Abstract: FR-OR62
Validation of Diagnostic, Prognostic, and Predictive Performances of a Novel Urinary Exosomal mRNA Clinical Test
Session Information
- Kidney Transplantation: Biomarkers, New and Old
November 03, 2023 | Location: Room 115, Pennsylvania Convention Center
Abstract Time: 04:39 PM - 04:48 PM
Category: Transplantation
- 2102 Transplantation: Clinical
Authors
- El Fekih, Rania, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
- Haynes, Brian C., Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, United States
- Merhej, Tamara, Transplant Research Center, Boston, Massachusetts, United States
- Halawi, Ahmad, Transplant Research Center, Boston, Massachusetts, United States
- Younis, Nour Khaled, Transplant Research Center, Boston, Massachusetts, United States
- Chandraker, Anil K., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
- Riella, Leonardo V., Mass General Brigham Inc, Boston, Massachusetts, United States
- Skog, Johan, Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, United States
- Azzi, Jamil R., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
Group or Team Name
- Transplant Research Center, Brigham and Women's Hospital.
Background
Urinary Exosomes contain a biological payload of proteins and nucleic acids that reflect the physiology of the parent cells (kidney cells and immune infiltrates). Here we further characterize diagnostic performances of a novel urinary exosomal mRNA multigene signature for the diagnosis of any-cause rejection in kidney transplant, and describe its prognostic and predictive performances.
Methods
A total of 411 urine samples -from 366 patients- were collected at time of clinically indicated or protocol kidney biopsy. The transcript of 17 gene targets were pre-amplified and evaluated by RT-qPCR. Cross validation was applied to estimate the performance of the gene signatures. A composite endpoint of subsequent events were determined using the electronic medical records, and outcomes in subjects with positive and negative exosome signature were compared.
Results
The multi-gene classifier accurately distinguished any-cause rejection from no rejection, in the for-cause cohort (AUC 0.731) and the protocol biopsies cohort (AUC 0.781). We further identified a 5-gene signature (IL18BP, CXCL11, CD74, CD44, C3) that accurately distinguishes TCMR from ABMR with an AUC of 0.756. Majority of rejection negative by biopsy classified as positive by our model (false positive) showed significant underlying inflammation on biopsy such as lymphoproliferative infiltrate, moderate to significant lymphocytic infiltration, interstitial nephritis (BKV nephritis or acute interstitial nephritis), glomerulopathy or immune complex deposition. Furthermore, the remaining inflammation negative but positive urinary exosome scores were associated with three-fold increase in risk development of composite outcomes of subsequent rejection, decrease eGFR and loss of allograft at 3 years. The exosomal score showed a mean decrease of -0.05666 (p 0.0431) in responders to rejection treatment.
Conclusion
Urinary exosomal mRNA is a non-invasive clinical test that offers an insight into the status of the immune activation in the kidney allograft, and complement other laboratory surveillance strategies as a diagnostic, prognostic and predictive marker and risk-stratification
tool in kidney transplant recipients. This assay is now ready for clinical use.
Funding
- Other NIH Support – ExosomeDx, a Biotechne brand