Effect of Cholecalciferol Supplementation on Inflammation and Cellular Alloimmunity in Hemodialysis Patients: Data from a Randomized Controlled Pilot Trial

Background: Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D-3 supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients. Methods and Findings: We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D-3) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH) D and phenotypic and functional properties of T-cells. Participants were randomized 2: 1 to active treatment versus control. D-3 supplementation increased serum 25(OH) D at 6 weeks (13.5 [ 11.2] ng/mL to 42.5 [ 18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFN gamma ELISPOT-based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/2330.8 vs 252.9+/2431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25). Conclusions: D-3 supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients.