AUTHOR=Gupta Gaurav , Wojciechowski David , Sener Alp , Gong Timothy , Dunn Ty B. , Costa Nadiesda , Odorico Jon S. , Daloul Reem , Rohan Vinayak S. , Biagini D. Giovanni , Barnes David , Kaur Navchetan , Gude Geethanjali , Ahmed Ebad , Xie Jing , Spellicy Catherine J. , Al Haj Baddar Nour , Bloom Michelle S. , Demko Zachary , Prewett Adam , Gauthier Phil , Bhorade Sangeeta , Tabriziani Hossein , Akkina Sanjeev K. TITLE=Donor-Derived Cell-Free DNA in Pancreas-Kidney, Heart-Kidney, and Liver-Kidney Multiorgan Transplant Recipients (MOTR) JOURNAL=Transplant International VOLUME=Volume 38 - 2025 YEAR=2026 URL=https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2025.15823 DOI=10.3389/ti.2025.15823 ISSN=1432-2277 ABSTRACT=Donor-derived cell free DNA (dd-cfDNA) is an established biomarker for detection of rejection in single organ transplants; data is limited in multi-organ transplant (MOT) recipients. “Use of dd-cfDNA in Multi-Organ Transplant Recipients” (MOTR) was a multicenter, prospective, cross-sectional study that assessed dd-cfDNA fraction (%) and donor quantity score (DQS, cp/mL) in pancreas-kidney (PKT), heart-kidney (HKT), and liver-kidney (LKT) recipients. We explored dd-cfDNA baseline levels across the different organ combinations, and compared them to kidney-only (KT) and heart-only (HT) transplant recipients. Among 347 MOT recipients from 18 sites (PKT = 183, HKT = 57, LKT = 107), most (88.2%) had simultaneous transplants. Median dd-cfDNA levels in PKT and HKT recipients were not significantly different from KT; median dd-cfDNA levels among HKT recipients were significantly higher than in HT recipients (p < 0.001). In LKT recipients, median dd-cfDNA was significantly higher compared to KT (p < 0.001). dd-cfDNA showed associations with organ impairment indicated by abnormal values of pancreatic and liver enzymes in PKT and LKT. As the largest multi-center study to date evaluating dd-cfDNA levels in MOT recipients, MOTR showed that organ-specific physiology affects dd-cfDNA levels across organ transplant combinations, laying the foundation for future efforts to use dd-cfDNA to assess organ-specific signatures of allograft injury in MOT recipients.