Sims-Lucas Laboratory Receives NIH R01 to Study New Target for Preventing Acute Kidney Injury
January 15, 2025
Sunder Sims-Lucas, PhD, associate professor of Pediatrics in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh, was awarded a new R01 grant from the National Institutes of Health (NIH) to explore a novel approach and potential therapeutic target to prevent acute kidney injury (AKI).
Dr. Sims-Lucas is collaborating on the project with Eric Goetzman, PhD, professor of Pediatrics from the Division of Genetic and Genomic Medicine at UPMC Children’s, along with other research labs at UPMC Children’s, including the Gittes Lab for Diabetes and Pancreatitis Research.
This new R01 study is focused on the potential use of dicarboxylic acids (DCAs) as a potential therapeutic strategy for preventing AKI.
AKI is particularly prevalent in hospital settings, affecting nearly half of critically ill inpatients, and it also has an outsized presence in cancer patients receiving nephrotoxic chemotherapy, and also patient requiring extensive surgeries, such as transplants. The long-term consequences of AKI are well-established and include increased risk for chronic kidney disease (CKD), end-stage renal disease, and other associated morbidities. Despite decades of research around the world, there are still no effective therapeutics that can prevent AKI or stop and reverse its affects once one occurs.
“What we can offer patients clinically hasn’t changed much over the years,” says Dr. Sims-Lucas. “But what if we had a therapeutic that we could give to patients at significant risk of sustaining an AKI that could ward off the injury in the first place? That’s what our research involves.”
A New Approach: How DCAs May Protect the Kidneys from AKI
The new research Dr. Sims-Lucas and his collaborators are working on builds on their prior promising preclinical findings where dietary supplementation with DCAs, specifically octanedioic acid (DC8), showed kidney-protective effects in mouse models of ischemia-reperfusion and cisplatin-induced AKI. The effects were seen in both types of models and were durable when DC8 was given 24 to 72 hours in advance of inducing the AKI.
"We found that DCAs act as an alternative energy source during kidney injury," says Dr. Sims-Lucas. "They bypass the usual mitochondrial fatty acid oxidation pathway, reducing reactive oxygen species and cellular damage."
The DC8 molecule is processed by peroxisomes in kidney cells, producing smaller energy-rich compounds that fuel mitochondria, boosting energy production even under conditions of extreme cellular and metabolic stress.
"It's like an energy drink for kidney cells," says Dr. Sims-Lucas. “What we are seeing is a kind of metabolic bypass that supports cellular resilience in the setting of an AKI.”
Research Objectives and Experimental Models
Dr. Sims-Lucas’s new R01 has three specific research aims. The first aim involves optimizing DCA molecular structures to improve energy production and reduce side effects.
"We are looking at modifying the chemical structure of DCAs to make them more bioavailable and effective," says Dr. Sims-Lucas.
The second aim of the grant will involves trying to unravel the molecular mechanisms underlying DCAs' protective effects in the kidneys, focusing on metabolic signaling pathways that sustain kidney cell health.
"Understanding how these compounds work at the molecular level is a necessary step in being able to make this potentially viable as a therapeutic,” says Dr. Sims-Lucas.
The third aim of the grant is designed around translating these findings into large-animal models. Dr. Sims-Lucas is collaborating with Dr. Gittes and his lab who have developed a nonhuman primate model for ischemic kidney injury.
"Our collaboration with Dr. Gittes’ lab really can’t be understated because of their expertise and how advanced their models are and what this ultimately means for our ability to rapidly translate our work into potential future human clinical trials," says Dr. Sims-Lucas. "The closer we get to a real-world system with our clinical data, the better our ability to predict therapeutic success and safety in human trials."
Potential Clinical Applications
The potential applications of this research extend beyond preventive care of AKI.
"We're investigating whether DCAs could also be used as a post-treatment therapy for patients who have already suffered kidney damage," says Dr. Sims-Lucas. “This could include patients undergoing kidney transplants, chemotherapy, or other high-risk treatments.”
The team will also explore various delivery methods, including oral and intravenous administration.
"We want to ensure that DCAs can be delivered effectively in real-world hospital settings, including ICU patients who might not be able to take oral medications," says Dr. Sims-Lucas. “We also want to understand the efficacy differences or potential off-target effects of one delivery route versus another.”
Expanding Research Potential
Dr. Sims-Lucas also is interested in exploring the broader systemic effects of DCAs, including how kidney-liver metabolic interactions may influence patient outcomes.
"We are looking at how kidney injury affects other organs, particularly the liver, since both are central to fatty acid metabolism," says Dr. Sims-Lucas.
Looking Ahead
“We believe this research could redefine how we approach AKI prevention," says Dr. Sims-Lucas. "If we’re successful with the R01, it could accelerate the translation of our findings into clinical studies in humans and potentially transform the standard of care for millions of patients worldwide. That’s our hope and what we are working toward.”
Grant Reference
Dicarboxylic acid therapy for prevention of kidney injury. NIH Project Number: R01DK134346. Contact PI: Sunder Sims-Lucas, PhD.
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