Improving the histologic detection of donor-specific antibody-negative antibody-mediated rejection in kidney transplants

Luis G Hidalgo¹, Katelynn S Madill-Thomsen², Jeff Reeve³, Martina Mackova³, Philippe Gauthier⁴, Zachary Demko⁴, Adam Prewett⁴, Michelle Lee³, Tarek Alhamad⁵, Sanjiv Anand⁶, Miha Arnol⁷, Rajendra Baliga⁸, Mirosław Banasik⁹, Christopher D Blosser², Sindhura Bobba¹⁰, Daniel Brennan¹¹, Jonathan Bromberg¹², Klemens Budde¹³, Andrzej Chamienia¹⁴, Kevin Chow¹⁵, Michał Ciszek¹⁶, Nadiesda Costa¹², Dominika Dęborska-Materkowska¹³, Alicja Debska-Ślizień¹⁴, Leszek Domański¹⁷, Richard Fatica¹⁸, Iman Francis¹⁹, Justyna Fryc²⁰, John Gill²¹, Jagbir Gill²¹, Maciej Glyda²², Sita Gourishankar²³, Marta Gryczman¹⁷, Gaurav Gupta¹⁰, Petra Hruba²⁴, Peter Hughes¹⁵, Arskarapurk Jittirat²⁵, Zeljka Jurekovic²⁶, Layla Kamal¹⁰, Mahmoud Kamel⁸, Sam Kant¹¹, Nika Kojc⁷, Joanna Konopa¹⁴, Dhiren Kumar¹⁰, James Lan²¹, David Lowe²⁷, Joanna Mazurkiewicz¹⁷, Marius Miglinas²⁸, Irfan Moinuddin¹⁰, Thomas Mueller²⁹, Marek Myślak¹⁷, Beata Naumnik²⁰, Leszek Pączek¹⁶, Anita Patel¹⁹, Agnieszka Perkowska-Ptasińska¹⁶, Grzegorz Piecha³⁰, Emilio Poggio¹⁸, Silvie Rajnochová Bloudíčkova²⁴, Heinz Regele³¹, Thomas Schachtner²⁹, Soroush Shojai²³, Majid L N Sikosana²³, Janka Slatinská²⁴, Katarzyna Smykal-Jankowiak²², Željka Veceric Haler⁷, Ondrej Viklicky²⁴, Ksenija Vucur²⁶, Matthew R Weir¹², Andrzej Wiecek³⁰, Ziad Zaky¹⁸, Philip F Halloran³²

Affiliations

¹ HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin, Madison, WI, USA.
² University of Washington, Seattle, WA, USA.
³ Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
⁴ Natera, Inc., San Carlos, CA, USA.
⁵ Division of Nephrology, Department of Internal Medicine, Washington University at St. Louis, St. Louis, MO, USA.
⁶ Intermountain Transplant Services, Murray, UT, USA.
⁷ Department of Nephrology, University of Ljubljana, Ljubljana, Slovenia.
⁸ Tampa General Hospital, Tampa, FL, USA.
⁹ Department of Nephrology and Transplantation Medicine, Medical University of Wrocław, Wrocław. Poland.
¹⁰ Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
¹¹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Surgery, University of Maryland, Baltimore, MD, USA.
¹³ Department of Nephrology, Charite-Medical University of Berlin, Berlin, Germany.
¹⁴ Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Gdańsk. Poland.
¹⁵ Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.
¹⁶ Department of Immunology, Transplantology and Internal Diseases, Warsaw Medical University, Warsaw, Poland.
¹⁷ Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland.
¹⁸ Department of Kidney Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹⁹ Henry Ford Transplant Institute, Detroit, MI, USA.
²⁰ 1st Department of Nephrology and Transplantation With Dialysis Unit, Medical University in Bialystok, Białystok, Poland.
²¹ St. Paul's Hospital, Vancouver, BC, Canada.
²² Wojewodzki Hospital, Poznan, Poland.
²³ Department of Medicine, University of Alberta, Edmonton, AB, Canada.
²⁴ Department of Nephrology, Transplant Center, Institute for Experimental and Clinical Medicine, Prague, Czech Republic.
²⁵ University Hospital Cleveland Medical Center, Cleveland, OH, USA.
²⁶ Renal Replacement Therapy, Department of Nephrology, University Hospital Merkur, Zagreb, Croatia.
²⁷ One Lambda Inc., West Hills, CA, USA.
²⁸ Nephrology and Kidney Transplantation Unit, Nephrology Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
²⁹ Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.
³⁰ Department of Nephrology, Transplantation and Internal Medicine, Silesian Medical University, Katowice, Poland.
³¹ Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
³² Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada. Electronic address: phallora@ualberta.ca.

PMID: 40854490
DOI: 10.1016/j.ajt.2025.08.029

Free article

Improving the histologic detection of donor-specific antibody-negative antibody-mediated rejection in kidney transplants

Luis G Hidalgo et al. Am J Transplant. 2025.

Free article

. 2025 Aug 23:S1600-6135(25)02943-0.

doi: 10.1016/j.ajt.2025.08.029. Online ahead of print.

Authors

Affiliations

¹ HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin, Madison, WI, USA.
² University of Washington, Seattle, WA, USA.
³ Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
⁴ Natera, Inc., San Carlos, CA, USA.
⁵ Division of Nephrology, Department of Internal Medicine, Washington University at St. Louis, St. Louis, MO, USA.
⁶ Intermountain Transplant Services, Murray, UT, USA.
⁷ Department of Nephrology, University of Ljubljana, Ljubljana, Slovenia.
⁸ Tampa General Hospital, Tampa, FL, USA.
⁹ Department of Nephrology and Transplantation Medicine, Medical University of Wrocław, Wrocław. Poland.
¹⁰ Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
¹¹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Surgery, University of Maryland, Baltimore, MD, USA.
¹³ Department of Nephrology, Charite-Medical University of Berlin, Berlin, Germany.
¹⁴ Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Gdańsk. Poland.
¹⁵ Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.
¹⁶ Department of Immunology, Transplantology and Internal Diseases, Warsaw Medical University, Warsaw, Poland.
¹⁷ Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland.
¹⁸ Department of Kidney Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹⁹ Henry Ford Transplant Institute, Detroit, MI, USA.
²⁰ 1st Department of Nephrology and Transplantation With Dialysis Unit, Medical University in Bialystok, Białystok, Poland.
²¹ St. Paul's Hospital, Vancouver, BC, Canada.
²² Wojewodzki Hospital, Poznan, Poland.
²³ Department of Medicine, University of Alberta, Edmonton, AB, Canada.
²⁴ Department of Nephrology, Transplant Center, Institute for Experimental and Clinical Medicine, Prague, Czech Republic.
²⁵ University Hospital Cleveland Medical Center, Cleveland, OH, USA.
²⁶ Renal Replacement Therapy, Department of Nephrology, University Hospital Merkur, Zagreb, Croatia.
²⁷ One Lambda Inc., West Hills, CA, USA.
²⁸ Nephrology and Kidney Transplantation Unit, Nephrology Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
²⁹ Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.
³⁰ Department of Nephrology, Transplantation and Internal Medicine, Silesian Medical University, Katowice, Poland.
³¹ Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
³² Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada. Electronic address: phallora@ualberta.ca.

PMID: 40854490
DOI: 10.1016/j.ajt.2025.08.029

Abstract

Emerging treatments for antibody-mediated rejection (ABMR, NEJM391 (2):122-132) have increased the importance of ABMR detection when donor-specific antibody (DSA) is negative. We addressed this issue in the Trifecta-Kidney study (ClinicalTrials.gov #NCT04239703) using 3 centralized tests in 690 kidney transplant biopsies: DSA (One Lambda Inc), blood donor-derived cell-free DNA (dd-cfDNA, Prospera™ test, Natera, Inc), and molecular biopsy assessment (MMDx). We used an "AutoBanff 2022" algorithm to model the impact of alternative DSA interpretations on the histologic diagnosis of DSA-negative ABMR following Banff guidelines, including agreement with dd-cfDNA and molecular ABMR. Lowering MFI cutoffs for DSA positivity did not improve the detection of DSA-negative ABMR. However, simply calling all DSA as positive allowed the Banff 2022 guidelines to identify 46% more ABMR cases with no measurable conventional DSA, and per net reclassification improvement increased agreement between histologic diagnoses and both dd-cfDNA (P = 7.72E-7) and molecular ABMR (P = 7.69E-7). New ABMR cases were as strongly positive for dd-cfDNA and molecular ABMR as those found using the conventional DSA interpretation. A validation set analysis using INTERCOMEX study data (ClinicalTrials.gov NCT#01299168) confirmed these findings and found that the new DSA-negative ABMR cases identified by calling all DSA-positive had the same risk for graft loss as those found with conventional DSA interpretation. Trifecta-Kidney Study ClinicalTrials.gov #NCT04239703.

Keywords: antibody-mediated rejection; donor-derived cell-free DNA; donor-specific antibody; kidney biopsy; kidney transplant rejection; microarrays.

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Conflict of interest statement

Declaration of competing interest P. Halloran has shares in Transcriptome Sciences Inc, a University of Alberta research company with an interest in molecular diagnostics, and is a consultant to Natera, Inc, and Argenx BV. All Natera, Inc, authors are employees and own equity at Natera, Inc.

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Improving the histologic detection of donor-specific antibody-negative antibody-mediated rejection in kidney transplants

Affiliations

Improving the histologic detection of donor-specific antibody-negative antibody-mediated rejection in kidney transplants

Authors

Affiliations

Abstract

Conflict of interest statement

Associated data

LinkOut - more resources

Full Text Sources

Medical