Algorithm of Graft Outcome in Renal Allotransplantation

Kidney transplant recipients must use immunosuppressive drugs for the rest of their lives to prevent the body from rejecting the new kidney. The immunosuppressive drugs unfortunately have a number of side effects and it is therefore important that these are dosed as low as possible. Exactly where the limit is for sufficient immunosuppression in each individual patient is difficult to know, since we have no clinically validated marker for the degree of immunosuppression in relation to this. Partners in this project have previously developed some advanced blood tests that can identify kidney transplant patients with a particularly low risk of rejecting the new kidney. The aim of the project is to validate this new blood analysis, first in samples that have already been collected from 300 patients at the various transplant centers and then in a clinical study on new patients. In the prospective clinical study, patients with a particularly low risk of losing the kidney, identified with the new blood analysis, will be randomized to receive either standard immunosuppressive treatment or greatly reduced doses of the immunosuppressive drugs. In addition to examining efficacy and safety in the clinical study, the effect on economy will also be evaluated. We will also explore users' perspectives by conducting sociological interviews to promote active involvement of patients in their clinical care and assist clinicians in decision-making. The project will hopefully be able to positively influence the health benefits of kidney transplantation by providing the attending physician with a reliable medical decision-making tool to better adapt the immunosuppressive treatment to each individual patient.

In renal transplantation, monitoring the risk of subclinical rejection (SCR) and graft failure remains challenging. AGORA partners developed and validated 1-year non-invasive biomarkers allowing the prediction of patients at high/low risk of subclinical rejection and graft failure: 1) the cSOT gene score and 2) donor-reactive memory B cells (mBC) to diagnose sub-clinical rejection, 3) the Kidney Transplant Failure Score (KTFS) and 4) the frequency of circulating TEMRA cells to stratify patients with a higher risk of immunological graft failure. The objectives of AGORA are thus to build an European non-invasive clinical decision-making tool for immunological risk stratification of graft failure through: 1) a retrospective study to validate our decision AGORA algorithm on an existing biocollection of 300 patients, and 2) according to the AGORA algorithm, a multicenter randomized open label trial of immunosuppression minimization AGORAC (extra-low Tacrolimus (TAC) vs standard of care) with stringent monitoring of TAC pharmacokinetics using finger-prick test. Economic efficiency of our new strategy will be evaluated during the multicenter randomized open label trial. We will integrate users’ perspectives by performing sociological interviews to promote the active involvement of patients in their clinical care and help clinicians for decision-making. Ancillary functional studies will reinforce the AGORA algorithm to assess immunological events following immunosuppression minimization. AGORA will be possible thanks to the collaboration of 4 European partners, internationally recognized in kidney transplantation and immunology, and who share previous experiences in collaboration. All the steps and biomarkers have already been validated by the 4 partners. AGORA could impact health care pathway for kidney transplant recipients by incorporating a medical decision tool, validated through European large studies for personalizing immunosuppressive therapy.