Chronic Kidney Disease, Blood Pressure, Anemia
Conditions
Keywords
Flow mediated dilatation
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.
Interventions
DRUGDarbepoetin
Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The groups are randomized not the study drug. The groups will be known by both the participant and the investigator.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | Baseline to 12 weeks | 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. |
| Within Group Change in Diastolic Blood Pressure in the Delayed Start Group | 12 to 24 weeks compared to baseline to 12 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | baseline to 12 weeks vs 12 weeks to 24 weeks | 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. |
| Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | Baseline to 12 weeks | 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. |
| Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group | Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks | 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) |
| Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group | Baseline to 4 weeks | 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. |
| Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls | Baseline to 12 weeks | 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. |
Countries
United States
Participant flow
Recruitment details
Between 18 December 2020, and 22 September 2023, 1699 individuals were assessed for study eligibility. These individuals were screened, 4398 times for a mean of 2.6 times per person. In all, 281 (17%) were noted to be potentially eligible, of which, 157 (56%) agreed to come for a consent visit.
Pre-assignment details
65 individuals (41%) consented, of which, 27 (42%) were enrolled in the trial and underwent randomization stratified by the level of albuminuria (KDIGO stage A1, A2, or A3). 16 were assigned to waitlisted and 11 to immediate start group. In each of the two groups, two patients did not complete the study. The most common reason for randomization failure was either Hgb out of range (39%) or ambulatory BP out of range (39%). The trial was stopped because of inability to reach target sample size.
Participants by arm
| Arm | Count |
|---|---|
| Early Start Participants given study drug immediately at randomization | 11 |
| Delayed Start Participants given study drugs 12 weeks after randomization | 16 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Early Start | Total | Delayed Start |
|---|---|---|---|
| Age, Customized Age - years (SD) | 74.6 Years STANDARD_DEVIATION 6 | 74.9 Years STANDARD_DEVIATION 8 | 75.1 Years STANDARD_DEVIATION 9.3 |
| Albuminuria category (A1-A3) A1 -- n (%) | 4 Participants | 9 Participants | 5 Participants |
| Albuminuria category (A1-A3) A2 -- n (%) | 5 Participants | 13 Participants | 8 Participants |
| Albuminuria category (A1-A3) A3 -- n (%) | 2 Participants | 5 Participants | 3 Participants |
| Antihypertensive drugs -- n (SD) | 3.5 Drugs STANDARD_DEVIATION 1.2 | 3.2 Drugs STANDARD_DEVIATION 1.2 | 3 Drugs STANDARD_DEVIATION 1.2 |
| Baseline clinic blood pressure Clinic diastolic blood pressure -- mmHg (SD) | 58.5 mmHg STANDARD_DEVIATION 12.1 | 57.2 mmHg STANDARD_DEVIATION 11.4 | 55.4 mmHg STANDARD_DEVIATION 10.6 |
| Baseline clinic blood pressure Clinic systolic blood pressure -- mmHg (SD) | 125.1 mmHg STANDARD_DEVIATION 22.1 | 124.4 mmHg STANDARD_DEVIATION 19.5 | 123.2 mmHg STANDARD_DEVIATION 15.8 |
| Baseline eGFR -- mL/min/1.73m^2 (SD) | 38.6 mL/min/1.73m^2 STANDARD_DEVIATION 11.7 | 37.1 mL/min/1.73m^2 STANDARD_DEVIATION 12.9 | 36 mL/min/1.73m^2 STANDARD_DEVIATION 13.9 |
| Baseline UACR -- mg/g creatinine median (25th-75th) | 39 mg/g | 56 mg/g | 79 mg/g |
| Clinic heart rate -- beats per minute (SD) | 71 beats per minutes STANDARD_DEVIATION 8 | 68 beats per minutes STANDARD_DEVIATION 9 | 65 beats per minutes STANDARD_DEVIATION 10 |
| Glomerular filtration rate (GFR) category (G1-G5) G2 -- n (%) | 0 Participants | 1 Participants | 1 Participants |
| Glomerular filtration rate (GFR) category (G1-G5) G3a -- n (%) | 5 Participants | 8 Participants | 3 Participants |
| Glomerular filtration rate (GFR) category (G1-G5) G3b -- n (%) | 4 Participants | 10 Participants | 6 Participants |
| Glomerular filtration rate (GFR) category (G1-G5) G4 -- n (%) | 2 Participants | 8 Participants | 6 Participants |
| Hemoglobin -- g/dL (SD) | 9.4 g/dL STANDARD_DEVIATION 0.6 | 9.4 g/dL STANDARD_DEVIATION 0.6 | 9.5 g/dL STANDARD_DEVIATION 0.7 |
| Medical History Coronary revascularization -- n (%) | 4 Participants | 10 Participants | 6 Participants |
| Medical History Diabetes -- n (%) | 8 Participants | 17 Participants | 9 Participants |
| Medical History Heart failure hospitalization -- n (%) | 5 Participants | 10 Participants | 5 Participants |
| Medical History Myocardial infarction -- n (%) | 2 Participants | 6 Participants | 4 Participants |
| Medical History Stroke -- n (%) | 1 Participants | 2 Participants | 1 Participants |
| Nature of antihypertensive drugs ACE inhibitors or ARBs -- n (%) | 7 Participants | 13 Participants | 6 Participants |
| Nature of antihypertensive drugs Alpha blockers -- n (%) | 5 Participants | 8 Participants | 3 Participants |
| Nature of antihypertensive drugs Beta blockers -- n (%) | 7 Participants | 21 Participants | 14 Participants |
| Nature of antihypertensive drugs Dihydropyridine Ca channel blockers -- n (%) | 6 Participants | 15 Participants | 9 Participants |
| Nature of antihypertensive drugs K sparing diuretics -- n (%) | 2 Participants | 5 Participants | 3 Participants |
| Nature of antihypertensive drugs Loop diuretics -- n (%) | 5 Participants | 9 Participants | 4 Participants |
| Nature of antihypertensive drugs Nondihydropyridine Ca channel blockers -- n (%) | 1 Participants | 1 Participants | 0 Participants |
| Nature of antihypertensive drugs Thiazide diuretics -- n (%) | 4 Participants | 8 Participants | 4 Participants |
| Nature of antihypertensive drugs Vasodilators -- n (%) | 1 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Self stated race Black | 1 Participants | 8 Participants | 7 Participants |
| Race/Ethnicity, Customized Self stated race White | 10 Participants | 19 Participants | 9 Participants |
| Serum ferritin -- ng/mL (25th-75th percentile) | 110 ng/mL | 95 ng/mL | 91 ng/mL |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 22 Participants | 12 Participants |
| Transferrin saturation -- percent (SD) | 21 % STANDARD_DEVIATION 9.8 | 23 % STANDARD_DEVIATION 13.3 | 24.2 % STANDARD_DEVIATION 15.5 |
| Weight -- kg (SD) | 99.3 kg STANDARD_DEVIATION 19.7 | 92.9 kg STANDARD_DEVIATION 22.9 | 88.5 kg STANDARD_DEVIATION 24.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 27 | 0 / 16 |
| other Total, other adverse events | 6 / 27 | 7 / 16 |
| serious Total, serious adverse events | 8 / 27 | 5 / 16 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Early Start | Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | 1.4 mmHg |
| Delayed Start | Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | -0.5 mmHg |
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Early Start | Within Group Change in Diastolic Blood Pressure in the Delayed Start Group | -1.9 mmHg |
| Delayed Start | Within Group Change in Diastolic Blood Pressure in the Delayed Start Group | 3.2 mmHg |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Early Start | Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group | 0.9 percentage of endothelial function |
| Delayed Start | Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group | -1.2 percentage of endothelial function |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Early Start | Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | 2 mmHg |
| Delayed Start | Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls | -3.6 mmHg |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Early Start | Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group | 22 percentage change in UACR from baseline |
| Delayed Start | Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group | 22 percentage change in UACR from baseline |
| 24 Weeks (12-week Darbepoetin Exposure) | Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group | 35 percentage change in UACR from baseline |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Start | 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 | 7 Participants |
| Delayed Start | 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 | 7 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Start | Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls | 3 Participants |
| Delayed Start | Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls | 7 Participants |