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CMV-specific Cell-mediated Immunity at 3-month Prophylaxis Withdrawal Discriminates D+/R+ Kidney Transplants at Risk of Late-onset CMV Infection Regardless the Type of Induction Therapy

Jarque, Marta, MS1; Melilli, Edoardo, MD, PhD2; Crespo, Elena, PhD1; Manonelles, Anna, MD2; Montero, Nuria, MD2; Torras, Joan, MD, PhD1,2; Cruzado, Josep M., MD, PhD1,2; Luque, Sergi, MS1; Gil-Vernet, Salvador, MD2; Grinyó, Josep M., MD, PhD1,2; Bestard, Oriol, MD, PhD1,2

doi: 10.1097/TP.0000000000002421
Original Clinical Science—General

Background Whether cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) at prophylaxis cessation predicts D+/R+ kidney transplants at risk of late-onset CMV infection after receiving distinct induction therapies is still not well characterized.

Methods We prospectively assessed CMV-specific CMI predicting late-onset CMV infection at prophylaxis withdrawal and at earlier time-points, in 96 consecutive D+/R+ patients receiving either anti-interleukin 2-receptor antibody (anti-IL2RA; n = 50) or rabbit antithymoglobulin (n = 46). CMV-specific CMI was evaluated against CMV antigens (IE-1, pp65) using an IFN-γ ELISpot assay.

Results Fourteen (14.6%) of 96 patients developed late-onset CMV infection and 2 (2.1%) of 96 displayed disease. At 3 months, CMV-specific CMI frequencies were significantly lower in patients developing late-onset CMV infection (P < 0.001 for IE-1, P = 0.030 for pp65), regardless the type of induction therapy. Receiver operating characteristic curve analyses showed accurate CMV-specific CMI cutoffs (25 and 130 IFN-γ spots for IE-1 and pp65, respectively) classifying patients into high risk, intermediate risk, or low risk (log-rank = 0.006; hazard ratio, 4.084; 95% confidence interval, 1.431-11.651; P = 0.009), being IE-1 CMI the strongest predictor (odds ratio, 5.554; 95% confidence interval, 1.486-20.766; P = 0.011). Although the profound posttransplant CMV-specific CMI inhibition among rabbit antithymocyte globulin–treated patients precludes its use for risk stratification both before and early after kidney transplant, a similar proportion of at-risk patients could be identified before month 3 within anti-interleukin 2-receptor antibody–treated patients.

Conclusions Monitoring CMV-specific CMI at 3-month prophylaxis cessation discriminates kidney transplant recipient at risk of late-onset CMV infection, regardless the type of induction therapy.

Cytomegalovirus (CMV)-specific cell-mediated immunity to predict late onset CMV after 3 months of prophylaxis maybe useful in those who receive anti-IL2RA but not rATG induction because the inhibition is more profound with rATG decreasing discriminatory power.

1 Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain.

2 Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.

Received 27 May 2018. Revision received 11 July 2018.

Accepted 21 July 2018.

The authors of this article declare no conflicts of interest.

This work was partially supported by 3 Spanish public grant “Instituto de Salud Carlos III” [FIS PI13/01263; ICI14/00242; PI16/01321] and 2 European Commission grants from the Biomarker-Driven Immunosuppression Minimization (BIODRIM) Consortium [FP7/2007-2013] and the Horizon 2020 EU research and innovation program (EU-TRAIN) [18CEE002]. O.B. was awarded with an intensification grant from the “Instituto de Salud Carlos III” [INT15/00112].

M.J. participated in the research design, performance of the experiments, analysis and interpretation of data, and in the writing of the paper, approving the final version of the article. E.M. participated in the analysis and interpretation of the data and in the final approval of the version to be published. E.C. participated in the research design, performance of the experiments, analysis and interpretation of data, and in the writing of the article, approving the final version of the article. A.M. participated in the analysis and interpretation of the data and in the final approval of the version to be published. N.M. participated in the analysis and interpretation of the data and in the final approval of the version to be published. J.T. participated in the analysis and interpretation of the data and in the final approval of the version to be published. J.M.C. participated in the analysis and interpretation of the data and in the final approval of the version to be published. S.L. participated in the performance of the experiments, analysis of the data, writing of the article and in the final approval of the version to be published. S.G.-V. participated in the analysis and interpretation of the data and in the final approval of the version to be published. J.M.G. participated in the conception and design of the work and in the writing of the article, revising it critically for intellectual content, approving the final version of the article. O.B. participated in the conception and design of the work, analysis and interpretation of data and in the writing of the article, revising it critically for intellectual content, approving the final version of the article.

Correspondence: Oriol Bestard, MD, PhD, Renal Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, IDIBELL, Barcelona, Spain. (obestard@bellvitgehospital.cat).

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