Serious damage to short-term kidney function-known as acute kidney injury, or AKI-can be fatal and also increase the risk of irreversible chronic kidney disease. It can be triggered by stressors ranging from sepsis to heart surgery, and it affects more than half of ICU patients. There are currently no drugs to treat AKI.
Now, researchers at University of Utah Health (U of U Health) have found that AKI is triggered by fatty molecules called ceramides, which cause serious injury by damaging kidney mitochondria. Using a backup drug candidate that changes ceramide metabolism, the team was able to preserve mitochondrial integrity and prevent kidney injury in mice.
"We completely reversed the pathology of acute kidney injury by inactivating ceramides," says Scott Summers, PhD, distinguished professor and Chair of the Department of Nutrition and Integrative Physiology in the University of Utah College of Health and senior author on a paper describing the results. "We were stunned-not only did kidney function stay normal, but the mitochondria were unscathed," Summers says. "It was truly remarkable."
An early warning sign for kidney injury
The Summers lab had previously shown that ceramides can damage tissues ranging from heart to liver. When the team profiled ceramides in models of AKI, the correlation was striking: ceramide levels spiked sharply after kidney injury in both mice and human urine samples.
"Ceramide levels are very elevated in kidney injury," says Rebekah Nicholson, PhD, first author on the study, who did the research as a graduate student in nutrition and integrative physiology at U of U Health and is now a postdoctoral fellow at the Arc Institute. "They go up quickly after damage to the kidneys, and they go up in relation to the severity of the injury. The worse the kidney injury is, the higher the ceramide levels will be."
These findings suggest that urinary ceramide levels could serve as an early biomarker for AKI, helping doctors identify patients at risk-such as those undergoing heart surgery-before symptoms appear. "If patients are undergoing a procedure that we know puts them at high risk of AKI, then we can better predict whether or not they're actually going to have one," Nicholson says.
Modifying ceramides prevents kidney injury
The researchers were able to almost completely prevent kidney injury in an animal model by changing how ceramides are made. By making a precise genetic change that affects ceramide production, the team created "super mice" that don't get AKI, even in conditions that would otherwise trigger it.
Similarly, pre-treating mice with a new ceramide-lowering drug candidate developed by Centaurus Therapeutics, a company co-founded by Summers, prevented kidney injury. Kidney function improved, mice stayed fully active, and the kidneys looked nearly normal under the microscope. The model the researchers use tends to put the kidneys under a lot of stress, Nicholson says, so "it's really remarkable that mice were protected from the injury."
"These mice looked incredible," Summers adds.
Ceramides cause kidney injury by damaging mitochondria, the part of the cell that produces energy, the researchers found. Mitochondria in injured kidney cells are visibly malformed under a microscope, and they can't produce energy as efficiently. Tweaking how ceramides are made, either genetically or with the drug, kept mitochondria healthy and functional even under stress.
Hope for acute kidney injury and other diseases
Summers emphasizes that the compound used in the study is closely related to, but not the same as, the ceramide-lowering drug that has advanced into human clinical testing. Results in mice don't always translate directly to humans, he notes, and additional studies are needed to establish safety.
"We're thrilled by how protective this backup compound was, but it's still preclinical," Summers says. "We need to be cautious and do our due diligence to make sure this approach is truly safe before moving it into patients."
But the researchers are optimistic. If the results hold true in humans, the researchers hope that the drug could be provided in advance to people at high risk of acute kidney injury-such as people undergoing heart surgery, about a quarter of whom experience AKI.
Because the drug seems to work by keeping mitochondria healthy, the researchers suspect that it might help treat or prevent many other diseases that affect mitochondria.
"Mitochondrial problems show up in so many diseases-heart failure, diabetes, fatty liver disease," Summers says. "So if we can truly restore mitochondrial health, the implications could be enormous."
