Ceramides Linked to Kidney Injury: New Drug Shows Promise in Mice

Acute kidney injury (AKI) is a serious and potentially life-threatening condition that can lead to long-term kidney disease. Affecting over half of all intensive care patients, AKI occurs after significant health stressors like sepsis or heart surgery, and currently has no approved medical treatments.

A New Understanding of AKI’s Origins

Researchers at University of Utah Health (U of U Health) have pinpointed fatty molecules called ceramides as key initiators of AKI. These ceramides damage the mitochondria – the energy suppliers – within kidney cells. In laboratory testing, a drug candidate designed to alter ceramide processing successfully protected mitochondrial structure and prevented kidney injury in mice.

Did You Know? Ceramides have previously been shown to cause harm to other organs, including the heart and liver.

“We completely reversed the pathology of acute kidney injury by inactivating ceramides,” stated Scott Summers, PhD, distinguished professor and Chair of the Department of Nutrition and Integrative Physiology at the University of Utah College of Health, and senior author of the study. “We were stunned – not only did kidney function stay normal, but the mitochondria were unscathed. It was truly remarkable.”

Ceramides as an Early Warning Signal

The research builds on earlier work from Dr. Summers’ lab, which demonstrated the harmful effects of ceramides on organs like the heart and liver. Measurements of ceramide levels in AKI models revealed a strong correlation: levels spiked sharply after kidney injury in both mice and human urine samples.

“Ceramide levels are very elevated in kidney injury,” explained Rebekah Nicholson, PhD, first author of the study. “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.”

This suggests that ceramide levels in urine could serve as an early biomarker for AKI, potentially allowing clinicians to identify patients at risk – including those preparing for high-risk procedures like heart surgery – before symptoms even appear.

Protecting Kidney Function Through Ceramide Control

The research team achieved near-elimination of kidney injury in a mouse model by genetically modifying the program controlling ceramide production. These “super mice” did not develop AKI even under conditions that typically cause severe damage.

Further testing involved a ceramide-lowering drug candidate developed by Centaurus Therapeutics. Mice treated with the drug prior to kidney stress avoided injury, maintained normal kidney function, remained active, and showed kidneys that appeared nearly normal under microscopic examination. Nicholson noted the model used placed “extreme stress” on the kidneys, making the protective effect of the drug even more significant.

Expert Insight: The ability to prevent kidney injury in a mouse model by targeting ceramide production represents a potentially significant shift in how AKI might be approached, moving from reactive treatment to proactive prevention.

The researchers found that ceramides directly harm mitochondria, causing them to become distorted and function poorly. Adjusting ceramide production, either genetically or with the drug, preserved mitochondrial integrity and function even under stress.

What’s Next?

The compound tested in the study is related to, but not identical to, a ceramide-lowering drug currently in human clinical trials. Dr. Summers cautioned that results in mice do not always translate to humans and that further research is essential to confirm safety. However, if the findings are replicated in people, the drug could potentially be administered proactively to high-risk individuals, such as those undergoing heart surgery, where approximately one quarter experience AKI.

The team also believes this approach could have broader implications, as mitochondrial dysfunction is linked to numerous other diseases, including heart failure, diabetes, and fatty liver disease. Restoring mitochondrial health could, offer benefits beyond kidney injury.

Frequently Asked Questions

What is acute kidney injury (AKI)?

AKI is a serious injury to short-term kidney function that can be life-threatening and increase the risk of developing permanent chronic kidney disease. It can occur after major health events like sepsis or heart surgery.

What role do ceramides play in AKI?

Researchers discovered that fatty molecules called ceramides initiate AKI by damaging the mitochondria within kidney cells, which are responsible for providing energy.

Is a treatment for AKI currently available?

No, We find currently no approved medications to treat acute kidney injury.

Could a future therapy focused on maintaining mitochondrial health offer hope for treating a wider range of diseases?