Vitamin D as a Modifier of Serum Hepcidin in Children With Chronic Kidney Disease

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.

Inclusion Criteria:

- Clinical diagnosis of stage 2-5 Chronic Kidney Disease (estimated glomerular
filtration rate [GFR] between 15 and < 90 ml/min/1.73m2) based on the new bedside
Schwartz formula estimation using serum creatinine and height [height in cm x
0.413/serum creatinine]

- 1-21 years of age

- Willingness and ability to provide informed consent and assent

Exclusion Criteria:

- Children less than 1 year of age (in whom risk of vitamin D toxicity may be
increased) or greater than 21 years at time of study screening

- Children with a documented history of hypercalcemia or nephrolithiasis

- Children with GI tract discontinuity (ostomy)

- Current pregnancy or pregnancy within the last 12 months

- Children with known anemia-related disorders including sickle cell anemia,
thalassemia

- Children with severe 25D deficiency (< 5 ng/mL) likely to be associated with severe
morbidity and requiring prompt high dose vitamin D supplementation, or with 25D
levels > 60 ng/mL which could be associated with increased risk of vitamin D toxicity