scholarly journals 24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
J. Nicholas O'Donnell ◽  
Nathaniel J. Rhodes ◽  
Thomas P. Lodise ◽  
Walter C. Prozialeck ◽  
Cristina M. Miglis ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
High Performance ◽  
Rat Kidney ◽  
Plasma Concentrations ◽  
Rank Correlation ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Sprague Dawley ◽  
Time Curve ◽  
Minimum Concentration

ABSTRACT Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (C max), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and C max were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for C max). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or C max.

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

2016 ◽  
Vol 60 (10) ◽  
pp. 5742-5751 ◽  
Author(s):  
Nathaniel J. Rhodes ◽  
Walter C. Prozialeck ◽  
Thomas P. Lodise ◽  
Natarajan Venkatesan ◽  
J. Nicholas O'Donnell ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
High Performance ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Lipocalin 2 ◽  
Sprague Dawley ◽  
Time Curve ◽  
Minimum Concentration ◽  
Exposure Response ◽  
Nonparametric Correlation

ABSTRACTVancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0–24), the maximum concentration in plasma during the first 24 h (Cmax0–24), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0–24). A total of 52 rats received vancomycin (n= 42) or NS (n= 10). The strongest exposure-response correlations were observed between AUC0–24and Cmax0–24and urinary AKI biomarkers. Exposure-response correlations (rsvalues) for AUC0–24, Cmax0–24, and Cmin0–24were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0–24or Cmax0–24correlates with increases in urinary AKI biomarkers.

scholarly journals 1335. A Translational Nephrotoxicity Model to Probe Acute Kidney Injury with Vancomycin and Piperacillin–Tazobactam

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S483-S483
Author(s):  
Gwendolyn M Pais ◽  
Jiajun Liu ◽  
Sean N Avedissian ◽  
Danielle Hiner ◽  
Theodoros Xanthos ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Repeated Measures ◽  
Hospital Setting ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Urinary Output ◽  
Plasma Creatinine ◽  
Sprague Dawley ◽  
Research Support ◽  
Drug Dosing

Abstract Background Vancomycin and piperacillin–tazobactam (VAN+TZP) are two of the most commonly utilized antibiotics in the hospital setting and are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic AKI occurs, only that serum creatinine increases with VAN+TZP. Previous preclinical work demonstrated that novel urinary biomarkers and histopathologic scores were not increased in the VAN+TZP group compared with VAN alone. The purpose of this study was to assess changes in urinary output and plasma creatinine between VAN, TZP, and VAN+TZP treatments. Methods Male Sprague–Dawley rats (n = 32) received either saline, VAN 150 mg/kg/day intravenously, TZP 1,400 mg/kg/day intraperitoneally, or VAN+TZP for 3 days. Animals were placed in metabolic cages pre-study and on drug dosing days 1–3. Urinary output, plasma creatinine, urinary biomarkers were compared daily and kidney histopathology was compared at the end of therapy between the groups. Mixed-effects, repeated-measures models were employed to assess differences between the groups. Results In the VAN-treated rats, urinary output was increased on days 1, 2 and 3 compared with baseline and saline (P < 0.01 for all), whereas it increased later for VAN+TZP (i.e., day 2 and 3 compared with saline, P < 0.001). No changes in urinary output were observed with saline and TZP alone. Plasma creatinine rose for VAN on days 1, 2, and 3 from baseline and VAN+TZP on day 3 (P < 0.02 for all), but no treatment group was different from saline. In the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 compared with controls (P < 0.001). Elevations were seen only after 3 days of treatment with VAN+TZP (P < 0.001 KIM-1, P < 0.05 clusterin). No changes in urinary biomarkers output were observed with saline and TZP alone. Histopathology was only elevated in the VAN group compared with saline (P < 0.002). No histopathology changes were noted with VAN+TZP. Conclusion All groups with VAN demonstrated kidney injury; however, VAN+TZP did not cause more kidney injury than VAN alone in a rat model of VIKI when using plasma creatinine, urinary output, or urinary biomarkers as outcomes. Histopathology data suggest that adding TZP did not worsen VAN-induced AKI and may even be protective. Disclosures Kevin J. Downes, MD, Merck: Grant/Research Support, Research Grant; Pfizer: Grant/Research Support.

The Effect of a Short Course of Tocolytic Indomethacin on Urinary Biomarkers in Premature Infants

2021 ◽  
Author(s):  
Ahmad El Samra ◽  
Ayesa Mian ◽  
Marc Lande ◽  
Hongyue Wang ◽  
Ronnie Guillet
Keyword(s):  
Acute Kidney Injury ◽  
Serum Creatinine ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Bivariate Analysis ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Short Course ◽  
Medication Exposure ◽  
Epidermal Growth ◽  
Neutrophil Gelatinase

Objective The aim of this study was to determine the effects of a 2-day prenatal course of indomethacin on the premature kidney as reflected by serum creatinine and urinary biomarkers. Study Design Urine of infants ≤ 32 weeks was collected for the first 14 days and analyzed for cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, β2 microglobulin, epidermal growth factor, uromodulin, and microalbumin. Bivariate analysis compared serum creatinine and biomarkers of exposed (INDO) and unexposed (CONT) subjects. Results Fifty-seven infants (35 CONT and 22 INDO) were studied. The cohorts were similar in gestational age, birthweight, race, gender, nephrotoxic medication exposure, and Apgar scores. CONT had more dopamine exposure and included more pre-eclamptic mothers (p = 0.005). No difference in creatinine-based acute kidney injury or the log transformed mean, maximum, and minimum values of urinary biomarkers was detected. Conclusion Our findings suggest that a short course of tocolytic indomethacin does not result in neonatal acute kidney injury. Key Points

Early diagnosis of acute kidney injury with urinary biomarkers in the newborn

2009 ◽  
Vol 22 (sup3) ◽  
pp. 62-66 ◽  
Author(s):  
Marco Zaffanello ◽  
Roberto Antonucci ◽  
Laura Cuzzolin ◽  
Luigi Cataldi ◽  
Vassilios Fanos
Keyword(s):  
Acute Kidney Injury ◽  
Early Diagnosis ◽  
Kidney Injury ◽  
Urinary Biomarkers

scholarly journals Comparison of Effects of Different Statins on Contrast-Induced Acute Kidney Injury in Rats: Histopathological and Biochemical Findings

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Xiao-lei Wang ◽  
Tuo Zhang ◽  
Liu-hua Hu ◽  
Shi-qun Sun ◽  
Wei-feng Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Lipid Lowering ◽  
Control Group ◽  
Sprague Dawley ◽  
Atorvastatin Group ◽  
New Strategy ◽  
Ameliorative Effect ◽  
Markers Of Oxidative Stress

Statins are a promising new strategy to prevent contrast-induced acute kidney injury (CI-AKI). In this study we compared the ameliorative effect of different statins in a rat model of CI-AKI. Sprague-Dawley rats were divided into five groups: control group; CI-AKI group; CI-AKI + rosuvastatin group (10 mg/kg/day); CI-AKI + simvastatin group (80 mg/kg/day); and CI-AKI + atorvastatin group (20 mg/kg/day). CI-AKI was induced by dehydration for 72 hours, followed by furosemide intramuscular injection 20 minutes before low-osmolar contrast media (CM) intravenous injection. Statins were administered by oral gavage once daily for 3 consecutive days before CM injection and once 4 hours after CM injection. Rats were sacrificed 24 hours after CM injection, and renal function, kidney histopathology, nitric oxide (NO) metabolites, and markers of oxidative stress, inflammation, and apoptosis were evaluated. The results showed that atorvastatin and rosuvastatin but not simvastatin ameliorated CM-induced serum creatinine elevation and histopathological alterations. Atorvastatin and rosuvastatin showed similar effectiveness against CM-induced oxidative stress, but simvastatin was less effective. Atorvastatin was most effective against NO system dysfunction and cell apoptosis, whereas rosuvastatin was most effective against inflammation. Our findings indicate that statins exhibit differential effects in preventing CI-AKI when given at equivalent lipid-lowering doses.

scholarly journals POS-084 THE ROLE OF SERUM AND URINARY BIOMARKERS IN PREDICTING ACUTE KIDNEY INJURY FOLLOWING SRI LANKAN HUMP-NOSED PIT VIPER ENVENOMING

2021 ◽  
Vol 6 (4) ◽  
pp. S35-S36
Author(s):  
E. Wijewickrama ◽  
F. Mohamed ◽  
N. Buckley ◽  
I. Gawarammana ◽  
G. Isbister
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Sri Lankan
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