scholarly journals Pathophysiology of Cisplatin-Induced Acute Kidney Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Abdullah Ozkok ◽  
Charles L. Edelstein
Keyword(s):  
Acute Kidney Injury ◽  
Proinflammatory Cytokines ◽  
Cell Injury ◽  
Germ Cell Tumors ◽  
Kidney Injury ◽  
Inflammatory Cells ◽  
Chemotherapeutic Agents ◽  
Testicular Germ Cell ◽  
Tubular Necrosis ◽  
Proximal Tubular

Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-αor IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

scholarly journals Acute Tubular Necrosis after Ingestion of a Fertilizer Containing Sodium Silicate

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Hyeon Woo Lee ◽  
Yong Jun Choi ◽  
Se Won Oh ◽  
Hye Kyeong Park ◽  
Kum Hyun Han ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Sodium Silicate ◽  
Acute Tubular Necrosis ◽  
Lung Fibrosis ◽  
Kidney Biopsy ◽  
Kidney Injury ◽  
Inflammatory Cells ◽  
Tubular Necrosis ◽  
Stage Renal Disease ◽  
End Stage

Silica nephropathy occurs after chronic heavy exposure to silica, resulting in the development of chronic kidney disease and progression to end-stage renal disease. However, acute kidney injury due to silica exposure is rare and its renal pathology remains unclear. Here, we report a case of acute sodium silica poisoning presenting as acute kidney injury. A 42-year-old man ingested a fertilizer containing sodium silicate. His serum creatinine increased by 5.06 mg/dL from 1.1 mg/dL 2 days after silicate ingestion. Owing to the decline in kidney function despite fluid therapy, a kidney biopsy was performed. The kidney showed acute tubular necrosis without infiltration of inflammatory cells. On day 5 of admission, hemodialysis was initiated to treat the hyperkalemia and oliguria, and treatment with methylprednisolone was initiated for the acute lung injury. The patient was administered 1 mg/kg of methylprednisolone intravenously daily for 2 weeks, followed by a 2-week taper. Hemodialysis was discontinued on day 10 and the patient’s renal function recovered completely. However, he died on day 40 of hospitalization owing to complicated lung fibrosis and persistent pneumothorax/pneumomediastinum.

scholarly journals Inhibition of Src Family Kinases Ameliorates LPS-Induced Acute Kidney Injury and Mitochondrial Dysfunction in Mice

2020 ◽  
Vol 21 (21) ◽  
pp. 8246
Author(s):  
Eun Seon Pak ◽  
Md Jamal Uddin ◽  
Hunjoo Ha
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Dysfunction ◽  
Kidney Function ◽  
Mitochondrial Biogenesis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Src Family Kinases ◽  
Src Kinases ◽  
Proximal Tubular

Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis.

KIDNEY INJURY IN CANCER THERAPY

2018 ◽  
Vol 22 (5) ◽  
pp. 17-24 ◽  
Author(s):  
E. V. Burnasheva ◽  
Y. V. Shatokhin ◽  
I. V. Snezhko ◽  
A. A. Matsuga
Keyword(s):  
Risk Factors ◽  
Acute Kidney Injury ◽  
Cancer Therapy ◽  
Cancer Patients ◽  
Cytotoxic Effect ◽  
Tumor Lysis Syndrome ◽  
Kidney Injury ◽  
Chemotherapeutic Agents ◽  
Oxygen Intermediates ◽  
Circulating Blood Volume

Кidney injury is a frequent and significant complication of cancer and cancer therapy. The kidneys are susceptible to injury from malignant infiltration, damage by metabolites of malignant cells, glomerular  injury, nephrotoxic drugs including chemotherapeutic agents. Also  bone marrow transplantation complications, infections with immune  suppression (including septicemia), tumor lysis syndrome should be  taken into account. Chemotherapeutic agents are a common cause  of acute kidney injury but can potentially lead to chronic kidney  disease development in cancer patients. This article summarizes risk  factors of acute kidney injury in cancer patients. Risk factors are  divided into two groups. The systemic are decrease of total  circulating blood volume, infiltration of kidney tissue by tumor cells,  dysproteinemia, electrolyte disturbances. The local (renal) risk  factors are microcirculation disturbances, drugs biotransformation  with formation of reactive oxygen intermediates, high concentration of nephrotoxic agents in proximal tubules and its  sensitivity to ischemia. Drug-related risk factors include: drugs  combination with cytotoxic effect high doses long term use necessity, direct cytotoxic effect of not only chemotherapeutic agents but also its metabolites, mean solubility forming intratubular  precipitates. Early diagnosis, timely prevention and treatment of  these complications provide significantly improve nononcologic results of treatment.

scholarly journals Combination therapy of cisplatin with cilastatin enables an increased dose of cisplatin, enhancing its antitumor effect by suppression of nephrotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masashi Arita ◽  
Satoshi Watanabe ◽  
Nobumasa Aoki ◽  
Shoji Kuwahara ◽  
Ryo Suzuki ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Cell Injury ◽  
Kidney Injury ◽  
Antitumor Effects ◽  
Cisplatin Nephrotoxicity ◽  
Proximal Tubular ◽  
Nephrotoxic Drugs ◽  
Kidney Injury Molecule 1 ◽  
Dose Dependent

AbstractCisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

scholarly journals NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 333-342
Author(s):  
Yawei Feng ◽  
Jun Liu ◽  
Ranliang Wu ◽  
Peng Yang ◽  
Zhiqiang Ye ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Cell Injury ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Western Blot Assay

AbstractBackground and aimAcute kidney injury (AKI) is a common complication of sepsis. Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays a vital role in various diseases, including AKI. This study aimed to investigate the function and mechanism of NEAT1 in sepsis-induced AKI.Materials and methodsA septic AKI model was established by treating HK-2 cells with lipopolysaccharide (LPS). The levels of NEAT1 and miR-22-3p were measured by quantitative real-time PCR. Cell apoptosis was assessed by flow cytometry. The levels of apoptosis-related protein and autophagy-related factors were examined by the western blot assay. An enzyme-linked immunosorbent assay was used to calculate the contents of inflammatory factors. The interaction between NEAT1 and miR-22-3p was validated by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. The levels of nuclear factor (NF)-κB pathway-related proteins were evaluated by the western blot assay.ResultsNEAT1 was upregulated, while miR-22-3p was downregulated in patients with sepsis and in LPS-stimulated HK-2 cells. LPS treatment triggered cell apoptosis, autophagy, and inflammatory response in HK-2 cells. NEAT1 knockdown attenuated LPS-induced cell injury. NEAT1 modulated LPS-triggered cell injury by targeting miR-22-3p. Furthermore, NEAT1 regulated the NF-κB pathway by modulating miR-22-3p.ConclusionDepletion of NEAT1 alleviated sepsis-induced AKI via regulating the miR-22-3p/NF-κB pathway.

scholarly journals DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

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.

scholarly journals Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling

2013 ◽  
Vol 304 (8) ◽  
pp. F1054-F1065 ◽  
Author(s):  
Punithavathi Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Transgenic Animals ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

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