Kidney transplantation is a lifesaving procedure for patients with end-stage kidney disease (ESKD). Organs derived from donation after cardiac death (DCD) are constantly increasing; however, DCD often leads to ischaemia-reperfusion (IR) and Acute Kidney Injury (AKI) events. These phenomena increase kidney cell turnover to replace damaged cells, which are voided in urine. Urine-derived renal epithelial cells (URECs) are rarely present in the urine of healthy subjects, and their loss has been associated with several kidney disorders. The present study aimed to characterize the phenotype and potential applications of URECs voided after transplant. The results indicate that URECs are highly proliferating cells, expressing several kidney markers, including markers of kidney epithelial progenitor cells. Since the regulation of the immune response is crucial in organ transplantation and new immunoregulatory strategies are needed, UREC immunomodulatory properties were investigated. Co-culture with peripheral blood mononuclear cells (PBMCs) revealed that URECs reduced PBMC apoptosis, inhibited lymphocyte proliferation, increased T regulatory (Treg) cells and reduced T helper 1 (Th1) cells. URECs from transplanted patients represent a promising cell source for the investigation of regenerative processes occurring in kidneys, and for cell-therapy applications based on the regulation of the immune response.

Kidney transplant monitoring and early identification of graft dysfunction are central needs for long-term graft survival. Although kidney biopsy represents the gold standard in diagnostic procedures, its invasiveness may limit frequent longitudinal evaluation, highlighting the necessity of non-invasive diagnostic tools. Urine has emerged over the years as an easily obtainable source of cellular and molecular components derived from transplanted kidneys. Particularly, exfoliated cells and extracellular vesicles (EVs) represent complementary and interconnected markers able to reflect tissue injury, inflammatory signals, immune cell infiltration, and regenerative processes occurring in the graft. Also, recent advances in transcriptomics, proteomics, metabolomics, and single-cell technologies have expanded the diagnostic and mechanistic value of urinary liquid biopsy, enabling the identification of disease-specific molecular signatures associated with rejection, delayed graft function, fibrosis, and graft loss. This review discusses the emerging concept of an integrated urinary cell–EV ecosystem and highlights how integrated multi-omic approaches may transform non-invasive graft surveillance and advance precision medicine in kidney transplantation.