COVID-19 and the kidney; mechanisms of tubular injury by SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic, reported to cause asymptomatic to severe disease and eventually death. Multi-organ failure and death in patients with severe COVID-19 is associated with increased release of pro-inflammatory cytokines into the blood stream. Renal impairment is reported in a significant proportion of COVID-19 patients and is associated with high mortality. Acute kidney injury (AKI) is multifactorial and involving overlapping pathogenic mechanisms. This review updates the reader of recent publications dealing with the mechanisms underlying AKI in patients with COVID-19. A full understanding of all the possible ways in which the system plays its role in AKI is still a matter of research. Further studies are warranted to better understand the causes of AKI in COVID-19 patients.

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Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on post-contrast acute kidney injury

Scientific Reports ◽

10.1038/s41598-021-94928-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hyewon Oh ◽

Arom Choi ◽

Nieun Seo ◽

Joon Seok Lim ◽

Je Sung You ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Contrast Media ◽

Protective Effect ◽

Inflammatory Cytokines ◽

Kidney Tissue ◽

Kidney Injury ◽

Enzyme Linked Immunosorbent Assay ◽

Post Contrast ◽

Pro Inflammatory Cytokines

AbstractPost contrast-acute kidney injury (PC-AKI) is defined as the deterioration of renal function after administration of iodinated contrast media. HMGB1 is known to play an important role in the development of acute kidney injury. The purpose of this study was to investigate the association between HMGB1 and PC-AKI and the protective effect of glycyrrhizin, a direct inhibitor of HMGB1, in rats. Rats were divided into three groups: control, PC-AKI and PC-AKI with glycyrrhizin. Oxidative stress was measured with MDA levels and H2DCFDA fluorescence intensity. The mRNA expressions of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) and kidney injury markers (KIM-1, NGAL and IL-18) were assessed using RT-PCR and ELISA in kidney tissue. In addition, the serum and intracellular protein levels of HMGB1were analyzed with the enzyme-linked immunosorbent assay (ELISA) and western blotting. Histologic changes were assessed with H&E staining using the transmission electron microscope (TEM). Moreover, serum creatinine (SCr), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) levels were assessed. Oxidative stress, pro-inflammatory cytokines, kidney injury markers and LDH were significantly higher in PC-AKI compared to the controls, but were lower in PC-AKI with glycyrrhizin. Intracellular and serum HMGB1 levels significantly increased after contrast media exposure, whereas they markedly decreased after glycyrrhizin pretreatment. SCr and BUN also decreased in PC-AKI with glycyrrhizin compared to PC-AKI. In PC-AKI, we could frequently observe tubular dilatation with H&E staining and cytoplasmic vacuoles on TEM, whereas these findings were attenuated in PC-AKI with glycyrrhizin. Our findings indicate that HMGB1 plays an important role in the development of PC-AKI and that glycyrrhizin has a protective effect against renal injury and dysfunction by inhibiting HMGB1 and reducing oxidative stress.

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Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice

Antioxidants ◽

10.3390/antiox8080322 ◽

2019 ◽

Vol 8 (8) ◽

pp. 322 ◽

Cited By ~ 14

Author(s):

Jung-Yeon Kim ◽

Jungmin Jo ◽

Kiryeong Kim ◽

Hyun-Jin An ◽

Mi-Gyeong Gwon ◽

...

Keyword(s):

Acute Kidney Injury ◽

Apoptotic Cell ◽

Therapeutic Option ◽

Kidney Injury ◽

Sirtuin 1 ◽

Therapeutic Effects ◽

Tubular Injury ◽

And Function ◽

Renal Expression ◽

Pro Inflammatory Cytokines

Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.

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Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species

International Journal of Molecular Sciences ◽

10.3390/ijms222011190 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11190

Author(s):

Tsung-Jui Wu ◽

Yi-Jen Hsieh ◽

Chia-Wen Lu ◽

Chung-Jen Lee ◽

Bang-Gee Hsu

Keyword(s):

Reactive Oxygen Species ◽

Acute Kidney Injury ◽

Inflammatory Cytokines ◽

Kidney Injury ◽

Endotoxin Shock ◽

Nuclear Factor ◽

Oxygen Species ◽

Ampk Pathway ◽

Tnf Α ◽

Pro Inflammatory Cytokines

Septic shock can increase pro-inflammatory cytokines, reactive oxygen species (ROS), and multiple organ dysfunction syndrome (MODs) and even lead to death. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been proven to exert potential antioxidant and anti-inflammatory effects. We investigated the effects of linagliptin on endotoxic shock and acute kidney injury (AKI) in animal and cell models. In the cell model, linagliptin attenuated ROS by activating the AMP-activated protein kinase (AMPK) pathway, restoring nuclear-factor-erythroid-2-related factor (Nrf2) and heme oxygenase 1 (HO-1) protein, and decreasing pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)). In the animal model, 14-week-old conscious Wistar–Kyoto rats were randomly divided into three groups (n = 8 in each group). Endotoxin shock with MODs was induced by the intravenous injection of Klebsiella pneumoniae lipopolysaccharide (LPS, 20 mg/kg). Linagliptin improved animal survival without affecting hemodynamic profiles. In the histopathology and immunohistochemistry examinations of the rat kidneys, linagliptin (10 mg/kg) suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide synthase (iNOS), decreased injury scores, and preserved E-cadherin expression from LPS damage. In conclusion, linagliptin ameliorated endotoxin-shock-induced AKI by reducing ROS via AMPK pathway activation and suppressing the release of TNF-α and IL-1β in conscious rats.

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Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on post-contrast acute kidney injury

10.21203/rs.3.rs-118496/v1 ◽

2020 ◽

Author(s):

Hyewon Oh ◽

Nieun Seo ◽

Joon Seok Lim ◽

Je Sung You ◽

Yong Eun Chung

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Contrast Media ◽

Protective Effect ◽

Inflammatory Cytokines ◽

Kidney Injury ◽

Post Contrast ◽

Protein Levels ◽

Iodinated Contrast ◽

Pro Inflammatory Cytokines

Abstract Post contrast-acute kidney injury (PC-AKI) is defined as the deterioration of renal function after administration of iodinated contrast media. The purpose of this study was to investigate the association between HMGB1 and PC-AKI and the protective effect of glycyrrhizin, a direct inhibitor of HMGB1, in rats. Rats were divided into three groups: control, PC-AKI and PC-AKI with glycyrrhizin. Oxidative stress, mRNA expressions of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) and kidney injury markers (Kim-1, NGAL and IL-18) were assessed. In addition, the serum and intracellular protein levels of HMGB1 were analyzed. Moreover, serum creatinine (SCr), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) levels were assessed. Oxidative stress, pro-inflammatory cytokines, kidney injury markers and LDH were significantly higher in PC-AKI compared to the controls, but were lower in PC-AKI with glycyrrhizin. Intracellular and serum HMGB1 levels significantly increased after contrast media exposure, whereas they markedly decreased after glycyrrhizin pretreatment. SCr and BUN also decreased in PC-AKI with glycyrrhizin compared to PC-AKI. Our findings indicate that HMGB1 plays an important role in the development of PC-AKI and that glycyrrhizin has a protective effect against renal injury and dysfunction by inhibiting HMGB1 and reducing oxidative stress.

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Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection

BMC Nephrology ◽

10.1186/s12882-020-02213-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Katarzyna Szajek ◽

Marie-Elisabeth Kajdi ◽

Valerie A. Luyckx ◽

Thomas Hans Fehr ◽

Ariana Gaspert ◽

...

Keyword(s):

Acute Kidney Injury ◽

Interstitial Nephritis ◽

Kidney Biopsy ◽

Kidney Diseases ◽

Case Reports ◽

Kidney Injury ◽

Maculopapular Rash ◽

Tubular Injury ◽

Granulomatous Interstitial Nephritis ◽

First Case

Abstract Background Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 – associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive. Case Presentation The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis. Conclusions Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.

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Surgical procedures suppress autophagic flux in the kidney

Cell Death and Disease ◽

10.1038/s41419-021-03518-w ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Carolyn N. Brown ◽

Daniel Atwood ◽

Deepak Pokhrel ◽

Sara J. Holditch ◽

Christopher Altmann ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Mammalian Target Of Rapamycin ◽

Kidney Injury ◽

Compensatory Hypertrophy ◽

Autophagic Flux ◽

Bafilomycin A1 ◽

Concomitant Increase ◽

Sham Surgery ◽

And Function ◽

Pro Inflammatory Cytokines

AbstractMany surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.

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Drug-Induced Acute Kidney Injury: A Study from the French Medical Administrative and the French National Pharmacovigilance Databases Using Capture-Recapture Method

Journal of Clinical Medicine ◽

10.3390/jcm10020168 ◽

2021 ◽

Vol 10 (2) ◽

pp. 168

Author(s):

Anne-Lise Rolland ◽

Anne-Sophie Garnier ◽

Katy Meunier ◽

Guillaume Drablier ◽

Marie Briet

Keyword(s):

Acute Kidney Injury ◽

Medical Information ◽

Significant Proportion ◽

Kidney Injury ◽

International Classification Of Diseases ◽

Administrative Databases ◽

Health Concern ◽

Medical Information System ◽

Drug Induced ◽

Capture Recapture

Background: Acute kidney injury (AKI) is a public health concern. Among the pathological situations leading to AKI, drugs are preventable factors but are still under-notified. We aimed to provide an overview of drug-induced AKI (DIAKI) using pharmacovigilance and medical administrative databases Methods: A query of the PMSI database (French Medical Information System Program) of adult inpatient hospital stays between 1 January 2017 and 31 December 2018 was performed using ICD-10 (International Classification of Diseases 10th revision) codes to identify AKI cases which were reviewed by a nephrologist and a pharmacovigilance expert to identify DIAKI cases. In parallel, DIAKIs notified in the French Pharmacovigilance Database (FPVDB) were collected. A capture-recapture method was performed to estimate the total number of DIAKIs. Results: The estimated total number of DIAKIs was 521 (95%CI 480; 563), representing 20.0% of all AKIs. The notification was at a rate of 12.9% (95%CI 10.0; 15.8). According to the KDIGO classification, 50.2% of the DIAKI cases were stage 1 and 49.8% stage 2 and 3. The mortality rate was 11.1% and 9.6% required hemodialysis. Conclusion: This study showed that drugs are involved in a significant proportion of patients developing AKI during a hospital stay and emphasizes the severity of DIAKI cases.

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Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

Molecular and Cellular Biology ◽

10.1128/mcb.00211-17 ◽

2017 ◽

Vol 37 (22) ◽

Cited By ~ 9

Author(s):

Lei Yu ◽

Takashi Moriguchi ◽

Hiroshi Kaneko ◽

Makiko Hayashi ◽

Atsushi Hasegawa ◽

...

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Ischemia Reperfusion Injury ◽

Collecting Duct ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cytokine Gene Expression ◽

Renal Tubular Cell

ABSTRACT Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

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Docosahexaenoic Acid-Acylated Astaxanthin Esters Exhibit Superior Renal Protective Effect to Recombination of Astaxanthin with DHA via Alleviating Oxidative Stress Coupled with Apoptosis in Vancomycin-Treated Mice with Nephrotoxicity

Marine Drugs ◽

10.3390/md19090499 ◽

2021 ◽

Vol 19 (9) ◽

pp. 499

Author(s):

Hao-Hao Shi ◽

Ying Guo ◽

Li-Pin Chen ◽

Cheng-Cheng Wang ◽

Qing-Rong Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Fatty Acid ◽

Docosahexaenoic Acid ◽

Kidney Injury ◽

Clinical Problem ◽

Kidney Dysfunction ◽

Serum Biochemical ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines

Prevention of acute kidney injury caused by drugs is still a clinical problem to be solved urgently. Astaxanthin (AST) and docosahexaenoic acid (DHA) are important marine-derived active ingredients, and they are reported to exhibit renal protective activity. It is noteworthy that the existing forms of AST in nature are mainly fatty acid-acylated AST monoesters and diesters, as well as unesterified AST, in which DHA is an esterified fatty acid. However, no reports focus on the different bioactivities of unesterified AST, monoesters and diesters, as well as the recombination of DHA and unesterified AST on nephrotoxicity. In the present study, vancomycin-treated mice were used to evaluate the effects of DHA-acylated AST monoesters, DHA-acylated AST diesters, unesterified AST, and the recombination of AST and DHA in alleviating nephrotoxicity by determining serum biochemical index, histopathological changes, and the enzyme activity related to oxidative stress. Results found that the intervention of DHA-acylated AST diesters significantly ameliorated kidney dysfunction by decreasing the levels of urea nitrogen and creatinine, alleviating pathological damage and oxidative stress compared to AST monoester, unesterified AST, and the recombination of AST and DHA. Further studies revealed that dietary DHA-acylated AST esters could inhibit the activation of the caspase cascade and MAPKs signaling pathway, and reduce the levels of pro-inflammatory cytokines. These findings indicated that the administration of DHA-acylated AST esters could alleviate vancomycin-induced nephrotoxicity, which represented a potentially novel candidate or therapeutic adjuvant for alleviating acute kidney injury.

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What nephrologist should know about COVID-19 outbreak?

10.31219/osf.io/tnvgj ◽

2020 ◽

Cited By ~ 1

Author(s):

Omar maoujoud

Keyword(s):

Acute Kidney Injury ◽

High Risk ◽

Renal Impairment ◽

High Mortality ◽

Medical Management ◽

Multiorgan Failure ◽

Kidney Injury ◽

Prognostic Indicator ◽

High Risk Patients ◽

Risk Patients

Acute Kidney injury is relatively uncommon in COVID-19 patients yet carries a high mortality. It occurs in patients complicated with ARDS or multiorgan failure, but further investigation about inflammatory and apopotic mechanisms during renal impairment are needed. Since the development of AKI is an important negative prognostic indicator for survival with CoV as reported in previous SAR-CoV and MERS-CoV outbreaks, adequate medical management of high risk patients with AKI may improve the results of previous outbreaks related to CoV.

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