Prognostic Significance of Early Donor-derived Cell-free DNA Trajectories After Kidney Transplantation

BACKGROUND: Early post-transplant elevations in donor-derived cell-free DNA are often attributed to ischemia-reperfusion injury, with uncertain prognostic significance. We assessed whether donor-derived cell-free DNA (dd-cfDNA) results during the first 4 mo post-transplantation are associated with long-term graft outcomes. METHODS: We analyzed 1137 kidney transplant recipients enrolled in the prospective multicenter Kidney Outcomes AlloSure Registry. Recipients were categorized into 4 trajectory groups based on dd-cfDNA measurements obtained within the first 4 mo post-transplant: consistently low, transient-elevation, late-elevation, and persistent-elevation. Associations with donor-specific antibody (DSA) development, rejection, graft dysfunction, and graft loss were evaluated over 3 y using hazard regression, with multivariable models adjusted for calculated Panel Reactive Antibody (cPRA) and retransplant. RESULTS: Among the 1137 recipients, 83.7% exhibited consistently low dd-cfDNA, 9.8% transient-elevation, 3.2% late-elevation, and 3.3% persistent-elevation. Late elevation was associated with the highest cumulative incidence of DSA development, whereas persistent-elevation had the highest incidence of rejection, graft dysfunction, and graft loss. Graft loss occurred in 20.0% of recipients with persistent-elevation and 8.8% with late-elevation and was uncommon among consistently low (2.2%) and transient (2.9%) groups. On multivariable analysis, late elevation was independently associated with DSA development, rejection, and graft loss, and persistent-elevation with rejection, graft dysfunction, and graft loss, regardless of prior transplantation or sensitization status. CONCLUSIONS: Early dd-cfDNA trajectories stratify kidney transplant recipients into clinically meaningful risk phenotypes. Persistent or late-emerging elevation identifies patients at independently increased risk of rejection and graft loss, with persistent-elevation also associated with graft dysfunction, supporting serial dd-cfDNA monitoring as a tool for early post-transplant risk stratification.

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Journal
Transplantation
Published
2026-11-02
DOI
https://doi.org/10.1097/tp.0000000000005959
Primary Topic
Renal Transplantation Outcomes and Treatments
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article
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article

Prognostic Significance of Early Donor-derived Cell-free DNA Trajectories After Kidney Transplantation

Suphamai Bunnapradist, Puneet Sood, Pranjal Jain, Didier A. Mandelbrot et al.
5 links
Transplantation
Renal Transplantation Outcomes and Treatments
article

Prognostic Significance of Early Donor-derived Cell-free DNA Trajectories After Kidney Transplantation

Suphamai Bunnapradist, Puneet Sood, Pranjal Jain, Didier A. Mandelbrot, Nicolae Leca, Edmund Huang, James B. Piper, Tarek Alhamad, Peale Chuang, Anil S. Paramesh, Alexander C. Wiseman, Dhiren Kumar, Jonathan S. Bromberg, Renata Glehn-Ponsirenas, Rashikh A. Choudhury, Kalathil K. Sureshkumar, Sandesh Parajuli, Yasir A. Qazi, Stuart J. Knechtle, David Wojciechowski, Divya Jain, Rafael Villicana, Nadiesda A. Costa, Jiashu Xue, Daniel C. Brennan, Thin Thin Maw, James Lu, Ling Shen, Yihung Huang, On behalf of the KOAR Investigators, Jeffrey A. Klein
article en

Abstract

BACKGROUND: Early post-transplant elevations in donor-derived cell-free DNA are often attributed to ischemia-reperfusion injury, with uncertain prognostic significance. We assessed whether donor-derived cell-free DNA (dd-cfDNA) results during the first 4 mo post-transplantation are associated with long-term graft outcomes. METHODS: We analyzed 1137 kidney transplant recipients enrolled in the prospective multicenter Kidney Outcomes AlloSure Registry. Recipients were categorized into 4 trajectory groups based on dd-cfDNA measurements obtained within the first 4 mo post-transplant: consistently low, transient-elevation, late-elevation, and persistent-elevation. Associations with donor-specific antibody (DSA) development, rejection, graft dysfunction, and graft loss were evaluated over 3 y using hazard regression, with multivariable models adjusted for calculated Panel Reactive Antibody (cPRA) and retransplant. RESULTS: Among the 1137 recipients, 83.7% exhibited consistently low dd-cfDNA, 9.8% transient-elevation, 3.2% late-elevation, and 3.3% persistent-elevation. Late elevation was associated with the highest cumulative incidence of DSA development, whereas persistent-elevation had the highest incidence of rejection, graft dysfunction, and graft loss. Graft loss occurred in 20.0% of recipients with persistent-elevation and 8.8% with late-elevation and was uncommon among consistently low (2.2%) and transient (2.9%) groups. On multivariable analysis, late elevation was independently associated with DSA development, rejection, and graft loss, and persistent-elevation with rejection, graft dysfunction, and graft loss, regardless of prior transplantation or sensitization status. CONCLUSIONS: Early dd-cfDNA trajectories stratify kidney transplant recipients into clinically meaningful risk phenotypes. Persistent or late-emerging elevation identifies patients at independently increased risk of rejection and graft loss, with persistent-elevation also associated with graft dysfunction, supporting serial dd-cfDNA monitoring as a tool for early post-transplant risk stratification.

Transplantation
Tulane University (US), University of Southern California (US), University of Maryland, Baltimore (US), Cedars-Sinai Medical Center (US), University of Colorado Hospital (US), Loma Linda University Medical Center (US), Loyola University Medical Center (US), University of Wisconsin System (US), University of Wisconsin–Madison (US), Johns Hopkins University (US), University of Kansas (US), University of California, Los Angeles (US), Duke University (US), University of California, San Francisco (US), Virginia Commonwealth University (US), University of Washington (US), Washington University in St. Louis (US), University of South Florida (US), Loma Linda University (US), Porter Adventist Hospital (US), Johns Hopkins Medicine (US), UW Health University Hospital (US), Allegheny General Hospital (US), Inova Fairfax Hospital (US), Tampa General Hospital (US), The University of Kansas Health System (US), MedStar Georgetown University Hospital (US), University of California System (US), St. Joseph Hospital (US), Loyola Medicine (US), CareDx, Inc. (United States) (US), AdventHealth (US), Virginia Commonwealth University Medical Center (US), University of California, Davis (US), The University of Texas Southwestern Medical Center (US), University of Colorado Denver (US)
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Openalex Percentile: Top 10%
Renal Transplantation Outcomes and Treatments
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