scholarly journals The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model

2020 ◽  
pp. AAC.01945-20
Author(s):  
Sean N. Avedissian ◽  
Gwendolyn Pais ◽  
Jiajun Liu ◽  
J. Nicholas O’Donnell ◽  
Thomas P. Lodise ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Information Criterion ◽  
Compartment Model ◽  
Model Fit ◽  
Sprague Dawley ◽  
P Values ◽  
Exposure Response ◽  
Sprague Dawley Rats ◽  
Kidney Injury Molecule 1 ◽  
Relationship Of

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0-24h, CMAX0-24h,) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2=0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure–response relationships were observed between KIM-1 vs CMAX0-24h and AUC0–24h (R2 =  0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95).While PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

scholarly journals The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model

2020 ◽  
Author(s):  
Sean N. Avedissian ◽  
Gwendolyn Pais ◽  
Jiajun Liu ◽  
J. Nicholas O’Donnell ◽  
Thomas P. Lodise ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Information Criterion ◽  
Compartment Model ◽  
Model Fit ◽  
Sprague Dawley ◽  
P Values ◽  
Exposure Response ◽  
Sprague Dawley Rats ◽  
Kidney Injury Molecule 1 ◽  
Relationship Of

ABSTRACTBackgroundVancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear.MethodsSprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0-24h, CMAX0-24h,) were calculated for each rat, and PK-TD relationships were discerned.ResultsA total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2=0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure–response relationships were observed between KIM-1 vs CMAX0–24h and AUC0-24h (R2□=□ 0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (−5.28 versus −1.95).ConclusionsWhile PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

scholarly journals Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model

2019 ◽  
Vol 74 (8) ◽  
pp. 2326-2334 ◽  
Author(s):  
Sean N Avedissian ◽  
Gwendolyn M Pais ◽  
J Nicholas O’Donnell ◽  
Thomas P Lodise ◽  
Jiajun Liu ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Compartment Model ◽  
Urinary Biomarkers ◽  
Daily Injection ◽  
Sprague Dawley ◽  
Exposure Response ◽  
Sprague Dawley Rats ◽  
Two Compartment Model ◽  
Kidney Injury Molecule 1 ◽  
Maximal Rise

Abstract Objectives To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury. Methods Male Sprague–Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0–24h, Cmax 0–24h and Cmin 0–24h) were calculated. PK/TD relationships were assessed with Spearman’s rank coefficient (rs) and the best-fit mathematical model. Results PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure–response relationships were found between AUC0–24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0–24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0–24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0–24h of 482.2 corresponded to a 90% of maximal rise in KIM-1. Conclusions Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0–24h of 482.2 mg·h/L may have direct relevance to human outcomes.

Pharmacological inhibition of galectin-3 protects against hypertensive nephropathy

2015 ◽  
Vol 308 (5) ◽  
pp. F500-F509 ◽  
Author(s):  
Anne-Roos S. Frenay ◽  
Lili Yu ◽  
A. Rogier van der Velde ◽  
Inge Vreeswijk-Baudoin ◽  
Natalia López-Andrés ◽  
...  
Keyword(s):  
Renal Damage ◽  
Smooth Muscle Actin ◽  
Kidney Injury ◽  
Glomerular Sclerosis ◽  
Sprague Dawley ◽  
Hypertensive Nephropathy ◽  
Sprague Dawley Rats ◽  
Focal Glomerular Sclerosis ◽  
Galectin 3 ◽  
Kidney Injury Molecule 1

Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data are available to suggest that galectin-3-targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease. Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with N-acetyllactosamine [galectin-3 inhibitor (Gal3i)] for 6 wk; untreated REN2 and Sprague-Dawley rats served as controls. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline and at 3 and 6 wk. Plasma creatinine was determined at 6 wk. Renal damage was assessed for focal glomerular sclerosis, glomerular desmin expression, glomerular and interstitial macrophages, kidney injury molecule-1 expression, and α-smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by quantitative real-time PCR. Systolic BP was higher in control REN2 rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in control REN2 rats; Gal3i treatment reduced both. Renal damage (focal glomerular sclerosis, desmin, interstitial macrophages, kidney injury molecule-1, α-smooth muscle actin, collagen type I, and collagen type III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, galectin-3, and monocyte chemoattractant protein-1) were elevated in control REN2 rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with Sprague-Dawley rats. In conclusion, galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of chronic kidney disease.

scholarly journals Enteral Baicalin, a Flavone Glycoside, Reduces Indicators of Cardiac Surgery-Associated Acute Kidney Injury in Rats

2018 ◽  
Vol 9 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Jing Shi ◽  
Guofeng Wu ◽  
Xiaohua Zou ◽  
Ke Jiang
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Cardiac Surgery ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Injury Index ◽  
Sprague Dawley Rats

Background/Aims: Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common postoperative complications in intensive care medicine. Baicalin has been shown to have anti-inflammatory and antioxidant roles in various disorders. We aimed to test the protective effects of baicalin on CSA-AKI using a rat model. Methods: Sprague-Dawley rats underwent 75 min of cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA) to establish the AKI model. Baicalin was administered at different doses intragastrically 1 h before CPB. The control and treated rats were subjected to the evaluation of different kidney injury index and inflammation biomarkers. Results: Baicalin significantly attenuated CPB/CA-induced AKI in rats, as evidenced by the lower levels of serum creatinine, serum NGAL, and Kim1. Baicalin remarkably inhibited oxidative stress, reflected in the decreased malondialdehyde and myeloperoxidase activity, and enhanced superoxide dismutase activity and glutathione in renal tissue. Baicalin suppressed the expression of IL-18 and iNOS, and activated the Nrf2/HO-1 pathway. Conclusion: Our data indicated that baicalin mediated CPB/CA-induced AKI by decreasing the oxidative stress and inflammation in the renal tissues, and that baicalin possesses the potential to be developed as a therapeutic tool in clinical use for CSA-AKI.

scholarly journals Comparative study of allogenic and xenogeneic mesenchymal stem cells on cisplatin-induced acute kidney injury in Sprague-Dawley rats

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Rehab H. Ashour ◽  
Mohamed-Ahdy Saad ◽  
Mohamed-Ahmed Sobh ◽  
Fatma Al-Husseiny ◽  
Mohamed Abouelkheir ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Kidney Injury ◽  
Mesenchymal Stem Cells ◽  
Comparative Study ◽  
Kidney Injury ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

scholarly journals Attenuation of Circulating Trimethylamine N-Oxide Prevents the Progression of Cardiac and Renal Dysfunction in a Rat Model of Chronic Cardiorenal Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Deling Zou ◽  
Yanyu Li ◽  
Guangping Sun
Keyword(s):  
Gene Expression ◽  
Renal Dysfunction ◽  
Treatment Options ◽  
Elevated Serum ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Current Treatment ◽  
Sprague Dawley ◽  
Kidney Injury Molecule 1 ◽  
And Control

Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.

scholarly journals ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS OF CURCUMIN CONTRIBUTE INTO ATTENUATION OF ACUTE GENTAMICIN-INDUCED NEPHROTOXICITY IN RATS

2019 ◽  
pp. 466-468 ◽  
Author(s):  
HAYDER M AL-KURAISHY ◽  
ALI I AL-GAREEB ◽  
HUDA ABDULBAKI RASHEED
Keyword(s):  
Oxidative Stress ◽  
Serum Creatinine ◽  
Cystatin C ◽  
Kidney Injury ◽  
Specific Situation ◽  
Distilled Water ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Group 2 ◽  
Nephroprotective Effect

Objectives: Nephrotoxicity is a renal-specific situation in which the excretion of toxic metabolites is reduced due to toxic agents and drugs. Gentamicin is an antibiotic belongs to aminoglycoside group which may induce nephrotoxicity due to induction of oxidative stress. Curcumin is a component of traditional medicine with significant nephroprotective effect. Therefore, the objective of the present study was to evaluate the nephroprotective effect of curcumin on gentamicin-induced nephrotoxicity. Methods: A total of 30 male Sprague-Dawley rats were used which divided into Group 1 (n=10): Rats treated with distilled water 5 ml/kg plus normal saline 5 ml/kg for 12 days, Group 2 (n=10): Rats treated with distilled water 5 ml/kg plus gentamicin 100 mg/kg for 12 days, and Group 3 (n=10): Rats treated with curcumin 100 mg/kg plus gentamicin 100 mg/kg for 12 days. Blood urea, serum creatinine, malondialdehyde (MDA), kidney injury molecule (KIM-1), and cystatin-C were measured in both control and experimental groups. Results: Rats treated with gentamicin showed nephrotoxicity as evident by significant elevation in blood urea, serum creatinine, KIM-1, MDA, and cystatin-C sera levels. Curcumin leads to significant reduction of blood urea and serum creatinine compared to gentamicin group, p<0.05. Curcumin also reduced MDA, KIM-1, and cystatin-C sera levels significantly compared to gentamicin group, p<0.01. Conclusion: Curcumin produced significant nephroprotective effect on gentamicin-induced nephrotoxicity through modulation of oxidative stress and inflammatory biomarkers.

Hesperidin Shows Protective Effects on Renal Function in Ischemia-induced Acute Kidney Injury (Sprague-Dawley Rats)

2019 ◽  
Vol 51 (8) ◽  
pp. 2838-2841
Author(s):  
Won Seo Park ◽  
Min Su Park ◽  
Sang Wook Kang ◽  
Seul A. Jin ◽  
Youngchul Jeon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Kidney Injury ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

Defect in the Renal Tubular Reabsorption of Water Associated With Potassium Depletion in Rats

1957 ◽  
Vol 189 (3) ◽  
pp. 557-563 ◽  
Author(s):  
Walter Hollander ◽  
Robert W. Winters ◽  
T. Franklin Williams ◽  
John Bradley ◽  
Jean Oliver ◽  
...  
Keyword(s):  
Urinary Concentration ◽  
Potassium Depletion ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Renal Tubular Reabsorption ◽  
Renal Concentrating Mechanism ◽  
Renal Tubular ◽  
Relationship Of ◽  
The Relationship ◽  
K Depletion

The effect of graded degrees of K depletion on the ability to produce a concentrated urine was studied in Sprague-Dawley rats. With increasing degrees of K depletion, as measured by the concentration of K in fat-free skeletal muscle, there was a progrossive decrease in the maximum urinary concentration. This defect of the renal concentrating mechanism appeared to be better correlated with the degree than with the duration of potassium depletion and could be demonstrated either by the use of exogenous vasopressin or by water deprivation. The potassium-deficient rats in at least one experiment developed a significant polydipsia. The data do not allow any conclusions with respect to the relationship of the polydipsia to the renal concentrating defect except that the latter at least was not severe at the onset of the increased water intake.

Distribution and metabolism of adrenocorticotropin in the rat

1979 ◽  
Vol 57 (9) ◽  
pp. 1024-1027 ◽  
Author(s):  
Maurice Normand ◽  
Josee Lalonde
Keyword(s):  
Standard Error ◽  
Time Course ◽  
Compartment Model ◽  
Sprague Dawley ◽  
Mean Values ◽  
Sprague Dawley Rats ◽  
Two Compartment Model ◽  
Rapid Fall ◽  
Significant Difference ◽  
Endogenous Release

The time course of plasma bioactive adrenocorticotropin (ACTH) concentrations measured following two rapid injections of the hormone at doses of 7.5 and 22.5 mU/100 g, iv, and one infusion over a period of 80 min at a rate of 1.3 mU/min per 100 g, to male Sprague–Dawley rats whose endogenous release of ACTH had been blocked, leads to the conclusion that the hormone is distributed in two compartments. Indeed, the rapid fall of plasma ACTH concentrations in the early minutes following either the injections or the stop of the infusion is followed by a much slower phase. There is no significant difference between the measurements and the two-compartment model outputs. The model represents, on the average, the mean values of the measurements plus or minus 1 standard error for the single injections and plus or minus 1.2 standard error for the infusion.

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