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

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

Dominic Stringer  1   2 , Leanne Gardner  2   3 , Olivia Shaw  4 , Brendan Clarke  5 , David Briggs  6 , Judith Worthington  7 , Matthew Buckland  8 , Guilherme Danzi  9 , Rachel Hilton  10 , Michael Picton  11 , Raj Thuraisingham  12 , Richard Borrows  13 , Richard Baker  14 , Keith McCullough  15 , John Stoves  16 , Mysore Phanish  17 , Sapna Shah  18 , Kin Yee Shiu  19 , Stephen B Walsh  19 , Aimun Ahmed  20 , Waqar Ayub  21 , Janet Hegarty  22 , Rose Tinch-Taylor  1   2 , Evangelos Georgiou  2 , Natalie Bidad  23 , Ayşenur Kılıç  23 , Zoe Moon  23 , Robert Horne  23 , Paul McCrone  2   24 , Joanna Kelly  2 , Caroline Murphy  2 , Janet Peacock  25   26 , Anthony Dorling  3
Affiliations

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

Dominic Stringer et al. EClinicalMedicine. .

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.

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Conflict of interest statement

DB declares consulting fees and speaker honoraria from Hansa Biopharma. RT declares membership of ESOT Education Committee (2018–2021) (expenses reimbursed). PM declares research funding from NIHR. AD declares research funding from the 10.13039/501100007155Medical Research Council, consulting fees (paid to KCL) from Hansa Biopharma, Verici Diagnostics, UCB Pharma and Quell Therapeutics, Membership of the Herperis Faculty 2019, 2021 and 2022 (expenses reimbursed), Membership of the UK Organ donation and transplantation research network executive since 2020 (unpaid), Membership of the EME funding Committee (2014–2019) and the EME funding committee subgroup (2018–2019) (both unpaid). The remaining authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
CONSORT diagram for OuTSMART. 1 Two patients were randomised in error to blinded HLA-Ab-negative standard care group. These were excluded from the intention to treat analysis. All other participants were included in the analysis. Refer to Supplementary File for further information.
Fig. 2
Fig. 2
Kaplan Meier curves comparing time to graft failure in the DSA+ groups (A), non-DSA+ groups (B), all biomarker led care (BLC) vs. all standard care (SC) participants (C), HLA Ab neg groups (D) and all 6 groups (E). In A-D, Blue (unbroken) line = patients in unblinded, BLC arm. Red (broken) line = patients in blinded SC arm. The number at risk of graft failure at each time point is shown beneath the graph, followed by (in brackets) the number of graft failures. NB. One HLA-Ab-negative participant in the blinded (SC) group who developed DSA on re-screening was not included in this analysis as the graft failed prior to re-screening, so they were not at risk for the purpose of this analysis.
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