Erythropoietin

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See also: Erythropoesis

Erythropoietin (Epo or EPO) is a protein hormone produced by the kidneys in response to hypoxia, and is also a prescription drug used for treating anemia. It is essential for normal development and maturation of red blood cells (RBC), and abnormally high levels of either the endogenous or drug form can lead to dangerously high hematocrit values.

History

Carnot and DeFlandre [1] made initial observations in rabbits that suggested the existence of a factor in peripheral blood that could stimulate production of reticulocytes. Their experiment involved bleeding a rabbit to induce accelerated RBC production, they then transferred some of the plasma to a recipient animal. The key observation of increased reticulocytes in the recipient animal prompted the search for a substance, which they named hemopoietin, that regulated the rate of RBC production.

A major breakthrough came in 1977, when small amounts of erythropoietin were purified from the urine of patients with aplastic anemia.[2] Amino acid sequence data from this protein were used in subsequent efforts to clone the gene for erythropoietin in 1983.[3] The gene was then inserted into a suitable mammalian cell line, Chinese hamster ovary cells, allowing large-scale manufactureof the protein as a commercial product. It was approved for use in 1991. About $10B was spent worldwide in 2006 for treatment of patients with rHuEpo, with about $2B for the cost of treating Medicare patients on renal dialysis.[4]

Available forms

Erythropoietin exists in several forms and goes by several names. The endogenous form is also referred to as 'epoetin alfa' and sometimes spelled as 'erythropoetin'; it can be abbreviated to Epo, EPO or EP. Various synthetic forms of recombinant (r) human (h) Epo are available, collectively referred to as rHuEpo or rhEpo. These include:

  • Procrit, the trade name of epoetin alfa marketed in the US by Ortho Biotech Products, L.P., a member of the Johnson & Johnson Family of Companies. It is approved for treatment of chemotherapy-related anemia in patients with most types of cancer; for the treatment of anemia in chronic kidney disease patients who are not on renal dialysis; for treatment of anemia related to zidovudine treatment in HIV patients; and for reducing the need for transfusions in patients undergoing some types surgery who are anemic or at significant risk for blood loss.
  • Eprex, the trade name of epoetin alfa marketed outside the US by Ortho Biotech Products, L.P., a member of the Johnson & Johnson Family of Companies.
  • Epogen, the trade name of epoetin alfa made and marketed by Amgen in the US for treatment of anemia in patients with chronic renal failure on renal dialysis.
  • NeoRecormon, the trade name of epoetin beta marketed by Roche in Europe for treatment of anemia in patients with chronic renal failure and for treatment of anemia in people with solid tumours who are receiving platinum-based chemotherapy. Even though epoetin alfa and epoetin beta are both synthesized in Chinese hamster ovary cells, they differ in their erythropoietin isoform compositions and biological properties.[5]
  • Aranesp, the trade name of darbepoetin alfa, a hyperglycosylated mutant form of Epo produced and marketed by Amgen for treating anemia associated with chronic renal failure (CRF), including patients on renal dialysis and patients not on renal dialysis, and for treating anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.

Structure

Epo is a glycoprotein with a molecular mass of 30.4 kD. Its structure includes a 165-amino acid backbone with three N-linked carbohydrates attached to asparagines at amino acid positions 24, 38, and 83 and one O-linked carbohydrate attached to Ser126 .[6] The carbohydrate residues allow for many possible isoforms and contribute to the stability of the hormone in vivo. Darbepoetin (see above) was created through site-directed mutation of two amino acid residues, allowing for two additional N-linked carbohydrate chains.

Production

Epo is produced by peritubular cells in the adult kidney, and in hepatocytes in the fetus. In adults, a small amount is also produced by the liver. The rate of Epo synthesis and secretion depends on local oxygen concentrations; hypoxia is the main stimulus for Epo production. The serum concentration of Epo in adults is normally 4-27 mU/mL. In adults with non-renal anemias, the serum concentration tends to increase with the severity of the anemia.

Actions

Epo's activities depend on successful interaction with its receptor, which is prominent on the surface of developing RBC in the bone marrow. Epo signaling acts to prevent or retard apoptosis, i.e., it acts as a survival factor for developing cells. The increase in RBC mass brought about by Epo stimulation of the bone marrow completes a self-regulating feedback loop, since (other things being equal), the increased RBC mass would lessen the hypoxia experienced by the kidney and thus, lessen Epo production.

Medical uses

Diagnostic test

Testing serum erythropoetin may help the evaluation of erythocytosis.

Treatment

Anemia in chronic kidney disease

In patients with chronic kidney disease, the goal hemoglobin should be 11.3 g per deciliter according to a randomized controlled trial of epoetin alfa that found targeting a hemoglobin level of 13.5 g per deciliter increased adverse events.[7] However, the setting or target hemoglobin levels may increase adverse effects.[8]

Erythropoietin may increase hypertension patients with chronic kidney disease.[9] The use of when the hemoglobin is less than 9 g per deciliter may increase the risk of stroke according to a randomized controlled trial.[10]

In patients who require renal dialysis, iron should be given with erythropoietin.[11]

Anemia related to cancer

Use of erythropoiesis-stimulating agents for anemia related to cancer may increase mortality.[12]

Anemia in critically ill patients

Although the use of erythropoietin has been studied in critically ill patients, erythropoietin has not been shown to be effectice in this setting. In a randomized controlled trial, erythropoietin insignificantly reduced mortality among critically ill patients.[13] The editorial accompanying the trial concluded that other commonly accepted interventions (such as primary prevention of coronary artery disease in patients with hypertriglyceridemia) were more useful for treatment.

A meta-analysis that included this trial does "not recommend the routine use of erythropoietin-receptor agonists in critically ill patients".[14]

Athletic performance

Erythropoietin is sometimes used by nonanemic athletes to increase their body's oxygen-carrying capacity and thus gain an unfair advantage in competition. Besides the risk of disqualification for cheating, athletes who participate in this illicit use of erythropoietin risk the complications of abnormally high red blood cell concentrations, which include abnormal blood clotting. Detection of illicit erythropoietin use is challenging because endogenous and exogenous (pharmaceutical) erythropoietin are almost identical. Several tests rely on altered patterns of glycosylation of erythropoietin shed in the urine. Other detection methods rely on altered parameters of red blood cell production such as hematocrit, reticulocyte hematocrit, the proportion of abnormally large red blood cell, the serum erythropoietin level, and the soluble transferrin receptor concentration.[15]

Other applications

Erythropoietin's activity in the bone marrow to increase red cell production hinges on its ability to inhibit apoptosis. Experimental treatment of diseases in which apoptosis is prominent have yielded promising initial results. For example, erythropoietin has been proposed as being both safe and beneficial in acute stroke.[16]

Adverse effects

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.[17]

The FDA released an advisory[18] on March 9, 2007, and a clinical alert[19] on February 16, 2007, about the use of erythropoeisis-stimulating agents. The advisory noted these drugs had a "higher chance of serious and life-threatening side effects and/or death...and had a higher rate of deep venous thrombosis".

Erythropoietin may increase blood pressure.[9]

References

  1. ↑ Carnot P, DeFlandre C (1906) "Sur l’activité hématopoiétique des différents organes au cours de la r´g´n´ration du sang". C R Acad Sci Paris 143:432–5
  2. ↑ Miyake T et al. (1977) "Purification of human erythropoietin". J Biol Chem 252:5558-64
  3. ↑ Lin FK, et al. (1985) "Cloning and expression of the human erythropoietin gene". PNAS 82: 7580-4
  4. ↑ Smith M. (2007) "Aggressive anemia treatment increases mortality". MedPage Today, February 2
  5. ↑ Storring PL et al. (1998) Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 100:79-89
  6. ↑ Browne JK et al. (1986)Erythropoietin: gene cloning, protein structure, and biological properties. Cold Spring Harb Symp Quant Biol. 51:693-702
  7. ↑ Singh AK, Szczech L, Tang KL, et al (2006). "Correction of anemia with epoetin alfa in chronic kidney disease". N. Engl. J. Med. 355 (20): 2085–98. DOI:10.1056/NEJMoa065485. PMID 17108343. Research Blogging.
  8. ↑ Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA et al. (2010). "Erythropoietic response and outcomes in kidney disease and type 2 diabetes.". N Engl J Med 363 (12): 1146-55. DOI:10.1056/NEJMoa1005109. PMID 20843249. Research Blogging.
  9. ↑ 9.0 9.1 Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW (1989). "Treatment of the anemia of progressive renal failure with recombinant human erythropoietin". N. Engl. J. Med. 321 (3): 158–63. PMID 2747747. [e]
  10. ↑ Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU et al. (2009). "A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.". N Engl J Med 361 (21): 2019-32. DOI:10.1056/NEJMoa0907845. PMID 19880844. Research Blogging. Review in: Ann Intern Med. 2010 Mar 16;152(6):JC3-9
  11. ↑ Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (1996). "A randomized controlled study of iron supplementation in patients treated with erythropoietin". Kidney Int. 50 (5): 1694-9. PMID 8914038. [e]
  12. ↑ Tonelli M, Hemmelgarn B, Reiman T, et al. (May 2009). "Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis". CMAJ 180 (11): E62–71. DOI:10.1503/cmaj.090470. PMID 19407261. PMC 2683210. Research Blogging.
  13. ↑ Corwin HL, Gettinger A, Fabian TC, et al (2007). "Efficacy and safety of epoetin alfa in critically ill patients". N. Engl. J. Med. 357 (10): 965–76. DOI:10.1056/NEJMoa071533. PMID 17804841. Research Blogging.
  14. ↑ Zarychanski R, Turgeon AF, McIntyre L, Fergusson DA (2007). "Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials". CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 177 (7): 725–34. DOI:10.1503/cmaj.071055. PMID 17823140. Research Blogging.
  15. ↑ Parisotto R, Wu M, Ashenden MJ, et al (2001). "Detection of recombinant human erythropoietin abuse in athletes utilizing markers of altered erythropoiesis". Haematologica 86 (2): 128–37. PMID 11224480. [e]
  16. ↑ Ehrenreich H, Hasselblatt M, Dembowski C, et al (2002). "Erythropoietin therapy for acute stroke is both safe and beneficial". Mol. Med. 8 (8): 495–505. PMID 12435860. [e]
  17. ↑ Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A (2006). "Normalization of hemoglobin level in patients with chronic kidney disease and anemia". N. Engl. J. Med. 355 (20): 2071-84. DOI:10.1056/NEJMoa062276. PMID 17108342. Research Blogging.
  18. ↑ FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp). Retrieved on 2007-06-05.
  19. ↑ Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA). Retrieved on 2007-06-05.
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