TY - JOUR
T1 - Donor-specific antibody is associated with increased expression of rejection transcripts in renal transplant biopsies classified as no rejection
AU - the INTERCOMEX Investigators
AU - Madill-Thomsen, Katelynn S.
AU - Böhmig, Georg A.
AU - Bromberg, Jonathan
AU - Einecke, Gunilla
AU - Eskandary, Farsad
AU - Gupta, Gaurav
AU - Hidalgo, Luis G.
AU - Myslak, Marek
AU - Viklicky, Ondrej
AU - Perkowska-Ptasinska, Agnieszka
AU - Halloran, Philip F.
AU - Mannon, Roslyn
AU - Serón, Daniel
AU - Sellarés, Joana
AU - Akalin, Enver
AU - de Freitas, Declan
AU - Picton, Michael
AU - Weir, Matt
AU - Budde, Klemens
AU - Heinbokel, Timm
AU - Yang, Harold
AU - Narins, Seth
AU - Samaniego-Picota, Milagros
AU - Lefaucheur, Carmen
AU - Loupy, Alexandre
AU - Bingaman, Adam
AU - Brennan, Daniel
AU - Malone, Andrew
AU - Kasiske, Bertram
AU - Matas, Arthur
AU - Djamali, Arjang
N1 - Funding Information:
This research has been principally supported by grants from Genome Canada, Canada Foundation for Innovation, the University of Alberta Hospital Foundation, the Alberta Ministry of Innovation and Advanced Education and Technology, the Mendez National Institute of Transplantation Foundation, and the Industrial Research Assistance Program. Partial support was also provided by funding from a licensing agreement with the One Lambda Division of Thermo Fisher.
Funding Information:
G.A. Bo€hmig reports Consultancy Agreements with Vitaeris Inc, Vancouver, Canada; Research Funding from CareDx and Vitaeris Inc.; Honoraria from Astellas, Fresenius Medical Care, OneLambda, and Sandoz; and Scientific Advisor or Membership with CSL Behring and Vitaeris Inc. J. Bromberg reports Consultancy Agreements with Eurofins; Research Funding from Angion, Astellas, CareDx, Natera, Novartis, and Quark; and Scientific Advisor or Membership with the NIH and Transplantation. G. Einecke reports Honoraria from Biotest AG, CareDx, Chiesi GmbH, and Novartis AG; Scientific Advisor or Membership with Biotest AG, CareDx, Chiesi GmbH, and Novartis AG; and Other Interests/Relationships as Committee member in the German Society for Immunogenetics and the German Society of Transplantation (DTG). G. Gupta reports Consultancy Agreements with CareDx; Research Funding from Gilead Pharmaceuticals; Honoraria from Alexion, CareDx, Mallinckrodt, Natera, and Veloxis; Scientific Advisor or Membership with Frontiers of Medicine; Speakers Bureau with Alexion, CareDx, Mallinckrodt, and Veloxis; and Other Interests/Relationships with AST KOP Executive Committee, AST Transplant Nephrology Fellowship Accreditation Committee, and the National Kidney Foundation Virginia. P.F. Halloran holds shares in Transcriptome Sciences Inc., a University of Alberta research company with an interest in molecular diagnostics; has given lectures for Thermo Fisher; and is a consultant for CSL Behring. P.F. Halloran also reports Honoraria from Astellas; Scientific Advisor or Membership as Chief Executive Officer of Transcriptome Sciences Inc.; Editor-in-chief emeritus of the American Journal of Transplantation; and Speakers Bureau from Astellas and One Lambda. P.F. Halloran held a Canada Research Chair in Transplant Immunology until 2008 and currently holds the Muttart Chair in Clinical Immunology. K.S. Madill-Thomsen reports current employment with Transcriptome Sciences Inc., a University of Alberta Research Company. L.G. Hidalgo reports Scientific Advisor or Membership a as member of the American Society of Histocompatibility and Immunogenetics Board of Directors. O. Viklicky reports Honoraria from Astellas, Chiesi, Fresenius; and Scientific Advisor or Membership with Bayer. A. Perkowska-Ptasinska reports Research Funding from Travere; and Honoraria from Chiesi, Roche, and Travere. All remaining authors have nothing to disclose.
Publisher Copyright:
Copyright © 2021 by the American Society of Nephrology
PY - 2021/11
Y1 - 2021/11
N2 - Background Donor -specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no rejection (NR). We explored whether in some NR kidneys DSA has subtle effects not currently being recognized. Methods We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). Results DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described “ABMR probability” classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2 3 10216). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over 3 years. Conclusions Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus, mild molecular ABMR-related pathology is more common than previously realized.
AB - Background Donor -specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no rejection (NR). We explored whether in some NR kidneys DSA has subtle effects not currently being recognized. Methods We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). Results DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described “ABMR probability” classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2 3 10216). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over 3 years. Conclusions Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus, mild molecular ABMR-related pathology is more common than previously realized.
UR - http://www.scopus.com/inward/record.url?scp=85119127225&partnerID=8YFLogxK
U2 - 10.1681/ASN.2021040433
DO - 10.1681/ASN.2021040433
M3 - Article
C2 - 34253587
AN - SCOPUS:85119127225
SN - 1046-6673
VL - 32
SP - 2743
EP - 2758
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 11
ER -