Mechanisms of EPO-induced Hypertension

Hypertension is a common but frequently overlooked and underreported adverse effect of
erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks
associated with normalization of hemoglobin. The risk of strokes is strongly related to
poorly controlled hypertension. Blood pressure was not measured the way it usually is in
hypertension trials, so the investigators cannot be completely confident that the risk of
strokes in this large randomized trial was not related to EPO-induced hypertension. New
therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it
remains to be seen whether these new drugs would have a lower or a higher risk for
hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced
hypertension is urgent. The investigators hypothesize that compared to untreated controls,
EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood
pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be
related to two factors. First, endothelial dysfunction and worsening of endothelial function
from baseline to 4 weeks and second, the modulation of forearm blood flow in response to
breathing oxygen and the change in this measure from baseline to 4 weeks. If the
investigators understood the time course, the magnitude, and the mechanisms of
exercise-induced hypertension (EIH) the investigators will better be able to design studies
to compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study
has the potential of improving the investigators' understanding of a common side effect of
EPO by precisely quantifying the magnitude of BP change, its effects on endothelial function,
and discovering the biomarkers of these adverse effects. Thus, the investigators can in the
future robustly compare these effects of EPO with HIF stabilizers. This study is innovative
because it will focus on the potential mechanisms by which EPO induces an increase in BP. The
time-course and magnitude of change in BP will be assessed using the gold-standard
measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using
validated methods will better allow us to track changes in BP over time. The investigators'
lab is uniquely qualified to carry out these experiments due to a large experience with such
types of studies. The investigators will examine endothelial function using a reference
method -- that of flow-mediated dilatation -- which is established in the investigators'
laboratory. The investigators will directly test the hypothesis whether hypoxia-sensitivity
of the vascular tissue is responsible for the BP increase.

Inclusion Criteria:

- Stage 3 or 4 chronic kidney disease

- Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than
130/80 mmHg at baseline and treatment with at least 1 antihypertensive medication

- Hemoglobin between 8 and 10 g/dL

- No treatment with erythropoiesis-stimulating agents (ESA) within 3 previous months

Exclusion Criteria:

- Need for packed red blood cells (RBC) transfusion in the previous 2 months

- Myocardial infarction, stroke or hospitalization for heart failure in the past 2
months

- In the assessment of the investigator, have hematologic, inflammatory, infectious, or
other conditions that might interfere with the erythropoietic response