Researchers at University of Utah Health have discovered that ceramides trigger acute kidney injury by damaging mitochondria in kidney cells. Using a drug candidate to alter ceramide metabolism, they completely prevented kidney injury in mice. The findings suggest potential for early biomarkers and preventive treatments in humans.
Acute kidney injury (AKI) is a serious condition that can be life-threatening and increase the risk of chronic kidney disease. It often occurs after major stressors like sepsis or heart surgery, affecting more than half of intensive care patients. Currently, no approved medications exist to treat AKI.
Scientists at University of Utah Health found that fatty molecules called ceramides initiate AKI by damaging the mitochondria that power kidney cells. In mouse models, ceramide levels rose sharply after injury, mirroring patterns in human urine samples. "Ceramide levels are very elevated in kidney injury," says Rebekah Nicholson, PhD, first author on the study. "They go up quickly after damage to the kidneys, and they go up in relation to the severity of the injury."
By genetically modifying ceramide production, the team created mice resistant to AKI even under severe stress. They also tested a ceramide-lowering drug candidate from Centaurus Therapeutics, co-founded by senior author Scott Summers, PhD. Mice pretreated with the drug avoided injury, maintained normal kidney function, and showed intact mitochondria. "We completely reversed the pathology of acute kidney injury by inactivating ceramides," Summers says. "We were stunned—not only did kidney function stay normal, but the mitochondria were unscathed."
The study indicates urinary ceramides could serve as an early biomarker to identify at-risk patients, such as those undergoing heart surgery where about one quarter develop AKI. While the drug is preclinical and related to one in human trials, Summers cautions that further safety research is needed. The approach may extend to other mitochondrial-related diseases like heart failure and diabetes.
The results are published in Cell Metabolism as "Therapeutic Remodeling of the Ceramide Backbone Prevents Kidney Injury."