BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

bioMérieux SA Centre Christophe Merieux Grenoble France

Center for Medical Statistics Informatics and Intelligent Systems Medical University of Vienna Vienna Austria

Charité Universitätsmedizin Berlin Berlin Germany

Clinical Trials Coordination Centre Medical University of Vienna Vienna Austria

Coordination Center for Clinical Trials Faculty of Medicine Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Clinical Pharmacology Medical University of Vienna Vienna Austria

Department of Emergency Medicine Medical University of Vienna Vienna Austria

Department of Internal Medicine 4 Nephrology and Hypertension Medical University Innsbruck Innsbruck Austria

Department of Internal Medicine Leiden University Medical Center Leiden The Netherlands

Department of Nephrology Hemodialysis Apheresis and Kidney Transplantation CHU Grenoble Alpes Grenoble France

Department of Nephrology University Hospital Regensburg Regensburg Germany

Department of Philosophy 1 FiloLab UGR University of Granada Granada Spain

Division of Infectious diseases and Tropical Medicine Department of Medicine 1 Medical University of Vienna Vienna Austria

Division of Nephrology and Dialysis Department of Medicine 3 Medical University of Vienna Vienna Austria

Division of Nephrology Department of Internal Medicine Medical University of Graz Graz Austria

Division of Nephrology Department of Internal Medicine University Medical Center Groningen University of Groningen Groningen The Netherlands

Institute for Advanced Social Studies Spanish National Research Council Madrid Spain

Laboratory of Virology National Institute for Infectious Diseases L Spallanzani Rome Italy

North Western Tuscany Blood Bank Pisa Italy

Ordensklinikum Linz GmbH Elisabethinen Linz Austria

Transplant Center Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czech Republic

Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden Dresden Germany

Zobrazit více v PubMed

Abramowicz D, Oberbauer R, Heemann U, Viklicky O, Peruzzi L, Mariat C, et al. Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board. Nephrol Dial Transplant. 2018;33(10):1699–1707. doi: 10.1093/ndt/gfx365. PubMed DOI PMC

Brunet M, van Gelder T, Asberg A, Haufroid V, Hesselink DA, Langman L, et al. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit. 2019;41(3):261–307. doi: 10.1097/FTD.0000000000000640. PubMed DOI

Bouamar R, Shuker N, Hesselink DA, Weimar W, Ekberg H, Kaplan B, et al. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials(dagger) Am J Transplant. 2013;13(5):1253–1261. doi: 10.1111/ajt.12191. PubMed DOI

Naesens M, Anglicheau D. Precision transplant medicine: biomarkers to the rescue. J Am Soc Nephrol. 2018;29(1):24–34. doi: 10.1681/ASN.2017010004. PubMed DOI PMC

Anglicheau D, Naesens M, Essig M, Gwinner W, Marquet P. Establishing biomarkers in transplant medicine: a critical review of current approaches. Transplantation. 2016;100(10):2024–2038. doi: 10.1097/TP.0000000000001321. PubMed DOI

Cippa PE, Schiesser M, Ekberg H, van Gelder T, Mueller NJ, Cao CA, et al. Risk stratification for rejection and infection after kidney transplantation. Clin J Am Soc Nephrol. 2015;10(12):2213–2220. doi: 10.2215/CJN.01790215. PubMed DOI PMC

Mian M, Natori Y, Ferreira V, Selzner N, Husain S, Singer L, et al. Evaluation of a novel global immunity assay to predict infection in organ transplant recipients. Clin Infect Dis. 2018;66(9):1392–1397. doi: 10.1093/cid/cix1008. PubMed DOI

Ravaioli M, Neri F, Lazzarotto T, Bertuzzo VR, Di Gioia P, Stacchini G, et al. Immunosuppression modifications based on an immune response assay: results of a randomized, controlled trial. Transplantation. 2015;99(8):1625–1632. doi: 10.1097/TP.0000000000000650. PubMed DOI

Ahlenstiel-Grunow T, Liu X, Schild R, Oh J, Taylan C, Weber LT, et al. Steering transplant immunosuppression by measuring virus-specific T cell levels: the randomized, controlled IVIST trial. J Am Soc Nephrol. 2021;32(2):502–516. doi: 10.1681/ASN.2020050645. PubMed DOI PMC

Jaksch P, Gorzer I, Puchhammer-Stockl E, Bond G. Integrated immunologic monitoring in solid organ transplantation: the road towards torque teno virus-guided immunosuppression. Transplantation. 2022;20(8):2081–2090. PubMed PMC

De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013;155(5):1178–1187. doi: 10.1016/j.cell.2013.10.034. PubMed DOI PMC

Macera L, Spezia PG, Medici C, Rofi E, Del Re M, Focosi D, et al. Comparative evaluation of molecular methods for the quantitative measure of torquetenovirus viremia, the new surrogate marker of immune competence. J Med Virol. 2022;94(2):491–498. doi: 10.1002/jmv.25488. PubMed DOI

Schiemann M, Puchhammer-Stockl E, Eskandary F, Kohlbeck P, Rasoul-Rockenschaub S, Heilos A, et al. Torque teno virus load-inverse association with antibody-mediated rejection after kidney transplantation. Transplantation. 2017;101(2):360–367. doi: 10.1097/TP.0000000000001455. PubMed DOI PMC

Doberer K, Schiemann M, Strassl R, Haupenthal F, Dermuth F, Gorzer I, et al. Torque teno virus for risk stratification of graft rejection and infection in kidney transplant recipients-a prospective observational trial. Am J Transplant. 2020. PubMed PMC

Fernandez-Ruiz M, Albert E, Gimenez E, Ruiz-Merlo T, Parra P, Lopez-Medrano F, et al. Monitoring of alphatorquevirus DNA levels for the prediction of immunosuppression-related complications after kidney transplantation. Am J Transplant. 2019;19(4):1139–1149. doi: 10.1111/ajt.15145. PubMed DOI

Strassl R, Doberer K, Rasoul-Rockenschaub S, Herkner H, Gorzer I, Klager JP, et al. Torque teno virus for risk stratification of acute biopsy-proven alloreactivity in kidney transplant recipients. J Infect Diseases. 2019;219(12):1934–1939. doi: 10.1093/infdis/jiz039. PubMed DOI PMC

Solis M, Velay A, Gantner P, Bausson J, Filipputtu A, Freitag R, et al. Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation. J Infect. 2019;79(1):56–60. doi: 10.1016/j.jinf.2019.05.010. PubMed DOI

van Rijn AL, Wunderink HF, Sidorov IA, de Brouwer CS, Kroes AC, Putter H, et al. Torque teno virus loads after kidney transplantation predict allograft rejection but not viral infection. J Clin Virol. 2021;140:104871. doi: 10.1016/j.jcv.2021.104871. PubMed DOI

Doberer K, Haupenthal F, Nackenhorst M, Bauernfeind F, Dermuth F, Eigenschink M, et al. Torque teno virus load is associated with subclinical alloreactivity in kidney transplant recipients: a prospective observational trial. Transplantation. 2021;105(9):2112–2118. doi: 10.1097/TP.0000000000003619. PubMed DOI PMC

Gore EJ, Gomes-Neto AW, Wang L, Bakker SJL, Niesters HGM, de Joode AAE, et al. Torquetenovirus serum load and long-term outcomes in renal transplant recipients. J Clin Med. 2020;9(2):440. doi: 10.3390/jcm9020440. PubMed DOI PMC

Handala L, Descamps V, Morel V, Castelain S, Francois C, Duverlie G, et al. No correlation between torque teno virus viral load and BK virus replication after kidney transplantation. J Clin Virol. 2019;116:4–6. doi: 10.1016/j.jcv.2019.03.018. PubMed DOI

Fernandez-Ruiz M, Albert E, Gimenez E, Rodriguez-Goncer I, Andres A, Navarro D, et al. Early kinetics of torque teno virus DNA load and BK polyomavirus viremia after kidney transplantation. Transplant Infect Disease. 2020;22(2):e13240. doi: 10.1111/tid.13240. PubMed DOI

Maggi F, Focosi D, Statzu M, Bianco G, Costa C, Macera L, et al. Early post-transplant torquetenovirus viremia predicts cytomegalovirus reactivations in solid organ transplant recipients. Scientific Rep. 2018;8(1):15490. doi: 10.1038/s41598-018-33909-7. PubMed DOI PMC

Strassl R, Schiemann M, Doberer K, Gorzer I, Puchhammer-Stockl E, Eskandary F, et al. Quantification of torque teno virus viremia as a prospective biomarker for infectious disease in kidney allograft recipients. J Infect Dis. 2018;218(8):1191–1199. doi: 10.1093/infdis/jiy306. PubMed DOI PMC

Uhl P, Heilos A, Bond G, Meyer E, Bohm M, Puchhammer-Stockl E, et al. Torque teno viral load reflects immunosuppression in paediatric kidney-transplanted patients-a pilot study. Pediatr Nephrol. 2021;36(1):153–162. doi: 10.1007/s00467-020-04606-3. PubMed DOI PMC

Görzer I, Haupenthal F, Maggi F, Gelas F, Kulifaj D, Brossault J, et al. Validation of plasma torque teno viral load applying a CE-certified PCR for risk stratification of rejection and infection post kidney transplantation. J Clin Virol. 2022;158:105348. doi: 10.1016/j.jcv.2022.105348. PubMed DOI

Focosi D, Macera L, Boggi U, Nelli LC, Maggi F. Short-term kinetics of torque teno virus viraemia after induction immunosuppression confirm T lymphocytes as the main replication-competent cells. J Gen Virol. 2015;96(Pt 1):115–117. doi: 10.1099/vir.0.070094-0. PubMed DOI

Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–2575. doi: 10.1056/NEJMoa067411. PubMed DOI

Kulifaj D, Niesters H, McCulloch E, Goerzer I, Bourgeois P, Barranger C, et al. Implementation of TTV R-GENE® to quantify torque tenovirus load in a randomized controlled trial assessing the value of TTV-guided immunosuppression post kidney transplantation. [poster presentation at the 24th congress of the European Society of Clinical Virology in Manchester]. In press 2022.