Introduction
Kidney transplantation (KTx) is the preferred treatment for children with stage 5 chronic kidney disease. Potent immunosuppressants such as tacrolimus (Tac), a calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF), as well as anti-infective prophylaxis, have significantly improved short-term transplant outcomes. Long-term graft survival is, however, limited. While CNI-induced nephrotoxicity was previously thought to be the most common cause of late graft function deterioration, new evidence suggests that the causes are multifactorial and complex. Alloantigen-dependent factors, particularly de novo donor-specific antibodies (dnDSA) directed against human leukocyte antigens (HLA), play an important role in this context. Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk.
Methods
This was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on the coefficient of variation (CV%) 6–12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes.
Results
In total, 566 Tac levels were measured with median 11.0 (6.0–17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18–35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0–11.1, P = 0.047; Kaplan–Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1–14.8, P = 0.033; Kaplan–Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results.
Conclusions
High TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered.
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