scholarly journals Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

2019 ◽  
Author(s):  
Jiajun Liu ◽  
Gwendolyn M. Pais ◽  
Sean N. Avedissian ◽  
Annette Gilchrist ◽  
Andrew Lee ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Compartment Model ◽  
Polymyxin B ◽  
In Vivo Model ◽  
Limiting Factor ◽  
Sprague Dawley ◽  
Clinical Model ◽  
The Impact

AbstractThe polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R2 of 0.129 mg/L, 0.729 mg2/L2 and 0.652, respectively. PB exposure (i.e. AUC24h) were similar across treatment groups over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 from day −1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day −1, 0.03 (−0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily resulted in the most injury in a rat model.

scholarly journals Evaluation of Dose-Fractionated Polymyxin B on Acute Kidney Injury Using a Translational In Vivo Rat Model

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Jiajun Liu ◽  
Gwendolyn M. Pais ◽  
Sean N. Avedissian ◽  
Annette Gilchrist ◽  
Andrew Lee ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Rat Model ◽  
Kidney Injury ◽  
Compartment Model ◽  
Polymyxin B ◽  
Time Curve ◽  
Daily Group ◽  
Concentration Time ◽  
Three Compartment Model

ABSTRACT We investigated dose-fractionated polymyxin B (PB) on acute kidney injury (AKI). PB at 12 mg of drug/kg of body weight per day (once, twice, and thrice daily) was administered in rats over 72 h. The thrice-daily group demonstrated the highest KIM-1 increase (P = 0.018) versus that of the controls (P = 0.99) and histopathological damage (P = 0.013). A three-compartment model best described the data (bias, 0.129 mg/liter; imprecision, 0.729 mg2/liter2; R2, 0.652,). Area under the concentration-time curve at 24 h (AUC24) values were similar (P = 0.87). The thrice-daily dosing scheme resulted in the most PB-associated AKI in a rat model.

scholarly journals Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury

2011 ◽  
Vol 300 (3) ◽  
pp. F721-F733 ◽  
Author(s):  
David P. Basile ◽  
Jessica L. Friedrich ◽  
Jasmina Spahic ◽  
Nicole Knipe ◽  
Henry Mang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endothelial Cells ◽  
Fluorescent Protein ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Yellow Fluorescent Protein ◽  
Kidney Injury ◽  
Sprague Dawley ◽  
Mesenchymal Transition

Acute kidney injury induces the loss of renal microvessels, but the fate of endothelial cells and the mechanism of potential vascular endothelial growth factor (VEGF)-mediated protection is unknown. Cumulative cell proliferation was analyzed in the kidney of Sprague-Dawley rats following ischemia-reperfusion (I/R) injury by repetitive administration of BrdU (twice daily) and colocalization in endothelial cells with CD31 or cablin. Proliferating endothelial cells were undetectable for up to 2 days following I/R and accounted for only ∼1% of BrdU-positive cells after 7 days. VEGF-121 preserved vascular loss following I/R but did not affect proliferation of endothelial, perivascular cells or tubular cells. Endothelial mesenchymal transition states were identified by localizing endothelial markers (CD31, cablin, or infused tomato lectin) with the fibroblast marker S100A4. Such structures were prominent within 6 h and sustained for at least 7 days following I/R. A Tie-2-cre transgenic crossed with a yellow fluorescent protein (YFP) reporter mouse was used to trace the fate of endothelial cells and demonstrated interstititial expansion of YFP-positive cells colocalizing with S100A4 and smooth muscle actin following I/R. The interstitial expansion of YFP cells was attenuated by VEGF-121. Multiphoton imaging of transgenic mice revealed the alteration of YFP-positive vascular cells associated with blood vessels characterized by limited perfusion in vivo. Taken together, these data indicate that vascular dropout post-AKI results from endothelial phenotypic transition combined with an impaired regenerative capacity, which may contribute to progressive chronic kidney disease.

scholarly journals Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dongdong Yuan ◽  
Xiaoyun Li ◽  
Chenfang Luo ◽  
Xianlong Li ◽  
Nan Cheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Cx43 Expression

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

scholarly journals The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110374
Author(s):  
Hai-Peng Fan ◽  
Zhi-Xia Zhu ◽  
Jia-Jun Xu ◽  
Yu-Tang Li ◽  
Chun-Wen Guo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Susceptibility ◽  
Kidney Injury ◽  
In Vivo Model ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Downstream Target ◽  
Renal Tubular

Objective This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). Methods A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. Results CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. Conclusions CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.

scholarly journals The Impact of Acute Kidney Injury on the Risk of Mortality and Health Care Utilization Among Patients Treated With Polymyxins for Severe Gram-Negative Infections

2018 ◽  
Vol 5 (8) ◽  
Author(s):  
Sarah Baradaran ◽  
Douglas J Black ◽  
Katelyn R Keyloun ◽  
Ryan N Hansen ◽  
Patrick J Gillard ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Linear Models ◽  
Kidney Injury ◽  
Polymyxin B ◽  
Care Utilization ◽  
Risk Of Mortality ◽  
Hospitalization Costs ◽  
Hospital Stays ◽  
Multivariable Analyses ◽  
The Impact

Abstract Background With the rise of antibiotic resistance, polymyxin use has re-emerged but with a concern of renal toxicity. This study aims to assess mortality, length of stay, and total hospitalization cost associated with acute kidney injury (AKI) among recipients of intravenous (IV) sodium colistimethate (CMS) or IV polymyxin B (PMB). Methods We conducted a retrospective database analysis using the Premier database from January 1, 2012, through September 30, 2015. Adults ≥18 years of age who were admitted for inpatient treatment with ≥3 consecutive days of CMS or PMB were included. Generalized linear models compared patients who developed AKI with those who did not. Models were adjusted for patient and clinical characteristics. Results A total of 4886 patients were included; 4103 patients received CMS, and 783 received PMB. In the multivariable analyses, the presence of AKI was associated with higher in-hospital mortality in both the CMS cohort (adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.9–2.7; P < .001) and the PMB cohort (aOR, 2.7; 95% CI, 1.8–4.2; P < .001). In both cohorts, patients who developed AKI experienced longer hospital stays (9.7 days and 11.6 days in the CMS and PMB cohorts, respectively; P < .001). The mean total hospitalization costs for patients who developed AKI were $47 820 higher (95% CI, $34 918–$60 722) in the CMS cohort and $35 244 higher (95% CI, $17 561–$52 928) in the PMB cohort. Conclusions The clinical and economic burden of AKI in the context of polymyxin use is substantial. The use of effective antibiotics with limited toxicity should remain a priority.

scholarly journals Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury

2012 ◽  
Vol 303 (1) ◽  
pp. F56-F63 ◽  
Author(s):  
Anja Bienholz ◽  
Frank Petrat ◽  
Patricia Wenzel ◽  
Philipp Ickerott ◽  
Joel M. Weinberg ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Rat Model ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Atp Depletion ◽  
Nonesterified Fatty Acid ◽  
Sprague Dawley ◽  
Plasma Parameters ◽  
Arterial Blood

Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of α-ketoglutarate+malate (αKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether αKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). αKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of αKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of αKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg αKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving αKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with αKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects.

scholarly journals Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury

2021 ◽  
Author(s):  
Mark Hepokoski ◽  
Jing Wang ◽  
Kefeng Li ◽  
Ying Li ◽  
Purva Gupta ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Lung Injury ◽  
Mitochondrial Dysfunction ◽  
Kidney Injury ◽  
Lavage Fluid ◽  
Acid Oxidation ◽  
Sham Operation ◽  
Lung Metabolism ◽  
The Impact

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury due to AKI.

scholarly journals A Biochemical and Pharmacological Characterization of Phospholipase A2 and Metalloproteinase Fractions from Eastern Russell’s Viper (Daboia siamensis) Venom: Two Major Components Associated with Acute Kidney Injury

Toxins ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 521
Author(s):  
Janeyuth Chaisakul ◽  
Orawan Khow ◽  
Kulachet Wiwatwarayos ◽  
Muhamad Rusdi Ahmad Rusmili ◽  
Watcharamon Prasert ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Phospholipase A2 ◽  
Protein Identification ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Factor X ◽  
Pharmacological Characterization ◽  
Russell’S Viper

Acute kidney injury (AKI) following Eastern Russell’s viper (Daboia siamensis) envenoming is a significant symptom in systemically envenomed victims. A number of venom components have been identified as causing the nephrotoxicity which leads to AKI. However, the precise mechanism of nephrotoxicity caused by these toxins is still unclear. In the present study, we purified two proteins from D. siamensis venom, namely RvPLA2 and RvMP. Protein identification using LCMS/MS confirmed the identity of RvPLA2 to be snake venom phospholipase A2 (SVPLA2) from Thai D. siamensis venom, whereas RvMP exhibited the presence of a factor X activator with two subunits. In vitro and in vivo pharmacological studies demonstrated myotoxicity and histopathological changes of kidney, heart, and spleen. RvPLA2 (3–10 µg/mL) caused inhibition of direct twitches of the chick biventer cervicis muscle preparation. After administration of RvPLA2 or RvMP (300 µg/kg, i.p.) for 24 h, diffuse glomerular congestion and tubular injury with minor loss of brush border were detected in envenomed mice. RvPLA2 and RvMP (300 µg/kg; i.p.) also induced congestion and tissue inflammation of heart muscle as well as diffuse congestion of mouse spleen. This study showed the significant roles of PLA2 and SVMP in snake bite envenoming caused by Thai D. siamensis and their similarities with observed clinical manifestations in envenomed victims. This study also indicated that there is a need to reevaluate the current treatment strategies for Thai D. siamensis envenoming, given the potential for irreversible nephrotoxicity.

scholarly journals Does deeper hypothermia reduce the risk of acute kidney injury after circulatory arrest for aortic arch surgery?

2021 ◽  
Author(s):  
Andrew M Vekstein ◽  
Babtunde A Yerokun ◽  
Oliver K Jawitz ◽  
Julie W Doberne ◽  
Jatin Anand ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Circulatory Arrest ◽  
Aortic Surgery ◽  
Multivariable Analysis ◽  
Kidney Injury ◽  
Deep Hypothermia ◽  
Moderate Hypothermia ◽  
Bladder Temperature ◽  
Increased Risk ◽  
The Impact

Abstract OBJECTIVES The impact of hypothermic circulatory arrest (HCA) temperature on postoperative acute kidney injury (AKI) has not been evaluated. This study examined the association between circulatory arrest temperatures and AKI in patients undergoing proximal aortic surgery with HCA. METHODS A total of 759 consecutive patients who underwent proximal aortic surgery (ascending ± valve ± root) including arch replacement requiring HCA between July 2005 and December 2016 were identified from a prospectively maintained institutional aortic surgery database. The primary outcome was AKI as defined by Risk, Injury, Failure, Loss, End Stage Renal Disease (ESRD) criteria. The association between minimum nasopharyngeal (NP) and bladder temperatures during HCA and postoperative AKI was assessed, adjusting for patient-level factors using multivariable logistic regression. RESULTS A total of 85% (n = 645) of patients underwent deep hypothermia (14.1–20.0°C), 11% (n = 83) low-moderate hypothermia (20.1–24.0°C) and 4% (n = 31) high-moderate hypothermia (24.1–28.0°C) as classified by NP temperature. When analysed by bladder temperature, 59% (n = 447) underwent deep hypothermia, 22% (n = 170) low-moderate, 16% (n = 118) high-moderate and 3% mild (n = 24) (28.1–34.0°C) hypothermia. The median systemic circulatory arrest time was 17 min. The incidence of AKI did not differ between hypothermia groups, whether analysed using minimum NP or bladder temperature. In the multivariable analysis, the association between degree of hypothermia and AKI remained non-significant whether analysed as a categorical variable (hypothermia group) or as a continuous variable (minimum NP or bladder temperature) (all P > 0.05). CONCLUSIONS In patients undergoing proximal aortic surgery including arch replacement requiring HCA, degree of systemic hypothermia was not associated with the risk of AKI. These data suggest that moderate hypothermia does not confer increased risk of AKI for patients requiring circulatory arrest, although additional prospective data are needed.

scholarly journals RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Ruizhao Li ◽  
Xingchen Zhao ◽  
Shu Zhang ◽  
Wei Dong ◽  
Li Zhang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Kidney Injury ◽  
Septic Acute Kidney Injury ◽  
Transcription Factor Eb ◽  
Autophagic Degradation ◽  
Lps Treatment

AbstractAutophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

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