Vitamin D as a Modifier of Serum Hepcidin in Children With Chronic Kidney Disease
Condition: Anemia of Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      This research is being done to study the effectiveness of vitamin D (cholecalciferol) to
      modify hepcidin levels in children with chronic kidney disease (CKD). Anemia is a common
      problem in children with CKD. Anemia is when the body does not have enough healthy red blood
      cells. Hepcidin is a protein in the blood which interferes with the body's production of red
      blood cells. This study will see if vitamin D lowers hepcidin levels in children and young
      adults with CKD. If so, it could be used as an additional treatment for anemia in these
      children, in addition to the current therapies already in use including iron supplements and
      erythropoietin. People between the ages of 1 and 21 with CKD may be considered for this
      study.
    

Detailed description: 
      Vitamin D Supplementation is a practical and inexpensive intervention which is safe, readily
      available and clinically indicated. Substantial recent evidence suggests vitamin D may modify
      inflammatory pathways in CKD. There is a high probability of benefit and a low probability of
      harm for this easily modifiable factor. 25D levels can be effectively modified through oral
      supplementation with cholecalciferol. To the best of our knowledge, no studies examining the
      effects of oral cholecalciferol supplementation on hepcidin levels have been conducted in
      children with either CKD or other diseases.

      We will conduct a randomized open-label controlled trial of oral cholecalciferol
      supplementation in children aged 1-21 years with stage 2-5 (pre-dialysis) CKD receiving
      regular nephrology follow-up at a tertiary-care children's hospital (Johns Hopkins Children's
      Center). The intervention model will be parallel assignment. Children will be randomly
      allocated to receive either cholecalciferol supplementation 4000 IU per day (28,000 IU
      weekly) according to the KDOQI recommended supplementation for children with mild 25D
      deficiency, or will be treated with 400 IU/day (2,800 IU/weekly), which is the recommended
      dietary allowance.(1) Allocation will be double-blinded to prevent knowledge of allocation
      status affecting interpretation of results. Study participants will be prescribed any
      clinically indicated additional cholecalciferol supplementation once the 3-month laboratory
      measures have been obtained, based on serum 25D levels at the end of the study period.(1) We
      are proposing a supplementation dose of 4000 IU/day in children with CKD, which is considered
      a safe dose by KDOQI standards; vitamin D2 doses as high as 10,000 IU/day have been given to
      French patients with CKD for > 1 year with no evidence of vitamin D toxicity.(2) 25D levels
      between 40 and 80 are indicative of "sufficiency", and a safe upper limit of intake, in which
      the risk of hypercalcemia is negligible, has been defined as 10,000 IU/day.(3, 4)
      Cholecalciferol will be provided in both tablet (vitamin D 2000 IU tablets and 400 IU
      tablets, National Vitamin Company, Casa Grande, AZ) and liquid (Enfamil® D-Vi-Sol™ Drops, 400
      IU per mL) form, based on the ability to tolerate and preference of the subject.

      Participants will be monitored for signs of 25D toxicity (hypercalcemia, hyperphosphatemia,
      hypercalciuria) during the follow up period of 1 month and 3 months from baseline.

      Data Safety Monitoring Board will review serum calcium, phosphorus, and urine
      calcium:creatinine ratio values at the one month visit; if subjects show evidence of
      hypercalcemia or hyperphosphatemia (serum values > upper limit of normal, age-specific
      values, see Table 3 below), study drug will be discontinued.(3) If subjects demonstrate
      evidence of hypercalciuria (urine calcium:cr ratio > 0.6 in 1-2 year olds or > 0.2 in > 2
      year olds) study drug will be discontinued.(5) In addition, if 25-hydroxy vitamin D levels >
      80 ng/mL are reached, the study drug will be discontinued. In any subject in whom study drug
      is discontinued, the 3-month laboratory data will still be collected.

      In the case of hypoalbuminemia (serum albumin < 3.5 g/dL) corrected total serum calcium will
      be calculated using the formula: Corrected calcium (mg/dL) = serum calcium (mg/dL) + 0.8 (4 -
      serum albumin [g/dL])(2) Standardized blood pressure measurement will include three manual BP
      measurements conducted after five minutes of rest with an aneroid sphygmomanometer, at least
      30 seconds apart.

        1. KDOQI Work Group. KDOQI clinical practice guideline for nutrition in children with CKD:
           2008 update. executive summary. Am J Kidney Dis. 2009 Mar;53(3 Suppl 2):S11-104.

        2. KDOQI clinical practice guidelines for bone metabolism and disease in children with
           chronic kidney disease. Am J Kidney Dis. 2005;46(Supplement 1):S1-S122.

        3. Querfeld U, Mak RH. Vitamin D deficiency and toxicity in chronic kidney disease: In
           search of the therapeutic window. Pediatr Nephrol. 2010 Jun 22.

        4. Shroff R, Knott C, Rees L. The virtues of vitamin D--but how much is too much? Pediatr
           Nephrol. 2010 Sep;25(9):1607-20.

        5. Kruse K, Kracht U, Kruse U. Reference values for urinary calcium excretion and screening
           for hypercalciuria in children and adolescents. Eur J Pediatr. 1984 Nov;143(1):25-31.
    

Intervention name(s): Cholecalciferol
Intervention type(s): Drug
Intervention description(s): Children will be randomly allocated to receive either cholecalciferol supplementation 4000 IU per day 400 IU/day. We are proposing a supplementation dose of 4000 IU/day in children with CKD, which is considered a safe dose by KDOQI standards; vitamin D2 doses as high as 10,000 IU/day have been given to French patients with CKD for > 1 year with no evidence of vitamin D toxicity. Cholecalciferol will be provided in both tablet and liquid form, based on the ability to tolerate and preference of the subject. Participants will be monitored for signs of 25D toxicity (hypercalcemia, hyperphosphatemia, hypercalciuria) during the follow up period of 1 month and 3 months from baseline.
Other intervention name(s): tablet: National Vitamin Company, Casa Grande, AZ; liquid: Enfamil® D-Vi-Sol™ Drops
Intervention MeSH terms: Cholecalciferol; Vitamin D
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: chronic kidney disease; anemia