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Background: Non-human leukocyte antigen (non-HLA) antibodies including antibodies targeting Angiotensin II type 1 (AT1R) and Endothelin-1 type A (ETAR) receptors represent a topic of interest in kidney transplantation (KTx). This exploratory substudy evaluated the impact of everolimus (EVR) or mycophenolic acid (MPA) in combination with tacrolimus (TAC) or cyclosporine A (CsA) in patients with preformed non-HLA antibodies, potentially associated rejections and/or their impact on renal function over 1 year., Methods: All eligible patients were randomized (1:1:1) before transplantation to receive either EVR/TAC, EVR/CsA, or MPA/TAC regimen. The effect of these regimens on the formation of non-HLA antibodies within one year post de novo KTx and the association with clinical events was evaluated descriptively in randomized ( n  = 268) population., Results: At Month 12, in EVR/TAC group, higher incidence of patients negative for AT1R- and ETAR-antibodies (82.2% and 76.7%, respectively) was noted, whereas the incidence of AT1R- and ETAR-antibodies positivity (28.1% and 34.7%, respectively) was higher in the MPA/TAC group. Non-HLA antibodies had no influence on clinical outcomes in any treatment group and no graft loss or death was reported., Conclusions: The studied combinations of immunosuppressants were safe with no influence on clinical outcomes and suggested minimal exposure of calcineurin inhibitors for better patient management., Clinical Trial Registration: https://clinicaltrials.gov/ (NCT01843348; EudraCT number: 2011-005238-21)., Competing Interests: WA received consulting honoraria from Novartis. IH was in the advisory board of Novartis and received honoraria for lectures from Takeda, Biotest, MSD, CareDx, Novartis, Astellas, Bayer, and Astra Zeneca. FT has received study honoraria from Novartis, Sanofi, Astellas, Alexion, Hexal, Chiesi, and Pfizer. BS received study honoraria and was in the advisory board of Novartis. JH, CS, and AE are employees of Novartis. BN was in the advisory board and received funding from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Philippe, Arns, Ditt, Hauser, Thaiss, Sommerer, Suwelack, Dragun, Hillen, Schiedel, Elsässer and Nashan.)

Background: Studies prospectively monitoring de novo donor-specific antibodies (dnDSAs) and their clinical impact are sparse. This substudy of ATHENA was initiated to evaluate the effect of everolimus (EVR) or mycophenolic acid (MPA) in combination with reduced calcineurin inhibitor (CNI, tacrolimus [TAC] or cyclosporine [CsA]) on the formation of human leukocyte antibodies (HLA), including dnDSA, and the impact on clinical outcomes in kidney transplant (KTx) recipients., Methods: All eligible patients were randomized 1:1:1 to receive either EVR + TAC, EVR + CsA or MPA + TAC, with basiliximab induction plus steroids after transplantation up to Month 12. The incidence of dnDSA by treatment group and the association with clinical events were evaluated descriptively as an exploratory objective in the intent-to-treat (ITT) and per-protocol (PP) populations with at least one antibody assessment., Results: Overall, none of the patients in the EVR + TAC group had either dnDSA or antibody mediated rejection (PP or ITT population) and only one patient with dnDSA in the TAC + MPA group had antibody mediated rejection., Conclusion: The EVR regimen was comparable to MPA regimen with an extremely low incidence of dnDSA over 1 year of treatment., Competing Interests: WA received consulting honoraria from Novartis. IAH was in the advisory board of Novartis and received honoraria for lectures from Takeda, Biotest, MSD, CareDx, Novartis, Astellas, Bayer, and Astra Zeneca. FT has received study honoraria from Novartis, Sanofi, Astellas, Alexion, Hexal, Chiesi, and Pfizer. BS received study honoraria and was in the advisory board of Novartis. JH, CS, and AE are employees of Novartis. BN was in the advisory board and received funding from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Arns, Philippe, Ditt, Hauser, Thaiss, Sommerer, Suwelack, Dragun, Hillen, Schiedel, Elsässer and Nashan.)