@article{4824a247fe8449998ae0b26707254710,
title = "Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection",
abstract = "Background: Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes thema potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. Methods: Using 192 of 220 urine samples withmatched biopsy samples from175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.Results: An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFRAUCof 0.57;95%CI, 0.49 to0.65). The exosome-based signature's negativepredictive value was 93.3% and its positive predictive valuewas 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with anAUCof 0.87; 95%CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%.Conclusions: Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.",
author = "Fekih, {Rania El} and James Hurley and Vasisht Tadigotla and Areej Alghamdi and Anand Srivastava and Christine Coticchia and John Choi and Hazim Allos and Karim Yatim and Ano Alhaddad and Siawosh Eskandari and Philip Chu and Mihali, {Albana B.} and Lape, {Isadora T.} and Filho, {Mauricio P.Lima} and Aoyama, {Bruno T.} and Anil Chandraker and Kassem Safa and Markmann, {James F.} and Riella, {Leonardo V.} and Formica, {Richard N.} and Johan Skog and Azzi, {Jamil R.}",
note = "Funding Information: This project was supported by American Heart Association award 13FTF17000018 (to J.R. Azzi) and National Institutes of Health (NIH) grant RO1 AI134842 (to J.R. Azzi). This project was also partially supported by Exosome Diagnostics, a Bio-Techne brand. A. Srivastava was supported by NIH Clinical Center grant F32DK11106. Funding Information: J.R. Azzi, C. Coticchia, J. Hurley, J. Skog, and V. Tadigotla have intellectual properties related to this work. J.R. Azzi reports having intellectual properties and receiving royalties from Accrue Health Inc.; receiving research funding from the American Diabetes Association, American Heart Association, and Qatar Research Fund; being a scientific advisor for CareDx; and having intellectual properties in ExosomeDx. C. Coticchia, J. Hurley, J. Skog, and V. Tadigotla are employees of Exosome Diagnostics, a Bio-Techne brand. R.N. Formica reports being the president of the American Society of Transplantation; having consultancy agreements with Genentech Pharmaceutical and Veloxis Pharmaceuticals; being on a speakers bureau for Novartis Pharmaceuticals; being on the visiting committee for the Scientific Registry of Transplant Recipients (January 1, 2018); and being a member of the United Network for Organ Sharing/Organ Procurement and Transplantation Network Membership and Professional Standards Committee. J.F. Markmann reports having consultancy agreements with, ownership interest in, and being a scientific advisor for (or member of) eGenesis and QihanBio. L.V. Riella reports receiving research funding from Bristol Myers Squibb and Visterra, and being a scientific advisor for or member of CareDx. J. Skog reports having ownership interest in Bio-Techne and patents and inventions with Massachusetts General Hospital. A. Srivastava reports being on a speakers bureau for AstraZeneca; receiving honoraria from AstraZeneca and Horizon Therapeutics PLC; and having consultancy agreements with CVS Caremark and Tate & Latham (medicolegal consulting). A. Chandraker reports consultancy agreements with Mitobridge, Shire, Amgen, Immucor, Natera, and Allovir; receiving research funding from ReNu, CSL, Shire, Amgen, and Allovir; receiving honoraria from Hansa, Natera, and eGenesis; reports being a scientific advisor or membership with American Society of Transplantation as Development Chair, Transplant Therapeutics Consortium as Governance Committee and Past Chair, CEoT as Co-Chair, Transplant Metrics as Chair, and Scientific American as Editor for Nephrology. All remaining authors have nothing to disclose. Publisher Copyright: {\textcopyright} 2021 American Society of Nephrology. All rights reserved.",
year = "2021",
month = apr,
doi = "10.1681/ASN.2020060850",
language = "English",
volume = "32",
pages = "994--1004",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "AMER SOC NEPHROLOGY",
number = "4",
}