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

Abstract

BackgroundRenal 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/DesignRecipients >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.DiscussionWe 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 registrationCurrent Controlled Trials ISRCTN46157828.

Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

“…All three such patients displayed a positive response to HLA peptide in an ELISPOT assay of indirect cellular immunity, whereas none of the patients developing dnDSA but not experiencing BPAR (and who displayed stable renal function and negligible proteinuria over follow-up) displayed a positive test at the time of antibody formation. This supports the concept that damage as a result of cellular activation and infiltration may be more important to graft outcome then the presence of antidonor antibody per se (18,23,24), thereby extending previous work to the specific situation of nonadherence-associated ABMR. We do acknowledge however that this observation, whilst interesting, remains preliminary and over-interpretation of this finding based on the low numbers of patients with ABMR in the current study should be avoided.…”

The Last Year Before Graft Failure Negatively Impacts Economic Outcomes and is Associated With Greater Healthcare Resource Utilization Compared With Previous Years in the United Kingdom: Results of a Retrospective Observational Study

“…Strategies that might accurately diagnose early graft failure would be beneficial. A study being conducted by Dorling et al 35 is evaluating the use of a combined antibody/treatment program in patients receiving a kidney transplant. The study aims to enhance graft function and delay graft failure through screening patients for antibodies against human leukocyte antigens to ensure that these patients, who are at a high risk of premature graft failure, are identified and treated accordingly.…”

Effect of Preformed or De Novo Anti-HLA Antibodies on Function and Graft Survival in Kidney Transplant Recipients

“…Maintenance therapy with tacrolimus and mycophenolate is also reported to be related to a lower prevalence of anti-HLA antibodies and with a lower AMR incidence and better outcomes at 2-year follow-up, increasing graft survival [ 21 ]. Moreover, the association of low doses of steroids in maintenance therapy, despite not finding direct evidence of this in transplant recipients, is widely used in situations of rapid and effective suppression of the immune response, such as in many autoimmune diseases [ 21 ]. All DSA+ patients had gradual reduction of steroids during the follow-up, with similar steroid and antiproliferative drugs doses in the immunosuppressive maintenance therapy at 12 months.…”