Erythropoietin, or its alternatives erythropoetin or erthropoyetin ( /ɨˌrɪθrɵˈpɔɪ.ɨtɨn/, /ɨˌrɪθrɵˈpɔɪtən/, or /ɨˌriːθrɵ-/) 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 interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial cells. It is also produced in perisinusoidal Ito cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. Erythropoietin 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.[1] EPO is also involved in the wound healing process.[2]
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.
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In 1906, Paul Carnot, a professor of medicine in Paris,France, and his assistant DeFlandres proposed the idea that hormones regulate the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and DeFlandre attributed an increase in red blood cells in rabbit subjects to a hemotropic 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.[3][4]
Haematologist John Adamson and nephrologist 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 anemia in humans. In 1968, Goldwasser and Kung began work to purify human EPO, and managed to purify milligram quantities of over 95% pure material by 1977.[5] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[6] Later an NIH-funded researcher at Columbia University discovered a way to synthesize EPO. Columbia University patented the technique, and licensed it to Amgen. Controversy has ensued over the fairness of the rewards that Amgen reaped from NIH-funded work, and Goldwasser was never financially rewarded for his work.[7]
In the 1980s, Adamson, Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing and Jeffrey K. Browne conducted a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen produced by Amgen. The trial was successful, and the results were published in the New England Journal of Medicine in January 1987.[8]
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.[9] 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. The industrial production of recombinant human erythropoietin (RhEpo) for treating anemia patients would begin soon after.
In 1989, the U.S. Food and Drug Administration approved the hormone, called Epogen, which remains in use today.
More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced.[10] 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.
EPO is produced mainly by peritubular capillary lining cells of the renal cortex; which are highly specialized epithelial-like cells. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver.[11][12] 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.[6] 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.
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. Specifically, the colony forming unit-erythroid (CFU-E) is completely dependent on erythropoietin. The burst forming unit-erythroid (BFU-E) is also responsive to erythropoietin.
Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, pro-erythroblast and basophilic erythroblast subsets in the differentiation.
It has a range of actions including vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing proliferation of smooth muscle fibers. It has also been shown that erythropoietin can increase iron absorption by suppressing the hormone hepcidin.[13]
Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anemia resulting from chronic kidney disease and myelodysplasia, from the treatment of cancer (chemotherapy and radiation). Current research suggests that, aminoacid R103 to E mutation in Erythropoietin makes it Neuroprotective and non-erythropoietic.
In patients who require dialysis (have stage 5 chronic kidney disease(CKD)), iron should be given with erythropoietin.[14] 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 anemia in people with chronic kidney disease who are not on dialysis (those in stage 3 or 4 CKD and those living with a kidney transplant). There are two types of erythropoietin for people with anemia due to chronic kidney disease (not on dialysis):
Brands in Epoetin Alpha are:
Brands in Epoetin Beta are:
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-anemia drugs. According to the FDA, evidence for increased rates of mortality exist in various cancers, including breast, lymphoid, cervical, head and neck, and non-small-cell lung cancer.[15]
There are two types of erythropoietin (and several brands) for people with anemia, due to critical illness. These are:
In a randomized controlled trial,[18] erythropoietin was shown to not change the number of blood transfusions required by critically ill patients. A surprising finding in this study was a small mortality reduction 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 for potential etiologies of this reduced mortality, but, given the known increase in thrombosis and increased benefit in trauma patients as well as marginal nonsignificant benefit (adjusted hazard ratio of 0.9) in surgery patients, it could be speculated 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 any, might benefit from administration of erythropoeitin. Any benefit of erythropoetin must be weighed against the 50% increase in thrombosis, which has been demonstrated in numerous trials .
ESAs have a history of use as blood doping agents in endurance sports such as horseracing, boxing.[19] ,cycling, rowing, distance running, race walking, cross country skiing, biathlon, and triathlons.
Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national anti-doping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete’s urine.
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, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports.[20]
In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout the majority of his career as a professional cyclist.[21]
Since 2002, EPO tests performed 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.[22][23]
Erythropoietin has been shown to be beneficial in certain neurological diseases like schizophrenia.[24] Research has suggested that EPO improves the survival rate in children suffering from cerebral malaria, caused by the malaria parasite's blocking of blood vessels in the brain.[25][26][27]
Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to increase hemoglobin levels above 13.0 g/dl.[28]
Early treatment with erythropoietin correlated with an increase in the risk of Retinopathy of prematurity in premature infants who had anemia of prematurity, raising concern that the angiogenic actions of erythropoietin may exacerbate retinopathy.[29][30] However, since anemia itself increases the risk of retinopathy, the correlation with erythropoietin treatment may be incidental, and merely reflect that anemia induces retinopathy.
Amgen sent a "dear doctor" letter in January 2007 that highlighted results from a recent anemia 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) regarding the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional cancer 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[31] on March 9, 2007, and a clinical alert[32] 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 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, the FDA notes significant risks associated with ESA use. ESAs should be used only 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.[33][34][35][36]
Erythropoietin has been shown to interact with the Erythropoietin receptor as its mechanism of action within the body.[37][38]
Drug interactions with Erythropoietin include: Major interaction:Lenalidomide--risk of thrombosis Moderate interaction:Cyclosporine--risk of high blood pressure may be greater in combination with EPO. EPO may lead to variability in blood levels of cyclosporine. Minor interactions: ACE inhibitors may interfere with hematopoiesis by decreasing the synthesis of endogenous erythropoietin or decreasing bone marrow production of red blood cells.[39]
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