Vancomycin-Associated Tubular Casts and Vancomycin Nephrotoxicity.

INTRODUCTION: Vancomycin nephrotoxicity is frequent and may be due to drug-induced acute tubular necrosis (ATN) or tubulointerstitial nephritis (TIN). Vancomycin-associated tubular cast (VTC) was recently described and may represent a novel cause of vancomycin nephrotoxicity. However, much is still unknown about VTC. MATERIALS AND METHODS: Thirty-seven kidney biopsy specimens from patients who were treated with vancomycin and developed acute kidney injury (AKI) were found among a total of 4673 biopsy samples between 2010 and 2019. These biopsy specimens were subjected to light microscopy, immunofluorescence, electron microscopy, and immunolocalization for vancomycin, uromodulin, myoglobin, tubular segment-specific markers, and examined for VTCs. The findings were correlated with the clinical course. RESULTS: VTCs displayed precipitated vancomycin casts in a background of uromodulin; the casts were limited to the distal tubules, and always associated with a background of more diffuse renal injury (ATN or TIN). The diagnosis of vancomycin nephrotoxicity was made in in 28 of 37 patients. VTC was noted in 25 of 28 biopsy samples from patients diagnosed with vancomycin nephrotoxicity and in one of nine biopsy samples from patients without this diagnosis. Vancomycin nephrotoxicity was diagnosed in 25 of 26 patients whose biopsy specimens showed VTC, but in only 3 of 11 patients without VTC in the biopsy samples. CONCLUSIONS: VTC displays a characteristic morphologic profile amenable to ready recognition in biopsy specimens. It results from coprecipitation of vancomycin and uromodulin. It facilitates the biopsy diagnosis of vancomycin nephrotoxicity. It may have a nephrotoxic effect superimposing on and independent from the ATN or interstitial nephritis in the pathogenesis of vancomycin nephrotoxicity.

Hypoxia-adaptation involves mitochondrial metabolic depression and decreased ROS leakage.

Through long-term laboratory selection, we have generated a Drosophila melanogaster population that tolerates severe, normally lethal, level of hypoxia. This strain lives perpetually under severe hypoxic conditions (4% O(2)). In order to shed light on the mechanisms involved in this adaptation, we studied the respiratory function of isolated mitochondria from the thorax of hypoxia-adapted flies (AF) using polarographic oxygen consumption while monitoring superoxide generation by electron paramagnetic resonance (EPR) techniques. AF mitochondria exhibited a significant 30% decrease in respiratory rate during state 3, while enhancing the resting respiratory rate during State 4-oligo by 220%. The activity of individual electron transport complexes I, II and III were 107%, 65%, and 120% in AF mitochondria as compared to those isolated from control flies. The sharp decrease in complex II activity and modest increase in complexes I and III resulted in >60% reduction in superoxide leakage from AF mitochondria during both NAD(+)-linked state 3 and State 4-oligo respirations. These results provide evidence that flies with mitochondria exhibiting decreased succinate dehydrogenase activity and reduced superoxide leakage give flies an advantage for survival in long-term hypoxia.