The investigators hypothesize that compared to untreated controls, erythropoietin (EPO) therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure (BP). 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 change of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks. Study procedures include fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow tests. The study hopes to accrue 160 subjects.
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 endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks. If the investigators understood the time course, the magnitude, and the mechanisms of EPO-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 endothelial function is responsible for the BP increase.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.
Richard L. Roudebush VA Medical Center, Indianapolis, IN
Indianapolis, Indiana, United States
Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
In the delayed start group (the control group), the investigators will measure the change in diastolic blood pressure from 0 weeks to 12 weeks compared to the change in diastolic BP from 0 to 12 weeks in the immediate start group.
Time frame: Baseline to 12 weeks
Within Group Change in Diastolic Blood Pressure in the Delayed Start Group
Within group change in diastolic blood pressure from 12 weeks to 24 weeks compared to change in diastolic blood pressure from baseline to 12 weeks in the delayed start group
Time frame: 12 to 24 weeks compared to baseline to 12 weeks
Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
In the delayed start group (the control group), the investigators will measure the change in systolic blood pressure change from 0 weeks to 12 weeks compared to the change in systolic BP from 0 to 12 weeks in the immediate start group.
Time frame: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls
Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Between-group change in hypertension status from baseline to 12 weeks will be compared in the immediate start and delayed start groups.
Time frame: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Delayed Start Group Participants When They Were Not on EPO Compared to When They Were on EPO
Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Within-group change in hypertension status from 12 weeks to 24 weeks will be compared to the control period of 0 weeks to 12 weeks in the delayed start group.
Time frame: baseline to 12 weeks vs 12 weeks to 24 weeks
Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group
The investigators used the high-resolution ultrasound of brachial artery to assess flow-mediated dilatation (FMD). FMD measures the dilation of blood vessels in response to increased blood flow and is the reference standard for assessing endothelial function. The mean percentage change in endothelial function of those treated with EPO were compared to that of the delayed start group. The hypothesis being tested is that EPO will cause impairment in endothelial function.
Time frame: Baseline to 4 weeks
Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group
Change in urine albumin to urine creatinine ratio in the delayed start group baseline to 16 weeks (which is 4 weeks of exposure to darbepoetin), from baseline to 20 weeks (8-week exposure), and from baseline to 24 weeks (12-week exposure)
Time frame: Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks
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