Prevention of Secondary Hyperparathyroidism With Vitamin D in Stage II/III Chronic Kidney Disease
Condition: Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperparathyroidism; Hyperparathyroidism, Secondary
Study type: Interventional

Summary: 
      This study will evaluate whether earlier intervention with vitamin D in stage II/III chronic
      kidney disease will prevent or delay secondary hyperparathyroidism. Subjects will receive
      vitamin D or placebo at study entry and will be followed for a period of one year. The
      hypothesis is that subjects given vitamin D will have lower PTH and higher 25(OH)D after 1
      year compared to placebo. Additionally, there will be less subjects who progress into
      secondary hyperparathyroidism in the vitamin D treated group compared to the placebo treated
      group.
    

Detailed description: 
      Vitamin D is important to maintain normal calcium homeostasis and optimal bone health (1, 2).
      The synthesis of vitamin D and its metabolism to 1,25(OH)2D is regulated by parathyroid
      hormone (PTH), serum calcium, and phosphorus levels. In response to low serum calcium level,
      serum PTH activates alpha-1-hydroxylase for increased 1,25(OH)2D production in the kidney and
      also enhances tubular reabsorption of calcium (3). The higher levels of 1, 25(OH)2D results
      in increased intestinal calcium absorption (4). Increased serum phosphorus levels which
      occurs in the early stages of chronic kidney disease (CKD) results in inhibition of the
      1-alpha-hydroxylase, which results in decreased 1, 25(OH)2 D production, decreased intestinal
      calcium absorption leading to secondary hyperparathyroidism with increased PTH levels.
      Circulating 1,25(OH)2D levels begin to fall when the glomerular filtration rate is less than
      40 mL/min occasionally even less than 80 mL/min (11) and almost always significantly reduced
      in subjects with end-stage renal failure (12). Furthermore, in CKD, decreased renal mass also
      results in decreased expression of 1-alpha-hydroxlase and less production of 1,25(OH)2D which
      also exacerbates secondary hyperparathyroidism (5-7).

      Therefore, in CKD there are three processes that lead to secondary hyperparathyroidism. 1)
      decreased renal mass leading to decreased production of 1,25(OH)2D leading to a compensatory
      rise in PTH to further enhance production of 1,25(OH)2D 2) inhibition of the renal
      1-alpha-hydroxylase by accumulating phosphorus levels leading to decreased 1,25(OH)2D which
      also leads to secondary hyperparathyroidism. 3) increased phosphorus leads to lower ionized
      calcium leading to increased parathyroid hormone secretion.

      Untreated secondary hyperparathyroidism can lead to renal osteodystrophy (9) and increased
      mortality due to cardiovascular disease (10). Prolonged secondary hyperparathyroidism can
      lead to bone resorption and eventually autonomous parathyroid hormone secretion termed
      tertiary hyperparathyroidism.

      Vitamin D status is one of the major factors that may prevent progression of secondary
      hyperparathyroidism in patients with CKD. Insufficient levels of 25-hydroxyvitamin D further
      exacerbate secondary hyperparathyroidism by not providing adequate substrate for the renal
      1-alpha-hydroxylase for conversion to the active form of vitamin D, 1,25(OH)2D. A recent
      cross-sectional study on patients with moderate to severe CKD not yet on dialysis therapy
      from 12 geographically diverse regions of the United States has shown that only 29% and 17%
      of them had sufficient level, respectively (13). Vitamin D status is easily corrected. In our
      previous study we concluded that weekly cholecalciferol supplementation was an effective
      treatment to correct vitamin D status in patients with CKD stages III and IV (14). However,
      PTH levels did not return to normal. Therefore, it is likely that earlier intervention with
      vitamin D is necessary to prevent rather than to treat secondary hyperparathyroidism. This is
      the major question that is being evaluated in this study. Can intervening with vitamin D at
      an earlier stage of chronic kidney disease result in decreased incidence of secondary
      hyperparathyroidism?

      2.0 Objectives

      2.1 Overall Objective

      The primary objective of this study is to assess that if improving and maintaining an optimal
      25(OH) D level ( by National Kidney Foundation should be greater than 30ng/ml) (15) in people
      with stage II/III Chronic Kidney disease would delay the progression of secondary
      hyperparathyroidism and translate into improved markers of bone turnover

      2.2 Specific Aims

      Primary: 1) To determine in a double blind, randomized study whether supplementation with
      50,000 IU of cholecalciferol (vitamin D3) given weekly for 12 weeks followed by maintenance
      cholecalciferol 50,000 IU every other week would improve and maintain vitamin D status in CKD
      patients stage 2/3 compared to placebo at 12 months.

      2) To determine whether early intervention with vitamin D therapy further decreases PTH
      levels after 12 weeks of therapy and 12 months of therapy.

      Secondary: 1) To determine whether early treatment with vitamin D results in improving levels
      of bone turnover markers- tartrate-resistant acid phosphatase isoform 5b(TRAP5b), procollagen
      Type 1 N-Terminal propeptide (PINP), serum C-Telopeptide and Alkaline phosphatase.
    

Intervention name(s): Vitamin D; Placebo
Intervention type(s): Dietary Supplement; Other
Intervention description(s): 50,000 IU once a week for 12 weeks then every other week for 40 weeks; Matching Placebo
Other intervention name(s): cholecalciferol; vitamin D3
Intervention MeSH terms: Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: vitamin D; Chronic Kidney Disease; parathyroid hormone; Chronic kidney disease Stage II and III