The Importance of Cytomegalovirus Re- Infection Following Renal Transplantation

Abstract

Introduction: Despite improvements in antiviral regimens, cytomegalovirus (CMV) reactivation and disease remains a significant complication in solid organ transplantation. In a study by Kliem (AJT 2008) increased CMV infection was demonstrated in the D+/R+ group (indicating super-infection) compared with the D-/R+ group. However, there was limited data on clinical disease. The purpose of our study was to: Assess risk of clinical CMV in the different serotype combinations D-/R+, D+/R+, D+/R-) in renal transplant recipients Compare CMV-specific cell mediated immune response in the D-/R+ and D+/R+ groups Evaluate the prognostic utility of cell mediated immunity assays in the above two groups Methods: In an audit of 569 patients transplanted at University Hospital Birmingham between 01/08/2007-30/06/2011 the incidence of CMV viraemia, syndrome and disease was evaluated. In a separate prospective study of 85 patients' serial assessment of CMV viral load, CD4 and CD8 T cell immune responses to CMV were performed. All patients received standard immunosuppression of basiliximab induction with maintenance tacrolimus, mycophenolate mofetil and corticosteroids. Results: Audit results revealed an increased incidence of CMV disease in the D+/R+ group (n=178) compared to D-/R+ group (n=121), suggesting super-infection with CMV increases risk of clinical disease. In recipients of kidneys from seropositive donors, we could not demonstrate the development of a cell mediated immune response to CMV presented in the context of donor HLA class I, when assessed using CMV peptides bound to major histocompatibility complex-tetramers. However, a CMV immune response in the context of recipient HLA was found in 60% of seropositive recipients and also developed in one seronegative recipient of a seropositive kidney. Baseline cell mediated immunity to CMV was moderately predictive for subsequent CMV disease, with area under the ROC curve of 0.6-0.7 depending on the assay used (either CMV lysate or peptide pools). In the D-/R+ group, the CD8 response was more predictive than the CD4 response with the reverse in the D+/R+ group. Higher percentages of CMV specific T cells were required in the D+/R+ group to protect against CMV compared to the D-/R+ group. Discussion: CMV super-infection is clinically relevant. The donor organ may act as an “immune privileged” reservoir for CMV latency. There is a difference in the strength and nature of the cell mediated immune response to control CMV in the D+/R+ group compared with the D-/R+ group in renal transplantation.