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UPMC Children’s Research Team Receives Pitt Innovation Challenge Grant to Study Novel Treatment Approach for Acute Kidney Injury

December 16, 2022

A multidisciplinary team of researchers from UPMC Children's Hospital of Pittsburgh was awarded a 2022 Pitt Innovation Challenge grant to study the effectiveness of a novel, patented version of dicarboxylic acid 8 (DC8), called Tri-DC8, to prevent or treat acute kidney injury (AKI).

Collaborating on the project, called Nephro-Safe, are UPMC Children’s Division of Pediatric Nephrology researcher and AKI specialist Sunder Sims-Lucas, PhD, associate professor of Pediatrics and principal investigator of the project.

Dr. Sims-Lucas is joined by co-investigator Eric Goetzman, PhD, associate professor of Pediatrics in the Division of Genetic and Genomic Medicine, who specializes in studying fatty acid metabolism.

Also collaborating on the studies are Division of Pediatric Nephrology Chief Jacqueline Ho, MD, MS, and George K. Gittes, MD, chair of Pediatric Surgery and Director of the Richard King Mellon Institute for Pediatric Research at UPMC Children’s.

To this day, no effective options are available to treat or prevent the development of acute kidney injury. AKI is a prevalent secondary effect seen in many patients needing intensive care unit stays, individuals who have experienced significant trauma or surgery, as a consequence of transplantation, and in those experiencing sepsis. Numerous chemotherapeutic agents also have nephrotoxic implications, notably the commonly used drug, cisplatin.

Once an individual has experienced an AKI through any mechanism and with any degree of severity, they are more susceptible to another AKI in the future, and they are also at an increased risk of developing chronic kidney disease and progression to end-stage renal failure.

"Even mild or less severe grades of AKI are potentially problematic and can lead to life-long kidney disease or organ failure, which is why preventive approaches for patient populations at greater risk are critical to develop," says Dr. Sims-Lucas. "We know with some clarity which populations are more susceptible, or what kinds of medical therapies may open the door to AKI, but we really can’t do anything about it at present.”

Project Details

At a basic level, AKI occurs when the cells of the kidney, in particular the proximal tubule of the nephron, are deprived of or experience a reduction in perfusion and hence oxygen. And this deprivation in oxygen can occur through numerous mechanisms.

“The cells of the proximal tubule derive their energy from the mitochondria through fatty acid oxidation,” explains Dr. Sims-Lucas. “This process requires lots of oxygen to work efficiently, and when those oxygen needs are not met, the cells can become injured, dysfunctional, and ultimately you can see fibrotic changes.”

So, to circumvent or bolster the cells' necessary energy requirements when faced with or experiencing an injurious condition, Drs. Sims-Lucas and Goetzman have developed and patented a novel type of fatty acid – Tri-DC8.

The form of Tri-DC8 they have created selectively targets cells of the proximal tubule and delivers the fatty acid to the peroxisome, where it can be metabolized to produce energy and keep the cells from suffering injury in the setting of limited oxygen supply.

"We hypothesize, based on the mechanisms of action and preliminary data that we have, that this could be a possible way to protect the kidney from AKI. For example, if someone is in the ICU or needs an extensive cardiac surgery that reduces perfusion to the kidney, we can proactively treat them with doses of Tri-DC8 as a prophylactic," says Dr. Sims-Lucas. "We also hypothesize that its mechanisms could work similarly in the face of nephrotoxic agents – like certain chemotherapy drugs, or in patients experiencing sepsis. If we can protect the cellular energy needs through an alternate pathway, we may be able to prevent an AKI from occurring."

The one-year grant will allow the team to perform investigations in preclinical small animal and nonhuman primate models to evaluate mechanisms of action efficacy in various AKI scenarios. If successful, the data and findings from these studies will support future grant applications through extramural funding to expand into human clinical trials and translational studies.

"Our team is very excited about the potential of the agent we have developed to prevent an AKI from occurring," says Dr. Sims-Lucas. "We're not certain about its use to stop or repair an AKI that has already occurred, but we'll investigate this scenario further as well."

With no viable therapeutics or treatment options available for preventing or repairing an AKI, any measure of successful translational of these studies into an approved treatment – even if for only subcategories of AKI or those at risk - has the potential to transformative for both clinical practice and further research efforts.

Learn more about the grant here.

Read more about the work of the investigators collaborating on the study through their laboratory websites: Sims-Lucas Laboratory; Goetzman Laboratory; Ho Laboratory; Gittes Laboratory.