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Monday 3rd May, 2004
Erythropoietin (or EPO) is a glycoprotein hormone produced in the human kidney. 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 the reduction of oxygen in the renal arteries.
It acts by binding to the specific erythropoietin receptor (EpoR). Erythropoietin produced in the kidney/bone marrow stimulates stem cells in the bone marrow to increase production of erythrocytes (red blood cells). The role of paracrine erythropoietin in the brain and uterus is not fully elucidated.
Recombinant human erythropoietin
The gene which encodes Erythropoietin production was cloned in 1985 and has been successfully implanted in guinea pigs in order to produce artificial Erythropoietin (also known as recombinant human erythropoietin) in the form of Epoetin a drug present on the market.
Patients with renal failure have low levels of erythropoietin which in turn leads to the chronic anemia that accompanies renal failure. The use of recombinant EPO has essentially eliminated anemia as a major cause of morbidity in dialysis patients. In the United States, where almost 90 percent of chronically dialyzed patients currently receive EPO.
The currently recommended target hemoglobin concentration ranges between 10 and 12 g/dL (original FDA approved range), The attainment of this narrow range of target hemoglobin levels may be difficult in standard clinical practice.
EPO should be administered to any dialysis patient with symptoms attributable at least in part to anemia. These include fatigue, decreased exercise tolerance, congestive heart failure, and angina. EPO should not be started until iron status has been evaluated. Iron supplements should be given first in patients with evidence of iron deficiency (plasma ferritin concentration less than 100 ng/mL or transferrin saturation below 20 percent). Other causes of anemia should also be excluded and hypertension corrected before EPO therapy is begun.
Raising the hemoglobin target
One would think that using EPO to raise the target hemoglobin to normal or near normal values would be even more beneficial. However, some studies have suggested it may even be harmful. In a retrospective study of nearly 100,000 hemodialysis patients in the United States, patients with a hematocrit of less than 30 percent had a 12 to 33 percent higher risk of death compared to those with hematocrits of 30 to 33 percent. An additional reduction in risk of 4 percent was observed among the group with hematocrits of 33 to 36 percent. In a prospective study patients were randomly assigned to a target hematocrit of either 42 or 30 percent. The primary end points were death or first nonfatal myocardial infarction. The study was terminated after 29 months for two reasons: the group targeted to normal values had a higher mortality which was approaching, but had not yet attained, statistical significance; and it was extremely unlikely (as determined statistically) that benefits would eventually be realized with higher target values if the study were to continue.
Whether the target hematocrit/hemoglobin levels may be extended to near normal values among other patient groups awaits the results of ongoing and future studies. There is limited evidence that higher target values may be safe and beneficial among dialysis patients without diabetes, heart failure, coronary heart disease, or cerebrovascular disease.
The current study is part of the ongoing effort to elucidate the value of raising the hemoglobin target in dialysis patients. Partial correction of anemia by erythropoietin improves hemodialysis (HD)-associated immunosuppression. The authors prospectively compared the immune function of HD patients with congestive heart failure or ischemic heart disease on erythropoietin therapy randomized to normal versus anemic blood hemoglobin concentration. Delayed-type hypersensitivity, CD4 and CD8 counts, anti?tetanus toxoid antibody levels taken after vaccination, erythrocyte complement receptor 1 expression, and lymphocyte proliferative responsiveness were taken as measures of their immune status. The observation period was 1 yr, and the trial was open label. Their data suggest that certain aspects of immune function, particularly delayed-type hypersensitivity, may be improved in HD patients by normalization of hemoglobin through the administration of increased doses of erythropoietin.
The most common side effects of EPO treatment are:
- Influenza-like syndrome
- Increase in the risk of thrombotic events
- Pure red cell aplasia
Renato M.B. Roman, Peter I. Lobo, Ronald P. Taylor, David A. Goodkin, John LaBrecque, Kathy L. Powers and W. Kline Bolton. Prospective Study of the Immune Effects of Normalizing the Hemoglobin Concentration in Hemodialysis Patients Who Receive Recombinant Human Erythropoietin. J Am Soc Nephrol 15:1339-1346, 2004.
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