Donor-derived cell-free DNA significantly improves rejection yield in kidney transplant biopsies

Jonathan S Bromberg¹, Daniel C Brennan², David J Taber³, Matthew Cooper⁴, Sanjiv Anand⁵, Enver Akalin⁶, Edmund Huang⁷, Jeffrey A Klein⁸, Renata Glehn-Ponsirenas⁹, Jeffrey Rogers⁹, Peale Chuang⁹, Ashish S Kothari⁹, Ling Shen⁹, Robert N Woodward⁹, Dhiren Kumar¹⁰, David Wojciechowski¹¹, Didier Mandelbrot¹², Nadiesda Costa¹³, Lihong Bu¹⁴, Matthew R Weir¹⁵; KOAR Investigators

Affiliations

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: jbromberg@som.umaryland.edu.
² Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
³ Division of Transplant Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
⁴ Department of Surgery, Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁵ Abdominal Transplant Service, InterMountain Medical Center, Murray, Utah, USA.
⁶ Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
⁷ Department of Medicine, Division of Nephrology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁸ Department of Internal Medicine, Division of Nephrology and Hypertension, University Of Kansas Medical Center, Kansas City, Kansas, USA.
⁹ Research and Development, CareDx Inc, Brisbane, California, USA.
¹⁰ Department of Internal Medicine, Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Division of Nephrology, University of Texas Southwestern, Dallas, Texas, USA.
¹² Division of Nephrology, Department of Medicine, School of Medicine and Public Health, University of Wisconsin Medical Center, Madison, Wisconsin, USA.
¹³ Department of Medicine, Division of Nephrology, Georgetown University Medical Center, Washington, DC, USA.
¹⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

PMID: 40780562
DOI: 10.1016/j.ajt.2025.07.2484

Free article

Donor-derived cell-free DNA significantly improves rejection yield in kidney transplant biopsies

Jonathan S Bromberg et al. Am J Transplant. 2025.

Free article

. 2025 Aug 6:S1600-6135(25)02875-8.

doi: 10.1016/j.ajt.2025.07.2484. Online ahead of print.

Authors

Affiliations

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: jbromberg@som.umaryland.edu.
² Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
³ Division of Transplant Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
⁴ Department of Surgery, Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁵ Abdominal Transplant Service, InterMountain Medical Center, Murray, Utah, USA.
⁶ Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
⁷ Department of Medicine, Division of Nephrology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁸ Department of Internal Medicine, Division of Nephrology and Hypertension, University Of Kansas Medical Center, Kansas City, Kansas, USA.
⁹ Research and Development, CareDx Inc, Brisbane, California, USA.
¹⁰ Department of Internal Medicine, Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Division of Nephrology, University of Texas Southwestern, Dallas, Texas, USA.
¹² Division of Nephrology, Department of Medicine, School of Medicine and Public Health, University of Wisconsin Medical Center, Madison, Wisconsin, USA.
¹³ Department of Medicine, Division of Nephrology, Georgetown University Medical Center, Washington, DC, USA.
¹⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

PMID: 40780562
DOI: 10.1016/j.ajt.2025.07.2484

Abstract

Donor-derived cell-free DNA (dd-cfDNA) is a biomarker that enables the early detection of immune-mediated graft injury. This study evaluated the clinical utility of dd-cfDNA in predicting the presence of biopsy-proven rejection (BPAR). We analyzed 1070 biopsies from 1743 kidney transplant recipients enrolled in the prospective, multicenter Kidney Allograft Outcomes AlloSure Registry. Biopsies were grouped into surveillance or for-cause groups and stratified by dd-cfDNA status: elevated, nonelevated, or not tested. Rejection yield was significantly higher when dd-cfDNA was elevated: 39% vs 7% in the surveillance group and 47% vs 12% in the for-cause group (P < .0001). Biopsies with elevated dd-cfDNA and rejection diagnoses more frequently demonstrated antibody-mediated rejection and mixed rejection, whereas biopsies performed with nonelevated dd-cfDNA most often showed no rejection, borderline, or T cell-mediated rejection 1A. The area under the receiving operating characteristic curve for BPAR detection was 0.789. These findings demonstrate that dd-cfDNA levels can improve the pretest probability of BPAR in both surveillance and for-cause settings. Therefore, dd-cfDNA can optimize biopsy utilization by identifying kidney transplant patients who are most likely to have histologic rejection.

Keywords: KOAR (Kidney Allograft Outcomes AlloSure Registry); biopsy yield; clinical utility of dd-cfDNA; dd-cfDNA (Donor derived cell-free DNA); post-kidney transplant surveillance; rejection yield; sub-clinical rejection.

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Conflict of interest statement

Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by American Journal of Transplantation. Jonathan S. Bromberg has funded research from CareDx, Natera, and Eurofins. Daniel C. Brennan is a consultant for CareDx, Medeor, Travere, and Vera Therapeutics. David J. Taber has grant funding from Merck, Veloxis, and Takeda, and serves as a consultant for Veloxis and CareDx. Sanjiv Anand is a speaker for CareDx. Enver Akalin has grant support from the NIH and Immucor and is on the advisory board and a consultant for CareDx, Immucor, Transplant Genomics, VericiDx, and Lifemine. Edmund Huang received grant funding from CSL Behring and Veloxis and is on the advisory board for Natera. Didier Mandelbrot is the editor-in-chief of Current Opinion in Organ Transplantation. Lihong Bu is a scientific consultant for CareDx. Jeffrey Rogers, Peale Chuang, Ashish S. Kothari, Ling Shen, Renata Glehn-Ponsirenas, and Robert N. Woodward are employees and shareholders of CareDx. Matthew Cooper, Jeffrey A. Klein, Dhiren Kumar, David Wojciechowski, Nadiesta Costa, and Matthew R. Weir have no relevant disclosures.

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Donor-derived cell-free DNA significantly improves rejection yield in kidney transplant biopsies

Affiliations

Donor-derived cell-free DNA significantly improves rejection yield in kidney transplant biopsies

Authors

Affiliations

Abstract

Conflict of interest statement

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