Impact of Everolimus Plus Calcineurin Inhibitor on Formation of Non-HLA Antibodies and Graft Outcomes in Kidney Transplant Recipients: 12-month Results from the ATHENA Substudy

Overview

Journal Front Transplant

Specialty General Surgery

Date 2024 Jul 12

PMID 38993854

Authors

Aurelie Philippe

Wolfgang Arns

Vanessa Ditt

Ingeborg A Hauser

Friedrich Thaiss

Claudia Sommerer

Barbara Suwelack

Duska Dragun

Jan Hillen

Christiane Schiedel

Anja Elsasser

Bjorn Nashan

Affiliations

Soon will be listed here.

Abstract

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 KTx and the association with clinical events was evaluated descriptively in randomized ( = 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).

Citing Articles

The Influence of Anti-ETAR and Anti-CXCR3 Antibody Levels on the Course of Specific Glomerulonephritis Types.

Szymczak M, Heidecke H, Zabinska M, Janek L, Wronowicz J, Kujawa K J Clin Med. 2025; 13(24.

PMID: 39768675 PMC: 11679591. DOI: 10.3390/jcm13247752.

References

Cibrik D, Tedesco Silva Jr H, Vathsala A, Lackova E, Cornu-Artis C, Walker R . Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation. 2013; 95(7):933-42. DOI: 10.1097/TP.0b013e3182848e03. View

Catar R, Wischnewski O, Chen L, Heidecke H, Rutz C, Schulein R . Non-HLA antibodies targeting angiotensin II Type 1 receptor and endothelin-1 Type A receptors induce endothelial injury via β2-arrestin link to mTOR pathway. Kidney Int. 2021; 101(3):498-509. DOI: 10.1016/j.kint.2021.09.029. View

Sorohan B, Ismail G, Berechet A, Obrisca B, Constantinescu I, Maruntelu I . The early impact of preformed angiotensin II type 1 receptor antibodies on graft function in a low immunological risk cohort of kidney transplant recipients. Transpl Immunol. 2021; 66:101389. DOI: 10.1016/j.trim.2021.101389. View

Pearl M, Chen L, ElChaki R, Elashoff D, Gjertson D, Rossetti M . Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation. Kidney Int Rep. 2020; 5(11):1925-1936. PMC: 7609952. DOI: 10.1016/j.ekir.2020.09.004. View

Banasik M, Boratynska M, Koscielska-Kasprzak K, Kaminska D, Bartoszek D, Zabinska M . The influence of non-HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes. Transpl Int. 2014; 27(10):1029-38. DOI: 10.1111/tri.12371. View

Wiwattanathum P, Ingsathit A, Thammanichanond D, Worawichawong S . Successful Treatment of Anti-angiotensin II Type 1 Receptor Antibody-Associated Rejection in Kidney Transplantation: A Case Report. Transplant Proc. 2018; 50(3):877-880. DOI: 10.1016/j.transproceed.2017.11.027. View

Dragun D, Muller D, Brasen J, Fritsche L, Nieminen-Kelha M, Dechend R . Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med. 2005; 352(6):558-69. DOI: 10.1056/NEJMoa035717. View

Hurvitz S, Andre F, Jiang Z, Shao Z, Mano M, Neciosup S . Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015; 16(7):816-29. DOI: 10.1016/S1470-2045(15)00051-0. View

Mao Q, Terasaki P, Cai J, Briley K, Catrou P, Haisch C . Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007; 7(4):864-71. DOI: 10.1111/j.1600-6143.2006.01711.x. View

10.

Hauser I, Marx S, Sommerer C, Suwelack B, Dragun D, Witzke O . Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results. Eur J Immunol. 2020; 51(4):943-955. DOI: 10.1002/eji.202048855. View

11.

Nashan B, Gaston R, Emery V, Saemann M, Mueller N, Couzi L . Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation. 2012; 93(11):1075-85. DOI: 10.1097/TP.0b013e31824810e6. View

12.

Bussalino E, Marsano L, Parodi A, Russo R, Massarino F, Ravera M . Everolimus for BKV nephropathy in kidney transplant recipients: a prospective, controlled study. J Nephrol. 2020; 34(2):531-538. DOI: 10.1007/s40620-020-00777-2. View

13.

Tedesco-Silva H, Pascual J, Viklicky O, Basic-Jukic N, Cassuto E, Kim D . Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study. Transplantation. 2019; 103(9):1953-1963. DOI: 10.1097/TP.0000000000002626. View

14.

Butler C, Hickey M, Jiang N, Zheng Y, Gjertson D, Zhang Q . Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside. Am J Transplant. 2020; 20(10):2768-2780. PMC: 7494540. DOI: 10.1111/ajt.15863. View

15.

Lee J, Huh K, Park Y, Park B, Yang J, Jeong J . The clinicopathological relevance of pretransplant anti-angiotensin II type 1 receptor antibodies in renal transplantation. Nephrol Dial Transplant. 2015; 32(7):1244-1250. DOI: 10.1093/ndt/gfv375. View

16.

Netti G, Infante B, Troise D, Mercuri S, Panico M, Spadaccino F . mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients. Am J Transplant. 2022; 22(5):1475-1482. PMC: 9303518. DOI: 10.1111/ajt.16958. View

17.

Mallat S, Tanios B, Itani H, Lotfi T, McMullan C, Gabardi S . CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. Clin J Am Soc Nephrol. 2017; 12(8):1321-1336. PMC: 5544521. DOI: 10.2215/CJN.13221216. View

18.

Kardol-Hoefnagel T, Otten H . A Comprehensive Overview of the Clinical Relevance and Treatment Options for Antibody-mediated Rejection Associated With Non-HLA Antibodies. Transplantation. 2020; 105(7):1459-1470. PMC: 8221725. DOI: 10.1097/TP.0000000000003551. View

19.

Sorohan B, Sinescu I, Tacu D, Bucsa C, Tincu C, Obrisca B . Immunosuppression as a Risk Factor for De Novo Angiotensin II Type Receptor Antibodies Development after Kidney Transplantation. J Clin Med. 2021; 10(22). PMC: 8625545. DOI: 10.3390/jcm10225390. View

20.

Avila C, Zimmerer J, Elzein S, Pham T, Abdel-Rasoul M, Bumgardner G . mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells. Transplantation. 2016; 100(9):1898-906. PMC: 4992451. DOI: 10.1097/TP.0000000000001291. View