DIVINE: Dialysis Infection and Vitamin D In New England

We hypothesize that a profound deficiency of nutritional vitamin D (25-hydroxyvitamin D, 25D)
in end-stage renal disease (ESRD) leads to an altered immune response, predisposing to early
morbidity and mortality from infection, the second-leading cause of death in ESRD. In
addition to impaired renal synthesis of the hormonal form of vitamin D (1,25-dihydroxyvitamin
D; 1,25D), ESRD is accompanied by near universal insufficiency of 25D. In-vitro, ex-vivo, and
retrospective human studies by our group and others suggest that 25D (and not 1,25D) is
intimately linked to immune defense via alterations in the production of inflammatory
cytokines and critical antimicrobial peptides including cathelicidin, which we have shown to
identify ESRD subjects at risk for infection-related mortality. Ergocalciferol, which is
rapidly converted to 25D, is the most widely available form of nutritional vitamin D in the
US, yet guidelines to treat ESRD patients with nutritional vitamin D are absent because of
limited data supporting its efficacy, safety, and biological effects in this population. To
determine effective and safe doses of ergocalciferol in ESRD, we will perform a double blind
placebo controlled randomized trial in 120 incident hemodialysis patients (40/arm x 3) with
25D levels < 30ng/ml, comparing two ergocalciferol dosing regimens (50,000 IU/week and 50,000
IU/month) and an identically appearing placebo. The primary outcome will be correction of
vitamin D insufficiency (25D >30 ng/ml) at 12 weeks. Serum calcium and phosphate levels will
be measured every 4 weeks to assess safety, and blood cytokine and cathelicidin levels will
be measured every 4 weeks to determine biological responses. To examine biological effects in
greater detail, a subset of subjects from each arm of the study will be further analyzed with
serial macrophage gene expression profiles and whole blood cytokine profiles following
ex-vivo stimulation with pro-inflammatory mediators (e.g., killed S. aureus). These
experiments will inform us on how individuals with ESRD, based on their vitamin D status and
the treatment they receive, may respond to infection. Laboratory measures will continue for
12 weeks. Clinical follow-up and monitoring for infection-associated events (including
antibiotic use, rates of bacteremia, and sepsis) will continue for 20 weeks. This pilot trial
addressing a significant unmet need in nephrology will involve basic, translational, and
clinical investigators experienced in vitamin D research, infection and inflammation, and in
trials involving ESRD subjects. These data will provide an important foundation for designing
future clinical trials rigorously assessing the effect of nutritional vitamin D on infectious
and other outcomes in ESRD.

Inclusion criteria

- Age ≥ 18 years

- Initiating chronic hemodialysis 3x/wk at Massachusetts General Hospital, Brigham and
Women's Hospital or Beth Israel Deaconess Medical Center with planned transfer to
Massachusetts chronic facility

- Serum 25D < 32 ng/ml

- Corrected serum calcium < 10.2 mg/dl

- Serum phosphate < 5.5 mg/dl

- Serum albumin > 3 g/dL

- Informed consent

Exclusion Criteria

- Pregnant or breastfeeding

- Women of childbearing potential not practicing one of the following measures of birth
control: double-barrier method, hormonal contraceptives for at least 3 months prior to
and during study, monogamous relationship with vasectomized partner, total abstinence
from sexual intercourse with men during study.

- HIV positive

- History of allergic reaction to ergocalciferol

- Investigator considers subject unsuitable for any reason