Biomarkers of persistent renal vulnerability after acute kidney injury recovery

AbstractAcute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.

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Endothelial progenitor cells-derived exosomal microRNA-21-5p alleviates sepsis-induced acute kidney injury by inhibiting RUNX1 expression

Cell Death and Disease ◽

10.1038/s41419-021-03578-y ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Yue Zhang ◽

Hongdong Huang ◽

Wenhu Liu ◽

Sha Liu ◽

Xue Yan Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Cecal Ligation ◽

Kidney Injury ◽

Renal Tissue ◽

Endothelial Glycocalyx ◽

Endothelial Progenitor ◽

Marker Proteins ◽

Related Transcription Factor

AbstractThe role of microRNA-21-5p (miR-21-5p) in sepsis-induced acute kidney injury (AKI) has been seldom discussed. Therefore, the objective of this present study was to investigate the mechanism of endothelial progenitor cells-derived exosomes (EPCs-exos) in sepsis-induced AKI via miR-21-5p/runt-related transcription factor 1 (RUNX1) axis. miR-21-5p was downregulated and RUNX1 was upregulated in the kidney of cecal ligation and puncture (CLP) rats, and miR-21-5p targeted RUNX1. Elevation of miR-21-5p improved renal function and renal tissue pathological damage, attenuated serum inflammatory response, as well as reduced apoptosis and oxidative stress response in renal tissues, and regulated endothelial glycocalyx damage marker proteins syndecan-1 and heparanase-1 in CLP rats. Overexpression of RUNX1 abolished the impacts of elevated miR-21-5p in CLP rats. Also, EPCs-exos upregulated miR-21-5p expression, and functioned similar to elevation of miR-21-5p for CLP rats. Downregulating miR-21-5p partially reversed the effects of EPCs-exos on sepsis-induced AKI. Collectively, our study suggests that EPCs release miR-21-5p-containing exosomes to alleviate sepsis-induced AKI through RUNX1 silencing.

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DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

Cell Death Discovery ◽

10.1038/s41420-021-00528-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yinwu Bao ◽

Mengqiu Bai ◽

Huanhuan Zhu ◽

Yuan Yuan ◽

Ying Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Signaling Pathway ◽

Cell Injury ◽

Inflammatory Responses ◽

Kidney Injury ◽

Renal Tissue ◽

Clinical Samples ◽

Mice Model ◽

Expression Levels ◽

Ppar Signaling

AbstractDemethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers’ expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

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Gene Microarray Integrated with High-Throughput Proteomics for the Discovery of Transthyretin in Rhabdomyolysis-Induced Acute Kidney Injury

Cellular Physiology and Biochemistry ◽

10.1159/000484028 ◽

2017 ◽

Vol 43 (4) ◽

pp. 1673-1688 ◽

Cited By ~ 1

Author(s):

Ou Li ◽

Xiaodong Geng ◽

Qian Ma ◽

Weiwei Wang ◽

Ran Liu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Western Blotting ◽

Kidney Injury ◽

Physical Exertion ◽

Renal Tissue ◽

Gene Microarray ◽

Absolute Quantitation ◽

Gene And Protein Expression ◽

Isobaric Tagging

Background/Aims: Rhabdomyolysis, one of the leading causes of acute kidney injury (AKI), develops after trauma, drug toxicity, infections, burns, and physical exertion. The aim of this study was to investigate differences in gene and protein expression to elucidate the pathogenesis of rhabdomyolysis (RM)-induced AKI. Methods: In this study, we used glycerol induced renal injury as a model of RM-induced AKI. Affymetrix U133 plus 2.0 microarrays were used to perform gene microarray analysis. Isobaric tagging with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS) was applied to screen and identify differentially expressed proteins between RM-induced AKI and normal murine renal tissue. Verification experiments included immunohistochemistry (IHC), real-time PCR, Western blotting, and the measurement of ATP and ROS production. HK-2 cells were incubated in vitro with ferrous myoglobin and pcDNA-TTR, followed by assays to detect cell proliferation, ROS and apoptosis. Results: According to gene microarray and iTRAQ-MS analysis, we screened 17 common elements. After multiple analyses, we selected transthyretin (TTR) as our focus and investigated TTR in the kidney. Verification experiments with IHC confirmed differential expression levels of TTR proteins. Furthermore, Western blotting showed a stepwise decrease in TTR in AKI renal tissues. Cell-based experiments showed that overexpression of TTR could improve HK-2 cell viability and inhibit apoptosis. TTR reduced apoptosis by decreasing the accumulation of reactive oxygen species (ROS). Conclusion: This study reports a possible mechanism for RM-induced AKI and suggests that reductions in TTR could increase the generation of ROS and induce apoptosis. TTR may be a potentially valuable target for RM-induced AKI.

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Renal tissue desaturation and acute kidney injury in infant cardiac surgery: a prospective propensity score-matched cohort study

British Journal of Anaesthesia ◽

10.1016/j.bja.2021.06.045 ◽

2021 ◽

Author(s):

Dongni Zhang ◽

Chuan Ouyang ◽

Xu Zhao ◽

Boqun Cui ◽

Feng Dai ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Cohort Study ◽

Propensity Score ◽

Kidney Injury ◽

Renal Tissue ◽

Matched Cohort ◽

Matched Cohort Study

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MO343SERUM RESPONSE FACTOR, A NOVEL EARLY DIAGNOSTIC BIOMARKER OF ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab084.0016 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Long Zhao ◽

Yan Xu

Keyword(s):

Acute Kidney Injury ◽

Serum Response Factor ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Diagnostic Value ◽

Renal Tissue ◽

Response Factor ◽

Diagnostic Biomarker ◽

Renal Tubular ◽

Early Diagnostic

Abstract Background and Aims Studies have shown that serum response factor (SRF) is increased in chronic kidney injury, such as diabetic nephropathy, hyperuricemic nephropathy and renal cell carcinoma. The objective is to explore the early diagnostic value of SRF in acute kidney injury (AKI). Method AKI-related microarray data were analyzed, and the expression and location of SRF were investigated in the early phase of AKI. Results Bioinformatics results demonstrated that SRF was dramatically elevated 2-4 h after ischemia/reperfusion (I/R) in mouse renal tissue. In I/R rats, SRF was mostly expressed and located in renal tubular epithelial cells (TECs). SRF started to increase at 1 h, peaked at 3-9 h and started to decrease at 12 h after I/R. The areas under the ROC curve of renal SRF mRNA, renal SRF protein, urinary SRF, serum SRF and serum creatinine (Scr) were 87.9%, 83.0%, 81.3%, 78.8%, 68.8%, respectively. Conclusion SRF is remarkably upregulated in early (before 24 h) AKI and can replace Scr as a potential new early diagnostic biomarker of AKI.

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Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

AJP Renal Physiology ◽

10.1152/ajprenal.00271.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. F284-F296 ◽

Cited By ~ 38

Author(s):

David R. Emlet ◽

Nuria Pastor-Soler ◽

Allison Marciszyn ◽

Xiaoyan Wen ◽

Hernando Gomez ◽

...

Keyword(s):

Cell Culture ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Human Kidney ◽

Distal Tubule ◽

Cell Types ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tubule Cell ◽

Tubule Cells

We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury.

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

Cardiorenal Medicine ◽

10.1159/000492159 ◽

2018 ◽

Vol 9 (1) ◽

pp. 31-40 ◽

Cited By ~ 3

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.

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Urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery

Critical Care ◽

10.1186/cc13571 ◽

2014 ◽

Vol 18 (Suppl 1) ◽

pp. P381

Author(s):

A Zarbock ◽

M Meersch ◽

C Schmidt ◽

S Martens ◽

J Rossaint ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Growth Factor ◽

Kidney Injury ◽

Renal Recovery ◽

Insulin Like Growth Factor ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor ◽

Factor Binding ◽

Early Biomarkers

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Furosemide stress test as a predictive marker of acute kidney injury progression or renal replacement therapy: a systemic review and meta-analysis

10.21203/rs.2.23355/v2 ◽

2020 ◽

Author(s):

Jia-Jin Chen ◽

Chih-Hsiang Chang ◽

Yen Ta Huang ◽

George Kuo

Keyword(s):

Acute Kidney Injury ◽

Renal Replacement Therapy ◽

Diagnostic Accuracy ◽

Replacement Therapy ◽

Sensitivity And Specificity ◽

Odds Ratio ◽

Diagnostic Performance ◽

Stress Test ◽

Kidney Injury ◽

Diagnostic Odds Ratio

Abstract Background: The use of the furosemide stress test (FST) as an acute kidney injury (AKI) severity marker has been described in several trials. However, the diagnostic performance of the FST in predicting AKI progression has not yet been fully discussed. Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the PubMed, Embase, Cochrane databases up to March, 2020. The diagnostic performance of the FST (in terms of sensitivity, specificity, number of events, true positive, false positive) was extracted and evaluated. Results: We identified eleven trials that enrolled a total of 1366 patients, including 517 patients and 1017 patients for whom the outcomes in terms of AKI stage progression and renal replacement therapy (RRT), respectively, were reported. The pooled sensitivity and specificity results of the FST for AKI progression prediction were 0.81 (95% CI: 0.74 - 0.87) and 0.88 (95% CI: 0.82- 0.92), respectively. The pooled positive likelihood ratio (LR) was 5.45 (95% CI: 3.96-7.50), the pooled negative LR was 0.26 (95% CI: 0.19-0.36), and the pooled diagnostic odds ratio (DOR) was 29.69 (95% CI: 17.00-51.85). The summary receiver operating characteristics (SROC) with pooled diagnostic accuracy was 0.88. The diagnostic performance of the FST in predicting AKI progression was not affected by different AKI criteria or underlying chronic kidney disease. The pooled sensitivity and specificity results of the FST for RRT prediction were 0.84 (95% CI: 0.72-0.91) and 0.77 (95% CI: 0.64-0.87), respectively. The pooled positive LR and pooled negative LR were 3.16 (95% CI: 2.06-4.86) and 0.25 (95% CI: 0.14-0.44), respectively. The pooled diagnostic odds ratio (DOR) was 13.59 (95% CI: 5.74-32.17) and SROC with pooled diagnostic accuracy was 0.86. The diagnostic performance of FST for RRT prediction is better in stage 1-2 AKI comparing to stage 3 AKI (relative DOR: 5.75, 95% CI: 2.51-13.33) Conclusion: The FST is a simple tool for the identification of AKI populations at high risk of AKI progression and the need for RRT and the diagnostic performance of FST in RRT prediction is better in early AKI population.

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