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

Trials

Caroline Murphy^1,11  Joanna Kelly^1,11  Paul McCrone⁵  Robert Horne^1,10  David Briggs⁸  Richard Borrows^1,12  Susan Martin²  Michael Picton^1,13  Matthew Buckland⁷  Raj C Thuraisingham¹  Brendan Clark³  Richard Baker⁹  Guilherme Danzi⁵  Leanne Gardner⁵  Robert Vaughan⁵  Janet L Peacock⁴  Rachel Hilton⁶  Irene Rebollo-Mesa⁵  Anthony Dorling⁵ 

[1] Renal Unit, The Royal London Hospital, London E1 1BB, UK;Transplantation Laboratory, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK;Transplant Immunology, Level 09 Gledhow Wing, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK;King’s College London, Capital House, 42 Weston Street, London SE1 3QD, UK;MRC Centre for Transplantation, King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK;Department of Nephrology and Transplantation, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK;Clinical Transplantation Laboratory, The Royal London Hospital, 2nd Floor, Pathology & Pharmacy Building, 80 Newark Street, London E1 1BB, UK;NHSBT Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2SG, UK;Renal Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK;Centre for Behavioural Medicine, UCL School of Pharmacy, University College London, London WC1H 9JP, UK;King’s Clinical Trials Unit, King’s College London, Institute of Psychiatry, PO64, M2.06, London, UK;Renal Unit, University Hospital Birmingham, Edgbaston, Birmingham B15 2LN, UK;Department of Renal Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

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

Others  :  807602
DOI  :  10.1186/1745-6215-15-30

 received in 2013-08-02, accepted in 2014-01-06,  发布年份 2014

【 摘 要 】

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 TrialsISRCTN46157828.

【 授权许可】

   
2014 Dorling et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Lamb KE, Lodhi S, Meier-Kriesche HU: Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011, 11:450-462.
• [2]Ravanan R, Udayaraj U, Bakran A, Steenkamp R, Williams AJ, Ansell D: Measures of care in adult renal transplant recipients in the United Kingdom (chapter 11). Nephrol Dial Transplant 2007, 22(Suppl 7):vii138-vii154.
• [3]Gaston RS, Cecka JM, Kasiske BL, Fieberg AM, Leduc R, Cosio FC, Gourishankar S, Grande J, Halloran P, Hunsicker L, Mannon R, Rush D, Matas AJ: Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation 2010, 90:68-74.
• [4]Mizutani K, Terasaki P, Rosen A, Esquenazi V, Miller J, Shih RN, Pei R, Ozawa M, Lee J: Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant 2005, 5:2265-2272.
• [5]Lee PC, Zhu L, Terasaki PI, Everly MJ: HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation 2009, 88:568-574.
• [6]Terasaki PI, Ozawa M: Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial. Transplantation 2005, 80:1194-1197.
• [7]Terasaki PI, Ozawa M, Castro R: Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant 2007, 7:408-415.
• [8]Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, Pratschke J, Rudolph B, Schmidt D, Salama A, Schonemann C: Anti-human leukocyte antigen and donor-specific antibodies detected by Luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation 2009, 87:1505-1513.
• [9]van Timmeren MM, Lems SP, Hepkema BG, Bakker SJ: Anti-human leukocyte antigen antibodies and development of graft failure after renal transplantation. Transplantation 2009, 88:1399-1400.
• [10]Gosho M, Nagashima K, Sato Y: Study designs and statistical analyses for biomarker research. Sensors (Basel) 2012, 12:8966-8986.
• [11]Mandrekar SJ, Sargent DJ: All-comers versus enrichment design strategy in phase II trials. J Thorac Oncol 2011, 6:658-660.
• [12]Barber J, Thompson S: Multiple regression of cost data: use of generalised linear models. J Health Serv Res Policy 2004, 9:197-204.
• [13]King’s Clinical Trials Unit http://www.ctu.co.uk webcite
• [14]Dudley C, Pohanka E, Riad H, Dedochova J, Wijngaard P, Sutter C, Silva HT Jr: Mycophenolate mofetil substitution for cyclosporine A in renal transplant recipients with chronic progressive allograft dysfunction: the ‘creeping creatinine’ study. Transplantation 2005, 79:466-475.
• [15]Curtis L: Unit Costs of Health and Social Care 2010. Canterbury: PSSRU, University of Kent; 2010.
• [16]Mora PA, Berkowitz A, Contrada RJ, Wisnivesky J, Horne R, Leventhal H, Halm EA: Factor structure and longitudinal invariance of the Medical Adherence Report Scale – Asthma. Psychol Health 2011, 26:713-727.
• [17]Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ, Halm EA: Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009, 103:325-331.
• [18]Butler JA, Peveler RC, Roderick P, Smith PW, Horne R, Mason JC: Modifiable risk factors for non-adherence to immunosuppressants in renal transplant recipients: a cross-sectional study. Nephrol Dial Transplant 2004, 19:3144-3149.
• [19]Butler JA, Peveler RC, Roderick P, Horne R, Mason JC: Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring. Transplantation 2004, 77:786-789.
• [20]Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J: Can simple clinical measurements detect patient noncompliance? Hypertension 1980, 2:757-764.
• [21]Gordis L: Conceptual and methodologic problems in measuring patient compliance. In Compliance in Health Care. Edited by Sackett DL, Taylor DW, Taylor DW RBH. London: John Hopkins University Press; 1979:23-45.
• [22]Horne R, Weinman J, Hankins M: The beliefs about medicines questionnaire: the development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999, 14:1-24.
• [23]Horne R, Hankins M, Jenkins R: The satisfaction with information about medicines scale (SIMS): a new measurement tool for audit and research. Qual Health Care 2001, 10:135-140.
• [24]Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 1983, 67:361-370.
• [25]Moss-Morris R, Weinman J, Petrie KJ, Horne R, Cameron LD, Buick D: The revised illness perception questionnaire (IPQ-R). Psychol Health 2002, 17:1-16.
• [26]Beatty PC, Willis GB: Research synthesis: the practice of cognitive interviewing. Public Opin Q 2007, 71:287-311.
• [27]Theruvath TP, Saidman SL, Mauiyyedi S, Delmonico FL, Williams WW, Tolkoff-Rubin N, Collins AB, Colvin RB, Cosimi AB, Pascual M: Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001, 72:77-83.
• [28]Billing H, Rieger S, Ovens J, Susal C, Melk A, Waldherr R, Opelz G, Tonshoff B: Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Transplantation 2008, 86:1214-1221.
• [29]Fehr T, Rusi B, Fischer A, Hopfer H, Wuthrich RP, Gaspert A: Rituximab and intravenous immunoglobulin treatment of chronic antibody-mediated kidney allograft rejection. Transplantation 2009, 87:1837-1841.
• [30]Rostaing L, Guilbeau-Frugier C, Fort M, Mekhlati L, Kamar N: Treatment of symptomatic transplant glomerulopathy with rituximab. Transpl Int 2009, 22:906-913.
• [31]Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C: Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. Transplantation 1997, 63:39-47.
• [32]Sola R, Diaz JM, Guirado L, Sainz Z, Gich I, Picazo M, Garcia R, Abreu E, Ortiz F, Alcaraz A: Tacrolimus in induction immunosuppressive treatment in renal transplantation: comparison with cyclosporine. Transplant Proc 2003, 35:1699-1700.
• [33]Ahsan N, Johnson C, Gonwa T, Halloran P, Stegall M, Hardy M, Metzger R, Shield C 3rd, Rocher L, Scandling J, Sorensen J, Mulloy L, Light J, Corwin C, Danovitch G, Wachs M, VanVeldhuisen P, Salm K, Tolzman D, Fitzsimmons WE: Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Transplantation 2001, 72:245-250.
• [34]Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC: Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005., 4CD003961
• [35]Lederer SR, Friedrich N, Banas B, Welser G, Albert ED, Sitter T: Effects of mycophenolate mofetil on donor-specific antibody formation in renal transplantation. Clin Transplant 2005, 19:168-174.
• [36]Van der Mast BJ, van Besouw NM, Witvliet MD, de Kuiper P, Smak Gregoor P, Van Gelder T, Weimar W, Claas FH: Formation of donor-specific human leukocyte antigen antibodies after kidney transplantation: correlation with acute rejection and tapering of immunosuppression. Transplantation 2003, 75:871-877.
• [37]Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF: Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007, 357:2562-2575.
• [38]Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, Wolfe RA, Agodoa LY, Kaplan B: Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000, 69:2405-2409.
• [39]Meier M, Nitschke M, Weidtmann B, Jabs WJ, Wong W, Suefke S, Steinhoff J, Fricke L: Slowing the progression of chronic allograft nephropathy by conversion from cyclosporine to tacrolimus: a randomized controlled trial. Transplantation 2006, 81:1035-1040.
• [40]Meier-Kriesche HU, Merville P, Tedesco-Silva H, Heemann U, Kes P, Haller H, Rostaing L, Gafner N, Bernasconi C: Mycophenolate mofetil initiation in renal transplant patients at different times posttransplantation: the TranCept Switch study. Transplantation 2011, 91:984-990.
• [41]Jevnikar A, Arlen D, Barrett B, Boucher A, Cardella C, Cockfield SM, Rush D, Paraskevas S, Shapiro J, Shoker A, Yilmaz S, Zaltzman JS, Kiberd B: Five-year study of tacrolimus as secondary intervention versus continuation of cyclosporine in renal transplant patients at risk for chronic renal allograft failure. Transplantation 2008, 86:953-960.
• [42]Remuzzi G, Cravedi P, Costantini M, Lesti M, Ganeva M, Gherardi G, Ene-Iordache B, Gotti E, Donati D, Salvadori M, Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P: Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. J Am Soc Nephrol 2007, 18:1973-1985.