DIVINE: Dialysis Infection and Vitamin D In New England

• Serum 25-OH vitamin D level [ Time Frame: every 2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  

• Cytokine profiles [ Time Frame: every 4 weeks for 12 weeks ] [ Designated as safety issue: No ]
  
• Serum Calcium [ Time Frame: every 2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  
• Serum Phosphate [ Time Frame: every 2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  
• Parathyroid Hormone [ Time Frame: Every 4 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  
• Serum 1,25-dihydroxyvitamin D levels [ Time Frame: every 2 weeks for 12 weeks ] [ Designated as safety issue: No ]
  
• Plasma cathelicidin [ Time Frame: every 4 weeks for 12 weeks ] [ Designated as safety issue: No ]
  
• All Cause Hospitalizations and Mortality [ Time Frame: Study duration ] [ Designated as safety issue: Yes ]
  
• Infectious Hospitalizations and Mortality [ Time Frame: study duration ] [ Designated as safety issue: Yes ]
  
• Cardiac Hospitalizations and Mortality [ Time Frame: study duration ] [ Designated as safety issue: Yes ]
  

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 2 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.