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Label-free Identification of Antibody-mediated Rejection in Cardiac Allograft Biopsies Using Infrared Spectroscopic Imaging

Uraizee, Imran, MD1; Varma, Vishal K., PhD2; Sreedhar, Hari, BS3; Gambacorta, Francesca, BS3; Nazeer, Shaiju S., PhD3; Husain, Aliya, MD1; Walsh, Michael J., PhD3,2

doi: 10.1097/TP.0000000000002465
Original Basic Science—General
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Background. Antibody-mediated rejection (AMR) in cardiac allograft recipients remains less well-understood than acute cellular rejection, is associated with worse outcomes, and portends a greater risk of developing chronic allograft vasculopathy. Diffuse immunohistochemical C4d staining of capillary endothelia in formalin-fixed, paraffin-embedded right ventricular endomyocardial biopsies is diagnostic of immunopathologic AMR but serves more as a late-stage marker. Infrared (IR) spectroscopy may be a useful tool in earlier detection of rejection. We performed mid-IR spectroscopy to identify a unique biochemical signature for AMR.

Methods. A total of 30 posttransplant formalin-fixed paraffin-embedded right ventricular tissue biopsies (14 positive for C4d and 16 negative for C4d) and 14 native heart biopsies were sectioned for IR analysis. Infrared images of entire sections were acquired and regions of interest from cardiomyocytes were identified. Extracted spectra were averaged across many pixels within each region of interest. Principal component analysis coupled with linear discriminant analysis and predictive classifiers were applied to the data.

Results. Comparison of averaged mid-IR spectra revealed unique features among C4d-positive, C4d-negative, and native heart biopsies. Principal component analysis coupled with linear discriminant analysis and classification models demonstrated that spectral features from the mid-IR fingerprint region of these 3 groups permitted accurate automated classification into each group.

Conclusions. In cardiac allograft biopsies with immunopathologic AMR, IR spectroscopy reveals a biochemical signature unique to AMR compared with that of nonrejecting cardiac allografts and native hearts. Future study will focus on the predictive capabilities of this IR signature.

1 Department of Pathology, University of Chicago, The University of Chicago Medicine, Chicago, IL.

2 Department of Bioengineering, University of Illinois at Chicago, Chicago, IL.

3 Department of Pathology, University of Illinois at Chicago, Chicago, IL.

Received 17 April 2018. Revision received 11 September 2018.

Accepted 12 September 2018.

I.U. and V.K.V. are co-first authors. A.H. and M.J.W. are co-senior authors. I.U. participated in research design, identifying patients, analyzing data, and writing the article. V.K.V. participated in research design, collecting spectral data, analyzing spectral data, and writing the article. H.S. participated in analyzing spectral data and writing the article. F.G. participated in collecting spectral data. S.N. participated in analyzing spectral data and writing the article. A.H. participated in research design, identifying patients, and writing the article. M.W. participated in research design, analyzing data, and writing the article.

The authors declare no conflicts of interest.

This work was funded by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (Husain and Walsh joint PIs).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Michael John Walsh, PhD, 840 S Wood St, Rm 130 CSN (MC847), 909 S Wolcott Ave, Chicago, IL 606012. (walshm@uic.edu).

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