Remember the phrase “what doesn’t kill you makes you stronger?” As it turns out, this idiom may in fact be spot on—and hold the key to improving patient outcomes following heart surgery. Dr. Richard Zager, a professor emeritus in the Clinical Research Division at Fred Hutch, has dedicated his career to studying the mechanisms and clinical ramifications of kidney injury in patients. In recent work appearing in Physiological Reports, Zager and colleagues report a promising strategy for preventing tissue damage which could greatly enhance doctors’ abilities to reduce post-procedure complications in patients undergoing invasive heart surgeries.
“The conceptual basis for this work,” noted Dr. Zager, “really began over twenty-five years ago, when we had a hypothesis that inducing mild injury to an organ would sensitize that organ to further ischemic or toxic insults.” Indeed, this concept—that damage weakens instead of strengthens—seems to hold true for breakable objects, public opinion, and even relationships. Why not kidneys too? “When we went to test this hypothesis, however, we were surprised to find nearly the exact opposite,” said Zager. Instead of finding that damaged kidneys were more susceptible to further damage, Zager and colleagues discovered that mild injury triggered a host of stress-response pathways that made damaged kidneys more resilient to further insult. This phenomenon has since been documented in most of our organs and is known as ‘preconditioning.’
From a purely academic standpoint, the existence of injury-induced adaptive stress responses in organs is fascinating. But can this knowledge be harnessed to improve medical care? For patients undergoing high-risk, invasive medical procedures—which are often risky precisely because they cause some amount of tissue stress or damage that can lead to post-procedure complications—the ability to trigger a protective stress response with a mild insult has the potential to make a real difference. As Zager explained, “We sought something a little more targeted: if we could mechanistically understand the stress responses that elicited this protection, could we design an agent to trigger that protective response without having to damage the organ at all?”
After several years of diligent research, the team’s efforts paid off: they found that a master stress response protein called NRF2 (which senses cellular stress and activates a host of proteins in response) was in large part responsible for protective preconditioning. They also designed a small molecule therapy called RBT-1 which, when administered to animal models or patients, activated NRF2 in lieu of an initial injury. While the researchers had initially focused their efforts on the kidney, they found that animal models administered RBT-1 activated protective responses in multiple organ systems, leading them to consider RBT-1 as a preconditioning agent in diverse clinical scenarios.
In this work, Zager and colleagues take advantage of a recent phase II clinical trial testing RBT-1 in patients undergoing ‘on-pump’ cardiac surgery. These surgeries commonly stress or injure the vascular systems of patients, resulting in shedding of endothelial proteins including syndecan-1 (SDC-1) into circulation. Oftentimes, the necessity of surgery is well worth the risk of this damage, but prior work has found that circulatory SDC-1 levels following surgery are associated with poorer patient outcomes. Drawing on data from patients given RBT-1 or placebo before cardiac surgery, Zager and colleagues measured SDC-1 levels in plasma samples taken before or after surgery in each patient population. Consistent with previous findings, they found a spike in plasma SDC-1 following cardiac surgery in the placebo group; in contrast, average plasma SDC-1 levels in patients receiving low- or high-dose RBT-1 did not significantly differ pre- to post-surgery.
This association supports the possibility that RBT-1 preconditioning could be effective in reducing vascular stress post-cardiac surgery, but was this effect replicable, and truly a result of RBT-1’s action on NRF2? To get at this, Zager and colleagues employed several mouse models of vascular injury. In all of these models, the team showed that SDC-1 plasma levels spiked following injury, and that RBT-1 blunted this increase. Furthermore, they also showed that RBT-1 induced the expression of a collection of NRF2 target genes and the iron-binding protein ferritin, strongly suggesting that it was exerting the preconditioning effect via its activation of NRF2, as the group had previously showed.
What’s next for RBT-1? Renibus Therapeutics, a biotechnology company where Dr. Zager is currently the senior vice president for translational research, is currently conducting a phase III clinical trial of RBT-1 in 400 patients undergoing ‘on-pump’ cardiac surgery which will help clarify to what extent this therapy actually improves post-surgery outcomes. If successful, this trial promises to give physicians a new tool to help patients, and a unique tool at that—one that leverages our bodies’ intrinsic damage-mitigating capabilities in the fight against disease.
The spotlighted work was funded by Renibus Therapeutics.
Johnson, A. C. M., & Zager, R. A. (2025). RBT ‐1, a “preconditioning” agent, mitigates syndecan‐1 shedding in patients undergoing “on pump” cardiac surgery and following experimental AKI. Physiological Reports, 13(3), e70218. https://doi.org/10.14814/phy2.70218
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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