BCRF Rheumatological And Mineral Complications F 08 Metabolic Complications

b-crf: rheumatological and mineral complications f- 08: metabolic complications h- 01: t-cell biology and physiology h- 04: inflammatio

B-CRF: rheumatological and mineral complications
F- 08: metabolic complications
H- 01: T-cell biology and physiology
H- 04: Inflammation
Effect of Cholecalciferol Supplementation on Inflammation and Cellular
Alloimmunity in Hemodialysis Patients: Data from a Randomized
Controlled Pilot Trial
Li L, Lin M, Krassilnikova M, Ostrow K, Bader A, et al.
PLoS ONE ; 2014; 9(10): e109998. doi:10.1371/journal.pone.0109998
ABSTRACT
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 D3 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 (D3) 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. D3 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 IFNγ 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+/−330.8
vs 252.9+/−431.3 in control), but these changes in PRT between groups
did not reach statistical significance (p = 0.25).
Conclusions
D3 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.
Trial Registration
Clinicaltrials.gov NCT01175798
COMMENTS
Alloreactive memory T-cells are pathogenic mediators of transplant
injury.
Memory T-cells can be induced by direct exposure to alloantigens
through transplantation, pregnancy, or blood transfusion. Evidence
also indicates that heterologous (cross-reactive) immune responses
initiated by environmental pathogens and homeostatic proliferation can
facilitate the induction and expansion of alloreactive memory T-cells.
The biologically active form of vitamin D, 1,25-dihydroxyvitamin D
[1,25(OH)2D] has immune-modulatory properties. T-cells and dendritic
cells (DCs), express the vitamin D receptor (VDR) and the 1α-hydroxylase
needed to convert 25-hydroxyvitamin D [25(OH)D] to 1,25(OH)2D.
1,25(OH)2D can directly modulate the function of T-cells and DCs
through a variety of mechanisms and can enhance tolerance induction in
mice.
Vitamin D deficiency is widespread among the general population , and
is prevalent in patients with end-stage renal disease (ESRD) on
hemodialysis (HD).
There is an elevation in the risk of experiencing adverse health
consequences of vitamin D deficiency at 25(OH)D levels <20 ng/mL .
Over 80% of HD patients have serum 25(OH)D concentrations within the
insufficient/deficient range despite ongoing treatment with activated
vitamin D [1,25(OH)2D] for prevention of uremic bone disease
The safety, efficacy, and immunological impact of nutritional vitamin
D repletion in HD patients, particularly in patients already receiving
1,25(OH)2D, has not been tested in controlled studies.
The authors have hypothesized that inadequate concentrations of
25(OH)D contribute to the development of alloreactive memory T-cells
by reducing the local synthesis of the 1,25(OH)2D that is needed to
achieve optimal levels in immune cells. To test this hypothesis and to
obtain preliminary data for power calculations for a larger
multi-center study, they performed a pilot, single-center, randomized,
controlled trial (RCT) of oral cholecalciferol (D3) (versus no
supplementation)
Subjects with serum 25(OH)D<25 ng/mL were eligible for randomization.
The study was an open-label pilot RCT of nutritional Vitamin D-
therapy (D3: cholecalciferol,). Participants were randomized in a 2:1
ratio into one of two groups: oral cholecalciferol or no treatment
(currently the standard of care at the dialysis units, as routine
screening for and treatment of 25(OH)D deficiency are not part of
practice guidelines for this population). Randomization was stratified
by baseline 25(OH)D (10–24 ng/mL and <10 ng/mL).
Those participants randomized to D3 had a target 25(OH)D concentration
of >35 ng/ml. The initial dose of D3 was 50,000/week for 6 weeks, at
which time 25(OH)D was re-measured. Subjects whose 25(OH)D remained
≤35 ng/ml continued on 50,000 IU weekly for another 6 weeks, at which
point 25(OH)D concentrations were repeated. Those subjects who
achieved 25(OH)D concentrations >35 ng/ml were transitioned to 10,000
IU/week. D3 therapy was directly observed by a study coordinator or
investigator. 25(OH)D was measured at baseline, 6 weeks, 3 months, and
6 months following randomization in both treatment and control groups.
The primary outcome was change in 25(OH)D at 6 weeks, 3 months, and 6
months. Secondary outcomes included change in clinical laboratory
values (intact parathyroid hormone [PTH], serum calcium, and
phosphorus), activated vitamin D requirements (mcg/treatment), and
laboratory-based phenotypic and functional T-cell assays.
Of 116 chronic hemodialysis patients screened, 99 (85.3%) had 25(OH)D
concentrations <25 ng/mL and qualified for randomization. The median
(IQR) 25(OH)D concentration of the 116 patients was 14.7 (10.5–21.6)
ng/mL.
Therapy with oral D3 resulted in a significant rise in serum 25(OH)D
by 6 weeks which was sustained throughout the 12 months of study.
Serum 25(OH)D in the control group did not change . They did not
observe any adverse events attributable to D3 supplementation.
D3 supplementation may inhibit the expansion of alloreactive T-cell
memory over 1 year on dialysis. Although the comparison of “delta” PRT
(1 year – baseline) in the treatment vs control group did not reach
statistical significance
In conclusion, the results of this pilot RCT show that nutritional
vitamin D (D3) supplementation is safe and effective in vitamin
D-deficient HD patients concurrently treated with 1,25(OH)2D, and may
prevent time-dependent increases in memory T-cell alloreactivity.
Because memory T-cell alloreactivity pre-transplantation negatively
affects post-transplant outcomes, and because vitamin D deficiency is
associated with higher rates of acute rejection in kidney transplant
recipients, treatment with vitamin D has the potential to improve
kidney transplant outcomes and needs to be evaluated prospectively in
transplant candidates/recipients.
Pr. Jacques CHANARD
Professor of Nephrology