Alpha-Adrenoceptor Vascular Function In Chronic Kidney Disease Focus On The Role Of Endothelial Nitric Oxide
Study Details
Study Description
Brief Summary
The purpose of this study is to learn more about why most patients with early stages of kidney disease have high blood pressure.
We know the body produces natural substances that cause blood vessels to open wider to carry more blood when needed. An example is during exercise. Other natural substances cause blood vessels to get smaller and slow down blood flow when needed. An example is when people are cold. The balance between these substances is important. People with kidney disease and high blood pressure do not have the normal balance of these substances.
This study will include 3 groups of people, people with normal blood pressure, people with high blood pressure and people with kidney disease.
-
Subjects will have a screening physical examination, including an ECG and laboratory tests
-
Subjects with high blood pressure may not take their regular blood pressure medication for 3 weeks prior to the inpatient GCRC study
-
Subjects will be given intra-arterial medications that will cause changes in the blood vessels during the in-patient study.
The study will then compare the responses of the three groups. A GFR test will be done to confirm the renal function of the group with chronic kidney disease.
These studies will provide insight into the mechanisms of the pathogenesis of enhanced α1 vasoreactivity in subjects with progressive renal disease. This will lay the groundwork for new strategies in the treatment and prevention of vascular disease among the rapidly growing group of individuals with CKD.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Enhanced adrenergic vascular reactivity may significantly contribute to hypertension and the excessive cardiovascular disease burden in patients with chronic kidney disease (CKD). Nitric oxide (NO), a modulator of neurovascular function, may be linked to adrenergic vascular responsiveness. The central HYPOTHESIS is that the reduction in endothelial nitric oxide (NO) bioavailability contributes to the enhancement of α1-adrenoceptor vasomotor function in patients with CKD.
Specific Aims: In patients with mild to moderate CKD, compared to matched hypertensive and normotensive controls without CKD:
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Determine if α1-adrenoceptor vasoreactivity is enhanced less by inhibition of endothelial NO
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Determine whether α1-adrenoceptor vasoreactivity correlates with plasma levels of the endogenous NO inhibitor, asymmetrical dimethylarginine.
Methods: CKD will be confirmed by I125-iothalamate glomerular filtration rate. Regional α1-adrenoceptor vasoreactivity (sensitivity [EC50], reactivity [slope]) will be assessed by venous plethsymography using a graded intra-arterial infusion of the α1-adrenoceptor agonist, phenylephrine. Comparisons of vasoreactivity at baseline and during infusions of L-NMMA will be made between hypertensive non-diabetic subjects with glomerular filtrations rates between 30-70 ml/min age-, gender-, ethnicity- and % body fat-matched hypertensive and normotensive subjects with normal kidney function. In addition, plasma levels of the endogenous NO inhibitor, asymmetric dimethylarginine will be measured in the hypertensive subjects with and without CKD and compared to vasoreactivity.
Significance. These studies will provide insight into the mechanisms of the pathogenesis of enhanced α1 vasoreactivity in subjects with progressive renal disease.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CKD
|
Drug: Procedure: Regional phenylephrine arterial infusion
|
| Active Comparator: Hypertension group
|
Drug: Procedure: Regional phenylephrine arterial infusion
|
| Active Comparator: Normotensive group
|
Drug: Procedure: Regional phenylephrine arterial infusion
|
Outcome Measures
Primary Outcome Measures
- α1-adrenoceptor Vasoreactivity With L-NMMA [up to 8 hours]
Vasoreactivity is defined as Forearm blood flow, dose response curve; ml per minute per log of phenylephrine, or FABF ml/min/logPE; The x axis is the ml/min value and the y axis is the log Phenylephrine concentration.
- α1-adrenoceptor Vasoreactivity With Endogenous ADMA [up to 8 hours]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Men and Women-18 to 55 years of age.
-
There are three groups of volunteers.
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Group A. People who are hypertensive with kidney disease. When not taking blood pressure medicines, blood pressure must have a systolic between 140-170 mmHg. Diastolic must be between 90-109 mmHg.Kidney function should be around half of normal. Urine protein must be no more than 1 gram in a 24-hour urine time period.
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Group B. People who are hypertensive without kidney disease. Blood pressure must have a systolic between 140-170 mmHg. Diastolic must be between 90-109 mmHg. Kidney function should be normal. Normal amounts of protein in their urine.
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Group C. People who are normotensive. Blood pressure must have a systolic below 131/mmHg. Diastolic must be below 81 mmHg. Kidney function should be normal. No more than normal amounts of protein in their urine.
Exclusion Criteria:
People with:
-
Diabetes
-
Lung disease
-
Stomach disease
-
Liver disease
-
Blood vessel disease
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Heart disease
-
Hereditary blood disorders
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Hematocrit (amount of red blood cells) less than 30%
-
Current tobacco use
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Kidney disease who require dialysis
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Women who are pregnant or breastfeeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Michigan Hospital | Ann Arbor | Michigan | United States | 48109 |
Sponsors and Collaborators
- University of Michigan
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Crystal A Gadegbeku, MD, Assistant Professor of Medicine, University of Michigan Health System, Department of Internal Medicine, Division of Nephrology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HUM 00000261
- 5R33DK071222
Study Results
Participant Flow
| Recruitment Details | Three screen failures |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Chronic Kidney Disease (CKD) | Hypertension Group | Normotensive Group |
|---|---|---|---|
| Arm/Group Description | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion |
| Period Title: Overall Study | |||
| STARTED | 7 | 2 | 6 |
| COMPLETED | 7 | 2 | 5 |
| NOT COMPLETED | 0 | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Chronic Kidney Disease | Hypertension Group | Normotensive Group | Total |
|---|---|---|---|---|
| Arm/Group Description | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | Total of all reporting groups |
| Overall Participants | 7 | 2 | 6 | 15 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
7
100%
|
2
100%
|
6
100%
|
15
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
2
28.6%
|
1
50%
|
4
66.7%
|
7
46.7%
|
| Male |
5
71.4%
|
1
50%
|
2
33.3%
|
8
53.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
1
14.3%
|
0
0%
|
0
0%
|
1
6.7%
|
| Not Hispanic or Latino |
6
85.7%
|
2
100%
|
6
100%
|
14
93.3%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
1
16.7%
|
1
6.7%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
7
100%
|
2
100%
|
5
83.3%
|
14
93.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
7
100%
|
2
100%
|
6
100%
|
15
100%
|
Outcome Measures
| Title | α1-adrenoceptor Vasoreactivity With L-NMMA |
|---|---|
| Description | Vasoreactivity is defined as Forearm blood flow, dose response curve; ml per minute per log of phenylephrine, or FABF ml/min/logPE; The x axis is the ml/min value and the y axis is the log Phenylephrine concentration. |
| Time Frame | up to 8 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| Based on the data from the 12 participants, and the early termination, no analysis was performed on the two hypertensive participants' data. |
| Arm/Group Title | Chronic Kidney Disease | Normotensive Group |
|---|---|---|
| Arm/Group Description | Procedure: Regional phenylephrine arterial infusion | |
| Measure Participants | 7 | 5 |
| before L-NMMA infusion |
-0.48
(0.10)
|
-0.22
(0.08)
|
| after L-NMMA infusion |
-0.31
(0.09)
|
-0.16
(0.11)
|
| Title | α1-adrenoceptor Vasoreactivity With Endogenous ADMA |
|---|---|
| Description | |
| Time Frame | up to 8 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| The main goal of the study was to compare vasoreactivity across the three groups. Given the fact that we struggled to recruit matched hypertensive and normotensive control population, we were not able to achieve the goals of the study and therefore, ADMA levels were not measured. |
| Arm/Group Title | Chronic Kidney Disease | Hypertension Group | Normotensive Group |
|---|---|---|---|
| Arm/Group Description | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion |
| Measure Participants | 0 | 0 | 0 |
Adverse Events
| Time Frame | Participants were interviewed for safety follow up approximately 7 - 10 days after procedure. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Chronic Kidney Disease | Hypertension Group | Normotensive Group | |||
| Arm/Group Description | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | Procedure: Regional phenylephrine arterial infusion | |||
All Cause Mortality |
||||||
| Chronic Kidney Disease | Hypertension Group | Normotensive Group | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Chronic Kidney Disease | Hypertension Group | Normotensive Group | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 0/2 (0%) | 0/6 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Chronic Kidney Disease | Hypertension Group | Normotensive Group | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 0/2 (0%) | 0/6 (0%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Crystal Gadegbeku |
|---|---|
| Organization | University of Michigan |
| Phone | |
| crystal.Gadebeku@tuhs.temple.edu |
- HUM 00000261
- 5R33DK071222