Philip F Halloran1, Luciano Potena2, Jean-Paul Duong Van Huyen3, Patrick Bruneval4, Ornella Leone2, Daniel H Kim5, Xavier Jouven6, Jeff Reeve7, Alexandre Loupy3. 1. Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address: collegamentointernetphallora@ualberta.ca. 2. Cardiovascular Department, University of Bologna, Bologna, Italy. 3. Paris Translational Research Centre for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale , UMR-S970, Paris, France. 4. Paris Translational Research Centre for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale , UMR-S970, Paris, France; Department of Pathology, Necker & Georges Pompidou Hospitals, Paris, France. 5. Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 6. Paris Translational Research Centre for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale , UMR-S970, Paris, France; Cardiology and Heart Transplant Department, Georges Pompidou Hospital, Paris, France. 7. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Abstract
BACKGROUND: The emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens. The present study developed a microarray-based system for assessing heart transplant endomyocardial biopsy (EMB) specimens. METHODS: We analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both. To compare EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection. RESULTS: The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology. Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection. This permitted each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score. There was significant agreement between molecular phenotype-archetype scores or clusters-and both histologic diagnoses and donor-specific antibody. Area under curve estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR. CONCLUSIONS: Rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines.
BACKGROUND: The emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens. The present study developed a microarray-based system for assessing heart transplant endomyocardial biopsy (EMB) specimens. METHODS: We analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both. To compare EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection. RESULTS: The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology. Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection. This permitted each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score. There was significant agreement between molecular phenotype-archetype scores or clusters-and both histologic diagnoses and donor-specific antibody. Area under curve estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR. CONCLUSIONS: Rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines.
Authors: Jana Lipkova; Tiffany Y Chen; Ming Y Lu; Richard J Chen; Maha Shady; Mane Williams; Jingwen Wang; Zahra Noor; Richard N Mitchell; Mehmet Turan; Gulfize Coskun; Funda Yilmaz; Derya Demir; Deniz Nart; Kayhan Basak; Nesrin Turhan; Selvinaz Ozkara; Yara Banz; Katja E Odening; Faisal Mahmood Journal: Nat Med Date: 2022-03-21 Impact factor: 87.241
Authors: Hidetoshi Tsuda; Nina Dvorina; Karen S Keslar; Jessica Nevarez-Mejia; Nicole M Valenzuela; Elaine F Reed; Robert L Fairchild; William M Baldwin Journal: Am J Pathol Date: 2022-04-29 Impact factor: 5.770
Authors: Philip F Halloran; Jeff Reeve; Arezu Z Aliabadi; Martin Cadeiras; Marisa G Crespo-Leiro; Mario Deng; Eugene C Depasquale; Johannes Goekler; Xavier Jouven; Daniel H Kim; Jon Kobashigawa; Alexandre Loupy; Peter Macdonald; Luciano Potena; Andreas Zuckermann; Michael D Parkes Journal: JCI Insight Date: 2018-10-18