Impact of vancomycin loading doses and dose escalation on glomerular function and kidney injury biomarkers in a translational rat model

Abstract

Vancomycin induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in glomerular filtration rate (GFR) and correlation with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had lower GFR and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2, compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high dose folic acid. Rats in both the low and high vancomycin dose groups had higher GFRs on all dosing days versus the positive control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFR on days 1, 2, and 4. Compared to low dose vancomycin, KIM-1 was elevated in high dose rats on dosing day 3. GFR correlated most closely with the urinary injury biomarker KIM-1, on all experimental days. Vancomycin loading doses were associated with significant loss of kidney function and elevation of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker rise corresponded to the magnitude of vancomycin dose (i.e. higher dose resulted in more kidney function decline and greater degree of urinary injury biomarker increase).