Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

Abstract

Background 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 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. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Patterns in Tacrolimus Variability and Association with De Novo Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients

“…We noted that tacrolimus intrapatient variability was initially high for all ages and stabilized at approximately 10 months post-transplant. Similar to previous studies, high tacrolimus intrapatient variability was associated with de novo DSA formation in our cohort (20,27,28). We observed that patients who formed de novo DSAs had patterns of higher intrapatient variability in the first 2 years after transplantation and rising tacrolimus variability even in the years prior to DSA detection compared with nonformers.…”

“…Studies in adults strongly suggest that highly variable tacrolimus levels are associated with poor longterm outcomes in kidney transplant recipients (12)(13)(14)(15)(16). Several studies in pediatric patients with kidney transplants have also reported this association between high intrapatient variability and poor graft outcomes (8,(17)(18)(19)(20). However, baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants have not been well described in the literature.…”

Kidney transplant from HCV viremic donors to HCV‐negative recipients and risk for de novo donor specific antibodies and acute rejection

“…Sofosbuvir based therapies could also have an interaction with Tacrolimus. Intra‐patient variation in tacrolimus trough levels have been associated with increased risk for rejection and development of de novo DSA 40–42 . Theoretically, it is possible that recipients of HCV NAT+ organs were more prone to intra‐patient variability in tacrolimus trough level due to such drug interaction which might have contributed to the higher incidence of de novo DSA.…”

DSA in solid organ transplantation: is it a matter of specificity, amount, or functional characteristics?

“…In addition, nonadherence, although difficult to quantify and measure, was proposed to be identified by calcineurin inhibitor (CNI) intra-patient variability. Nonadherence and especially tacrolimus trough levels <5ng/ml were found to be strongly associated with subsequent development of de-novo HLA-DSAs [56,57 ▪▪ ]. In addition, among patients with suboptimal CNI levels, a high HLA epitope mismatch score was helpful to identify patients with higher risk of de-novo HLA-DSA development [58 ▪▪ ].…”