Urinary Exosome Mrna Signature for the Diagnosis of Human Kidney Transplant Rejection

R. El Fekih¹, J. Hurley², V. Tadigotla², A. Alghamdi³, A. Srivastava⁴, C. Coticchia², J. Choi¹, H. Allos⁵, k. yatim⁵, J. Alhaddad⁵, S. Eskandari⁵, P. Chu⁵, A. Mihali⁵, I. Lape⁵, M. Lima Filho⁵, B. Ayoma⁵, A. Chandraker⁵, K. Safa⁶, J. Markmann⁶, L. Riella⁶, R. Formica⁷, J. Skog², J. Azzi⁵

¹Medecine, Brigham and Women Hospital, Boston, MA, ²Exosome Diagnostics, Boston, MA, ³Boston Children Hospital, Boston, MA, ⁴Center for Translational Metabolism and Health, Chicago, IL, ⁵Transplantation Research Center, Boston, MA, ⁶Massachusetts General Hospital, Boston, MA, ⁷Yale School of Medicine, New Haven, CT

Meeting: 2021 American Transplant Congress

Abstract number: 639

Keywords: Genomic markers, Kidney, Rejection

Topic: Clinical Science » Biomarkers, Immune Assessment and Clinical Outcomes

Session Information

Session Name: Biomarkers, Immune Assessment and Clinical Outcomes

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*Purpose: Traditional biomarkers currently used to monitor the kidney allograft, such as creatinine and proteinuria, are late markers of injury and lack sensitivity, specificity and predictive abilities. The stability of urinary exosomes makes them a potentially powerful tool for liquid-biopsy and an ideal non-invasive diagnostic biomarker for kidney-transplant rejection

*Methods: We collected 220 urine samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy. Urinary exosomal mRNA were isolated using Exosome Diagnostics’ EXOPRO Urine Clinical Sample Concentrator Kit and a differential gene-expression was used to develop rejection signatures. An initial panel of 586 TaqMan assays (TaqMan® OpenArray® Human Inflammation) for genes that have been studied as targets for a range of inflammatory diseases, and a subset 112 TaqMan assays were used to analyze the urine samples. The Boruta algorithm was used for feature selection. We used a repeated K-fold cross-validation (K=10, repeats=10) to generate the rejection probabilities. This allowed us to identify a 15-gene signature that distinguished biopsy with any cause rejection from no rejection. Furthermore, using the same approach, we have identified a 5-genes signature that distinguished TCMR from ABMR

*Results: We have identified a 15-gene signature that discriminated biopsies with any-cause rejection from no-rejection. The area under the curve (AUC) was 0.90 (95% CI 0.85 – 0.96). Negative predictive value (NPV) for active rejection was 93.3% (95% CI 87.7% – 96.4%) and the sensitivity was 84.7% (95% CI 73.5% – 91.8%). The AUC for delta eGFR, was 0.57 (95% CI 0.49 – 0.65), which was significantly inferior (p < 0.001) to the performance of the multi-gene signature. A 5-gene signature that could distinguish TCMR from ABMR, was subsequently identified. The AUC for this signature was 0.87 (95% CI 0.76 - 0.97). If the second signature is negative, the patient has TCMR, and ABMR is ruled out with an NPV of 90.6% (95% CI 75.8% - 96.8%) and a sensitivity of 87.5% (95% CI 69.0% - 95.7%).

*Conclusions: We show here that mRNA signatures derived from urinary exosomes represent a powerful and non-invasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision-making

To cite this abstract in AMA style:

Fekih REl, Hurley J, Tadigotla V, Alghamdi A, Srivastava A, Coticchia C, Choi J, Allos H, yatim k, Alhaddad J, Eskandari S, Chu P, Mihali A, Lape I, Filho MLima, Ayoma B, Chandraker A, Safa K, Markmann J, Riella L, Formica R, Skog J, Azzi J. Urinary Exosome Mrna Signature for the Diagnosis of Human Kidney Transplant Rejection [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/urinary-exosome-mrna-signature-for-the-diagnosis-of-human-kidney-transplant-rejection/. Accessed November 25, 2024.

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