University of Calgary researchers identify key inflammation pathway that causes acute kidney injury

Many people suffering from shock due to blood loss, severe infection like sepsis, those undergoing major surgery or having a kidney transplant are at risk of acute kidney injury (AKI). The debilitating condition affects up to seven per cent of all patients who are hospitalized — that adds up to more than 200,000 people in Canada at any given time.

AKI occurs in approximately 30 per cent of patients that undergo cardiac bypass surgery, with about five per cent of patients requiring dialysis. Currently there are no specific therapies to prevent AKI.

A new study, published in Science Advances, by a research team headed by Dr. Daniel Muruve, MD, and Dr. Justin Chun, MD, PhD, with the Cumming School of Medicine’s (CSM) Snyder Institute for Chronic Diseases, opens the door to the first potential therapy for AKI.

“What our study shows is a very important mechanism that causes acute kidney injury,” says Muruve.

The research team identified a molecular pathway in mice and humans where a protein, called dipeptidase-1 (DPEP1), regulates the inflammation in the kidney during AKI. Although some inflammation is helpful in repairing tissues and preventing infection, too much inflammation can cause harm. With the knowledge of the pathway, the team found two drugs that were effective in blocking the DPEP1 pathway and protecting the kidney.   

Two drugs reduce severity of acute kidney injury

“We’ve shown in mice that we have two drugs which can block the DPEP1 pathway, which lessens the inflammation and thereby reduces the severity of acute kidney injury,” Muruve says.

One of the potential therapies, a drug called cilastatin, has been used safely in patients for more than 30 years and was originally developed to prevent the biochemical degradation in the body of a class of antibiotics.

The other potential therapy, a new drug called LSALT peptide (Metablok), was discovered by CSM researchers Drs. Paul Kubes, PhD, Stephen Robbins and Donna Senger (the latter two are now at McGill University) and has advanced to Phase II clinical trials in humans.

“AKI is a significant cause of kidney disease, so having the opportunity to prevent its occurrence in the first place will have a considerable impact on the prevalence of kidney disease as whole,” says Leanne Stalker, national director of research at The Kidney Foundation of Canada.

Calgarian Pat Taverner got AKI after having open heart surgery and complications from that operation. Her kidneys failed, she was in a coma for about a month, and then on dialysis for three-and-a-half years until she received a kidney transplant.

“It would have been amazingly life-changing if a treatment could have been given to me to prevent the AKI,” Taverner says. “The work that’s being done by Dr. Muruve and the research team is so very important and valuable, to prevent others from having to go through what I did.”

A health solution that evolved from basic science

The Muruve team’s study builds on previous research supported by the Canadian Institutes of Health Research (CIHR) and The Kidney Foundation of Canada, which provided grants to several researchers in the Snyder Institute to study the role of molecules in inflammation and chronic disease. That work resulted in Kubes, Robbins and Senger first describing, in a study published in Cell in 2019, DPEP-1’s role in inflammation in the lungs and liver.

Since then, Muruve and his group have been working on explaining how the DPEP-1 pathway regulates kidney inflammation in AKI, and on developing potential new therapies. To develop and commercialize a new treatment for AKI and other acute organ inflammation, Muruve co-founded a spinoff company, Arch Biopartners Inc. The Toronto-based company will manufacture both cilastatin and LSALT.