BTS 2013 Report – Optimised tacrolimus and MMF for HLA antibodies after renal transplantation – the OUTSMART study

by Maria Dalby reporting on the presentation by Anthony Dorling, King’s College London.  The presence of Human Leukocyte Antigen (HLA) antibodies in renal transplant recipients is increasingly recognised as an important biomarker of premature graft failure.

The Optimized Tacrolimus and MMF for HLA Antibodies after Renal Transplantation (OUTSMART) will begin recruiting this year with the aim of establishing whether optimisation of the immunosuppressive regimen in renal transplant recipients with HLA antibodies is capable of prolonging the life of the graft and avoiding dialysis. Professor Anthony Dorling of King’s College London, who is principal investigator of the OUTSMART study, outlined the design and research objectives.

 

That transplant recipients who develop donor-specific antibodies (DSA) have significantly poorer prognosis than those who do not is a well-established fact (1). Importantly, this is true also for patients who develop de novo DSA post-transplant and thus are found to be HLA positive on re-testing (1). An observational study carried out at Professor Dorling’s lab has shown that a significant proportion of indirect anti-donor alloreactivity in patients with signs of antibody-mediated rejection on protocol or for-cause biopsy is dependent on B-cell antigen presentation and processing, suggesting that targeting the cellular immune response through optimised oral immunosuppression may be beneficial (Shiu KY et al, abstract presented at BTS/RA 2013).

 

Based on these findings, the OUTSMART study is designed to determine graft failure rates (defined as return to dialysis) in HLA antibody-positive renal transplant recipients randomised to either biomarker-led immunosuppressive intervention or standard care during a follow-up period of three years. Secondary outcomes include graft failure rates in HLA-negative patients, patient survival rates, acute rejection rates, health-economic outcomes, and analysis of adherence and risk perception. Eligible for inclusion will be adult (age 18-70 years) patients who have undergone a renal transplantation more than one year prior to inclusion, with an estimated glomerular filtration rate at screening of ≥30ml/min/ 1.73m². Patients known to be HLA antibody-positive and who have already been given specific intervention for this will be excluded from the study. The optimised treatment protocol will comprise tailored treatment with the maximum tolerated dose of mycophenolate mofetil (MMF) and tacrolimus, the latter administered once daily or twice daily according to local preference and titrated to achieve 12-hour post-dose levels of 4-8 ng/mL. Included in this protocol is also a two-week course of prednisolone, 20mg once daily, followed by tapering. The study is classified as a Type A study as regards the requirement for adverse event reporting.

 

A key element of the study is that patients will be randomised to either blinded or un-blinded screening prior to any intervention. In the former group, only the tissue typist will know the antibody status of the patient. Patients who test negative on the initial screening will be re-screened every eight months, and patients who develop de novo DSA will be reassigned to the respective positive group and given intervention with no further screening.

 

The OUTSMART study will be carried out at five centres (Guy’s and Royal London hospitals, and Birmingham, Manchester and Leeds) and recruitment is expected to begin in June 2013. The results analyses will assume that biomarker-led intervention is superior to standard care, and that un-blinded screening is as effective (non-inferior) as blinded screening and will have no effect on the overall outcome. Professor Dorling concluded by inviting prospective collaborators to contact him for further details.

 

 

1.  Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-13. Epub 2009/05/23.