Effect of Vitamin D3 Supplementation on Arterial and Bone Remodeling in Chronic Kidney Disease Patients

February 12, 2021 updated by: Mark L. Lipman, Jewish General Hospital
To evaluate in patients with chronic kidney disease the impact of two dosages of per os vitamin D3 supplementation (cholecalciferol) on large arterial stiffness (evaluated non invasively by pulse wave velocity and high-resolution echotracking system). We will also study arterial calcification (lateral abdominal radiography and echocardiogram), arterial remodeling (high-resolution echotracking system), endothelial function (evaluated by a non-invasive finger biosensor device), and bone remodeling (evaluated by serum biomarkers and bone mineral density).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Structural changes to large arteries and abnormalities in mineral and bone metabolism are frequent manifestations in patients with chronic kidney disease (CKD). Together, they contribute in a large part to the heightened morbidity and mortality observed in this population.

Epidemiological data in end stage renal disease and in the general population suggest the existence of a bone-vascular axis. Metabolic bone disease (MBD) in CKD encompasses altered bone remodeling and the propensity for vascular calcification. These pathological processes are driven by the multiple disorders of mineral metabolism in CKD, among them, abnormalities of vitamin D metabolism.

Vitamin D deficiency [25(OH)D] is widely observed in CKD patients and has been associated with an increased rate of cardiovascular events in both the general population and in CKD patients. The mechanisms involved are not clearly established. Vitamin D influences blood pressure through effects on the renin-angiotensin system (via a vitamin D response element in the renin gene), vascular smooth muscle cells and cardiomyocyte proliferation and hypertrophy, vascular inflammation and calcification. Vitamin D deficiency has been associated with large arterial stiffness in end-stage renal disease patients. Aortic and carotid stiffness are independent predictors of cardiovascular and overall mortality in end-stage renal disease patients. Large arterial remodeling and stiffening could be the missing pathogenic link between vitamin D deficiency and increased cardiovascular event rate.

In terms of mineral metabolism, many CKD patients develop secondary hyperparathyroidism. This results from a combination of hyperphosphatemia, hypocalcemia and low levels of active Vitamin D [1,25(OH)D2]. Since several observational studies have shown that parathyroid hormone (PTH) levels are inversely correlated with blood 25(OH)D levels, it is possible that 25(OH)D deficiency may also be contributing to the hyperparathyroid state. Secondary hyperparathyroidism contributes to cardiovascular risk and to bone disease. Elevated PTH has been associated with large arterial stiffness and remodeling. Elevated PTH is also associated with high bone turnover and participates in the development of bone disease of CKD-MBD. Bone disease in CKD-MBD comprises abnormalities in bone turnover, mineralization, linear growth and strength. Bone biopsy remains the gold standard for evaluation of bone disease in CKD but its invasive nature limits its practice. Serum biomarkers of bone remodeling allow direct estimation of bone remodeling but lack evaluation and precision. Among them, guidelines issued by Kidney Disease Improving Global Outcomes (KDIGO) recommend PTH (1-84) and bone specific alkaline phosphatase (BSALP). Other biomarkers exist including osteocalcin, osteoprotegerin, tartrate-resistant acid phosphate-5b (TRAP-5b), pyridinoline and deoxypyridinoline, procollagen type 1 amino-terminal extension peptides, C terminal cross-link (CTX) , FGF-23 and fetuin-A. The major limitation of the use of these biomarkers is their kidney-dependent elimination that affects their measured levels depending on the degree of kidney dysfunction. We have chosen to study, in addition to PTH (1-84) and BSALP, CTX, osteoprotegerin, osteocalcin, fetuin-A and fibroblast growth factor-23 (FGF-23) because a relationship between these biomarkers and arterial disease has never been demonstrated.

This study seeks to compare the impact of standard versus aggressive Vitamin D3 supplementation (in Vitamin D deficient CKD patients) on important vascular and bone health endpoints.

Study Type

Interventional

Enrollment (Actual)

57

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montreal, Quebec, Canada, H3T1E2
        • Jewish General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with CKD stage 3-4 [estimated glomerular filtration rate (GFR) by modification of diet in renal disease (MDRD) formula between 15 and 60 ml/min/1.73m2].
  • Serum vitamin D level<50 nmol/L.

Exclusion Criteria:

  • Patient with estimated GFR by MDRD formula below 15 or above 60 ml/min/1.73m2).
  • Serum vitamin D level >50 nmol/L.
  • Liver disease manifested by elevated alanine aminotransferase (ALT) more than 3 times the upper limit of normal reference range, elevated gamma-glutamyl transferase (GGT) and total bilirubin levels.
  • History of malabsorption or chronic diarrhea.
  • Patients on biphosphonates, estrogen replacement therapy, PTH analogs, glucocorticosteroids, calcimimetics, and active vitamin D [1,25(OH)].
  • Patients on antiepileptic medications or other medications affecting vitamin D metabolism (e.g. phenobarbital, phenytoin, rifampicin).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Vitamin D3 5,000 units per week
Patient receive a dose that is considered within the standard dosing range for Vitamin D3 for one year.
Drug: Vitamin D3
Two different doses of Vitamin D3
Other Names:
  • cholecalciferol
Experimental: Vitamin D3 50,000 units per week
Patients receive a more aggressive Vitamin D3 dosing regimen of 50,000 units weekly for the first 3 months. At this point Vitamin D3 levels are measured. If the patient is Vitamin D3 replete (>75 nmol/L) then the dose is reduced to the equivalent of 25,000 units per week for the next 9 months. If the level is below this threshold then 50,000 units per week is continued for the next 9 months
Drug: Vitamin D3
Two different doses of Vitamin D3
Other Names:
  • cholecalciferol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Aortic stiffness evaluated by pulse wave velocity (PWV) (Sphygmocor ® )
Time Frame: 12 months
Parameter measured in meters per second.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Carotid stiffness evaluated by high resolution echotracking system (Art-lab®).
Time Frame: 12 months
Parameter measured as the difference in millimeters in carotid artery diameter between systole and diastole.
12 months
Endothelial function evaluated by Endo-PAT2000® system
Time Frame: 12 months
Parameter measured as the reactive hyperemia index as calculated by the Endo-PAT2000® system software.
12 months
Aortic valve calcification obtained from echocardiography.
Time Frame: 12 months

Parameter measured using a semi-quantitative scoring system based on scale of 1-4 as described by Rosenhek et al, New England Journal of Medicine 2000;343 (9):611.

1-no calcification, 2-mildly calcified (small isolated spots), 3-moderately calcified (multiple larger spots), 4-heavily calcified (extensive thickening and calcification of all cusps).
12 months
Calcification of the aorta obtained by plain lateral radiography.
Time Frame: 12 months

Parameter measured using a semi-quantitative scoring system based on a scale of 0-3 as described by Kauppila et al, Atherosclerosis 1997;132:245.

0-no calcification, 1-small scattered calcific deposits filling less than 1/3 of the longitudinal wall of the aorta, 2-one third or more, but less than two thirds of the longitudinal wall of the aorta calcified, 3-two thirds or more of the longitudinal wall of the aorta calcified.
12 months
Bone mineral density
Time Frame: 12 months
Osteodensitometry of the lumbar spine, hip, and distal radius, using dual-energy X-ray absorptiometry and reported in grams per square centimeter.
12 months
Parathyroid hormone levels
Time Frame: 12 months
Measurement of parathyroid hormone levels using a commercially available intact parathyroid hormone ELISA kit with values reported in ng/L.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jewish General Hospital

Investigators

  • Principal Investigator: Mark L Lipman, M.D., Jewish General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2015

Primary Completion (Actual)

September 23, 2020

Study Completion (Actual)

October 1, 2020

Study Registration Dates

First Submitted

August 29, 2016

First Submitted That Met QC Criteria

December 16, 2016

First Posted (Estimate)

December 21, 2016

Study Record Updates

Last Update Posted (Actual)

February 16, 2021

Last Update Submitted That Met QC Criteria

February 12, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • #10-010

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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