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bioRxiv · 10.1101/2022.03.31.486613

Mass red blood cell extravasation and tubular uptake results in toxic injury to the tubules during kidney ischemia from venous clamping

McLarnon, S. R.·Johnson, C.·Sun, J.·O'Herron, P.·Marshall, B.·Barrett, A.·O'Connor, P. M.
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Abstract

Vascular congestion is common in ischemic acute kidney injury (AKI) and represents densely packed red blood cells (RBC) in the kidney circulation. In this study we tested the hypothesis that vascular congestion directly promotes tubular injury. Studies were performed in male and female Wistar-Kyoto rats. Vascular congestion and tubular injury were examined between renal venous clamping, arterial clamping and venous clamping of blood perfused and blood free kidneys. Vessels were occluded for either 15 or 45 minutes without reperfusion. We found that venous clamping resulted in greater vascular congestion than arterial clamping, particularly in the outer-medullary region (P<0.001). Venous clamping resulted in significant tubular injury, including cell swelling, tubular degeneration and luminal cast formation following as little as 15 minutes of occlusion. Tubular injury was significantly less following arterial clamping (P<0.001). Numerous red droplets were observed within tubular cells which were most prominent following venous clamping. Electron microscopy and immunohistochemistry identified these as derived from RBCs and indicated that RBCs from congested renal capillaries were extravasated and phagocytosed by tubular cells. CD235a staining confirmed tubular uptake and secretion of RBCs. Cast formation and tubular swelling were absent from blood free kidneys following venous clamping (P<0.001). Our data demonstrate that congestion of the kidney results in the rapid, mass extravasation and uptake of RBCs by tubular cells causing toxic injury to the tubules. Tubular toxicity from extravasation of RBCs appears to be a major component of tubular injury in ischemic AKI which has not previously been recognized.

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McLarnon, S. R., Johnson, C., Sun, J., O'Herron, P., Marshall, B., Barrett, A., O'Connor, P. M.. 2022-04-01. Mass red blood cell extravasation and tubular uptake results in toxic injury to the tubules during kidney ischemia from venous clamping. https://doi.org/10.1101/2022.03.31.486613

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