scholarly journals Immunopathogenesis of Acute Kidney Injury

2018 ◽  
Vol 46 (8) ◽  
pp. 930-943 ◽  
Author(s):  
Zaher A. Radi
Keyword(s):  
Acute Kidney Injury ◽  
T Cells ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Drug Induced ◽  
Inflammatory Damage ◽  
Anti Inflammatory ◽  
Renal Tubular ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

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 PSTPIP2 inhibits cisplatin-induced acute kidney injury by suppressing apoptosis of renal tubular epithelial cells

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hong Zhu ◽  
Wenjuan Jiang ◽  
Huizi Zhao ◽  
Changsheng He ◽  
Xiaohan Tang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Histone Acetylation ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Cisplatin Nephrotoxicity ◽  
Renal Tubular

AbstractCisplatin (CP) is an effective chemotherapeutic agent widely used in the treatment of various solid tumours. However, CP nephrotoxicity is an important limitation for CP use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Recently, we identified a specific role of proline–serine–threonine phosphatase-interacting protein 2 (PSTPIP2) in cisplatin-induced AKI. PSTPIP2 was reported to play an important role in a variety of diseases. However, the functions of PSTPIP2 in experimental models of cisplatin-induced AKI have not been extensively studied. The present study demonstrated that cisplatin downregulated the expression of PSTPIP2 in the kidney tissue. Administration of AAV-PSTPIP2 or epithelial cell-specific overexpression of PSTPIP2 reduced cisplatin-induced kidney dysfunction and inhibited apoptosis of renal tubular epithelial cells. Small interfering RNA-based knockdown of PSTPIP2 expression abolished PSTPIP2 regulation of epithelial cell apoptosis in vitro. Histone acetylation may impact gene expression at the epigenetic level, and histone deacetylase (HDAC) inhibitors were reported to prevent cisplatin-induced nephrotoxicity. The UCSC database was used to predict that acetylation of histone H3 at lysine 27 (H3K27ac) induces binding to the PSTPIP2 promoter, and this prediction was validated by a ChIP assay. Interestingly, an HDAC-specific inhibitor (TSA) was sufficient to potently upregulate PSTPIP2 in epithelial cells. Histone acetylation-mediated silencing of PSTPIP2 may contribute to cisplatin nephrotoxicity. PSTPIP2 may serve as a potential therapeutic target in the prevention of cisplatin nephrotoxicity.

Macrophages in Kidney Injury, Inflammation, and Fibrosis

Physiology ◽  
2015 ◽  
Vol 30 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Qi Cao ◽  
David C. H. Harris ◽  
Yiping Wang
Keyword(s):  
Kidney Disease ◽  
Tissue Injury ◽  
Kidney Diseases ◽  
Treatment Options ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Anti Inflammatory ◽  
Molecular Patterns ◽  
Inflammatory Macrophages

Macrophages are found in normal kidney and in increased numbers in diseased kidney, where they act as key players in renal injury, inflammation, and fibrosis. Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics in response to various stimuli in the local microenvironment in different types of kidney disease. In kidney tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce pro-inflammatory macrophages, which contribute to further tissue injury, inflammation, and subsequent fibrosis. Apoptotic cells and anti-inflammatory factors in post-inflammatory tissues induced anti-inflammatory macrophages, which can mediate kidney repair and regeneration. This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Understanding alterations of kidney microenvironment and the factors that control the phenotype and functions of macrophages may offer an avenue for the development of new cellular and cytokine/growth factor-based therapies as alternative treatment options for patients with kidney disease.

Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases

2020 ◽  
Vol 27 (34) ◽  
pp. 5829-5854 ◽  
Author(s):  
Qian Ren ◽  
Lu Cheng ◽  
Jing Yi ◽  
Liang Ma ◽  
Jing Pan ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Host Immunity ◽  
Toll Like Receptors ◽  
Chronic Kidney Diseases ◽  
Inflammatory Cascade ◽  
Molecular Patterns ◽  
Dying Cells ◽  
Damage Associated Molecular Patterns

Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.

scholarly journals Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery

2021 ◽  
Vol 12 ◽  
Author(s):  
Pierre-Olivier Ludes ◽  
Charles de Roquetaillade ◽  
Benjamin Glenn Chousterman ◽  
Julien Pottecher ◽  
Alexandre Mebazaa
Keyword(s):  
Acute Kidney Injury ◽  
Tissue Injury ◽  
High Mobility ◽  
Kidney Injury ◽  
Blood Perfusion ◽  
Tubular Damage ◽  
Organ Protection ◽  
Tubular Necrosis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

scholarly journals Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

2015 ◽  
Vol 112 (16) ◽  
pp. 5231-5236 ◽  
Author(s):  
Navjotsingh Pabla ◽  
Alice A. Gibson ◽  
Mike Buege ◽  
Su Sien Ong ◽  
Lie Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Kidney Injury ◽  
Cell Cycle Progression ◽  
Kidney Injury ◽  
Rapid Decline ◽  
Drug Induced ◽  
Cycle Progression ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

scholarly journals Nonsteroidal anti-inflammatory drug induced acute kidney injury; A review and case study

2020 ◽  
Vol 9 (4) ◽  
pp. e30-e30
Author(s):  
David Sabatino ◽  
Michael Tillman ◽  
Jayne Pawasauskas ◽  
Todd Brothers
Keyword(s):  
Risk Factors ◽  
Acute Kidney Injury ◽  
High Risk ◽  
Renal Injury ◽  
Kidney Injury ◽  
Patient Specific ◽  
Drug Induced ◽  
Suitable Alternative ◽  
Severity Of Injury ◽  
Anti Inflammatory

Introduction: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly therapeutic classes and are responsible for ten percent of medications dispensed annually. Twelve percent of individuals currently report taking a NSAID daily. Renal injury caused by these agents can present in various forms, resulting from either acute or chronic use. Historically approximately five percent of patients initiated on NSAIDs experience a kidney-related adverse event. Drug-induced renal injury accounts for twenty percent of episodes of acute kidney injury (AKI). Patients requiring renal replacement therapy (RRT) have experienced an increased length of stay with associated healthcare costs per incident. The adverse effects of NSAIDs contribute to a significant economic burden, both to the patient and to the healthcare system. Methods: A medical literature review was composed. Results: Numerous risk factors contribute to the development of drug-induced renal injury and disease. Patient specific factors include volume depletion and comorbid conditions. External risk factors such as use of high-risk medications and diagnostic contrast dyes contribute to the increased risk. Implementation of risk mitigation and educational strategies targeting healthcare professionals has the potential to decrease negative clinical and economic outcomes. Conclusion: Healthcare providers’ understanding of the pathophysiology, diagnostic criteria, and risk factors associated with AKI is vital to improve patient outcomes. Proactively screening high risk patients and utilizing appropriate mitigation strategies contributes to limiting the incidence and severity of injury. When the use of NSAIDs cannot be avoided, utilization of lower doses may be a suitable alternative.

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