Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

Fuchs, T; Frick, Karina; Emde, Barbara; Czasch, Stephanie; Landenberg, Friedrich von; Hewitt, Philip

doi:10.1177/0192623312444618

Cited by 69 publications

(52 citation statements)

References 82 publications

(45 reference statements)

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“…Increases in KIM-1 urinary expression greater than 1.87-fold compared with that for the controls has over 95% specificity for AKI (8). Ample preclinical (8,9,38) and clinical (39,40) data demonstrate that vancomycin can induce proximal tubular damage. Although the exact mechanism by which vancomycin causes proximal tubule damage remains unclear, data suggest that this damage may be due to oxidative stress and mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…All together there were 2 control groups and 8 treatment groups. The rationale for the choice of these doses was partially based on previous studies that found that these doses produce some renal dysfunction while avoiding overt kidney failure or death in animals (8,9,(14)(15)(16). Likewise, when the principle of allometry is applied, the human equivalent daily dose of vancomycin for rat doses of 150 and 200 mg/kg would approximate to 24.2 and 32.3 mg/kg, respectively, which are doses that are routinely administered according to current clinical practice guidelines (17,18).…”

Section: Methodsmentioning

confidence: 99%

“…To date, animal models of AKI have confirmed that vancomycin is a nephrotoxin. Dose-ranging studies have revealed that an increase in the vancomycin dose and an increase in the duration of treatment in rats are associated with increases in histopathological damage and elevations in novel urinary biomarkers of AKI (8)(9)(10). However, a prospectively derived ex-posure-AKI (i.e., a pharmacokinetic [PK]/toxicodynamic [TD]) threshold for vancomycin has not been defined.…”

mentioning

confidence: 99%

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Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Rhodes

Prozialeck

Lodise

et al. 2016

Antimicrob Agents Chemother

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Vancomycin has been associated with acute kidney injury (AKI).A cute kidney injury (AKI) is a major contributor to patient morbidity and mortality in the hospital setting (1, 2). While the etiology of AKI is multifactorial, many cases among hospital patients are related to medication exposure (2). Not surprisingly, the risk of drug-induced AKI is highest among critically ill, hospitalized patients (3), who carry multiple risk factors for the development and progression of AKI. Vancomycin, the antibiotic most frequently administered in the hospital setting (4), has been implicated as a cause of AKI in a number of clinical (5-7) and animal (8-10) studies. Among the clinical studies, the incidence of vancomycin-induced AKI has been associated with higher doses of vancomycin (11, 12), increasing numbers of vancomycin doses (12), and elevated trough concentrations (7, 13).While a number of clinical studies have shown that more intensive vancomycin dosing regimens are associated with an increased risk of AKI, these studies could only suggest an association with kidney injury. As these studies were largely observational in nature, it is difficult to discern if the association was reflective of a true effect or was biased due to confounders. For example, patient confounder factors, such as severity of illness, residence in an intensive care unit, and concurrent receipt of nephrotoxins, may influence the vancomycin exposure-response profile that best predicts clinical AKI.Animal systems are ideally suited to define exposure-response relationships, as they provide flexibility to titrate dosing groups and minimize the influence of external covariates on the observed results. To date, animal models of AKI have confirmed that vancomycin is a nephrotoxin. Dose-ranging studies have revealed that an increase in the vancomycin dose and an increase in the duration of treatment in rats are associated with increases in histopathological damage and elevations in novel urinary biomarkers of AKI (8-10). However, a prospectively derived ex-

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Rhodes

Prozialeck

Lodise

et al. 2016

Antimicrob Agents Chemother

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“…The regression trend of urinary KIM-1 concentrations over time was unlikely to be fully explained by the variability in pH and urine volume. The utility of KIM-1 as a biomarker for early kidney injury in drug development was investigated previously (9,10). Whereas the injury site is specific to the proximal tubules, it remains unclear if the magnitude of KIM-1 elevation is well correlated to the extent of kidney injury.…”

mentioning

confidence: 99%

Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

Tam

Ledesma

Bowers

et al. 2015

Antimicrob Agents Chemother

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The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.T elavancin is a lipoglycopeptide antibiotic which exerts its antibacterial activity by inhibiting peptidoglycan synthesis and causing membrane depolarization (1). In view of its activity against organisms nonsusceptible to vancomycin, daptomycin, or linezolid, it has great potential for use against drug-resistant bacterial infections. Pharmacokinetic-pharmacodynamic studies in an animal infection model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy (2), which suggested that dosing frequency had little influence on antibacterial activity. In the registration trials, all patients randomized to telavancin therapy were given a standard dose of 10 mg/kg of body weight once daily. An elevation in serum creatinine levels was found in an unexpectedly high proportion of the patients (6% to 16%) (3, 4). The impact on these elevations by the dosing frequency is unknown, and the responsible renal histological changes are not well characterized. Our clinical experience suggested that vancomycin nephrotoxicity can be delayed with a nonconventional drug administration schedule (5). The objectives of this study were to (i) investigate the relationship between the pharmacokinetics of telavancin and the onset of kidney injury and (ii) characterize the renal histological changes associated with telavancin in an animal model. Sprague-Dawley CD IGS rats (female, 200 to 250 g; male, 325 to 375 g) were used (Charles River, Raleigh, NC). The jugular veins of the animals were cannulated to facilitate blood sampling. The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Houston. Each animal was given a single telavancin dose of 15 mg/kg, 30 mg/kg, or 60 mg/kg intravenously (n ϭ at least 3 in each group). Six blood samples were obtained from each animal serially (0.5, 1, 2, 4, 6, and 8 h) after the end of drug infusion. The plasma samples were spiked with an internal standard, AMI-13616 (Covance, Princeton, NJ), and assayed for telavancin concentrations by the qualified liquid chromatography tandem mass spectrometry method (6). The assay was linear over the range of 0.0125 g/ml to 250,000 g/ml. The intra-assay and interassay precision levels for the calibration standards were within 10%. The concentrations observed at each time point for each dosing group were averaged, and a pharmacokinetic model was fit to each average concentrationtime profile using ADAPT 5 (University of Southern ...

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“…The blood analyses were done by Meril's auto-analyser. [17][18][19] (Merilyzer Auto-Quant 100); this is a fully automatic biochemical analyser.…”

Section: Methodsmentioning

confidence: 99%

Proton pump inhibitors: are they safe on kidneys: a histopathological study

Limaye

Pendhari

Joshi

2016

Int J Basic Clin Pharmacol

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Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

Cited by 69 publications

References 82 publications

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

Proton pump inhibitors: are they safe on kidneys: a histopathological study

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