Effect of Vitamin D3 Supplementation on Arterial and Bone Remodeling in Chronic Kidney Disease Patients
Condition: Renal Insufficiency, Chronic; Vascular Stiffness; Bone Diseases, Metabolic
MeSH terms: Bone Diseases; Bone Diseases, Metabolic; Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Metabolic Diseases
Study type: Interventional
Phase: Phase 4

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).
    

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.
    

Intervention name(s): Vitamin D3
Intervention type(s): Drug
Intervention description(s): Two different doses of Vitamin D3
Other intervention name(s): cholecalciferol
Intervention MeSH terms: Vitamin D; Cholecalciferol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment