Cholecalciferol (Vitamin D3) Therapy in Chronic Kidney Disease (CKD) Subjects

Vitamin D supplementation in reducing secondary hyperparathyroidism in chronic kidney
disease patients, stage 3 and 4: A randomized, placebo controlled pilot study Problem of
interest Chronic Kidney Disease (CKD) patients suffer from severe metabolic bone disease,
which represents a formidable challenge to physicians. Defective vitamin D metabolism, and
secondary parathyroid activation have been suggested as possible causes. Vitamin D is
important for musculoskeletal health. Vitamin D can be obtained from the diet or made in the
skin from exposure to sunlight, but it has to be converted by the kidneys into calcitriol,
the active form in order to be effective. Decreased kidney mass in CKD patients causes
reduced capability to convert vitamin D into calcitriol due to less 1-alpha hydroxylase
enzyme levels. Current standard of care for patients with chronic renal disease is treatment
with vitamin D analogues such as Rocaltrol or Hectoral. However, these medications have the
potential to cause hypercalcemia. Studies have shown that calcitriol production becoming
dependent on 25- hydroxyvitamin D availability in moderate CKD patients. There is
speculation that there is still some "reserve" left for the generation of calcitriol from
vitamin D in these patients.

The main question being posed in this study is:

Primary: Can a weekly high dose supplementation of cholecalciferol be effective in raising
25(OH)D levels in patients with CKD and can this reduce parathyroid hormone levels in
pre-dialysis chronic kidney disease patients?

Study Design This is an 12 week pilot and feasibility study with an enrollment goal of 30
subjects. Half of the subjects will be randomized to vitamin D3 and the other half will
receive a placebo. Subjects will be referred from the nutrition or renal clinic at Emory.
CKD stage 3 and 4 patients will be eligible for participation if they have been determined
to have vitamin D deficiency and are not on treatment with vitamin D or vitamin D analogues.
Subjects will sign an informed consent form after reviewing the protocol in detail with the
principal investigator. A questionnaire would collect information about dietary vitamin D
intake, sunlight exposure, and any symptoms of vitamin D deficiency. The subject will have
baseline levels of serum vitamin D (25-hydroxyvitamin D), parathyroid hormone (PTH), serum
calcium and phosphate, creatinine and other markers of bone turnover. The questionnaires and
the blood draws would be repeated on the 6th and 12th week of the study. Subjects will be
given 12 pills of each containing either 50,000 IU vitamin D3 or placebo and asked to take
one pill a week. They would be scheduled to return to the clinic after 6 weeks and blood
measurements would be repeated. Subjects will be asked to revisit for their final visit at
the 12th week when they would have their last blood draw and assessment.

Treatment This is a randomized control trial. Only half of the subjects will receive vitamin
D treatment and the other half placebo. If at the end of the study, the subject is still
vitamin D deficiency, they will be referred to an endocrinologist or to their primary doctor
for treatment.

Scientific advancement If successful, this study would provide the necessary preliminary
data in order to conduct a larger randomized controlled study supplementing vitamin D in
chronic kidney disease patients. One potential area of study would be to see whether
subjects supplemented with vitamin D were able to raise their active vitamin D levels using
the "reserve" hydroxylase enzyme in the kidneys compared to those subjects who were just
supplemented with a placebo. This study is necessary in order to determine whether weekly
intake of a high dose vitamin D is sufficient to decrease the parathyroid hormone levels in
the given time frame.

Inclusion Criteria:

- Age 18-85

- CKD stage 3-4 (GFR 15-59 ml/min/1.73 m2 body surface area, calculated by using the
MDRD Study equation GFR Calculator)

- serum 25(OH)D concentrations ≤ 30 ng/mL, and serum PTH levels >70 pg/mL documented
within the last six months

Exclusion Criteria:

- History of liver failure (serum AST or ALT > 3-fold the upper limit of normal)

- requiring dialysis at any stage of the study

- history of intestinal malabsorption or chronic diarrhea

- serum calcium level (corrected for serum albumin) > 10.5 mg/dL

- calcium x phosphorus product >70

- treatment with more than 1000 IU of vitamin D per day, or current treatment with a
vitamin D analogue or calcimimetic

- an anti-epileptic medication and other medications which can affect vitamin D
metabolism (e.g., phenobarbital, phenytoin, rifampicin)