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

Renal Insufficiency, Chronic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02999204
• Other study ID #: #10-010
• Status: Completed
• Phase: Phase 4
• Start date: January 2015
• Est. completion date: October 1, 2020

Study information

• Verified date: February 2021
• Source: Jewish General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: October 1, 2020
• Est. primary completion date: September 23, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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).

Related Conditions & MeSH terms

• Bone Diseases
• Bone Diseases, Metabolic
• Kidney Diseases
• Metabolic Diseases
• Renal Insufficiency
• Renal Insufficiency, Chronic
• Vascular Stiffness

Intervention

Drug:
• Vitamin D3
Two different doses of Vitamin D3

Locations

Country	Name	City	State
Canada	Jewish General Hospital	Montreal	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
Jewish General Hospital

Country where clinical trial is conducted

Canada, 

References & Publications (6)

Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol. 2009 Sep;4(9):1515-22. doi: 10.2215/CJN.02260409. Epub 2009 Aug 20. Review. — View Citation

Barreto DV, Barreto FC, Liabeuf S, Temmar M, Boitte F, Choukroun G, Fournier A, Massy ZA. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clin J Am Soc Nephrol. 2009 Jun;4(6):1128-35. doi: 10.2215/CJN.00260109 — View Citation

Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001 Feb 20;103(7):987-92. — View Citation

Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 2009 Jul;205(1):255-60. doi: 10.1016/j.ather — View Citation

London GM, Guérin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Mëtivier F. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007 Feb;18(2):613-20. Epub 2007 — View Citation

Motiwala SR, Wang TJ. Vitamin D and cardiovascular disease. Curr Opin Nephrol Hypertens. 2011 Jul;20(4):345-53. doi: 10.1097/MNH.0b013e3283474985. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Aortic stiffness evaluated by pulse wave velocity (PWV) (Sphygmocor ® )	Parameter measured in meters per second.	12 months
Secondary	Carotid stiffness evaluated by high resolution echotracking system (Art-lab®).	Parameter measured as the difference in millimeters in carotid artery diameter between systole and diastole.	12 months
Secondary	Endothelial function evaluated by Endo-PAT2000® system	Parameter measured as the reactive hyperemia index as calculated by the Endo-PAT2000® system software.	12 months
Secondary	Aortic valve calcification obtained from echocardiography.	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
Secondary	Calcification of the aorta obtained by plain lateral radiography.	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
Secondary	Bone mineral density	Osteodensitometry of the lumbar spine, hip, and distal radius, using dual-energy X-ray absorptiometry and reported in grams per square centimeter.	12 months
Secondary	Parathyroid hormone levels	Measurement of parathyroid hormone levels using a commercially available intact parathyroid hormone ELISA kit with values reported in ng/L.	12 months