Pathophysiological response in experimental trauma-related acute kidney injury

Halbgebauer, R.; Schult, L.; Borgel, O.; Maes, A.; Weisshaupt, F.; Rastner, C.; Ast, A.; Lupu, L.; Palmer, A.; Wachter, U.; Schmidt, S. A.; Boor, P.; Rösler, R.; Wiese, S.; Kerckhofs, G.; Huber-Lang, M.

doi:10.1101/2024.08.02.606294

bioRxiv · 10.1101/2024.08.02.606294

Pathophysiological response in experimental trauma-related acute kidney injury

Halbgebauer, R.·Schult, L.·Borgel, O.·Maes, A.·Weisshaupt, F.·Rastner, C.·Ast, A.·Lupu, L.·Palmer, A.·Wachter, U.·Schmidt, S. A.·Boor, P.·Rösler, R.·Wiese, S.·Kerckhofs, G.·Huber-Lang, M.

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Abstract

BackgroundTrauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. MethodsTo study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI. ResultsThe mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5. ConclusionsOur novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.

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Halbgebauer, R., Schult, L., Borgel, O., Maes, A., Weisshaupt, F., Rastner, C., Ast, A., Lupu, L., Palmer, A., Wachter, U., Schmidt, S. A., Boor, P., Rösler, R., Wiese, S., Kerckhofs, G., Huber-Lang, M.. 2024-08-07. Pathophysiological response in experimental trauma-related acute kidney injury. https://doi.org/10.1101/2024.08.02.606294

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