Advances on novel biomarkers of alloimmunity in kidney transplantation

Over the past decade, important advancements in the understanding of transplant physiopathology and refinement of immunosuppressive strategies have been achieved. Yet, this has not been translated into significant improvement on graft and patient survival rates, which is due, at least in part, to the lack of implementation of biomarkers for alloimmune-risk stratification at the patient individual level. In order to individualize non-invasive diagnosis of rejection and treatment decision-making, sensitive and specific biomarkers have been developed for its implementation at different transplant timepoints and clinical contexts, which are at distinct development phases: at pretransplant to refine the baseline donor/recipient immunological risk, for early and non-invasively detection of subclinical rejection post-transplantation; and long-term evaluation for immunosuppression management to either optimize or minimize immunosuppressive burden. Biomarkers may be stratified in those aiming at tracking alloimmune responses, whereas others are devoted to early and non-invasively diagnose the advent of allograft rejection. More advanced biomarkers aiming at monitoring alloimmune responses include donor/recipient HLA molecular matching, donor-specific antibodies (DSA), donor-reactive memory T cells and donor (HLA)-specific B cells as well as some circulating cellular immune, whereas other biomarkers non-invasively assessing allograft injury are circulating donor-derived cell free DNA (dd-cfDNA) and some specific gene expression (GEP) signatures and urinary chemokines. Most importantly, these biomarkers may be fully complementary, while some of them may describe the alloimmune status of a given transplant patient and thus guide treatment decision-making, others could be used for alerting of early allograft damage and injury before any clinical sign is detected. While some of these biomarkers have significantly advanced on their validation process and showed robust data demonstrating their capacity to diagnose, prognosticate or even predict distinct transplant outcomes, others are still on their preliminary validation stages. Thus, interventional clinical trials are highly warranted to demonstrate their value and clinical context of use. This review aims to examine the most promising and advanced biomarkers and immune assays in the field, categorizing them by their diagnostic, prognostic and predictive capabilities. The current validation status of these biomarkers and their roles in clinical trials, aiming to enhance patient outcomes through precision medicine, is also thoroughly discussed.