Low 25-hydroxyvitamin D Levels and the Risk of Late CMV Infection After Kidney Transplantation: Role for CMV-specific Mediated Immunity.

Abstract

We have read with interest the article by Astor et al investigating the impact of vitamin D levels on the risk of late cytomegalovirus (CMV) infection after kidney transplantation (KT).1 Following adjustment for clinical covariates, the authors found that vitamin D deficiency, defined as serum 25-hydroxyvitamin D (25(OH)D) levels <20 ng/mL measured at least 6 months after transplantation,2 was associated with a 1.81-fold higher risk of late CMV infection compared with vitamin D sufficiency.1 Our group has recently analyzed a single-center prospective cohort of 246 KT recipients with serial measurements of serum 25(OH)D through post-transplant month 12. We reported that the risk of opportunistic infection (which included CMV disease but not asymptomatic viremia) was significantly increased in the presence of vitamin D deficiency, defined as per the criteria proposed by the Institute of Medicine (25(OH)D levels < 12 ng/mL),3 at post-transplant month 1, whereas such association did not reach statistical significance at months 3 or 6.4 To attempt to replicate the findings by Astor et al, we have reanalyzed our database by taking into account any episode of late (>6 mo after transplantation) CMV infection regardless of the presence of symptoms or the need of antiviral therapy. Only patients with 25(OH)D measurement at post-transplant month 6 were included (n = 215). We applied the same definition for vitamin D deficiency (25(OH)D levels <20 ng/mL).2 When the entire cohort was considered, no significant differences in the cumulative incidence of CMV infection beyond month 6 were observed between patients with or without vitamin D deficiency (25.2% [34/135] vs 17.5% [14/80]; P = 0.191). However, when high-risk patients according to their donor/recipient CMV serostatus (D+/R−) were excluded (n = 23), we found a trend suggesting a higher incidence of late CMV infection in recipients with vitamin D deficiency (23.1% [27/117] vs 13.3% [10/75]; P = 0.095). It is likely that the comparatively minor role of vitamin D status on the functionality of CMV-specific immunity would only be evident once major risk contributors (such as D+/R− mismatch) have been controlled for. To gain insight into the etiopathogenetic mechanisms linking vitamin D status and susceptibility to CMV infection, we investigated the correlation between 25(OH)D levels and the CMV-specific cell-mediated immunity (CMV-CMI) assessed at month 6 in a subgroup of 76 patients. The CMV-CMI was quantified with the QuantiFERON-CMV (QTF-CMV) assay (Qiagen, Hilden, Germany), which measures the release of interferon (IFN)-γ in response to a pool of epitopes mapped within viral proteins, following manufacturer’s instructions.5 We found a significant positive correlation between serum 25(OH)D levels and the production of IFN-γ (Figure 1A). In addition, 25(OH)D levels also correlated with absolute lymphocyte count at month 6 (Spearman’s rho = 0.358; P = 0.002). We next explored whether the association observed between vitamin D status and CMV-CMI remained in a multivariate analysis adjusted for patient age, CD8+ T-cell count (since the QTF-CMV assay mostly reflects CD8+ functionality), and markers of nutritional status (body mass index and serum albumin levels). Multiple linear stepwise regression analysis confirmed that 25(OH)D levels at month 6 were independently associated with IFN-γ production (β = 0.288; P = 0.021). This correlation was not found for nonpathogen-specific stimulation with phytohemagglutinin. Accordingly, those recipients with vitamin D deficiency at month 6 were significantly less likely to have a protective CMV-CMI response (IFN-γ production ≥ 0.2 IU/mL) (Figure 1B).FIGURE 1.: Impact of vitamin D status on the CMV-CMI quantified with the QuantiFERON-CMV assay at post-transplant month 6 (n = 76). A, Correlation (solid line) with 95% confidence interval (dashed lines) between serum 25(OH)D levels and production of IFNγ (CMV-specific antigen minus nil); the horizontal dotted line represents the cut-off value usually established for defining protective CMV-CMI responses (IFNγ production [CMV-specific antigen minus nil] ≥ 0.2 IU/mL). B, Proportion of patients with protective CMV-CMI response across different categories (deficient, insufficient, sufficient) of vitamin D status as per the Endocrine Society criteria. 25(OH)D, 25-hydroxyvitamin D; CMV-CMI, cytomegalovirus-specific cell-mediated immunity; IFNγ, interferon γ.This experience suggests a potential mechanistic explanation for the deleterious impact exerted by vitamin D deficiency on the risk of late CMV infection found in our cohort and that of Astor et al.1 Currently available evidence does not support vitamin D supplementation for purposes other than bone health. Nevertheless, if our results linking 25(OH) levels and CMV-CMI are validated on independent cohorts, future studies should evaluate the feasibility of such an intervention to eventually minimize the susceptibility to CMV after KT.