Innovative Discovery Could Revolutionize Kidney Transplant Rejection Diagnostics: Collaboration for Translation to Clinic

For over three decades, Weill Cornell Medicine nephrologist Dr. Manikkam Suthanthiran has been dedicated to one goal: making transplanted organs work better and longer in more patients.

Dr. Manikkam Suthanthiran (Provided)

Any organ transplant will be subject to rejection since it is a foreign object in a patient’s body. Dr. Suthanthiran, chief of the Division of Nephrology and Hypertension, chief of transplantation medicine and the Stanton Griffis Distinguished Professor of Medicine, began looking for a way to prevent organ rejection as early as the 1980s, when his laboratory initiated studies of T cell activation given the central role of T cells in mediating rejection. The Suthanthiran laboratory discovered that the CD2, a surface protein expressed on T cells, plays a pivotal role in the activation process essential for the rejection response. Importantly, the laboratory demonstrated that an anti-CD2 monoclonal antibody not only blocks rejection but also induces transplant tolerance in a preclinical model. In a landmark study published in the New England Journal of Medicine, tolerance to human kidney transplants was successfully induced using anti-CD2 antibodies, marking a significant advance in the field of transplantation immunology. Additional discoveries from the Suthanthiran laboratory include elucidating the mechanisms of action of immunosuppressive drugs used to prevent organ graft rejection and uncovering the molecular pathways of cytotoxic T cells and natural killer cells, both of which are key contributors to transplant rejection.   

Then in 2001, the Suthanthiran laboratory discovered that the biological evidence of kidney transplant rejection can be detected in urine—a finding that culminated in a patented urine gene expression biomarker test that has been licensed to a biotech specialized in transplantation for further commercialization. This noninvasive technology has the potential to predict kidney transplant rejection so that clinicians can intervene early and individualize treatments for patients.

Liquid Gold

The current standard for diagnosing kidney allograft rejection is the kidney allograft biopsy. This procedure is invasive, complicated and risky. Although it’s uncommon that patients die from a kidney allograft biopsy nowadays, putting a needle into the kidney transplant can lead to bleeding, which may not be an option for patients who are on anticoagulants.

While reviewing kidney transplant biopsies, Dr. Suthanthiran observed that during rejection, several immune cell types exit their vascular niche, infiltrate the kidney tissue, and gain access to urine. This observation led him to explore urine as a noninvasive alternative to biopsy for monitoring rejection. A series of thematically related studies from the Suthanthiran laboratory have demonstrated that profiling urine for cytotoxic lymphocytes and other immune cell subsets offer a unique and noninvasive window into the molecular events unfolding within the kidney transplant during episodes of rejection. This approach, pioneered at Weill Cornell, has gained traction globally, with researchers within and outside the United States now leveraging urinary immune cell signatures to interrogate transplant rejection. The development of a urine-based assay holds transformative potential for kidney transplantation, promising to reduce reliance on invasive biopsy procedures and to advance the field towards precision transplantation medicine.

Dr. Suthanthiran and his team demonstrated in a 2001 New England Journal of Medicine article that molecular signatures in urine reflect what happens in a kidney transplant and are comparable to biopsy findings. The study, funded by a prestigious, decade-long National Institutes of Health Merit Grant*, identified elevated levels of messenger RNA (mRNA) for perforin and granzyme B, two proteins released by immune killer cells to cause cell death, in urine correlate to acute kidney transplant rejection. The Suthanthiran laboratory was able to achieve this result by innovating a quantitative PCR assay to detect the amount of mRNA in urine.

Building on this earlier work, Dr. Suthanthiran published a 2013 New England Journal of Medicine study on urine cell mRNA and kidney allograft rejection, which the Clinical Research Forum named one of the top 10 research papers in the United States that year and the NIH identified as a model of great discoveries.

“Urine is even better than biopsy. When you do a biopsy, you're only getting a small piece of one kidney; whereas, urine is a collection of the whole kidney transplant,” said Dr. Suthanthiran. “I think urine is liquid gold.”

In recent years, he continues to research other aspects of urine gene expressions, refine his PCR assay to study T cell biology and employ RNA sequencing technology so that he can “look into the whole universe of genes” available.

For these and other contributions, Dr. Suthanthiran was awarded The Medawar Prize from The Transplantation Society in 2022, the highest honor bestowed by the International Transplantation Society. Dr. Suthanthiran is also the recipient of the Jean Hamburger award, the highest honor bestowed by the International Society of Nephrology, in recognition of his outstanding contributions to the field of nephrology.

Road to Commercialization

As a dedicated scientist and mentor, Dr. Suthanthiran has always prioritized research and teaching over entrepreneurship. When fellow transplantation colleagues and biotech companies approached Dr. Suthanthiran about joining them or founding startups, he declined.

He focused on writing papers and grants over patents, Dr. Suthanthiran said, even though the business development and licensing staff from the Center for Technology Licensing (CTL) at Weill Cornell were enthusiastic about obtaining patents for his innovations because they saw the commercial potentials.

He felt surprised when the former CEO of CareDx, one of the major players of molecular diagnostics that already had a test in the market generating substantial revenue, asked him to collaborate with them at an international transplantation meeting. “My test was complementary to his. He was able to see the big picture,” reminisced Dr. Suthanthiran. “He had a good vision.”

As a result, CTL helped negotiate a research collaboration agreement with CareDx for Dr. Suthanthiran’s patented technology. On top of funding continued research for the biomarker test, CareDx will also get it to clinics and apply for Medicare approval.

Currently, Dr. Suthanthiran, his industry collaborator and Dr. Louise Sarup, his technology portfolio manager at CTL, are developing a device for patients to collect urine samples at home and send those to a laboratory for tests. Compared to biopsy, the advantage of a urine test is that patient samples can be collected more frequently to monitor transplant rejection as opposed to every six to 12 months. However, urine collection, preservation and transportation could be challenging if not done in a clinical setting.

The Suthanthiran laboratory is also conducting more experiments to get robust data to ensure the urine gene expression test gets to the clinic. “This test could make a huge impact on transplantation practice and transplant care,” Dr. Suthanthiran said. “My major goal is to reach patients. We have joined forces with CareDx to help bring our discovery to the clinic. I am deeply grateful to our Center for Technology Licensing and to Dr. Sarup for their instrumental role in facilitating this collaboration and advancing the clinical translation of our research. Our work has always been guided by a commitment to addressing patients’ needs, and I am optimistic that our noninvasive assay will be available in clinical practice within the next few years.”