Early tacrolimus exposure is associated with BK-viremia in kidney transplant recipients
Soufian Meziyerh1,2, Aline L. van Rijn3, Danny van der Helm2, Teun van Gelder4, Paul J.M. van der Boog1,2, Aloysius C.M. Kroes3, Johan W. de Fijter1,2, Dirk Jan A.R. Moes4, Joris I. Rotmans1,2, Mariet C. Feltkamp3, Aiko P.J. de Vries1,2.
1Dept. of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, Netherlands; 2LUMC Transplant Center, Leiden University Medical Center, Leiden, Netherlands; 3Dept. of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands; 4Dept. of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands
Introduction: There is scant evidence to what extent maintenance immunosuppression is quantitatively associated with BK viremia. We investigated the association between tacrolimus (tac) whole blood exposure and mycophenolic acid (mpa) plasma exposure with consecutive BK viremia within the first year posttransplant.
Methods: For this retrospective cohort study, 713 kidney transplant recipients (KTRs) transplanted at our center between 2013-2018 and treated with Tac, mpa and prednisolone, were selected from the local database. Both trough levels (C0) and area-under-the-curve (AUC) measurements of tac and BK viral loads were determined according to local protocol. Exposure measurements were carried backwards to assess exposure on landmarks: month 1.5, 3 and 6. Patients with no measurements of tac or mpa exposure within the first year due to switches were excluded, leaving 508 patients for analysis. Incidence and time to BK viremia (with load > limit of detection (LOD) and load > log 4) in the first year posttransplant were outcomes of interest. Hazard ratios (HR) of exposure to tac and mpa were assessed and adjusted for confounders such as donor and recipient age and gender, number of human leukocyte antigen (HLA) mismatch, days on dialysis, induction therapy, and living or deceased donation.
Results: In total, 83 out of 508 (16%) KTRs developed a BK viremia (>LOD) in their first year post-transplant. Tac exposure (both C0 and AUC) on day 45 was significantly associated with subsequent development of BK viremia (load > LOD & load >log 4) with respectively unadjusted and adjusted HRs of 1.08 (95% CI: 1.02-1.14) and 1.08 (95% CI: 1.01-1.15) for 1 μg/L increase in C0 and 20 μg*h/L increase in AUC0-12h. Exposure of tac on day 90 or 120 was not associated with incident BK viremia. No association between exposure to mpa and BK-viremia was identified. Moreover, HR for tac remained unchanged if adjusted for mpa exposure and other transplant characteristics.
Conclusion: In our population, tac exposure on month 1.5 seems associated with incident BK viremia in a concentration-dependent manner. This was not found for mpa. The explanation for this finding could be that tacrolimus is a more potent suppressor of Th-lymphocytes which play a vital role in boosting viral immunity and memory. To the best of our knowledge, this is the first time that exposure to immunosuppressive drugs has been quantitatively associated with BK viremia. Future research is warranted to investigate causative and predictive impact of tac exposure on BK-incidence, which may aid physicians balance between toxicity and efficacy within the first year of transplantation.
