A Multicenter Randomized Controlled Trial to Treat Acute T Cell Mediated Rejection in Kidney and Kidney-Pancreas Transplant Recipients

Histological resolution of biopsy-proven acute rejection

Histological resolution of biopsy-proven acute rejection is defined by the absence of any biopsy proven acute rejection (BPAR) on follow-up biopsy, including Banff Borderline (i1 t1), mixed rejection, ABMR and chronic active TCMR using Banff 2022 criteria.

Improvement in allograft function for clinical rejection; and defined by an average of at least 2 serum creatinine at baseline and at least 2 serum creatinine from 11-13 weeks

Reduction in serum creatinine ≥20% is defined as the relative reduction in serum creatinine from baseline and at 11-13 weeks after randomisation, in the absence of dialysis or achieving freedom from dialysis. Staff are required to record the serum creatinine at each visit; or dates and modality of dialysis initiation and / or discontinuation.

Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function

Use of rescue therapy is defined as: the use of any adjunctive T and B cell depleting therapies such as intravenous thymoglobulin, alemtuzumab, bortezomib, or rituximab, or additional doses of IV MP within the first 12 weeks after randomisation.

All cause death and death-censored graft loss

All cause death and death-censored graft loss have been identified as the core outcomes for kidney transplant recipients. However, death and death-censored graft loss are anticipated to have a very low incidence at the 12 weeks post-randomization primary outcome ascertainment and were therefore not included in the primary composite outcome. They will be reported as principal secondary endpoints. All-cause death also includes cause-specific death (infections, cancers, cardiovascular-related, and other causes of death) at 12 weeks after randomisation.

Estimated glomerular filtration rate (eGFR)

* Absolute eGFR (2021 CKD-EPI eGFR without race modifier for adults, and the CKiD U25 equation to estimate GFR in children \<18 years) 12, 24 and 48 weeks. * Decline in eGFR (slope) from randomization to 48 weeks.

Urine albumin: creatinine ratios

Urine ACR is measured as standard of care. Rationale: ACR screens for graft dysfunction and is a marker for graft outcomes

Trajectories of serum creatinine changes

Steroid-related adverse effects

Adaption from the Steroid Patient Reported Outcome (Steroid PRO).

Integrative Box Risk Prediction Score (iBOX)

Graft survival prediction will be assessed using the Integrative Box Risk Prediction Score (iBOX), a validated composite risk prediction tool for kidney transplant outcomes. The iBOX score integrates clinical, functional, and immunological parameters including serum creatinine, proteinuria, biopsy findings, and presence of donor-specific antibodies to estimate the risk of allograft failure. The iBox score essentially assigns a numerical value based on these parameters, indicating the risk of allograft loss (kidney transplant failure).

Economic evaluation: Incremental costs and benefits

Incremental costs and benefits (life years and quality adjusted life years gained) between the two treatment arms.

Process evaluation: patients' and clinicians' perspectives on the treatment of acute TCMR

Semi-structured interviews will be conducted to elicit patients' perspectives and experiences of having acute TCMR, the adverse effects of the treatments. Health professionals' will also be interviewed to elicit their perspectives and experiences regarding the barriers, challenges, and enablers for implementing the intervention, the perceived benefits, and harms of the intervention and how the intervention should be delivered such that maximal interactions of the intervention are reached for the intended participants.