Advancements in noninvasive techniques for transplant rejection: from biomarker detection to molecular imaging

Transplant rejection remains a significant barrier to the long-term success of organ transplantation. Biopsy, although considered the gold standard, is invasive, costly, and unsuitable for routine monitoring. Traditional biomarkers, such as creatinine and troponin, offer limited predictive value owing to their low specificity, and conventional imaging techniques often fail to detect early organ damage, increasing the risk of undiagnosed rejection episodes. Considering these limitations, emerging noninvasive biomarkers and molecular imaging techniques hold promise for the early and accurate detection of transplant rejection, enabling personalized management strategies. This review highlights noninvasive biomarkers that predict, diagnose, and assess transplant prognosis by reflecting graft injury, inflammation, and immune responses. For example, donor-derived cell-free DNA (dd-cfDNA) is highly sensitive in detecting early graft injury, whereas gene expression profiling effectively excludes moderate-to-severe acute rejection (AR). Additionally, microRNA (miRNA) profiling enhances the diagnostic specificity for precise AR detection. Advanced molecular imaging techniques further augment the monitoring of rejection. Fluorescence imaging provides a high spatiotemporal resolution for AR grading, ultrasound offers real-time and portable monitoring, and magnetic resonance delivers high tissue contrast for anatomical assessments. Nuclear imaging modalities such as single photon emission computed tomography and positron emission tomography, enable dynamic visualization of immune responses within transplanted organs. Notably, dd-cfDNA and nuclear medicine imaging have already been integrated into clinical practice, thereby demonstrating the translational potential of these techniques. Unlike previous reviews, this work uniquely synthesizes advancements in both noninvasive biomarkers and molecular imaging, emphasizing their complementary strengths. Biomarkers deliver molecular-level insights, whereas imaging provides spatial and temporal resolution. Together, they create a synergistic framework for comprehensive and precise transplant monitoring. By bridging these domains, this review underscores their individual contributions and collective potential to enhance diagnostic accuracy, improve patient outcomes, and guide future research and clinical applications in transplant medicine.