Erythropoietin

Categories: Hormones of the kidneys | Growth factors

Erythropoietin (or EPO) is a glycoprotein hormone that is a growth factor for erythrocyte (red blood cell) precursors in the bone marrow. It increases the number of red blood cells in the blood. Synthetic erythropoietin is available as an expensive injectable therapeutic agent produced by recombinant DNA technology.

Contents 1 Production 2 Action 3 Deficiency of erythropoietin 4 Erythropoietin as a therapeutic agent 5 Erythropoietin as a doping agent 5.1 References 6 See also

Production

Most erythropoietin is produced in the renal cortex. It has been found that it is also produced in the liver (mainly in the fetus), the brain and uterus. Erythropoietin production is stimulated by low oxygen levels in interstitial cells of the peritubular capillaries in the kidneys. It is not known exactly where in the kidneys erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen consuming tubular cells, thus stimulating erythropoietin production.

Action

Like other protein hormones, erythropoietin acts by binding to a specific erythropoietin receptor (EpoR) embedded in the plasma membrane of target cells, the red cell precursors in the bone marrow, stimulating them to transform into mature erythrocytes (red blood cells). This increases the number of circulating red blood cells. It is reflected as increases of the hematocrit, hemoglobin, and RBC counts in a CBC). As a result the oxygen levels in the kidney rise and the amount of erythropoietin produced decreases.

The role of paracrine erythropoietin in the brain and uterus is not fully known. However, in several animal models of stroke and inflammatory disease EPO provides neuroprotection, presumably not by improving oxygen delivery, but by activation of anti-apoptotic and anti-oxidative pathways.

Deficiency of erythropoietin

Because the kidneys are the primary source of erythropoietin, chronic renal failure often results in deficiency, and consequently a hypoplastic anemia. Synthetic erythropoietin was originally developed primarily for this use.

Erythropoietin as a therapeutic agent

Administered erythropoietin produces the same effect as a transfusion of red blood cells, but can be given chronically without the risks of repeated transfusions. It is most often given to people with anemia associated with chronic renal failure, but can be beneficial in many types of anemia due to diseases that interfere with RBC production, such as that due to cancer chemotherapy. Epogen and Procrit are 2 US brands; at least one has been advertised on television as a treatment for tiredness in cancer patients.

Erythropoietin is also sometimes given in advance of a surgical operation for patients who cannot or do not wish to receive blood transfusions, such as Jehovah's Witnesses, in an attempt to increase the body's red blood count to an extent sufficient to counteract possible blood loss during the operation without requiring a transfusion.

The gene which encodes erythropoietin production was cloned in 1985 and has been successfully implanted in guinea pigs in order to produce artificial erythropoietin in the form of Epoetin.

There are differences between human erythropoietin and the erythropoietin of the pig. Because of this difference there are concerns that xenotransplants of pig kidneys into humans may lead to a lack of red blood cells in the recipient.

Another substance in the same class is darbepoetin.

Erythropoietin as a doping agent

EPO has been extensively used as an ergogenic aid, a doping drug, in some sports, particularly cycling and long-distance running, because higher amounts of red blood cells can increase the oxygen carrying capacity of the blood and improve endurance. (See Tour de France.) In cycling, EPO is most useful for multiple-stage races, because it avoids the ordinary effects of increased tiredness on the athletes.

Most of the information below was found in books written by insider sources of the cycling world. See references.

EPO results in an increased hematocrit (the proportion of blood volume occupied by red blood cells); doped-up racers can reach rates higher than those reachable by normal means. Prior to the infamous doping scandal in which he was caught, the doctor of the Festina cycling team, Eric Rijkaert, limited the amount of EPO doping to hematocrit of 54%. Racer Bjarne Riis was nicknamed "Mr 60%" (he was once tested at 56% [1] ), a probable allusion to his alleged hematocrit while using EPO. The use of team, then individual centrifugation machines to test the hematocrit rate became de rigueur in teams using EPO.

While EPO provides some supplemental endurance, high usage has severe adverse effects. Under EPO usage, blood becomes thicker. Blood then has difficulty passing through thin capillaries; this may, for instance, result in nose bleeding. A more severe problem is that, when an athlete under EPO sleeps, his heart may come to beat very slowly; he or she then risks a heart attack. In the early days of EPO usage in cycling, athletes were sometimes awakened at night and made to do push ups and other exercises in order to prevent adverse effects. In later usage, blood thinning products were used; but using these is risky in case of bodily harm (for instance resulting from bicycle falls) because they impair normal blood clotting.

Another reported side effect of EPO usage is insufficiency of white cells, resulting in a compromised immune system, which renders an athlete more susceptible to illness. Prescription drugs for fighting viral infections were found in the medical gear of teams using EPO. However, in many clinical trials of recombinant erythropoietin in patients with renal failure and cancer, no adverse impact on white cell production has been noted and no increased risk of infection reported.

When the widespread usage of EPO became known, particularly after the arrests and seizures performed during the 1998 Tour de France, cycling authorities imposed a limit of 50% of hematocrit: athletes found above that limit were prevented from racing for health reasons. At the time, it was impossible to detect the usage of exogen EPO, thus finding such a rate is technically not considered a proof of doping. Doped racers then sought to obtain hematocrit rates as close as reasonable to, but not exceeding, 50%. One possible evasion method for athletes with rates slightly above 50%, and selected for blood tests, was to take perfusions of water/glucose mixtures, which dilute the blood, prior to testing. Erwann Menthéour reports that a well-known doping doctor gave him some special preparation that, taken orally, would quickly reduce the hematocrit rate.

References

• Erwann Menthéour, Secret défonce (the author is a former professional cyclist who describes how he and others took doping drugs)
• Willy Voet, Massacre à la chaîne (the author is a former cycling health practicioner, convicted of having trafficked and delivered doping drugs)
• Christophe Bassons, Positif (the author is a former professional cyclist who always refused doping, but who describes the events that he witnessed in that respect)

See also

• Amgen, producer of artificial EPO (Brand Name: Epogen)
• Dynepo, trademark name for an erythropoiesis stimulating protein, by TKTde:Erythropoetin

es:Eritropoyetina fr:Érythropoïétine nl:Erytropoïetine ja:エリスロポエチン pl:Erytropoetyna pt:Erythropoietina sv:Erytropoietin