Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development

Abstract

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II donor-specific antibody (DSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before DSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor ofDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of DSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before DSA development were significantly lower than the levels>6 months before DSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developingDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of DSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels<5 ng/ml unless essential, and monitoring for DSA may be advisable in this setting.

Which is the best predictor of de novo donor‐specific antibodies in a cohort of non‐sensitized first kidney transplantation: Antigenic, allelic, epitope, or physiochemical HLA mismatches?

“…Ideally, as recently described by Wiebe et al, 29 our capacity to predict the appearance of anti-HLA antibodies could allow adapting immunosuppressive treatments to each immunological risk and to minimize the risks of infections and neoplasia related to unnecessary over-immunosuppression. In this cohort of non-sensitized first graft recipients, we did not observe any single approach (antigenic, allelic, epitope, amino acid, or physicochemical disparities) to be more predictive than another.…”

Impact of donor‐related arteriosclerosis in pretransplant biopsy on long‐term outcome of living‐kidney transplantation: A propensity score‐matched cohort study

“…Recently, de novo DSA development was reported to be correlated with tacrolimus trough levels. 26,27 Kidneys with AS might be prone to showing CNI nephrotoxicity, even under the same tacrolimus concentration. When kidney grafts with AS show CNI nephrotoxicity in the early periods after kidney transplantation, careful reduction of CNI dose might be required to avoid the production of de novo DSA and chronic ABMR.…”

B cells in transplant tolerance and rejection: friends or foes?

“…The development of post‐transplant de novo DSA can occur in the absence of pretransplant HLA sensitization and has been shown to impact long‐term allograft survival. DSA that arises post‐transplant is primarily directed toward donor HLA class II mismatches and occurs in the setting of inadequate immunosuppression and/or increased HLA class II mismatching . The incidence of de novo DSA depends upon allograft type ranging from 12% in primary kidney transplants with a median time to development of 4 years and up to 30% in lung recipients within the first year post‐transplant .…”