Advances on Novel Biomarkers of Alloimmunity in Kidney Transplantation

Despite major advancements in transplant rejection physiopathology and the refinement of immunosuppressive therapies over the past decades, improvements in graft and patient survival remains limited. A potential explanation is the insufficient implementation of biomarkers for individualized alloimmune risk stratification in clinical transplantation. Enormous efforts have focused in the last decades on developing sensitive and specific biomarkers to enable more personalized, non-invasive rejection diagnostics and informed treatment decisions in the transplant process. These biomarkers have distinct purposes; pre-transplantation, biomarkers aim to improve current donor-recipient immunological matching and rule out preformed anti-donor immune memory, whereas post-transplantation, their main aim focuses on identifying anti-donor alloimmune activation and on-going subclinical rejection in a non-invasive manner. This review summarizes the most advanced biomarkers and immune assays in the field, categorizing them by their diagnostic, prognostic, and predictive capabilities, and discusses their current validation status and integration into clinical trial designs aimed at improving transplant outcomes. Among them, we here highlight those assessing alloimmune susceptibility or activation, such as donor/recipient HLA molecular matching, donor (HLA/non-HLA)-specific antibodies (DSA), donor-reactive memory T and B cells, peripheral gene expression profiling (GEP) as well as some specific circulating immune cell phenotypes; and furthermore, we discuss those biomarkers diagnosing on-going subclinical graft injury, including donor-derived cell-free DNA (dd-cfDNA), and urinary chemokines or transcriptional biomarkers. Most importantly, these biomarkers are often complementary: some reflect ongoing alloimmune responses and may guide immunosuppression decisions, while others may provide early warnings of allograft injury prior to clinical manifestation. While some have progressed to advanced validation stages with strong diagnostic and prognostic value, others remain in early development. Rigorous interventional clinical trials are warranted to establish their clinical utility and define their role in transplant precision medicine to ultimately improve current clinical outcomes.