*Purpose: Pharmakokinetic monitoring of immunosuppressants alone is insufficient to estimate the individual intensity of immunosuppression after kidney transplantation (Tx). Virus-specific T cells (Tvis) correlate with virus-specific as well as with general cellular immune defense. Additional steering by Tvis level may optimize dosing of immunosuppressants (effect-related drug monitoring).

*Methods: In an investigator-initiated, multicenter, prospective trial, 64 pediatric kidney recipients (mean age 10.8 ± 4.2 yrs; ♂ 57.8%) were randomized 4 weeks after Tx either to a non-intervention group (n=33) with classical trough level monitoring of immunosuppressants or to an intervention group (n=31) with additional steering by Tvis levels. Tvis against cytomegalovirus, adenovirus and herpes simplex virus were quantified by intracellular cytokine staining followed by flow cytometry. Both groups received the same immunosuppressive regimen consisting of cyclosporine A (CsA) and everolimus (Eve) with the same target range of trough levels. The primary endpoint was the estimated glomerular filtration rate (eGFR) two years after Tx.

*Results: Two years after Tx, we observed an increase of eGFR from 55.0 ± 17.5 (baseline) to 60.7 ± 22.8 mL/min/1.73 m² in the intervention group and no substantial difference in the control group (from 61.5 ± 21.3 to 59.6 ± 22.3 mL/min/1.73 m²). The respective mean difference (intervention-control) was 7.52 ± 27.61 mL/min/1.73 m². As the variability of eGFR was larger than assumed, this difference was not statistically significant. We additionally observed several benefits on secondary endpoints for patients in the intervention group. They received lower daily doses of Eve (0.8 ± 0.3 vs. 1.2 ± 0.5 mg/m², t-test p=0.004) and CsA (78.4 ± 20.0 vs. 88.4 ± 26.5 mg/m², t-test p=0.13) resulting in lower trough levels of Eve (3.5 ± 0.7 vs. 4.5 ± 0.8 µg/L, t-test p <0.0001) and CsA (47.4 ± 9.9 vs. 64.1 ± 11.1 µg/L, t-test p<0.0001). Fewer patients in the intervention group received glucocorticoids (20% vs. 47%, χ²-test p=0.038) two years after Tx. Patients in the non-intervention group had a higher risk for rejections (logrank p=0.0786) and EBV viremia (logrank p=0.0896). Donor-specific antibodies were detected in 8 patients of the intervention and 9 of the control group. Numbers of adverse and serious adverse events were comparable.

*Conclusions: Additional steering of immunosuppressive therapy by Tvis levels is safe and personalizes immunosuppressive therapy by reducing exposure to immunosuppressants, resulting in stabilization of eGFR and reduced risk for rejection and EBV viremia.

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