'''Erythropoietin''' ({{pronEng|ɨˌrɪθoʊˈpɔɪɨtɨn}}, {{IPA|/ɨˌrɪθroʊˈpɔɪtən/}}, or {{IPA|/ɨˌriːθroʊ-/}}) or '''EPO''' is a [[glycoprotein]] [[hormone]] that 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 the red blood cell production.
==Historical Perspective==
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[[Hematologist]] 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 anemia 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.
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In 1989, the Food and Drug Administration approved the hormone, called Epogen, which remains in use.
==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.<ref name="Jacobson1957">{{wikicite|id=Jacobson1957|reference=Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature 179:633. (1957)}}</ref><ref name="Fisher1996">{{wikicite|id=Fisher1996|reference=Fisher JW, Koury S, Ducey T, Mendel S. Erythropoietin (Epo) production by interstitial cells of hypoxic monkey kidneys. Br J Jaematol 95:27-32. (1996)}}</ref> 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.<ref name="pmid17253966">{{cite journal |author=Jelkmann, W |title=Erythropoietin after a century of research: younger than ever |journal=Eur J Haematol. |volume=78 |issue=3 |pages=183–205 |year=2007 |pmid=17253966|doi=10.1111/j.1600-0609.2007.00818.x}}</ref> 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, lymphocytes, and peripheral/central nerve cells, many of which activate intracellular biological pathways upon binding with Epo.
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===Primary Role in Red Cell Blood Line===
a
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==
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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]], from the treatment of [[cancer]] ([[chemotherapy]] & [[radiation]]) and from other critical illnesses ([[heart failure]]).
===Anemia due to chronic kidney disease ===
In patients who require dialysis (have stage 5 [[chronic kidney disease]](CKD)), iron should be given with erythropoietin.<ref name="pmid8914038">{{cite journal |author=Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE |title=A randomized controlled study of iron supplementation in patients treated with erythropoietin |journal=Kidney Int. |volume=50 |issue=5 |pages=1694-9 |year=1996 |pmid=8914038 |doi=}}</ref> People in the US and on dialysis are most often given Epogen®, outside the US other brands of epoetin may be used.
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Outside of people on dialysis, erythropoietin is used most commonly to treat anemia in people with chronic kidney disease and 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 anemia due to chronic kidney disease (not on dialysis), these are:
* epoetin (Procrit®(also known as Eprex®), NeoRecormon®)
* darbepoetin (Aranesp®).
=== Anemia due to treatment for cancer ===
In March 2008 a panel of advisers for the [[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.<ref>[http://money.cnn.com/2008/03/13/news/companies/amgen/?postversion=2008031317]CNN Money article</ref>
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===Anemia in critically ill patients===
Yes
There are two types of erythropoietin (and three brands) for people with anemia, due to critical illness. These are:
* epoetin (Procrit®(also known as Eprex®), NeoRecormon®)
* darbepoetin (Aranesp®).
In a recent [[randomized controlled trial]]<ref>Howard L. Corwin et al., “Efficacy and Safety of Epoetin Alfa in Critically Ill Patients,” N Engl J Med 357, no. 10 (September 6, 2007): 965-976, http://content.nejm.org/cgi/content/abstract/357/10/965 (accessed September 6, 2007).</ref>, 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 benefit in patients receiving erythropoietin. This result was [[Statistical significance|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 hypothesis 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.
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===Blood doping===
It has a history of usage as a [[blood doping]] agent in endurance sports such as cycling, triathlons and marathon running.
==Adverse effects==
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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.<ref name="pmid17108342">{{cite journal |author=Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A |title=Normalization of hemoglobin level in patients with chronic kidney disease and anemia |journal=N. Engl. J. Med. |volume=355 |issue=20 |pages=2071-84 |year=2006 |pmid=17108342 |doi=10.1056/NEJMoa062276}}</ref>
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 use|off-label]] indication with caution.
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Amgen advised the United States [[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).
<!--Adult Indications and Dosage-->
In response to these advisories, the [[FDA]] released a Public Health Advisory<ref>{{cite web |url=http://www.fda.gov/cder/drug/advisory/RHE2007.htm |title=FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp) |format= |work=}}</ref> on March 9, 2007, and a clinical alert<ref>{{cite web |url=http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm |title=Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA) |format= |work=}}</ref> for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents 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.
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In addition, on March 9, 2007, drug manufacturers agreed to new [[black box warning]]s about the safety of these drugs.
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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.
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== See also ==
* Dosing Information
* [[Amgen]], producer of artificial EPO (Brand Names: Epogen and Aranesp)
* [[Dynepo]], trademark name for an erythropoiesis stimulating protein, by [[Transkaryotic Therapies|TKT]]
* [[Blood doping]], transfusions and EPO use as doping methods; testing and enforcement
* [[Jehovah's Witnesses and blood transfusions]]
* The german company AplaGen Biopharmaceuticals[http://www.aplagen.com] has developed a new EPO-mimetic peptide, HemoMer™. The active compound is bound to a polysacharid-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.<ref>[http://www.aplagen.com]</ref>
Image:JAK-STAT-Signaltransduktion nach EPO-Bindung.png|[[JAK-STAT signaling pathway]]
Image:EPO.png|EPO structure
Image:EPO sales.png|EPO sales
Image:Epo-Blotting.png|Epo blotting
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==References==
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{{Reflist|2}}
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*{{cite journal | author=Takeuchi M, Kobata A |title=Structures and functional roles of the sugar chains of human erythropoietins. |journal=Glycobiology |volume=1 |issue= 4 |pages= 337-46 |year= 1992 |pmid= 1820196 |doi= }}
* Dosing Information
*{{cite journal | author=Semba RD, Juul SE |title=Erythropoietin in human milk: physiology and role in infant health. |journal=Journal of human lactation : official journal of International Lactation Consultant Association |volume=18 |issue= 3 |pages= 252-61 |year= 2002 |pmid= 12192960 |doi= }}
*{{cite journal | author=Ratcliffe PJ |title=From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway. |journal=Blood Purif. |volume=20 |issue= 5 |pages= 445-50 |year= 2003 |pmid= 12207089 |doi= }}
*{{cite journal | author=Juul S |title=Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models. |journal=Clinics in perinatology |volume=31 |issue= 1 |pages= 129-42 |year= 2004 |pmid= 15183662 |doi= 10.1016/j.clp.2004.03.004 }}
*{{cite journal | author=Buemi M, Caccamo C, Nostro L, ''et al.'' |title=Brain and cancer: the protective role of erythropoietin. |journal=Med Res Rev |volume=25 |issue= 2 |pages= 245-59 |year= 2005 |pmid= 15389732 |doi= 10.1002/med.20012 }}
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*{{cite journal | author=Sytkowski AJ |title=Does erythropoietin have a dark side? Epo signaling and cancer cells. |journal=Sci. STKE |volume=2007 |issue= 395 |pages= pe38 |year= 2007 |pmid= 17636183 |doi= 10.1126/stke.3952007pe38 }}
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==External links==
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* [http://query.nytimes.com/gst/fullpage.html?res=9B0DE2D81138F93BA35752C0A961948260&sec=&spon=&partner=permalink&exprod=permalink NYT] 1987 announcement of Epogen's clinical success
* [http://www.epogen.com/ Patient information on Epogen]
* [http://www.aranesp.com/ Patient information on Aranesp]
* [http://www.procrit.com/ Patient information on Procrit]
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Black Box Warning
Title
See full prescribing information for complete Boxed Warning.
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Content
Overview
Erythropoietin is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
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There is limited information regarding Off-Label Guideline-Supported Use of Erythropoietin in adult patients.
Non–Guideline-Supported Use
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Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
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There is limited information regarding FDA-Labeled Use of Erythropoietin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
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There is limited information regarding Off-Label Guideline-Supported Use of Erythropoietin in pediatric patients.
Non–Guideline-Supported Use
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Erythropoietin in pediatric patients.
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Warnings
Title
See full prescribing information for complete Boxed Warning.
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Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Erythropoietin in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Erythropoietin in the drug label.
