The use of immunosuppressant drugs to facilitate allograft success in kidney transplant recipients “does not delay failure of renal transplants after development of donor specific antibodies (DSAs)”. That’s the conclusion of the OuTSMART trial, which has been published in eClinicalMedicine and coordinated by Dominic Stringer, corresponding author Anthony Dorling (King’s College London, London, UK) and colleagues.
Kidney transplant recipients can experience graft dysfunction, followed by graft failure, as a result of “chronic immune-mediated injury”, according to the OuTSMART authors, who outline the context and purpose of the investigation. These failures lead to tens of thousands of patients a year returning to dialysis after a transplant has failed, and have been linked to the development of antibodies (Abs) to human leukocyte antigens (HLAs) in the transplant recipient. This study’s results help to probe this link. The first randomised controlled trial on the subject, it was performed by screening for development of HLA Ab before a “patient-tailored optimisation of oral immunosuppression to a combination of tacrolimus, mycophenolate mofetil and prednisolone”.
DSAs have been associated by other studies with “a higher risk of graft loss compared to [antibodies] that are not donor-specific”. This has led to the use of immunosuppression as a strategy against “immune-mediated damage”. Previous small-scale trials are recalled by Stringer et al in their introduction, including a 2017 study led by Kin Yee Shiu (Royal Free Hospital, London, UK), which have indicated “optimised treatment with tacrolimus and mycophenolate mofetil (MMF)”, but large-scale trials before OuTSMART have not been forthcoming.
To rectify this, the study authors designed a trial that took place across 13 UK transplant centres, where 2037 transplant patients were randomised, 1028 to unblinded care and 1009 to double-blinded care. Patients were grouped according to HLA Ab status, which was known at time of transplant for 91% of patients. Most recruited patients were taking tacrolimus (73%), MMF (67%) or prednisolone (55%) at randomisation, while 27% were taking all three and “baseline immunosuppression was balanced across groups”. The primary outcome of the study was time to graft failure in an intention to treat analysis, and was measured at 43 months remotely due to the COVID-19 pandemic.
From the cohort, 198 patients were found with DSA and 818 with non-DSA. DSA development, though not non-DSA development was found by the authors to be “predictive of graft failure”. Patients with antibodies were offered tailored regimens, and monitored to encourage adherence. Patients were stratified by HLA Ab status, “to generate three groups within each arm (DSA+, non-DSA+ or HLA Ab-negative)”, as well as by current immunosuppression “to ensure balanced numbers specific immunosuppressives”, and also by site.
The authors state that their results “confirm the prognostic value of monitoring DSA” but fail to show any statistically significant change to graft failure rates with optimised oral immunosuppression, with “confirmatory 95% confidence intervals for hazard ratios that included the null value”. They found that 15–20% of grafts failed for DSA-positive patients, compared with 7% for negative patients, but for those undergoing immunosuppression optimisation “we failed to see an impact on time to graft failure”. While rejection was reduced by immunosuppression, this did not translate into decreased rates of transplant failure.
Speaking on the implications of their findings, Stringer et al state that the data “will impact significantly on how transplant centres around the world organise their post-transplant monitoring”. They make the case that it should also spark an international effort to find new approaches to the question of ensuring graft success.
