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Erythropoietin
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Erythropoietin, or its alternative erythropoetin ( or ) or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine for erythrocyte (red blood cell) precursors in the bone marrow. Also called hematopoietin or hemopoietin, it is produced by the kidney, and is the hormone that regulates red blood cell production. It also has other known biological functions. For example, erythropoietin plays an important role in the brain's response to neuronal injury.
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Erythropoietin, or its alternative erythropoetin ( or ) or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine for erythrocyte (red blood cell) precursors in the bone marrow. Also called hematopoietin or hemopoietin, it is produced by the kidney, and is the hormone that regulates red blood cell production. It also has other known biological functions. For example, erythropoietin plays an important role in the brain's response to neuronal injury. EPO is also involved in the wound healing process.
When exogenous EPO is used as a performance-enhancing drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous EPO can often be detected in blood, due to slight difference from the endogenous protein, for example in features of posttranslational modification.
History
In 1906, Paul Carnot, a Professor of Medicine in Paris, and his assistant DeFlandre proposed the idea that red blood cell production is regulated by hormones. After conducting experiments on rabbits subject to bloodletting, Carnot and DeFlandre attributed an increase in red blood cells in rabbit subjects to a hemotopic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto continued to study red cell production and later called the hemopoietic substance ‘erythropoietin.’ Further studies investigating the existence of Epo by Reissman, and Erslev demonstrated that a certain substance circulated in the blood is able to stimulate red blood cell production and increase hematocrit. This substance was finally purified and confirmed as erythropoietin, opening doors to therapeutic uses for EPO in diseases like anemia.
Haematologist Dr. John Adamson and nephrologist Dr. Joseph W. Eschbach looked at various forms of renal failure and the role of the natural hormone EPO in the formation of red blood cells. Studying sheep and other animals in the 1970s, the two scientists helped establish that EPO stimulates the production of red cells in bone marrow and could lead to a treatment for anaemia in humans.
In the 1980s, Adamson, Eschbach and others helped lead a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen produced by Amgen. The trial was successful; its results were published in The New England Journal of Medicine in January 1987. The study authors were Dr. Adamson, Dr. Joseph W. Eschbach, Dr. Joan C. Egrie, Dr. Michael R. Downing and Dr. Jeffrey K. Browne.
In 1985, Lin et al. isolated the human erythropoietin gene from a genomic phage library and were able to characterize it for research and production. Their research demonstrated that the gene for erythropoietin encoded the production of EPO in mammalian cells that is biologically active in vitro and in vivo. This opened up the door for the industrial production of recombinant erythropoietin (RhEpo) for treating anemia patients.
In 1989, the U.S. Food and Drug Administration approved the hormone, called Epogen, which remains in use.
More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced. This glycoprotein demonstrates anti-anemic capabilities and has a longer terminal half-life than erythropoietin. NESP offers chronic renal failure patients a lower dose of hormones to maintain normal hemoglobin levels.
Regulation
EPO is produced mainly by peritubular fibroblasts of the renal cortex. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver. Regulation is believed to rely on a feed-back mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors (HIFs), are hydroxylated and proteosomally digested in the presence of oxygen. It binds to the erythropoietin receptor (EpoR) on the red cell surface and activates a JAK2 cascade. This receptor is also found in a large number of tissues such as bone marrow cells and peripheral/central nerve cells, many of which activate intracellular biological pathways upon binding with Epo.
Primary role in red cell blood line
Erythropoietin has its primary effect on red blood cells by promoting red blood cell survival through protecting these cells from apoptosis. It also cooperates with various growth factors involved in the development of precursor red cells. It has a range of actions including vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing proliferation of smooth muscle fibers.
Uses
Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anaemia resulting from chronic kidney disease, from the treatment of cancer (chemotherapy and radiation), and from other critical illnesses (heart failure).
Available forms as biomedicine
Anemia due to chronic kidney disease
In patients that require dialysis (have stage 5 chronic kidney disease(CKD)), iron should be given with erythropoietin. Dialysis patients in the US are most often given Epogen; outside of the US other brands of epoetin may be used.
Outside of people on dialysis, erythropoietin is used most commonly to treat anaemia in people with chronic kidney disease that are not on dialysis (those in stage 3 or 4 CKD and those living with a kidney transplant). There are two types of erythropoietin (and three brands) for people with anaemia due to chronic kidney disease (not on dialysis):
- Epoetin (Procrit (also known as Eprex), NeoRecormon)
- Darbepoetin (Aranesp).
- Brands available in the USA include: Epoetin (Procrit and Epogen).
Anemia due to treatment for cancer
In March 2008, a panel of advisers for the U.S. Food and Drug Administration (FDA) supported keeping ESAs from Amgen and Johnson & Johnson on the market for use in cancer patients. The FDA has focused its concern on study results showing an increased risk of death and tumor growth in chemo patients taking the anti-anaemia drugs. According to the FDA, increases have been seen in various types of cancer, including breast, lymphoid, cervical, head and neck, and the "non-small-cell" type of lung cancer.
Anemia in critically ill patients
There are two types of erythropoietin (and several brands) for people with anaemia, due to critical illness. These are:
- Epoetin (Procrit (also known as Eprex) or NeoRecormon)
- Darbepoetin (Aranesp)
- Epoetin delta (Dynepo)
- PDpoetin (an erythropoietin produced in Iran by Pooyesh Darou pharmaceuticals)
- Methoxy polyethylene glycol-epoetin beta (Mircera) by Roche
In a recent randomized controlled trial, erythropoietin was shown to not change the number of blood transfusions required by critically ill patients. A surprising finding in this study is that a small mortality benefit in patients receiving erythropoietin. This result was statistically significant after 29 days but not at 140 days. This mortality difference was most marked in patients admitted to the ICU for trauma. The authors speculate several hypotheses of potential etiologies for reduced mortality, but, given the known increase in thrombosis and increase benefit in trauma patients as well as marginal nonsignificant benefit (adjusted hazard ratio of 0.9) in surgery patients, one might speculate that some of the benefit might be secondary to the procoagulant effect of erythropoetin. Regardless, this study suggests further research may be necessary to see which critical care patients, if anyone, might benefit from administration of erythropoeitin. Any benefit of erythropoetin must be weighed against the 50% increase in thrombosis, which has been well substantiated by numerous trials.
Blood doping
ESAs have a history of usage as a blood doping agent in endurance sports such as cycling, rowing, distance running, cross country skiing, biathlon, triathlons, and, most recently, billiards.
In 2002, at the Winter Olympic Games in Salt Lake City, Don Catlin, MD, the founder and then-director of the UCLA Olympic Analytical Lab and now head of the Los Angeles-based nonprofit Anti-Doping Research, reported darbepoetin alfa, a form of erythropoietin, for the first time in sports.
Since 2002, EPO tests done by U.S. sports authorities have consisted of only a urine or “direct” test. From 2000-2006, EPO tests at the Olympics were conducted on both blood and urine.
Neurodegenerative diseases
Erythropoietin has been shown to be beneficial in certain neurodegenerative diseases like schizophrenia.
Adverse effects
Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to increase haemoglobin levels above 13.0 g/dl.
Early treatment with erythropoietin has been shown to significantly increase the risk of Retinopathy of prematurity in premature infants, and is not recommended.
Safety advisories in anaemic cancer patients
Amgen sent a "dear doctor" letter in January 2007 that highlighted results from a recent anaemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.
Amgen advised the U.S. Food and Drug Administration (FDA) as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).
In response to these advisories, the FDA released a Public Health Advisory
on March 9, 2007, and a clinical alert for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents (ESAs) such as epogen and darbepoetin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.
In addition, on March 9, 2007, drug manufacturers agreed to new black box warnings about the safety of these drugs.
On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.
Several recent publications and FDA communications have increased the level of concern related to adverse effects of ESA therapy in selected groups. In a revised Black Box Warning FDA notes significant risks associated with use. ESAs should only be used in patients with cancer when treating anemia specifically caused by chemotherapy and not for other causes of anemia. Further, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed. For more information visit the FDA website at:
http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2,
http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf,
http://www.fda.gov/cder/foi/label/2007/103951s5164lbl.pdf and
http://www.fda.gov/cder/drug/infopage/RHE/default.htm.
See also
- Don Catlin
- Erythropoiesis
- Amgen, producer of artificial EPO (Brand Names: Epogen and Aranesp)
- Dynepo, trademark name for an erythropoiesis stimulating protein, by TKT
- Blood doping, transfusions and EPO use as doping methods; testing and enforcement
- Jehovah's Witnesses and blood transfusions
- The German company AplaGen Biopharmaceuticals has developed a new EPO-mimetic peptide, HemoMer. The active compound is bound to a polysaccharide-based polymeric carrier (Hydroxyethylstarch). Half-Life is increased by increase of molecular weight above the filtration threshold of the kidney, comparable to PEGylation. The so-called supravalence concept has significant advantages to PEGylation, because Half-Life and efficacy are improved simultaneously but not of the cost of the each other. The drug is completely biodegradable and can thus be eliminated even by dialysis patients. At the moment the drug is still preclinical.
Additional images
Further reading
External links
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- 1987 announcement of Epogen's clinical success
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