Steering of immunosuppression by virus-specific T cells after pediatric kidney transplantation in the randomized controlled IVIST trial
Thurid Ahlenstiel-Grunow1, Xiaofei Liu2, Raphael Schild3, Jun Oh3, Christina Taylan4, Lutz T. Weber4, Hagen Staude5, Anika Großhennig2, Lars Pape1.
1Pediatrics II, University Hospital of Essen, Essen, Germany; 2Institute of Biostatistics, Hannover Medical School, Hannover, Germany; 3Department of Pediatric Nephrology, University Hospital of Eppendorf, Hamburg, Germany; 4Pediatric Nephrology, University Hospital of Cologne, Cologne, Germany; 5Pediatric Nephrology, University Hospital of Rostock, ROstock, Germany
Objectives: Pharmacokinetic monitoring alone is insufficient to estimate the intensity of immunosuppression after kidney transplantation. Levels of virus-specific CD4 T cells(CD4Tvis) have been shown to identify overimmunosuppression. The IVIST trial has demonstrated that additional steering of immunosuppressive therapy by CD4Tvis levels is safe and reduces exposure to immunosuppressants with significantly lower trough levels but without increasing the risk of acute rejections.
Methods: In the multicenter, randomized controlled IVIST trial, 64 pediatric kidney recipients were randomized 1:1 to a control group with trough level monitoring of immunosuppressants or to an intervention group with additional steering by CD4Tvis levels against adenovirus(ADV), cytomegalovirus(CMV) and herpes simplex virus(HSV). The immunosuppression consisted of cyclosporine A, everolimus and glucocorticoids. CD4Tvis were quantified by cytokine flow cytometry in 20 visits during the two-year study period. In the intervention group we have analyzed the CD4Tvis levels and the number of Tvis-based dose adjustments of immmunosuppressants.
Results: At time of transplantation, ADV-CD4Tvis were detectable in 30/31 patients from the intervention group, CMV-CD4Tvis and HSV-CD4Tvis only in 12/31. No significant ADV- or HSV-DNAemia was found; only two patients showed transient CMV-DNAemia based on CMV-reactivation. Five primary CMV-infections with seroconversion and boost of CMV-CD4Tvis were observed without significant CMV-DNAemia. The mean level of ADV-CD4Tvis was 1.63(SD1.25), 2.03(SD1.8), 2.18(SD2.51) and 1.97 cells/µl(SD1.34) 1,6,12 and 24 months after transplantation. In case of CD4Tvis <2cells/µl 125 dose reductions of immunosuppressants (96% based on ADV-CD4Tvis) were performed in 28/31 children with a median of 4 Tvis-based dose reductions (range 0-10) per patient. 48% of the Tvis-based dose reductions were carried out in the first six months, 36.8% between month 7 and 12 and 15.2% in the second year after transplantation.
Conclusions: Under the intensified immunosuppression during the initial post-transplant period low ADV-CD4Tvis levels were observed with subsequent increase after dose reduction of the immunosuppressive therapy. ADV-CD4Tvis are most suitable for immune monitoring because of their high prevalence (even in children) and stability combined with absence of ADV-DNAemia. Routine monitoring of ADV-CD4Tvis is recommendable especially in the first post-transplant year to prematurely identify overimmunosuppression.