Abstract
Kidney transplantation is the treatment of choice for patients with end-stage kidney disease, but alloimmune responses triggered by transplantation remain a leading cause of graft failure. Despite advances in immunosuppressive therapy, acute rejection occurs in approximately 15% of kidney transplant recipients and may lead to irreversible damage or even graft loss if not detected early. Currently, kidney transplant monitoring relies on nonspecific biomarkers such as serum creatinine and proteinuria. These markers have significant limitations and typically detect acute rejection only after substantial damage to the kidney has already occurred. The "gold standard" for diagnosis is an invasive kidney biopsy, which poses high burden to the patient and carries a risk of serious complications. This underscores the urgent need for reliable, non-invasive biomarkers capable of detecting rejection at an early stage. T-cell receptor (TCR) sequencing shows promising potential as an alternative strategy, as clonal expansion of donor-reactive T cells drives T cell-mediated rejection and contributes to antibody-mediated rejection through help to B cells in generating donor-specific antibodies. While prior studies have shown marked clonal expansion of donor-reactive TCRs in blood during biopsy-proven rejection, the urinary TCR landscape remains largely unexplored. This project aims to develop a urine-based TCR biomarker assay and define a computational model to classify rejection risk based on urinary TCR signatures. Such a tool could transform transplant monitoring by enabling early, non-invasive detection of rejection episodes. Ultimately, this approach paves the way for individualized immunosuppressive management, leading to better long-term graft survival, better quality of life, and reduced healthcare costs.
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