Chaudhari, Harshad

Currently, approximately 90,000 patients are on the kidney transplant waitlist in the United States, including 10,000 individuals awaiting re-transplantation due to prior graft failure. Allograft rejection remains a leading cause of kidney transplant failure. While the current gold standard for diagnosing rejection is tissue biopsy, it is invasive and impractical for routine or longitudinal graft surveillance. This review summarizes the current landscape of non-invasive biomarkers for detecting and predicting kidney transplant rejection, with a focus on both historical context and recent advancements. In particular, we highlight the roles of donor-derived cell-free DNA (dd-cfDNA) and gene expression profiling (GEP) in identifying acute rejection. We also discuss emerging biomarkers such as torque teno virus (TTV), which has shown potential as an indirect indicator of immunosuppression levels and rejection risk. Importantly, this review excludes biomarker studies that rely on tissue biopsy, emphasizing non-invasive approaches to rejection monitoring.

Kidney transplantation remains the gold standard for managing end-stage kidney disease, providing superior survival and quality-of-life outcomes compared to dialysis. Despite the ongoing gap between organ availability and demand, it is inevitable that kidney transplantation will continue to grow. This is owed to broader organ sharing, increased comfort of transplant programs with marginal kidney utilization, and the expansion of paired exchange among living donor kidneys. The evolution of kidney transplantation could not have been possible without the availability of effective immunosuppressive regimens that prevent rejection and maintain graft function. Mycophenolic acid and calcineurin inhibitors continue to serve as the foundation of modern maintenance immunosuppression. While these agents have markedly reduced acute rejection rates, their long-term efficacy in graft survival remains suboptimal. Alternative immunosuppressive therapies, including belatacept and mammalian target of rapamycin inhibitors, have demonstrated potential benefits. However, concerns regarding an increased risk of rejection have limited their widespread adoption as primary treatment options. In addition to ongoing efforts to refine steroid- and calcineurin inhibitor-sparing strategies, the identification of practical and quantifiable biomarkers for predicting long-term graft survival remains a critical objective. This review evaluates contemporary immunosuppressive protocols, highlights existing challenges, and explores future directions for optimizing long-term transplant outcomes.