{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:55:23Z","timestamp":1790772923667,"version":"4.1.0"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","funder":[{"DOI":"10.13039\/100008762","name":"Genome Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000190","name":"University of Alberta","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005263","name":"Ministry of Innovation and Advanced Education and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013148","name":"Mendez National Institute of Transplantation Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013148","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Industrial Research Assistance Program"},{"name":"One Lambda Division"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,11]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Many kidney transplant patients in INTERCOMEX whose biopsy specimens are diagnosed molecularly or histologically as no rejection have donor-specific HLA antibodies (DSAs, 32%). Although the significance of DSA in no rejection has been unclear, we hypothesized that current diagnostic thresholds miss some DSA-positive patients who may have subtle antibody-mediated rejection (ABMR)\u2013related stress, with potential effect on outcomes. To search for subtle ABMR-related gene expression in \u201cno rejection\u201d biopsy samples, we developed a \u201cDSA-probability\u201d classifier (trained on DSA positivity) in microarray results from 1679 biopsy samples that detected ABMR-related transcripts (\n e.g.,<\/jats:italic>\n NK cell and IFNG-inducible). Many no rejection biopsy samples had mildly increased expression of ABMR-related transcripts, associated with DSA positivity, and these kidneys had increased risk of failure. Thus, mild ABMR-related stress is more common than previously thought.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 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%).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)\u2013related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSA\n Prob<\/jats:sub>\n ) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSA\n Prob<\/jats:sub>\n classifier was very similar to a previously described \u201cABMR probability\u201d 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 (\n P<\/jats:italic>\n <2\u2009\u00d7\u200910\n \u221216<\/jats:sup>\n ). In biopsies with no molecular or histologic rejection, increased DSA\n Prob<\/jats:sub>\n or ABMR probability scores were associated with increased risk of kidney failure over 3 years.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021040433","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T14:45:14Z","timestamp":1626101114000},"page":"2743-2758","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":45,"title":["Donor-Specific Antibody Is Associated with Increased Expression of Rejection Transcripts in Renal Transplant Biopsies Classified as No Rejection"],"prefix":"10.1681","volume":"32","clinical-trial-number":[{"clinical-trial-number":"nct01299168","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Katelynn S.","family":"Madill-Thomsen","sequence":"first","affiliation":[{"name":"Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg A.","family":"B\u00f6hmig","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Bromberg","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Microbiology and Immunology, University of Maryland, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunilla","family":"Einecke","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farsad","family":"Eskandary","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1919-1970","authenticated-orcid":false,"given":"Gaurav","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis G.","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Myslak","sequence":"additional","affiliation":[{"name":"Pomeranian Medical University, Department of Clinical Interventions and Department of Nephrology and Kidney Transplantation, Samodzielny Publiczny Wojewodzki Szpital Zespolony, Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondrej","family":"Viklicky","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Perkowska-Ptasinska","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Warsaw, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1371-1947","authenticated-orcid":false,"given":"Philip F.","family":"Halloran","sequence":"additional","affiliation":[{"name":"Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada"},{"name":"Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the INTERCOMEX 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