Chronic Kidney Disease
Conditions
Keywords
chronic kidney disease, vitamin d catabolism
Brief summary
The goal of this study is to better understand vitamin D catabolism and how it is affected by CKD and race.
Detailed description
Specifically, the study team will evaluate the metabolic clearance of 25-hydroxyvitamin D3 in individuals with varying degrees of CKD and among participants who self-report race as Caucasian, African American or African. The long-term goal of this work is to enhance the clinical evaluation and treatment of impaired vitamin D metabolism.
Interventions
Intravenous administration of a deuterium-labeled 25(OH)D3 to evaluate the metabolic clearance of 25(OH)D3
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Self-reported race Caucasian, African American, or African * Serum total 25(OH)D 10-50 ng/mL * Estimated GFR: * 60 mL/min/1.73m2 (N=40) 15-45 mL/min/1.73m2 (N=40) \<15 mL/min/1.73m2, treated with hemodialysis (N=40)
Exclusion criteria
* Primary hyperparathyroidism * Gastric bypass * Tuberculosis or sarcoidosis * Current pregnancy * Child-Pugh Class B or C cirrhosis (i.e. cirrhosis with ascites, hepatic encephalopathy, bilirubin \>=2 mg/dL, serum albumin \<=3.5 g/dL, or PT \>= 4 seconds) * Use of vitamin D3, or vitamin D2 supplements exceeding a mean daily dose of 400 IU, within 3 months (wash-out allowed) * Use of 1,25(OH)2D3 or an analogue, calcimimetics, or medications known to induce CYP24A1 within 4 weeks (wash-out allowed) * Serum calcium \> 10.1 mg/dL * Hemoglobin \< 10 g/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Clearance of D6-25(OH)D3 | 8 weeks | Metabolic clearance is calculated as the administered dose of 25(OH)D3 divided by the area under the plasma concentration-time curve (AUC). AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of D6-25(OH)D3 | 8 weeks | AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. |
| Terminal Half-life of D6-25(OH)D3 | 8 weeks | Terminal half-life is equal to ln2/k, where k is the slope of the terminal regression line estimated using ≥3 plasma concentrations. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. |
| Volume of Distribution of D6-25(OH)D3 | 8 weeks | Volume of distribution in the central compartment is calculated as dose/C0, where dose is the administered dose of 25(OH)D3 and C0 is the initial (estimated) concentration of drug in plasma. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | 8 weeks | Metabolic formation clearance is calculated as the daughter metabolite plasma AUC divided by the AUC of D6-25(OH)D3 (metabolite/parent AUC ratio). AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. |
| Change in the Serum Concentration of ALT | Baseline, 7 days | Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3 administration |
| Change in the Serum Concentration of Calcium | 7 days | Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3 administration |
| Change in the Serum Concentration of Creatinine | Baseline, 7 days | Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3 administration |
| Change in the Serum Concentration of AST | Baseline, 7 days | Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3 administration |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Healthy controls defined as normal eGFR (\>60 ml/min per 1.73m2) | 43 |
| CKD Group CKD group defined as those with eGFR \<60ml/min per 1.73 m2) | 24 |
| Kidney Failure Group Kidney failure group defined as those with ESKD treated with dialysis | 20 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Controls | Total | Kidney Failure Group | CKD Group |
|---|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 10 | 64 years STANDARD_DEVIATION 11 | 58 years STANDARD_DEVIATION 9 | 67 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Black or African American | 12 Participants | 26 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) Race More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race White | 31 Participants | 61 Participants | 14 Participants | 16 Participants |
| Sex: Female, Male Female | 24 Participants | 36 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 19 Participants | 51 Participants | 16 Participants | 16 Participants |
| Vitamin-D3 Supplement Use | 6 participants | 8 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 87 |
| other Total, other adverse events | 16 / 87 |
| serious Total, serious adverse events | 1 / 87 |
Outcome results
Primary
Metabolic Clearance of D6-25(OH)D3
Metabolic clearance is calculated as the administered dose of 25(OH)D3 divided by the area under the plasma concentration-time curve (AUC). AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Metabolic Clearance of D6-25(OH)D3 | 360 milliliter per day (ml/d) | Standard Deviation 108 |
| CKD Group | Metabolic Clearance of D6-25(OH)D3 | 313 milliliter per day (ml/d) | Standard Deviation 86 |
| Kidney Failure Group | Metabolic Clearance of D6-25(OH)D3 | 263 milliliter per day (ml/d) | Standard Deviation 163 |
Secondary
AUC of D6-25(OH)D3
AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | AUC of D6-25(OH)D3 | 59.8 nanograms x day/mL (ngxd/mL) | Standard Deviation 10.2 |
| CKD Group | AUC of D6-25(OH)D3 | 68.7 nanograms x day/mL (ngxd/mL) | Standard Deviation 10.2 |
| Kidney Failure Group | AUC of D6-25(OH)D3 | 76.6 nanograms x day/mL (ngxd/mL) | Standard Deviation 12 |
Secondary
Terminal Half-life of D6-25(OH)D3
Terminal half-life is equal to ln2/k, where k is the slope of the terminal regression line estimated using ≥3 plasma concentrations. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Terminal Half-life of D6-25(OH)D3 | 21.9 days (d) | Standard Deviation 5.7 |
| CKD Group | Terminal Half-life of D6-25(OH)D3 | 25.5 days (d) | Standard Deviation 6.5 |
| Kidney Failure Group | Terminal Half-life of D6-25(OH)D3 | 35.6 days (d) | Standard Deviation 8.1 |
Secondary
Volume of Distribution of D6-25(OH)D3
Volume of distribution in the central compartment is calculated as dose/C0, where dose is the administered dose of 25(OH)D3 and C0 is the initial (estimated) concentration of drug in plasma. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Volume of Distribution of D6-25(OH)D3 | 11.0 Liters (L) | Standard Deviation 2.9 |
| CKD Group | Volume of Distribution of D6-25(OH)D3 | 11.1 Liters (L) | Standard Deviation 2.8 |
| Kidney Failure Group | Volume of Distribution of D6-25(OH)D3 | 12.5 Liters (L) | Standard Deviation 4 |
Other Pre-specified
Change in the Serum Concentration of ALT
Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3 administration
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of ALT | 0.16 units/Liter (u/L) | Standard Deviation 3.71 |
| CKD Group | Change in the Serum Concentration of ALT | 1.52 units/Liter (u/L) | Standard Deviation 6.92 |
| Kidney Failure Group | Change in the Serum Concentration of ALT | 0.45 units/Liter (u/L) | Standard Deviation 3.66 |
Other Pre-specified
Change in the Serum Concentration of AST
Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3 administration
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of AST | 0.40 units/Liter (u/L) | Standard Deviation 3.43 |
| CKD Group | Change in the Serum Concentration of AST | 0.57 units/Liter (u/L) | Standard Deviation 5.98 |
| Kidney Failure Group | Change in the Serum Concentration of AST | 0.10 units/Liter (u/L) | Standard Deviation 5.22 |
Other Pre-specified
Change in the Serum Concentration of Calcium
Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3 administration
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of Calcium | 0.42 milligrams/deciliter (mg/dl) | Standard Deviation 1.75 |
| CKD Group | Change in the Serum Concentration of Calcium | 0.16 milligrams/deciliter (mg/dl) | Standard Deviation 0.26 |
| Kidney Failure Group | Change in the Serum Concentration of Calcium | -0.27 milligrams/deciliter (mg/dl) | Standard Deviation 0.48 |
Other Pre-specified
Change in the Serum Concentration of Creatinine
Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3 administration
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of Creatinine | 0.04 milligrams/deciliter (mg/dl) | Standard Deviation 0.09 |
| CKD Group | Change in the Serum Concentration of Creatinine | -0.05 milligrams/deciliter (mg/dl) | Standard Deviation 0.27 |
| Kidney Failure Group | Change in the Serum Concentration of Creatinine | 2.81 milligrams/deciliter (mg/dl) | Standard Deviation 2.26 |
Other Pre-specified
Metabolic Formation Clearance of D6-25(OH)D3 Metabolites.
Metabolic formation clearance is calculated as the daughter metabolite plasma AUC divided by the AUC of D6-25(OH)D3 (metabolite/parent AUC ratio). AUC is calculated using the linear trapezoidal method. Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | 0.12 ratio | Standard Deviation 0.04 |
| CKD Group | Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | 0.08 ratio | Standard Deviation 0.03 |
| Kidney Failure Group | Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | 0.03 ratio | Standard Deviation 0.03 |