ArticlePloS one2026
A kappa opioid receptor agonist, difelikefalin, improves acute kidney injury in experimental sepsis models.
Article in PloS one, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
There is a pressing need for therapies that can lessen the severity of acute kidney injury (AKI) and subsequent critical illness. Difelikefalin, a peripherally acting kappa opioid receptor agonist, shows promise in controlling postoperative pain and chronic kidney disease-associated pruritis. Here, we report that difelikefalin attenuated AKI in experimental mouse models of critical illness. Preconditioning with difelikefalin significantly reduced oliguria in both lipopolysaccharide (LPS)-induced and cecum ligation and puncture-induced models. Moreover, difelikefalin treatment after renal ischemia/reperfusion substantially decreased the LPS-induced mortality rate on day 6 post-ischemia/reperfusion. We hypothesized that the reno-protective effects of difelikefalin are mediated through receptors expressed in either the neural system, immune cells, or the renal parenchyma. Denervation of nerves around the renal pedicle improved urine flow; difelikefalin further enhanced this improvement, regardless of renal denervation. Difelikefalin did not affect plasma cytokine levels after LPS administration at 3 and 6 hours. Renal kappa receptor expression overlapped with the pattern of neural crest-derived interstitial cells. LPS administration tended to increase cytokine expression in isolated renal kappa receptor-positive cells, and difelikefalin suppressed these changes. Overall, difelikefalin demonstrated renal protective effects against AKI in murine endotoxemia and polymicrobial sepsis models and improved survival in post-ischemia/reperfusion endotoxemia.
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