Category: Professional Posters
Purpose: Vitamin D has been linked to immunity regulation. Calcitriol, the active form of vitamin D, can inhibit interleukin-2 production and decrease expression of co-stimulatory molecules CD 28 and CD 86 on leukocytes, all implicated in promoting rejection. Adding calcitriol supplementation to standard immunosuppression has decreased acute rejection in rat models. Waitlisted end stage renal disease (ESRD) patients often exhibit vitamin D deficiency due to impaired renal production of calcitriol. The purpose of this study was to investigate if low vitamin D levels at time of transplant associates with an increased risk of rejection post-transplant.
Methods: This was a non-interventional, retrospective, cohort study. Included were adult transplant recipients receiving a kidney-only allograft between October 2015 and March 2018 who had an available vitamin D level (calcidiol) at time of transplant and at least six months of follow-up. Exclusion criteria were recipients experiencing rejection or death during index hospital admission, not receiving per-protocol immunosuppression at transplant, or transfer of care within first six months. Collected data included demographics, transplant characteristics, calcidiol levels and supplementation, and both protocol and for-cause biopsies. Vitamin D deficiency was defined as a calcidiol level < 20 ng/mL. Rejection was a composite of biopsy proven acute cellular or antibody-mediated rejection, including borderline/suspicious. The primary outcome was time to first rejection. Data was described using mean (standard deviation, SD) or median (interquartile range, IQR) for continuous variables and counts (percentages) for categorical variables. Group comparisons used student t or Mann-Whitney U test and Pearson’s chi-square or Fisher’s exact test as appropriate. The primary outcome was estimated by Kaplan-Meier survival curves and log-rank test. Cox proportional hazards model was utilized to identify independent risk factors for time to rejection and compare risk of rejection between groups with adjustment of covariates. All p values were two-sided, with 0.05 as level of significance. Analysis was performed using R software version 3.5.0. The study was approved by the Institutional Review Board.
Results: 293 subjects were transplanted during the study period; after exclusion of 15 subjects, 278 were included. There were n=110 vitamin D deficient subjects (mean level 13.7 ng/mL) and n=168 vitamin D non-deficient (31.9 ng/mL). There were significantly more non-deficient group subjects on vitamin D supplementation (64.3% vs 43.6%, p=0.001), but more deficient group subjects taking calcitriol (54.2% vs 32.4%, p=0.017). The non-deficient group was older (51.9 vs 48.6 yrs, p=0.033) and had longer cold ischemia time (CIT) (10.5 vs 7.1hrs, p=0.036).
Overall rejection incidence was 25.9%, being lower in the deficient group than non-deficient (18.2% vs. 31.0%). The unadjusted risk of rejection in the deficient group was 43% lower than non-deficient group (HR [95%CI]: 0.57 [0.34;0.95], p=0.032). In multivariable analysis (adjusting for CIT and recipient age), rejection risk in the deficient group remained lower than non-deficient group (HR [95%CI]: 0.53 [0.31;0.89], p=0.017).
In post-hoc analysis, rejection risk no longer had significant association with vitamin D deficiency when using the first calcidiol level measured post-transplant (HR[95%CI]: 1.06 [0.65;1.73], p=0.81). Subgroup analysis revealed no statistically significant difference in rejection survival between calcitriol supplementation use versus non-use at time of transplant in 156 subjects taking vitamin D supplementation (p=0.42).
Conclusion: Lower rejection risk in the deficient group was contrary to our hypothesis. While calcitriol is a known immune-regulator, it is not measured due to its short half-life, and calcidiol is measured to assess vitamin D deficiency. We identified significantly higher calcitriol use in the deficient group. Many subjects were not taking vitamin D supplements or intermediate forms that may not convert to calcitriol due to ESRD. This could suggest calcitriol use while awaiting transplant is a more immunologically beneficial supplement choice, and calcidiol levels are not indicative of calcitriol’s immunomodulatory benefits peri-transplant. Further studies are necessary to corroborate this suggestion.