Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial

Dominic Stringer; Leanne Gardner; Olivia Shaw; Brendan Clarke; David Briggs; Judith Worthington; Matthew Buckland; Guilherme Danzi; Rachel Hilton; Michael Picton; Raj Thuraisingham; Richard Borrows; Richard Baker; Keith McCullough; John Stoves; Mysore Phanish; Sapna Shah; Kin Yee Shiu; Stephen B Walsh; Aimun Ahmed; Waqar Ayub; Janet Hegarty; Rose Tinch-Taylor; Evangelos Georgiou; Natalie Bidad; Ayşenur Kılıç; Zoe Moon; Robert Horne; Paul McCrone; Joanna Kelly; Caroline Murphy; Janet Peacock; Anthony Dorling

doi:10.1016/j.eclinm.2022.101819

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial

EClinicalMedicine. 2023 Jan 12:56:101819. doi: 10.1016/j.eclinm.2022.101819. eCollection 2023 Feb.

Authors

Dominic Stringer^{1

2}, Leanne Gardner^{2

3}, Olivia Shaw⁴, Brendan Clarke⁵, David Briggs⁶, Judith Worthington⁷, Matthew Buckland⁸, Guilherme Danzi⁹, Rachel Hilton¹⁰, Michael Picton¹¹, Raj Thuraisingham¹², Richard Borrows¹³, Richard Baker¹⁴, Keith McCullough¹⁵, John Stoves¹⁶, Mysore Phanish¹⁷, Sapna Shah¹⁸, Kin Yee Shiu¹⁹, Stephen B Walsh¹⁹, Aimun Ahmed²⁰, Waqar Ayub²¹, Janet Hegarty²², Rose Tinch-Taylor^{1

2}, Evangelos Georgiou², Natalie Bidad²³, Ayşenur Kılıç²³, Zoe Moon²³, Robert Horne²³, Paul McCrone^{2

24}, Joanna Kelly², Caroline Murphy², Janet Peacock^{25

26}, Anthony Dorling³

Affiliations

¹ Biostatistics and Health Informatics, The Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
² King's Clinical Trials Unit, King's College London, London, UK.
³ Centre for Nephrology, Urology and Transplantation, Department of Inflammation Biology, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
⁴ Clinical Transplantation Laboratory, Viapath Analytics LLP, London, UK.
⁵ Transplant Immunology, Level 09 Gledhow Wing, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
⁶ NHSBT Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2SG, UK.
⁷ Transplantation Laboratory, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK.
⁸ Clinical Transplantation Laboratory, The Royal London Hospital, 2nd Floor, Pathology and Pharmacy Building, 80 Newark Street, London, E1 1BB, UK.
⁹ Renal Unit, Hospital das Clínicas da Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235 - Cidade Universitária, Recife - PE, 50670-901, Brazil.
¹⁰ Department of Nephrology and Transplantation, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
¹¹ Department of Renal Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK.
¹² Department of Renal Medicine and Transplantation, Barts Health NHS Trust, London, E1 1BB, UK.
¹³ Renal Unit, University Hospital Birmingham, Edgbaston, Birmingham, B15 2LN, UK.
¹⁴ Renal Unit, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
¹⁵ Renal Unit, York Teaching Hospital NHS Foundation Trust, York, YO31 8HE, UK.
¹⁶ Renal Unit, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, BD5 0NA, UK.
¹⁷ Renal Unit, Epsom and St Helier University Hospitals NHS Trust, Surrey, UK.
¹⁸ Renal Unit, King's College Hospital, London, SE5 9RJ, UK.
¹⁹ UCL Department of Renal Medicine, Royal Free London NHS Foundation Trust, London, NW3 2QG, UK.
²⁰ Renal Unit, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, PR2 9HT, UK.
²¹ Renal Unit, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
²² Renal Unit, Salford Royal NHS Foundation Trust, Salford, M6 8HD, UK.
²³ Centre for Behavioural Medicine, UCL School of Pharmacy, University College London, London, WC1H 9JP, UK.
²⁴ Faculty of Education, Health and Human Sciences, University of Greenwich, London, UK.
²⁵ School of Life Course and Population Sciences, King's College London, London, UK.
²⁶ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth College, USA.

Abstract

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure.

Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients.

Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection.

Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy.

Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).

Keywords: HLA antibodies; Kidney allograft failure; Kidney transplantation; Optimised immunosuppression; Stratified medicine.

Grants and funding

MR/J006742/1/MRC_/Medical Research Council/United Kingdom