scholarly journals Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

2019 ◽  
Author(s):  
Gwendolyn M. Pais ◽  
Jiajun Liu ◽  
Sean N. Avedissian ◽  
Theodoros Xanthos ◽  
Athanasios Chalkias ◽  
...  
Keyword(s):  
Rat Model ◽  
Rat Kidney ◽  
Hospital Setting ◽  
Kidney Injury ◽  
Sprague Dawley ◽  
Drug Dosing ◽  
Viability Assay ◽  
Sprague Dawley Rats ◽  
Kidney Epithelial Cell ◽  
High Doses

AbstractIntroductionVancomycin 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 toxicity occurs, only that serum creatinine (SCr) increases with VAN+TZP. The purpose of this study was to assess biologic plausibility by quantifying kidney injury between VAN, TZP, and VAN+TZP treatments using a translational rat model of AKI and rat kidney epithelial cell studies.Methods(i) Male Sprague-Dawley rats (n=32) received either saline, VAN 150 mg/kg/day intravenously, TZP 1400 mg/kg/day via intraperitoneal injection, or VAN+TZP. Animals were placed in metabolic cages pre-study and on drug dosing days 1-3. Urinary biomarkers and histopathology were analyzed. (ii) Cellular injury of VAN+TZP was assessed in serum-deprived rat kidney cells (NRK-52E) using an alamarBlue® viability assay. Cells were incubated with antibiotics VAN, TZP, cefepime, and gentamicin alone or combined with the same drugs plus VAN 1 mg/mL.ResultsIn the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 compared to 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). Histopathology was only elevated in the VAN group when compared to TZP as a control (P=0.04). Results were consistent across biomarkers and histopathology suggesting that adding TZP did not worsen VAN induced AKI and may even be protective. In NRK-52E cells, VAN alone caused moderate cell death with high doses (IC5048.76 mg/mL). TZP alone did not cause cellular death under the same conditions. VAN+TZP was not different from VAN alone in NRK-52E cells (P>0.2).ConclusionsVAN+TZP does not cause more kidney injury than VAN alone in a rat model of VIKI or in rat kidney epithelial cells.

scholarly journals Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model

2020 ◽  
Vol 75 (5) ◽  
pp. 1228-1236 ◽  
Author(s):  
Gwendolyn M Pais ◽  
Jiajun Liu ◽  
Sean N Avedissian ◽  
Danielle Hiner ◽  
Theodoros Xanthos ◽  
...  
Keyword(s):  
Rat Model ◽  
Kidney Injury ◽  
Cellular Injury ◽  
Cellular Model ◽  
Sprague Dawley ◽  
Injury Score ◽  
Sprague Dawley Rats ◽  
High Doses ◽  
Vancomycin Group ◽  
Synergistic Toxicity

Abstract Background Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases. Objectives To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies. Methods (i) Male Sprague–Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®. Results Urinary output increased from Day −1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P &lt; 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P &lt; 0.001, KIM-1; P &lt; 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin. Conclusions All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.

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.

scholarly journals Effect of Qingxin Kaiqiao Fang on Hippocampus mRNA Expression of the Inflammation-Related Genes IL-1β, GFAP, and Aβin an Alzheimer’s Disease Rat Model

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Dan-Dan Mao ◽  
Wen-Yu Yang ◽  
Yan Li ◽  
Jian-Wei Lin ◽  
Shi-Yu Gao ◽  
...  
Keyword(s):  
Rat Model ◽  
Particle Deposition ◽  
Therapeutic Potential ◽  
Interleukin 1 ◽  
Control Group ◽  
Model Group ◽  
Sprague Dawley ◽  
Amyloid A ◽  
Sprague Dawley Rats ◽  
High Doses

Objective. To investigate the effects of QKF on expression of amyloid-beta (Aβ), interleukin-1 beta (IL-1β), and glial fibrillary acidic protein (GFAP) using a rat model of AD.Materials and Methods. Fifty-six male Sprague-Dawley rats were randomly divided into seven groups (eight rats each): control group, sham-operated group, AD model group, groups of AD rats administered with low, medium, and high doses of QKF, and the donepezil group. AD was established by bilateral injection ofβ-amyloid (Aβ) 1–40 into the hippocampus. Two days after AD was established, drugs were administered by gavage. After 14 days of treatment, we used RT-PCR, Western blotting, and immunohistochemistry to measure the transcript expression and protein abundance of Aβ, IL-1β, and GFAP, and methenamine silver staining was used to detect amyloid protein particle deposition.Results. Compared to the control group, the rats from the AD model group showed significantly greater expression levels of Aβ, IL-1β, and GFAP. However, these differences in expression were abolished by treatment with QKF or donepezil.Conclusion. QKF possesses therapeutic potential against AD because it downregulated Aβ, IL-1β, and GFAP in the hippocampus of AD rats. Future studies should further examine the mechanisms through which QKF produces its effects and the consequences of long-term QKF administration.

Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney

2006 ◽  
Vol 290 (5) ◽  
pp. F1034-F1043 ◽  
Author(s):  
Tarek M. El-Achkar ◽  
Xiaoping Huang ◽  
Zoya Plotkin ◽  
Ruben M. Sandoval ◽  
Georges J. Rhodes ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Expression Patterns ◽  
Cecal Ligation ◽  
Proximal Tubules ◽  
Microbial Pathogens ◽  
Sprague Dawley ◽  
Renal Vasculature ◽  
Two Photon Microscopy ◽  
Sprague Dawley Rats ◽  
Cellular Signal

Toll-like receptors (TLRs) are now recognized as the major receptors for microbial pathogens on cells of the innate immune system. Recently, TLRs were also identified in many organs including the kidney. However, the cellular distribution and role of these renal TLRs remain largely unknown. In this paper, we investigated the expression of TLR4 in a cecal ligation and puncture (CLP) model of sepsis in Sprague-Dawley rats utilizing fluorescence microscopy. In sham animals, TLR4 was expressed predominantly in Tamm-Horsfall protein (THP)-positive tubules. In CLP animals, TLR4 expression increased markedly in all tubules (proximal and distal), glomeruli, and the renal vasculature. The staining showed a strong apical distribution in all tubules. A moderately less intense cellular signal colocalized partially with the Golgi apparatus. In addition, kidneys from septic rats showed increased expression of CD14 and THP. They each colocalized strongly with TLR4, albeit in different tubular segments. We also imaged the kidneys of live septic animals with two-photon microscopy after fluorescent lipopolysaccharide (LPS) injection. Within 10 min, LPS was seen at the brush border of some proximal tubules. Within 60 min, LPS was fully cytoplasmic in proximal tubules. Conversely, distal tubules showed no LPS uptake. We conclude that TLR4, CD14, and THP have specific renal cellular and tubular expression patterns that are markedly affected by sepsis. Systemic endotoxin can freely access the tubular and cellular sites where these proteins are present. Therefore, locally expressed TLRs and other interacting proteins could potentially modulate the renal response to systemic sepsis.

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 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.

scholarly journals Alteration of the Fatty Acid Metabolism in the Rat Kidney Caused by the Injection of Serum from Patients with Collapsing Glomerulopathy

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 388
Author(s):  
Elizabeth Soria-Castro ◽  
Verónica Guarner-Lans ◽  
María Elena Soto ◽  
María del Carmen Avila-Casado ◽  
Linaloe Manzano Pech ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Acid Metabolism ◽  
Rat Kidney ◽  
Group Iv ◽  
Sprague Dawley ◽  
Group Iii ◽  
Collapsing Glomerulopathy ◽  
Fa Composition ◽  
Group I ◽  
Sprague Dawley Rats

Patients with collapsing glomerulopathy (CG) have marked proteinuria that rapidly progresses to chronic renal failure. In this study, we investigated if the nephropathy produced in a rat model by the injection of serum from CG patients induced alterations in fatty acid (FA) metabolism. Twenty-four female Sprague-Dawley rats were divided into four groups of six rats each: Group I, control rats (C); Group II, rats that received injections of 1 mL of 0.9% NaCl saline solution (SS); Group III, rats injected with 25 mg/mL of serum from healthy subjects (HS); and Group IV, rats injected with 25 mg/mL of serum from CG patients. In all groups, the systolic blood pressure (SBP), proteinuria, creatinine clearance (CC), cholesterol and total FA composition in the kidney and serum were evaluated. The administration of serum from CG patients to rats induced glomerular collapse, proteinuria, reduced CC and elevated SBP (p ≤ 0.01) in comparison with the C, SS and HS rats. The FA composition of the serum of rats that received the CG serum showed an increase in palmitic acid (PA) and a decrease in arachidonic acid (AA) when compared to serum from HS (p ≤ 0.02). In rats receiving the CG serum, there was also a decrease in the AA in the kidney but there was an increase in the PA in the serum and kidney (p ≤ 0.01). These results suggest that the administration of serum from CG patients to rats induces alterations in FA metabolism including changes in PA and in AA, which are precursors for the biosynthesis of the prostaglandins that are involved in the elevation of SBP and in renal injury. These changes may contribute to collapsing glomerulopathy disease.

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

Ontogeny of glycine transport in isolated rat renal tubules

1977 ◽  
Vol 233 (3) ◽  
pp. F241-F246
Author(s):  
K. S. Roth ◽  
S. M. Hwang ◽  
J. W. London ◽  
S. Segal
Keyword(s):  
Rat Kidney ◽  
Renal Tubules ◽  
Sprague Dawley ◽  
Entry Rate ◽  
Glycine Uptake ◽  
Adult Rat ◽  
High Affinity ◽  
Sprague Dawley Rats ◽  
Rate Kinetics ◽  
Isolated Renal Tubule

Isolated renal tubule preparations were made from newborn Sprague-Dawley rats and used to study initial entry rate kinetics of glycine. The results were compared to those obtained in the isolated tubule preparation from the adult rat kidney. While initial rates of glycine uptake were identical for newborn and adult tubules, significant differences in influx kinetics were demonstrated. Of the two apparent transport Km systems shown to be present in the newborn tubule, the high-affinity, low-capacity system accounts for about 40% of total glycine uptake at physiologic concentrations. The high-affinity, low-capacity system of the adult tissue accounts for about 10% of total uptake at the same concentration range. The data lend strength to the argument against the concept that the physiologic hyperglycinuria of the newborn rat is due to either impaired ability to concentrate glycine intracellularly or to absence of one or more transport mechanisms for glycine.

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