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. 2025 Jan;25(1):72-87.
doi: 10.1016/j.ajt.2024.07.034. Epub 2024 Aug 6.

Subthreshold rejection activity in many kidney transplants currently classified as having no rejection

Philip F Halloran  1 , Katelynn S Madill-Thomsen  2 , Georg Böhmig  3 , Jonathan Bromberg  4 , Klemens Budde  5 , Meagan Barner  6 , Martina Mackova  2 , Jessica Chang  2 , Gunilla Einecke  7 , Farsad Eskandary  3 , Gaurav Gupta  8 , Marek Myślak  9 , Ondrej Viklicky  10 , Enver Akalin  11 , Tarek Alhamad  12 , Sanjiv Anand  13 , Miha Arnol  14 , Rajendra Baliga  15 , Mirosław Banasik  16 , Adam Bingaman  17 , Christopher D Blosser  18 , Daniel Brennan  19 , Andrzej Chamienia  20 , Kevin Chow  21 , Michał Ciszek  22 , Declan de Freitas  23 , Dominika Dęborska-Materkowska  24 , Alicja Debska-Ślizień  25 , Arjang Djamali  26 , Leszek Domański  27 , Magdalena Durlik  28 , Richard Fatica  29 , Iman Francis  30 , Justyna Fryc  31 , John Gill  32 , Jagbir Gill  32 , Maciej Glyda  33 , Sita Gourishankar  1 , Ryszard Grenda  34 , Marta Gryczman  35 , Petra Hruba  36 , Peter Hughes  21 , Arskarapurk Jittirat  37 , Zeljka Jurekovic  38 , Layla Kamal  39 , Mahmoud Kamel  15 , Sam Kant  40 , Bertram Kasiske  41 , Nika Kojc  42 , Joanna Konopa  20 , James Lan  32 , Roslyn Mannon  43 , Arthur Matas  44 , Joanna Mazurkiewicz  45 , Marius Miglinas  46 , Thomas Müller  47 , Seth Narins  48 , Beata Naumnik  31 , Anita Patel  30 , Agnieszka Perkowska-Ptasińska  24 , Michael Picton  49 , Grzegorz Piecha  50 , Emilio Poggio  51 , Silvie Rajnochová Bloudíčkova  52 , Milagros Samaniego-Picota  53 , Thomas Schachtner  54 , Sung Shin  55 , Soroush Shojai  56 , Majid L N Sikosana  1 , Janka Slatinská  36 , Katarzyna Smykal-Jankowiak  33 , Ashish Solanki  57 , Željka Veceric Haler  14 , Ksenija Vucur  58 , Matthew R Weir  59 , Andrzej Wiecek  50 , Zbigniew Włodarczyk  60 , Harold Yang  61 , Ziad Zaky  62
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Free article

Subthreshold rejection activity in many kidney transplants currently classified as having no rejection

Philip F Halloran et al. Am J Transplant. 2025 Jan.
Free article

Abstract

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

Keywords: ABMR; TCMR; biopsy; gene expression; gradients; kidney transplant; microarray; transplant 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 the American Journal of Transplantation. P.F. Halloran holds shares in Transcriptome Sciences Inc., a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between Transcriptome Sciences Inc. and Thermo Fisher Scientific, and by a research grant from Natera, Inc. P.F. Halloran is a consultant to Natera, Inc. and Argenx BV. The other authors have declared no conflict of interest exists.