12 Mar Urine Test Can Predict Kidney Transplant Rejection, Avoiding Need for Biopsy
MedicalResearch.com Interview with:
Jamil R. Azzi MD
Associate Professor of Medicine, Harvard Medical School
Medical Director, Vascularized Composite Allotransplantation
Associate Director, Kidney and Pancreas Transplantation
Director, Kidney Transplant Fellowship
Engineering in Medicine, Brigham and Women’s Hospital
Renal Division, Brigham and Women’s Hospital
MedicalResearch.com: What is the background for this study? Would you explain what is meant by an exosome?
Response: Kidney transplant recipients are always at risk of developing rejection where the immune system recognizes the transplanted kidney as “foreign body” and attacks it. The risk is up to 20% the first year after transplant and many more develop chronic rejection which ultimately leads to kidney failure. Currently, most clinicians monitor for kidney rejection by measuring serum creatinine and urine protein. However, creatinine is neither sensitive nor specific for rejection. On the other hand, performing kidney biopsies to make accurate diagnosis of rejection is invasive and has many complications. In our study, when clinicians decided on performing biopsies based on the clinical informations they have including changes in serum creatinine, the biopsies did not show rejection in almost 70% of the cases. Furthermore, serum creatinine can remain stable while the patient may be undergoing a rejection (subclinical rejection). In fact, some centers currently perform routine biopsies at different time points for all their patients regardless of creatinine despite the high risks, costs and inconveniences of doing biopsies.
Out of this frustration with the current tools, we have been working on novel technologies to diagnose rejection through the urine. The idea started from the bench as we were studying exosomes, those are tiny vesicles (less than 100 nm in size) released by all cells. We were interested on how immune cells communicate via those vesicles so we developed assays to identify them. We then showed that if immune cells are invading the kidney during rejection, vesicles derived from those immune cells are found in the urine. This gave us the idea of developing a urine test based on these findings.
MedicalResearch.com: What are the main findings? Would this urine test be widely available?
Response: Based on analysis of over 200 urine samples taken from patients undergoing a kidney biopsy, we identified an exosomal multigene signature that can discriminate between rejection and no rejection with a negative predictive value of 93.3% and a positive predictive value of 86.2% and can also differentiates between “T-cell mediated rejection (TCMR) vs. antibody mediated rejection (ABMR)” with a NPV of 90.6%. The exciting part is that the exosomal vesicles protect mRNA from degrading, allowing for reproducibility of the signature overtime and allow for at home base testing. The work has been done in collaboration with ExosomeDx that will be offering the test under the name ExoTRU (Exosome Transplant Rejection Urine) in 2021.
MedicalResearch.com: What should readers take away from your report?
Response: We developed a non-invasive urine test that can accurately predict rejection in kidney transplant recipients with clinical suspicion of rejection and hence prevent unnecessary biopsies. ExoTRU test can be done without the patients leaving their homes.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are currently investigating whether ExoTRU can predict rejection before it clinically manifests and if it can detect hidden rejection or what we call subclinical rejections.
Any disclosures? Azzi reports having intellectual properties and receiving royalties from Accrue Health Inc.; receiving research funding from NIH, the American Diabetes Association, American Heart Association, and Qatar Research Fund; being a scientific advisor for CareDx; and having intellectual properties in ExosomeDx. Co-authors are employees of Exosome Diagnostics, a Bio-Techne brand.
Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection
Rania El Fekih, James Hurley, Vasisht Tadigotla, Areej Alghamdi, Anand Srivastava, Christine Coticchia, John Choi, Hazim Allos, Karim Yatim, Juliano Alhaddad, Siawosh Eskandari, Philip Chu, Albana B. Mihali, Isadora T. Lape, Mauricio P. Lima Filho, Bruno T. Aoyama, Anil Chandraker, Kassem Safa, James F. Markmann, Leonardo V. Riella, Richard N. Formica, Johan Skog and Jamil R. Azzi
JASN March 2021, ASN.2020060850; DOI: https://doi.org/10.1681/ASN.2020060850
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