Preventing kidney transplant failure by screening for antibodies against human leucocyte antigens followed by optimised immunosuppression: OuTSMART RCT

Design: Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background: Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants: Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions: Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective: To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome: Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding: Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised: From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed: Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome: The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms: No significant differences in other secondary endpoints or adverse events. Limitations: Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions: No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work: We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration: This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure. Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients. Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54–1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection. Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

The endothelial L-argine-nitric oxide pathway in experimental uraemia

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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

© 2014 Dorling et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Assessment of a Dedicated Transplant Low Clearance Clinic and Patient Outcomes on Dialysis After Renal Allograft Loss at 2 UK Transplant Centers

Background. Low clearance transplant clinics (LCTCs) are recommended for the management of recipients with a failing kidney transplant (RFKT) but data to support their use is limited. We conducted a retrospective study to assess management of RFKT at 2 transplant centers, 1 with a LCTC (center A) and 1 without (center B). Methods. Patients who transitioned to an alternative form of renal replacement therapy (RRT) between January 1, 2012, and November 30, 2016, were included. Patients with graft failure within a year of transplantation or due to an unpredictable acute event were excluded. Clinical data were collected after review of medical records. Results. One hundred seventy-nine patients (age, 48.6 ± 13.4 years, 99 [55.3%] male, and mean transplant duration 10.3 ± 7.8 years) were included. RRT counseling occurred in 79 (91%) and 68 (74%) patients at centers A and B (P = 0.003), at median 135 (61-319) and 133 (69-260) days before dialysis after graft loss (P = 0.92). Sixty-one (34.1%) patients were waitlisted for retransplantation; 18 (32.7%) nonwaitlisted patients were still undergoing workup at center A compared with 37 (58.7%) at center B (P = 0.028). Preemptive retransplantation occurred in 4 (4.6%) and 5 (5.4%) patients at centers A and B (P = 0.35). At 1 year after initiation of dialysis after graft loss, 11 (15.3%) and 11 (17.2%) patients were retransplanted (P = 0.12), and mortality was 6.6% overall. Conclusions. A dedicated LCTC improved RRT counseling and transplant work-up but did not lead to improved rates of retransplantation. Earlier consideration of retransplantation in LCTCs is required to improve RFKT outcomes