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Raising the target hematocrit/hemoglobin levels to near normal values has beneficial effects for dialysis patients. |
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A prospective study, published in this month's edition of Journal of
the American Society of Nephrology, was set to evaluate the immune effects
of normalizing the hemoglobin concentration in hemodialysis patients who
receive recombinant human erythropoietin.
Erythropoietin
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.
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Indications
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.
Study details
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:
- Hypertension
- Headache
- Influenza-like syndrome
- Increase in the risk of thrombotic events
- Pure red cell aplasia
References
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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