Mechanisms of EPO-induced Hypertension

NCT ID: NCT03810911

Last Updated: 2025-12-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-04
• Study Completion Date: 2025-07-31

Brief Summary

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.

Detailed Description

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.

Conditions

Chronic Kidney Disease; Blood Pressure; Anemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Early start

Participants given study drug immediately at randomization

Group Type: ACTIVE_COMPARATOR

Darbepoetin

Intervention Type: DRUG

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

Delayed start

Participants given study drugs 12 weeks after randomization

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Darbepoetin

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

Intervention Type: DRUG

Other Intervention Names

EPO

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rajiv Agarwal, MD MBBS

Role: PRINCIPAL_INVESTIGATOR

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Locations

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Indianapolis, Indiana, United States

Countries

United States

References

Georgianos PI, Agarwal R. Resistant Hypertension in Dialysis: Epidemiology, Diagnosis, and Management. J Am Soc Nephrol. 2024 Apr 1;35(4):505-514. doi: 10.1681/ASN.0000000000000315. Epub 2024 Jan 16.

Reference Type: DERIVED

PMID: 38227447 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

052387

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NEPH-005-18S

Identifier Type: -

Identifier Source: org_study_id