Potential new therapy offers promising approach to treat rare, incurable form of kidney stone resistance

A study led by investigators at the University of Utah Health System (U of U Health) has revealed that a single immunotherapy treatment based on the use of a vaccine developed in partnership with St. Jude Children’s Research Hospital resulted in a significant drops in markers indicating kidney stones in test animals. The discovery, reported today in Science Translational Medicine, could open a new path to treating the severe form of kidney stone resistance found in many people with the rare condition. The immunotherapy could also be used to treat relapses following kidney transplants.

“I think kids are looking at one in three who undergo kidney transplants with kidney stones and not all have the immunosuppressive drugs,” said Joel B. Snyder, MD, reporting lead author and deputy director of the St. Jude Laboratory Developmental Therapeutics Program. “This immuno-oncology approach involves finding inhibitors (drugs) for specific antibodies that recognize the abnormal protein fragments (~70%) expressed by kidney stones in the recipient.”

A common therapy, immunosuppressive drugs called ACE2 inhibitors, cause long-term uncontrolled inflammation of the kidneys. These drugs have limited ability to reach the vulnerable cells within the kidneys. In this study, Snyder’s team got a dose of the standard immunosuppressive drug drusen plasminogen activator 2 (DROMIUM) in mice with kidney stones. After giving the mice the standard of care, it was shown that immunosuppression with DROMIUM is associated with persistent kidney stone-binding in the treated mice, demonstration of previous research suggested.

The study deployed GRASNA (GlycoT-FOX-like immune reaction) against a human protein (not found in human kidney stones) on the surface of kidney stones and gained significant immunosuppressive and anti-inflammatory responses. The immunosuppressive drugs provided lifelong immunosuppression and anti-inflammatory responses, anti-vascular cell death, and improved glucose and lipid metabolism. Using a human chimeric antigen receptor (CAM-R) system, the researchers found that DROMIUM-treated mice were able to overcome severe kidney stone-induced inflammation and blocked and normalized normal tail cells, swelling, and glucose intolerance.

It also showed that CD8+CD4+ T cells, which are the type of T cells involved in immune response to foreign or foreign-laden macrophages, reduced inflammation and increased apoptosis, all supportive of the body’s tissue response to kidney stones in test animals.

The next step in our research is to have this approach translate into clinical trial for humans.”

Dr. Joel B. Snyder, MS, study’s senior author, associate professor of pediatrics, and director of U of U Health’s Juvenile Liver Disease and Inflammation Research Program.

“There are so many drug-resistant people, and this is really a never-ending problem. The first line that comes to mind is immunocompromised patients” said study first author and senior author John Wilhelm, PhD, an M.D., co-director of the Laura and Ken Rample Kidney Center.

“If immunotherapies could work for patients, which is the objective as it creates immunity to loss of function, we will be able to secure drug treatment for a very long time and be able to fight cancer for a significant period of time.”

Even with the success of novel drugs against ADA-resistant tumors, developing and implementing an extensive immunotherapy program for renal failure is one of the biggest challenges in the field. Further, a comprehensive anti-drug-based immunotherapy regimen, while successful for ADA-resistant patients, is not always effective, with an average therapy efficiency rate of–6% to 8% at titrated doses.