**6. Conclusions**

Development of Omics technology and expanding knowledge of new tools, such as EVs and dd-cfDNA, has led to an increased availability of a wide range of new potential biomarkers, which may be applied to all key settings of early and late graft dysfunction. Non-invasive biomarkers measured in urine or blood appear promising in providing very early diagnosis of pathological processes, such as subclinical AR, or in stratifying risk of DGF or of rejection, potentially reducing need for surveillance biopsies to monitor low-risk recipients. Tissue biomarkers have also proved effective in integrating traditional histology, leading to improved disease nosology and more accurate prognosis. Tolerance biomarkers and progress in AI are opening new frontiers, which may revolutionize transplant medicine.

Although larger, multi-center validation studies are needed before combination of biomarkers can be widely implemented in the clinic, the transplant physician should rise to the challenge of becoming familiar with this new landscape, in order to start taking advantage of the various facets of its huge potential.

**Author Contributions:** M.Q. and V.C. designed and wrote the initial manuscript; G.M. designed Figure and Tables; G.G. organized References; G.C. contributed to specific parts concerning Complement-related biomarkers. All authors critically revised, discussed and edited the article until it reached its current form and agreed to the published version of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was (partially) funded by the Italian Ministry of Education, University and Research (MIUR) program "Departments of Excellence 2018–2022", AGING Project—Department of Translational Medicine, University of Piemonte Orientale (UPO) and by local grants of the University of Piemonte Orientale (UPO, FAR) to M.Q. and V.C.

**Conflicts of Interest:** The authors declare no conflict of interest.
