scholarly journals Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response

2018 ◽  
Vol 314 (6) ◽  
pp. F1166-F1176 ◽  
Author(s):  
Ritesh K. Srivastava ◽  
Amie M. Traylor ◽  
Changzhao Li ◽  
Wenguang Feng ◽  
Lingling Guo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Chemical Warfare Agent ◽  
Renal Tubules ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Enhanced Production ◽  
Exposed Population ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

Lewisite (2-chlorovinyldichloroarsine) is an organic arsenical chemical warfare agent that was developed and weaponized during World Wars I/II. Stockpiles of lewisite still exist in many parts of the world and pose potential environmental and human health threat. Exposure to lewisite and similar chemicals causes intense cutaneous inflammatory response. However, morbidity and mortality in the exposed population is not only the result of cutaneous damage but is also a result of systemic injury. Here, we provide data delineating the pathogenesis of acute kidney injury (AKI) following cutaneous exposure to lewisite and its analog phenylarsine oxide (PAO) in a murine model. Both agents caused renal tubular injury, characterized by loss of brush border in proximal tubules and tubular cell apoptosis accompanied by increases in serum creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Interestingly, lewisite exposure enhanced production of reactive oxygen species (ROS) in the kidney and resulted in the activation of autophagic and DNA damage response (DDR) signaling pathways with increased expression of beclin-1, autophagy-related gene 7, and LC-3A/B-II and increased phosphorylation of γ-H2A.X and checkpoint kinase 1/2, respectively. Terminal deoxyribonucleotide-transferase-mediated dUTP nick-end labeling-positive cells were detected in renal tubules along with enhanced proapoptotic BAX/cleaved caspase-3 and reduced antiapoptotic BCL2. Scavenging ROS by cutaneous postexposure application of the antioxidant N-acetyl-l-cysteine reduced lewisite-induced autophagy and DNA damage. In summary, we provide evidence that topical exposure to lewisite causes AKI. The molecular mechanism underlying these changes involves ROS-dependent activation of autophagy and DDR pathway associated with the induction of apoptosis.

scholarly journals Screening of early diagnostic markers of gentamicin-induced acute kidney injury in canines

2019 ◽  
Vol 63 (3) ◽  
pp. 405-411
Author(s):  
Jia-San Zheng ◽  
Jing-Nie ◽  
Ting-Ting Zhu ◽  
Hong-Ri Ruan ◽  
Xue-Wei ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Characteristic Curve ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Fatty Acid Binding ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Transmission Electron ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1 ◽  
Neutrophil Gelatinase

Abstract Introduction The value of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), and liver-type fatty acid binding protein (L-FABP) was assessed in early diagnosis of gentamicin-induced acute kidney injury (AKI) in dogs. Material and Methods Subcutaneous gentamicin injection in 16 healthy adult beagles made the AKI model. Blood was sampled every 6 h to detect NGAL, Kim-1, L-FABP, and serum creatinine (SCr) concentrations. Kidney tissue of two dogs was taken before the injection, as soon as SCr was elevated (78 μmol/L), and when it had risen to 1.5 times the baseline, and haematoxylin-eosin staining and transmission electron microscopy (TEM) were used to observe changes. Results NGAL, Kim-1, and SCr levels were significantly increased (P < 0.05) at 18, 30, and 78 h post injection, but L-FABP concentration was not associated with renal injury. At the earliest SCr elevation stage, findings were mild oedema, degeneration, and vacuolisation in renal tubular epithelial cells in pathology, and mild cytoplasmic and mitochondrial oedema in TEM. At this time point, NGAL and Kim-1 concentrations were significantly increased (P < 0.05), indicating that these two molecules biomark early kidney injury in dogs. Using receiver operating characteristic curve analysis, their warning levels were > 25.31 ng/mL and > 48.52 pg/mL. Conclusion Plasma NGAL and Kim-1 above warning levels are early indicators of gentamicin-induced AKI in dogs.

scholarly journals Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy

2017 ◽  
Vol 243 (3) ◽  
pp. 272-282 ◽  
Author(s):  
Blessy George ◽  
Melanie S Joy ◽  
Lauren M Aleksunes
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Urinary Proteins ◽  
Protein Biomarkers ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Chemotactic Protein ◽  
Trefoil Factor 3 ◽  
Beta 2 Microglobulin ◽  
Kidney Injury Molecule 1 ◽  
Neutrophil Gelatinase

Despite recent progress in the development of novel approaches to treat cancer, traditional antineoplastic drugs, such as cisplatin, remain a mainstay of regimens targeting solid tumors. Use of cisplatin is limited by acute kidney injury, which occurs in approximately 30% of patients. Current clinical measures, such as serum creatinine and estimated glomerular filtration rate, are inadequate in their ability to detect acute kidney injury, particularly when there is only a moderate degree of injury. Thus, there is an urgent need for improved diagnostic biomarkers to predict nephrotoxicity. There is also interest by the U.S. Food and Drug Administration to validate and implement new biomarkers to identify clinical and subclinical acute kidney injury in patients during the drug approval process. This minireview provides an overview of the current literature regarding the utility of urinary proteins (albumin, beta-2-microglobulin, N-acetyl-D-glucosaminidase, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C) as biomarkers for cisplatin-induced AKI. Many of the well-studied urinary proteins (KIM-1, NGAL, B2M, albumin) as well as emerging biomarkers (calbindin, monocyte chemotactic protein-1, and trefoil factor 3) display distinct patterns of time-dependent excretion after cisplatin administration. Implementation of these biomarker proteins in the oncology clinic has been hampered by a lack of validation studies. To address these issues, large head-to-head studies are needed to fully characterize time-dependent responses and establish accurate cutoff values and ranges, particularly in cancer patients. Impact statement There is growing interest in using urinary protein biomarkers to detect acute kidney injury in oncology patients prescribed the nephrotoxic anticancer drug cisplatin. We aim to synthesize and organize the existing literature on biomarkers examined clinically in patients receiving cisplatin-containing chemotherapy regimens. This minireview highlights several proteins (kidney injury molecule-1, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, calbindin, monocyte chemotactic protein-1, trefoil factor 3) with the greatest promise for detecting cisplatin-induced acute kidney injury in humans. A comprehensive review of the existing literature may aid in the design of larger studies needed to implement the clinical use of these urinary proteins as biomarkers of kidney injury.

scholarly journals Urine Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 to Detect Pediatric Cisplatin-Associated Acute Kidney Injury

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004802021
Author(s):  
Kelly R. McMahon ◽  
Hayton Chui ◽  
Shahrad Rod Rassekh ◽  
Kirk R. Schultz ◽  
Tom D. Blydt-Hansen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Hospital Discharge ◽  
Characteristic Curve ◽  
Kidney Injury ◽  
Urine Ngal ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Post Infusion ◽  
Kidney Injury Molecule 1 ◽  
Stage 1 ◽  
Neutrophil Gelatinase

Background: Few studies have described associations between acute kidney injury (AKI) biomarkers, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), and AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin. Methods: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin based on Kidney Disease: Improving Global Outcomes guidelines criteria (≥stage 1). Results: Of 159 children, 156 (median [interquartile (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty-six of 156 (29%) and 22/127 (17%) developed AKI within 10 days of cisplatin administration following early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with vs. without AKI (near hospital discharge of late cisplatin infusion, median [IQR]: NGAL: 76.1 [10.0-232.7] vs. 14.9 [5.4-29.7] ng/mg creatinine; KIM-1: 4415 [2083-9077] vs. 1049 [358-3326] pg/mg creatinine; P<.01). These markers modestly discriminated for AKI (area under receiver-operating characteristic curve (AUC-ROC) range: NGAL: 0.56-0.72; KIM-1: 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROCs range: 0.54-0.75) vs. early infusions (AUC-ROCs range: 0.48-0.65). Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and late kidney outcomes associations.

scholarly journals Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish

2018 ◽  
Author(s):  
Lauren Brilli Skvarca ◽  
Hwa In Han ◽  
Eugenel B. Espiritu ◽  
Maria A. Missinato ◽  
Elizabeth R. Rochon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Cardiac Injury ◽  
Kidney Injury ◽  
Acute Injury ◽  
Cardiomyocyte Proliferation ◽  
Deacetylase Inhibitor ◽  
Summary Statement ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

ABSTRACTAcute kidney injury (AKI) is a serious disorder for which there is no approved pharmaceutical treatment. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 expression, and lowers the number of infiltrating macrophages. Further, we find that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.SUMMARY STATEMENTMortality associated with acute kidney injury (AKI) is in part due to limited treatments available to ameliorate kidney injury. We identified a compound that enhances AKI recovery by promoting cellular dedifferentiation.

scholarly journals The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 20 (20) ◽  
pp. 5238 ◽  
Author(s):  
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Smaranda Radu ◽  
Claudia Florida Costea ◽  
Manuela Ciocoiu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

scholarly journals A Novel Biomarker for Acute Kidney Injury, Vanin-1, for Obstructive Nephropathy: A Prospective Cohort Pilot Study

2019 ◽  
Vol 20 (4) ◽  
pp. 899 ◽  
Author(s):  
Satoshi Washino ◽  
Keiko Hosohata ◽  
Masashi Oshima ◽  
Tomohisa Okochi ◽  
Tsuzumi Konishi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Diagnostic Value ◽  
Obstructive Nephropathy ◽  
Control Group ◽  
Operating Characteristics ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Receiver Operating Characteristics Curve ◽  
Kidney Injury Molecule 1 ◽  
Neutrophil Gelatinase

Background: Vanin-1 is a novel acute kidney injury (AKI) biomarker that has not been clinically investigated as a biomarker for obstructive nephropathy. This study investigated the diagnostic value of vanin-1 as a biomarker for adult obstructive nephropathy by comparing it to existing AKI biomarkers. Methods: A total of 49 patients, 21 controls, and 28 hydronephrosis (HN) cases were assessed. AKI biomarkers in bladder (BL) urine and renal pelvic (RP) urine in the HN group were compared to each BL marker in the control group. In a subgroup of cases receiving interventions for obstructive nephropathy, the BL values of each biomarker were assessed after the intervention. Results: RP vanin-1 levels were significantly higher while BL vanin-1 levels were marginally higher in the HN group than in the control group. The area under the receiver operating characteristics curve values for RP and BL vanin-1 were 0.9778 and 0.6386, respectively. In multivariate analyses, BL vanin-1 and N-acetyl-β-D-glucosaminidase (NAG), but not kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL), were independent factors for predicting the presence of HN. In cases receiving interventions, vanin-1 decreased significantly from 1 week after the intervention in cases of moderate to severe obstructive nephropathy compared to RP values at baseline. Conclusion: Urinary vanin-1 is a useful biomarker to detect and monitor the clinical course of obstructive nephropathy.

Different Biomarkers of Acute kidney Injury in Cancer Patients

2021 ◽  
Author(s):  
Reza Kazemi ◽  
Shirin Saberianpour ◽  
Hanieh Salehi ◽  
Mohammad Hatampour ◽  
Elnaz Sheikhpour
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Patients ◽  
Early Stage ◽  
Kidney Injury ◽  
The Body ◽  
Main Task ◽  
Waste Products ◽  
Fatty Acid Binding ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Kidney Injury Molecule 1

Acute Kidney Injury (AKI) occurs if the kidneys suddenly lose their ability to remove waste products. When the kidneys lose their ability to filter, dangerous levels of waste products can accumulate, which can upset the chemical composition of the blood and urine. Chemotherapy is one of the methods used to treat or temporarily reduce cancer by using certain medications. The main task of this treatment is to kill cancer cells without seriously damaging the surrounding tissues. However, this type of treatment also has destructive effects on healthy cells and tissues in the body. Researchers studying cancer patients undergoing chemotherapy found that people undergoing this type of treatment may develop serious kidney problems and be forced to use treatments such as dialysis and kidney transplants. Research showed that people with more severe cancers and advanced tumors are more likely to have acute kidney injury than those with early-stage cancer. AKI biomarkers can be selected from the patient's serum, urine, or body imaging components. Various studies showed that urine is a source of the best markers in AKI. Biomarkers in plasma and urine, such as N-acetyl-β-glucosaminidase, Cystatin-C, β2-microglobulin , Cysteine-Rich Protein, Osteopontin, Fetuin-A, Kidney Injury Molecule-1, Liver-type fatty acid-binding protein, Netrin-1, Neutrophil gelatinase-associated lipocalin, and interleukin-18 are effective tools for early detection of AKI. In this review study, an attempt was made to collect biomarkers related to AKI disease.

scholarly journals Curcumin-Loaded Nanoparticles Protect Against Rhabdomyolysis-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 2143-2154 ◽  
Author(s):  
Xiaoling Chen ◽  
Jian Sun ◽  
Hailun Li ◽  
Hongwu Wang ◽  
Yongtao Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Treatment Efficacy ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubules ◽  
Drug Release Profile ◽  
Renal Tubular

Background/Aims: Rhabdomyolysis (RM) is a potentially life-threatening condition that results from the breakdown of muscle and consequent release of toxic compounds into circulation. The most common and severe complication of RM is acute kidney injury (AKI). This study aimed to evaluate the efficacy and mechanisms of action of curcumin-loaded nanoparticles (Cur-NP) for treatment of RM-induced AKI. Methods: Curcumin-NP was synthesized using the nanocarrier distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to achieve a prolonged and constant drug release profile compared with the curcumin-free group. The anti-AKI effects of Curcumin-NP were examined both in vitro (myoglobin-treated renal tubular epithelial HK-2 cells) and in vivo (glycerol-induced AKI model). Results: Our results indicated that Curcumin-NP reversed oxidative stress, growth inhibition and cell apoptosis accompanied with down-regulation of apoptotic markers Caspase-3 and GRP-78 in vitro. In vivo studies revealed enhanced AKI treatment efficacy with Curcumin-NP as characterized by reduced serum creatine phosphokinase (CPK), creatinine (Cr) and urea and less severe histological damage in renal tubules. In addition, kidney tissues from Curcumin-NP-treated AKI rats exhibited reduced oxidative stress, apoptosis, and cleaved Capase-3 and GRP-78 expression. Conclusion: Our results suggest that nanoparticle-loaded curcumin enhances treatment efficacy for RM-induced AKI both in vitro and in vivo.

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