Mechanisms of EPO-induced Hypertension (EPIC)

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.

All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.

The groups are randomized not the study drug. The groups will be known by both the participant and the investigator.

Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.

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.

Those treated with EPO compared to the delayed start group. The hypothesis being tested is that EPO will cause impairment in endothelial function.

A multivariable model will be created to predict the change in FMD from baseline to 4 w. Model 1 will have an indicator variable of those treated with EPO compared to time controls (this is outcome 2 essentially). Model 2 will have the following predictors of this change in addition: baseline values of urine albumin/creat ratio, asymmetric dimethylarginine (ADMA), urine nitrate and nitrite, renin, aldosterone, and plasma endothelin-1. Model 3 will include all the variables in Model 1 and 2 and also include change from baseline to 4 weeks in the same variables reported in Model 2.

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.

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.

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.

Inclusion Criteria: Stage 3 or 4 chronic kidney disease Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than 140/90 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