) produced mainly by the kidney; erythropoietin receptor (EPOR) agonist; erythropoiesis-stimulating agent (ESA)
Erythropoietin (EPO) is the hormone that tells the bone marrow to make red blood cells. It is made mainly by the kidneys in response to low oxygen. Recombinant human EPO (epoetin alfa) was made possible by cloning of the human EPO gene in 1985 and was FDA-approved in 1989. It is a well-established prescription drug for anemia caused by: • Chronic kidney disease • Certain chemotherapy regimens • Zidovudine treatment in HIV • Reducing transfusions around some surgeries. Large trials also showed that pushing hemoglobin too high with ESAs increases the risk of death, heart problems and stroke. ESAs carry an FDA boxed warning, and hemoglobin targets are kept deliberately modest. EPO is prohibited in sport (WADA) because it raises oxygen-carrying capacity.
What Is EPO (Erythropoietin)?
EPO is a glycoprotein: a protein chain carrying sugar groups that strongly affect how long it lasts in the blood. Epoetin alfa / beta → recombinant EPO with the native amino-acid sequence Darbepoetin alfa → engineered EPO analog with extra sugar chains, longer-acting Methoxy polyethylene glycol-epoetin beta → PEGylated, very long-acting ESA ARA-290 (cibinetide) → small peptide based on part of EPO, designed for tissue-protective signaling without stimulating red-cell production These share biology but are not interchangeable.
What Are Researchers Studying?
Anemia of kidney disease
In the first combined phase I/II trial, recombinant EPO given to 25 anemic hemodialysis patients produced dose-dependent increases in red-cell production; 12 of 18 transfusion-dependent patients on effective doses no longer needed transfusions. Blood pressure rose in four.
Hemoglobin targets and cardiovascular risk
In CHOIR (1,432 patients with CKD), targeting hemoglobin 13.5 g/dL instead of 11.3 g/dL increased the composite of death, heart attack, heart-failure hospitalization and stroke (HR 1.34), with no added quality-of-life benefit. In TREAT (4,038 patients with diabetes and CKD), the long-acting ESA darbepoetin did not reduce death, cardiovascular or kidney events versus placebo, and stroke nearly doubled (HR 1.92).
Athletic performance and doping
In a double-blind trial of 48 well-trained amateur cyclists, eight weeks of epoetin beta raised hemoglobin, maximal power and VO2max in lab tests, but did not improve submaximal performance or race time up Mont Ventoux.
Tissue protection
EPO receptors exist outside the bone marrow, and EPO has been studied for nerve, heart and kidney protection. This line of research led to non-erythropoietic derivatives such as ARA-290.
How Does It Work?
EPO ↓ EPO receptor homodimer on red-cell progenitors in bone marrow ↓ JAK2 / STAT5 signaling ↓ progenitor survival, proliferation and maturation ↓ more red blood cells and higher hemoglobin. Higher hemoglobin also raises blood viscosity, and ESAs can raise blood pressure and clotting risk, which helps explain the harm seen with aggressive targets.
What Does the Research Show?
Human research
VERY HIGH for treating anemia of chronic kidney disease. HIGH for harm with aggressive hemoglobin targets (CHOIR, TREAT). LIMITED and mixed for real-world athletic performance (one RCT showed lab but not race gains).
Animal research
Extensive animal work underpins EPO physiology and tissue-protection research; human data dominate for clinical questions.
In-vitro research
Extensive receptor and signaling biology; the EPO gene was cloned and expressed in 1985.
Notable Studies
Cloning and expression of the human erythropoietin gene
in-vitroJournal: Proceedings of the National Academy of Sciences of the USA. Isolation and expression of the human EPO gene, enabling production of biologically active recombinant human erythropoietin, the foundation of epoetin therapy.
Limitations: Molecular biology study; no clinical outcomes.
View publication →Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial
humanJournal: New England Journal of Medicine. 25 anemic hemodialysis patients received IV recombinant EPO three times weekly. Red-cell production rose with dose; at the highest dose hematocrit rose up to 10 points within three weeks. Of 18 patients on effective doses, 12 transfusion-dependent patients no longer needed transfusions; four had increased blood pressure.
Limitations: Small, uncontrolled early-phase trial.
View publication →Correction of anemia with epoetin alfa in chronic kidney disease
humanJournal: New England Journal of Medicine. CHOIR: 1,432 CKD patients randomized to epoetin alfa targeting hemoglobin 13.5 vs 11.3 g/dL. The higher target increased the composite of death, MI, CHF hospitalization and stroke (HR 1.34) without better quality of life.
Limitations: Open-label; tests hemoglobin targets rather than EPO versus no EPO.
View publication →A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease
humanJournal: New England Journal of Medicine. TREAT: 4,038 patients with diabetes, CKD and anemia randomized to darbepoetin (target about 13 g/dL) or placebo with rescue. No reduction in death/cardiovascular events (HR 1.05) or death/ESRD (HR 1.06); stroke increased (HR 1.92); fewer transfusions.
Limitations: Used darbepoetin, a long-acting EPO analog, not native-sequence epoetin; class-level inference to EPO.
View publication →Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial
humanJournal: The Lancet Haematology. 48 well-trained non-professional male cyclists received epoetin beta or placebo for 8 weeks. Hemoglobin, maximal power output and VO2max rose in lab testing, but submaximal performance and Mont Ventoux race times did not differ.
Limitations: Amateur athletes; modest sample; short exposure; not powered for rare adverse events like thrombosis.
View publication →What We Still Don't Know
• Optimal hemoglobin targets for individual patients (trials argue against high targets) • Whether non-erythropoietic tissue-protective effects can be used clinically without red-cell risks • Effects on elite-level performance in real competition (evidence is limited) • Long-term cardiovascular, thrombotic and tumor-progression risks outside approved use • Quality of non-pharmaceutical EPO sources
Related Compounds
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Sources & References
- Lin FK et al. Cloning and expression of the human erythropoietin gene. Proceedings of the National Academy of Sciences of the USA. 1985.
- Eschbach JW et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. New England Journal of Medicine. 1987.
- Singh AK et al. Correction of anemia with epoetin alfa in chronic kidney disease. New England Journal of Medicine. 2006.
- Pfeffer MA et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. New England Journal of Medicine. 2009.
- Heuberger JAAC et al. Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial. The Lancet Haematology. 2017.
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