The complement system in pediatric acute kidney injury

Stenson, Erin K.; Kendrick, Jessica; Dixon, Bradley P.; Thurman, Joshua M.

doi:10.1007/s00467-022-05755-3

Cited by 9 publications

(5 citation statements)

References 123 publications

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“…However, its excessive activation in the later phases of sepsis could contribute to the development of MOF. It has been reported that the complement system is activated in AKI [4] and that C5b-9 deposition is observed in the tubulointerstitial area of an SA-AKI model [19]. Although the serum levels of C3 and C4 were normal, those of both C5a and C5b-9 were elevated in the patients in this study at the time of CRRT introduction.…”

Section: Resultscontrasting

confidence: 51%

“…The complicated pathogenesis of AKI is thought to contribute to the poor prognosis of SA-AKI; therefore, it is crucial to understand the pathogenesis of AKI more precisely. In addition to hemodynamic changes, cell apoptosis, cytokines or reactive oxygen species, and the immune system (including both innate as well as adaptive immune responses) have recently attracted much attention as important components of the pathogenesis of AKI [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Innate Immune System in the Pathogenesis of Sepsis-Associated Acute Kidney Injury

Uchida,

Yamada,

Inoue

et al. 2023

IJMS

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Although experimental models have shown that the innate immune system is a main contributor to acute kidney injury (AKI), its involvement in human sepsis-associated AKI (SA-AKI) remains unclear. We retrospectively evaluated 19 patients with SA-AKI who were treated with continuous renal replacement therapy (CRRT). Serum cytokine, complement components, and the proportion and functions of innate immune cells, such as CD56+ T cells, CD56+ natural killer (NK) cells, and monocytes, were analyzed. There were no differences in the proportions of CD56+ T and NK cells between patients with SA-AKI and healthy controls. In patients with SA-AKI, fas ligand (FasL) expression in CD56+ T cells was significantly upregulated, and the proportion of perforin-positive CD56+ T cells tended to be higher than that in healthy controls. The positive rate of both FasL and perforin of CD56+ T cells was significantly higher than that of CD56- T cells, which include cytotoxic T cells. Antigen-presenting capacity and phagocytic activity of monocytes in patients with SA-AKI were significantly decreased compared to those of healthy controls and did not recover soon after the initiation of CRRT. CD56+ T cells are involved in the disease processes of human SA-AKI through effector molecules such as FasL or perforin.

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Section: Resultscontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Involvement of Innate Immune System in the Pathogenesis of Sepsis-Associated Acute Kidney Injury

Uchida,

Yamada,

Inoue

et al. 2023

IJMS

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“…Enrichment analysis showed that these genes were mainly enriched in Complement and Coagulation Cascades, Cell Cycle, and Oxidoreductase Activity. Recent studies have shown that the complement system is activated in pediatric patients with AKI, and complement proteins may serve as biomarkers and therapeutic targets for AKI ( Stenson et al, 2023 ). Our recently study has reported that EGR1 increased SOX9 expression in renal tubular epithelial cells by directly binding to the promoter of the Sox9 gene, thereby promoting proliferation of SOX9 + cells after AKI ( Chen et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of the diagnostic signature associated with immune microenvironment of acute kidney injury based on ferroptosis-related genes through integrated bioinformatics analysis and machine learning

Chen

Liu

et al. 2023

Front. Cell Dev. Biol.

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Background: Acute kidney injury (AKI) is a common and severe disease, which poses a global health burden with high morbidity and mortality. In recent years, ferroptosis has been recognized as being deeply related to Acute kidney injury. Our aim is to develop a diagnostic signature for Acute kidney injury based on ferroptosis-related genes (FRGs) through integrated bioinformatics analysis and machine learning.Methods: Our previously uploaded mouse Acute kidney injury dataset GSE192883 and another dataset, GSE153625, were downloaded to identify commonly expressed differentially expressed genes (coDEGs) through bioinformatic analysis. The FRGs were then overlapped with the coDEGs to identify differentially expressed FRGs (deFRGs). Immune cell infiltration was used to investigate immune cell dysregulation in Acute kidney injury. Functional enrichment analysis and protein-protein interaction network analysis were applied to identify candidate hub genes for Acute kidney injury. Then, receiver operator characteristic curve analysis and machine learning analysis (Lasso) were used to screen for diagnostic markers in two human datasets. Finally, these potential biomarkers were validated by quantitative real-time PCR in an Acute kidney injury model and across multiple datasets.Results: A total of 885 coDEGs and 33 deFRGs were commonly identified as differentially expressed in both GSE192883 and GSE153625 datasets. In cluster 1 of the coDEGs PPI network, we found a group of 20 genes clustered together with deFRGs, resulting in a total of 48 upregulated hub genes being identified. After ROC analysis, we discovered that 25 hub genes had an area under the curve (AUC) greater than 0.7; Lcn2, Plin2, and Atf3 all had AUCs over than this threshold in both human datasets GSE217427 and GSE139061. Through Lasso analysis, four hub genes (Lcn2, Atf3, Pir, and Mcm3) were screened for building a nomogram and evaluating diagnostic value. Finally, the expression of these four genes was validated in Acute kidney injury datasets and laboratory investigations, revealing that they may serve as ideal ferroptosis markers for Acute kidney injury.Conclusion: Four hub genes (Lcn2, Atf3, Pir, and Mcm3) were identified. After verification, the signature’s versatility was confirmed and a nomogram model based on these four genes effectively distinguished Acute kidney injury samples. Our findings provide critical insight into the progression of Acute kidney injury and can guide individualized diagnosis and treatment.

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“…Activation of the complement system in AKI, with resultant amplification of the inflammatory response, has received recent attention [23 ▪ ]. A predominant role for C5a in ischemic AKI has been identified during formation of the final membrane attack complex.…”

Section: Alterations In the Inflammatory Responsementioning

confidence: 99%

Pathogenesis of intrinsic acute kidney injury

Devarajan

2022

Current Opinion in Pediatrics

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Purpose of reviewThis review focuses on the pathogenesis of intrinsic acute kidney injury (AKI), emphasizing recent advances that hold therapeutic promise.Recent findingsEnhanced endothelin and reduced endothelium-derived nitric oxide release in AKI can be blocked using endothelin receptor antagonists or nitric oxide supplementation. Vasodilatory agents such as theophylline and caffeine may prevent AKI. Free labile iron is a potent factor in the generation of reactive oxygen species and tubule damage in AKI. Apoptosis via induction of p53 is an important mechanism of cell death in AKI, which can be blocked using small interfering RNA. The AKI-driven reduction in nicotinamide adenine dinucleotide can be countered using oral supplements. Surviving tubule cells regenerate after AKI, by upregulating genes encoding growth factors, such as hepatocyte growth factor. Pro-angiogenic agents (statins and erythropoietin) that can mobilize endothelial progenitor cells after AKI are currently being tested. The inflammatory response in AKI, including activation of C5a, can be therapeutically targeted. Contemporary single cell profiling technologies have identified novel genes with altered expression, new signalling pathways and drug targets in AKI.SummaryRecent advances in the pathogenesis of intrinsic AKI have provided a better understanding of the clinical continuum and the rational deployment of promising therapeutics.

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The complement system in pediatric acute kidney injury

Cited by 9 publications

References 123 publications

Involvement of Innate Immune System in the Pathogenesis of Sepsis-Associated Acute Kidney Injury

Involvement of Innate Immune System in the Pathogenesis of Sepsis-Associated Acute Kidney Injury

Identification and validation of the diagnostic signature associated with immune microenvironment of acute kidney injury based on ferroptosis-related genes through integrated bioinformatics analysis and machine learning

Pathogenesis of intrinsic acute kidney injury

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