Elevations in Donor-Derived Cell-Free DNA and Allograft Outcomes in Kidney Transplantation

KEY POINTS: We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor-derived cell-free DNA states were independently associated with 3.7-fold and 6.4-fold higher risks of allograft loss, respectively. Persistently low donor-derived cell-free DNA levels were associated with low rates of rejection and allograft loss, identifying a low-risk population. BACKGROUND: Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss. METHODS: The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15-60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%-1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models. RESULTS: Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n=216; high n=233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m2 in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high) while mortality did not differ by dd-cfDNA state. CONCLUSIONS: Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.

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Journal
Journal of the American Society of Nephrology
Published
2026-06-16
DOI
https://doi.org/10.1681/asn.0000001133
Primary Topic
Renal Transplantation Outcomes and Treatments
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article
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article

Elevations in Donor-Derived Cell-Free DNA and Allograft Outcomes in Kidney Transplantation

R. Woodward, Suphamai Bunnapradist, Sanjiv Anand, David J. Taber et al.
Journal of the American Society of Nephrology
Renal Transplantation Outcomes and Treatments
article

Elevations in Donor-Derived Cell-Free DNA and Allograft Outcomes in Kidney Transplantation

R. Woodward, Suphamai Bunnapradist, Sanjiv Anand, David J. Taber, Bekir Tanrıöver, Michelle A. Josephson, David B. Leeser, Anthony Langone, Pranjal Jain, Didier A. Mandelbrot, Nicolae Leca, Todd E. Pesavento, Matthew R. Weir, Daniel C. Brennan, Emilio D. Poggio, Matthew Cooper, Tarek Alhamad, Mohanram Narayanan, Yihung Huang, Peale Chuang, Chun‐Po Steve Fan, Anil Paramesh, Martina M. McGrath, Maria Ajaimy, Alexander C. Wiseman, Dhiren Kumar, Jonathan S. Bromberg, Nitipong Permpalung, Renata Glehn-Ponsirenas, Anup Patel, Pradeep Vaitla, Rashikh A. Choudhury, Sanjay Kulkarni, Giselle Guerra, Enver Akalin, Massini Merzkani, Oyedolamu Olaitan, George W. Burke, Prince Mohan, Ibrahim H. Tawhari, Fuad S. Shihab, Ling Shen, David Wojciechowski, Thin Thin Maw, Ziad Zaky, Diane Cibrik, Abd A. Qannus, on behalf of the KOAR Study Investigators, James Lu, Nadiesda Costa, Eric Langewisch, Jeffrey A. Klein, Bernard Fischbach, Kalathil Sureshkumar
article en

Abstract

KEY POINTS: We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor-derived cell-free DNA states were independently associated with 3.7-fold and 6.4-fold higher risks of allograft loss, respectively. Persistently low donor-derived cell-free DNA levels were associated with low rates of rejection and allograft loss, identifying a low-risk population. BACKGROUND: Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss. METHODS: The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15-60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%-1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models. RESULTS: Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n=216; high n=233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m2 in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high) while mortality did not differ by dd-cfDNA state. CONCLUSIONS: Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.

Journal of the American Society of Nephrology
Intermountain Healthcare (US), Tulane University (US), University of Nebraska at Omaha (US), University of Maryland, Baltimore (US), Saint Barnabas Medical Center (US), Brigham and Women's Hospital (US), Rush University Medical Center (US), University of Colorado Hospital (US), Albert Einstein College of Medicine (US), Cleveland Clinic (US), Montefiore Medical Center (US), Vidant Medical Center (US), University of Arizona (US), Johns Hopkins University (US), University of Miami (US), University of Kansas (US), Medical University of South Carolina (US), University of California, Los Angeles (US), Illinois College (US), Virginia Commonwealth University (US), University of Washington (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), University of Utah (US), University of South Florida (US), Johns Hopkins Medicine (US), UW Health University Hospital (US), Keck Hospital of USC (US), Allegheny General Hospital (US), Tampa General Hospital (US), The University of Kansas Health System (US), Baylor University Medical Center (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Yale University (US), University of Illinois Chicago (US), University of Chicago (US), Baylor Scott & White Medical Center - Temple (US), Medical Care Development (US), University of Kansas Medical Center (US), Miami Transplant Institute (US), MedStar Heart & Vascular Institute (US), Adventist Heart Institute (US), The Ohio State University (US), University of California, Davis (US), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), University of South Carolina Lancaster (US), University of Colorado Denver (US)
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Renal Transplantation Outcomes and Treatments
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