Biology Reference
In-Depth Information
rHuEPO therapy, occurring in approximately 20% to 30% of patients treated.
The risk of developing a significant increase in blood pressure appears to be
independent of a previous history of hypertension, the rate of increase of the
hematocrit, or the target hemoglobin achieved. Most hypertensive problems
occur during the acute correction of anemia, however, rather than during the
maintenance phase. Interestingly, this side-effect of rHuEPO appears to be
peculiar to patients with renal disease and is very rare in other groups of
patients receiving this treatment, such as those with rheumatoid arthritis.
The mechanism of rHuEPO-induced hypertension remains poorly under-
stood although factors that have been suggested to contribute include an inad-
equate reversal of the increased cardiac output of anemia, a relative increase in
peripheral resistance as the compensatory hypoxic peripheral vasodilatation of
anemia is reversed, an increase in blood viscosity, increased endothelin pro-
duction, and possibly a direct pressor effect of EPO [34]. In most instances,
blood pressure is easily controlled by fluid removal and the use of standard
antihypertensive drugs; it is unusual to need to discontinue rHuEPO therapy
for severe uncontrollable hypertension.
A number of the early studies had anecdotal reports of seizures or hyper-
tensive encephalopathy occurring in patients receiving rHuEPO, usually with-
in the first three months of treatment [35]. The pathogenesis of these adverse
effects remains poorly understood, although loss of autoregulation of cerebral
blood flow and/or reduced cerebral perfusion may play a part. This complica-
tion of erythropoietic therapy no longer seems to be a problem, perhaps
because patients treated now have a less severe anemia, and are managed at an
earlier stage in the course of their disease.
In the early studies, up to 10% of patients receiving hemodialysis who were
treated with rHuEPO developed thrombosis of their vascular access [3]. This
event may be more common with prosthetic grafts than with native fistulae
[36], and possible pathogenetic factors include an increase in blood viscosity,
shortening of the bleeding time, enhanced platelet aggregation and adhesion, a
reduction in protein C and protein S concentrations, an increase in thrombin-
antithrombin III levels, enhanced Factor VIII-related activities, and a margin-
al increase in platelet count in some patients (see above).
Occasionally, patients receiving rHuEPO therapy show an increase in serum
potassium, phosphate, and creatinine [1, 3] that may be due to enhanced
dietary intake and/or reduced dialyzer clearance of these molecules secondary
to the increased hematocrit. Heparin requirements for hemodialysis may
increase in some patients. Other adverse effects of rHuEPO therapy include
transient myalgia or influenza-like symptoms after the first few injections only,
and skin irritation around the injection site caused by citrate buffer in one of
the early formulations of the drug [37].
Recently, a new and potentially serious adverse effect of rHuEPO therapy
has been identified,that of pure red cell aplasia with detectable neutralizing
antibodies against EPO [38]. The features of this condition are summarized in
Table4,and the exact cause of this problem, which was extremely rare before
