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Low 25-hydroxyvitamin D Levels and the Risk of Late CMV Infection After Kidney Transplantation

Role for CMV-specific Mediated Immunity

Fernández-Ruiz, Mario MD, PhD1; Rodríguez-Goncer, Isabel MD1; Ruiz-Merlo, Tamara RN1; Parra, Patricia HND1; López-Medrano, Francisco MD, PhD1; Andrés, Amado MD, PhD2; Aguado, José María MD, PhD1

doi: 10.1097/TP.0000000000002770

1 Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Hospital “12 de Octubre” (imas12), School of Medicine, Universidad Complutense, Madrid, Spain.

2 Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Hospital “12 de Octubre” (imas12), School of Medicine, Universidad Complutense, Madrid, Spain.

Received 25 March 2019. Revision received 4 April 2019.

Accepted 5 April 2019.

This work was supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III (Proyecto Integrado de Excelencia [PIE] 13/00045) and the Fundación Mutua Madrileña de Investigación Médica (FMM Grant 2014/0092). M.F.-R. is the recipient of a “Miguel Servet” research contract (CP 18/00073) from the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III.

The authors declare no conflicts of interest.

M.F.-R. and J.M.A. designed the original research. M.F.-R., I.R.-G., T.R.-M., P.P., F.L.-M., and A.A. performed the research. M.F.-R. wrote the letter. A.A. and J.M.A. critically reviewed and completed the final draft of the article.

Correspondence: Mario Fernández-Ruiz, MD, PhD, Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Centro de Actividades Ambulatorias, 2ª planta, bloque D. Avda. de Córdoba, s/n. 28041, Madrid, Spain. (

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).



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.

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1. Astor BC, Djamali A, Mandelbrot DA, et al. The association of 25-hydroxyvitamin D levels with late cytomegalovirus infection in kidney transplant recipients: the Wisconsin Allograft Recipient Database (WisARD). Transplantation. 2019. doi:10.1097/TP.0000000000002672.
2. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930.
3. Ross AC, Taylor CL, Yaktine AL, et al. Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. 2011.Washington, DC: The National Academies Press.
4. Fernández-Ruiz M, Corbella L, Morales-Cartagena A, et al. Vitamin D deficiency and infection risk in kidney transplant recipients: a single-center cohort study. Transpl Infect Dis. 2018;20:e12988.
5. Giulieri S, Manuel O. Quantiferon®-CMV assay for the assessment of cytomegalovirus cell-mediated immunity. Expert Rev Mol Diagn. 2011;11:17–25.
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