Open Access Study protocol

Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial

Anthony Dorling1*, Irene Rebollo-Mesa1, Rachel Hilton2, Janet L Peacock3, Robert Vaughan1, Leanne Gardner1, Guilherme Danzi1, Richard Baker4, Brendan Clark5, Raj C Thuraisingham6, Matthew Buckland7, Michael Picton8, Susan Martin9, Richard Borrows10, David Briggs11, Robert Horne12, Paul McCrone1, Joanna Kelly13 and Caroline Murphy13

Author Affiliations

1 MRC Centre for Transplantation, King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK

2 Department of Nephrology and Transplantation, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK

3 King’s College London, Capital House, 42 Weston Street, London SE1 3QD, UK

4 Renal Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK

5 Transplant Immunology, Level 09 Gledhow Wing, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK

6 Renal Unit, The Royal London Hospital, London E1 1BB, UK

7 Clinical Transplantation Laboratory, The Royal London Hospital, 2nd Floor, Pathology & Pharmacy Building, 80 Newark Street, London E1 1BB, UK

8 Department of Renal Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

9 Transplantation Laboratory, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

10 Renal Unit, University Hospital Birmingham, Edgbaston, Birmingham B15 2LN, UK

11 NHSBT Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2SG, UK

12 Centre for Behavioural Medicine, UCL School of Pharmacy, University College London, London WC1H 9JP, UK

13 King’s Clinical Trials Unit, King’s College London, Institute of Psychiatry, PO64, M2.06, London, UK

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Trials 2014, 15:30  doi:10.1186/1745-6215-15-30

Published: 21 January 2014

Abstract

Background

Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients.

Methods/Design

Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes.

Discussion

We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer.

Trial registration

Current Controlled Trials ISRCTN46157828.

Keywords:
Human leukocyte antigen antibodies; renal transplantation; premature allograft failure; chronic rejection; screening; tacrolimus; mycophenolate mofetil; clinical trial; randomised controlled trial; randomized controlled trial; KCTU; CTU; trials unit; diabetes; kidney; graft failure; biomarker; biomarker-led care; DSA; non-DSA; multicentre; immunosuppression; usual care; treatment as usual; standard care; blinded; unblinded; EME funded; NIHR; optimised; optimized; intention-to-treat; per protocol