Search

Background: In sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity. Methods: In this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion. Results: 32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38–5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61–4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56–2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12–0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55–0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64–0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74–0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64–0.97), and a specificity of 0.96 (95%-CI 0.88–0.99). Conclusions: The combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation. [ABSTRACT FROM AUTHOR]

Approximately 60% of septic patients developed acute kidney injury (AKI). The mortality rate of septic AKI (SA-AKI) is two to three times higher than that of septic without AKI (SA-non-AKI). The actual functions and mechanisms of CircRNAs in the pathophysiology of SA-AKI remain incompletely understood. Herein, we observed that the mmu_Circ_26986 could be induced by lipopolysaccharide (LPS) and cecum ligation and puncture (CLP) in BUMPT cell line and C57BL/6 mouse kidney, respectively. Functionally, mmu_Circ_26986 suppressed BUMPT cell apoptosis induced by LPS. Mechanistically, mmu_Circ_26986 sponged miRNA-29b-1-5p to upregulate the expression of PAK7. Overexpression of mmu_Circ_26986 ameliorated the progression of CLP-stimulated AKI through miRNA-29b-1-5p/PAK7 axis. In addition, we found that hsa_Circ_0072463, homologous to mmu_Circ_26986, suppressed LPS-induced HK-2 cells apoptosis via regulation of miRNA-29b-1-5p/PAK7 axis. Furthermore, sepsis patients with AKI had a higher level of hsa_Circ_0072463 compared to those without AKI. The sensitivity, specificity and AUC of hsa_Circ_0072463 were 78.8%, 87.9% and 0.866, respectively. Spearman's test indicated a noticeable positive correlation between plasma hsa_Circ_0072463 and serum creatinine in sepsis patients (r = 0.725). In summary, this study reveals that the mmu_Circ_26986/hsa_Circ_0072463 miRNA-29b-1-5p/PAK7 axis mediates septic AKI, and hsa_Circ_0072463 is a potential diagnostic marker for septic AKI. [ABSTRACT FROM AUTHOR]

The mortality rate of patients with sepsis-associated acute kidney injury (SA-AKI) in the intensive care unit (ICU) is high, and there is a need for early identification of SA-AKI patients with poor prognoses. This study investigated the relationship between the lactate dehydrogenase to serum albumin ratio (LAR) and prognosis in patients with SA-AKI. We performed a retrospective cohort study of patients with SA-AKI who are represented in the Medical Information Mart for Intensive Care IV (MIMIC-IV). We used multivariable Cox regression analysis to determine adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analysis, survival curves, and curve fitting were used to evaluate a connection between the LAR and prognosis in patients with SA-AKI. There were a total of 6453 participants in this research. The average age of the participants was 63.9 ± 16.1 years, and the average LAR was 11.0 (7.6, 17.7)/IU/g. After controlling for variables, the HRs for 28-day mortality were 1.20 (HR: 1.20, 95% CI: 1.05–1.38, p = 0.008) and 1.61 (HR: 1.61, 95% CI: 1.41–1.84, p < 0.001) for Tertile 2 (T2, 8.59≤ LAR< 14.66) and Tertile 3 (T3, LAR ≥ 14.66), respectively, compared to Tertile 1 (T1, LAR < 8.59). The outcomes for 90-day mortality and in-hospital death rate were comparable. The Kaplan–Meier (KM) analysis revealed that the group with greater LAR had higher 28-day and 90-day death rates. Our study shows that LAR is associated with poor prognosis in patients with SA-AKI. Higher LAR is associated with higher 28-day, 90-day, and in-hospital mortality. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (SA-AKI) is a severe and life-threatening condition with high morbidity and mortality among emergency patients, and it poses a significant risk of chronic renal failure. Clinical treatments for SA-AKI remain reactive and non-specific, lacking effective diagnostic biomarkers or treatment targets. In this study, we established an SA-AKI mouse model using lipopolysaccharide (LPS) and performed proteomics and metabolomics analyses. A variety of bioinformatic analyses, including gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), protein and protein interactions (PPI), and MetaboAnalyst analysis, were conducted to investigate the key molecules of SA-AKI. Integrated proteomics and metabolomics analysis revealed that sepsis led to impaired renal mitochondrial function and metabolic disorders. Immune-related pathways were found to be activated in kidneys upon septic infection. The catabolic products of polyamines accumulated in septic kidneys. Overall, our integrated analysis provides a multidimensional understanding of SA-AKI and identifies potential pathways for this condition. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) has been manifested to be involved in the development of human diseases, including sepsis-associated acute kidney injury (SA-AKI). However, the function and mechanism of circ_0006944 in SA-AKI has not been validated. Lipopolysaccharide (LPS) was utilised to induce AKI cell model. Levels of genes and proteins were monitored by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell counting kit 8 assay, EdU assay and flow cytometry were exploited to estimate cell proliferation and apoptosis. The concentrations of inflammation factors were measured via using ELISA assay. The levels of MDA and SOD were tested by the corresponding kits. The relationship between miR-205-5p and circ_0006944 or UBL4A was verified by dual-luciferase reporter assay and RIP assay. Circ_0006944 was overexpressed in SA-AKI patients, and interference of circ_0006944 restrained LPS-stimulated HK2 cell proliferation repression, apoptosis, inflammation and oxidative stress. Mechanistically, circ_0006944 could sponge miR-205-5p, and miR-205-5p interference counteracted circ_0006944 inhibition-mediated impact on the biological functions in LPS-induced HK2 cell. Additionally, UBL4A was targeted by miR-205-5p, and UBL4A overexpression also partially abolished the repressive impacts of miR-205-5p on LPS-triggered HK2 cell damage. Importantly, circ_0006944 sponged miR-205-5p to mediate the expression of UBL4A. Our outcomes identified that circ_0006944 exacerbated SA-AKI development via miR-205-5p/UBL4A axis, which might be a potential treatment and diagnosis biomarker for SA-AKI. [ABSTRACT FROM AUTHOR]

This study investigates the role of S100A9 in sepsis-associated AKI (SA-AKI) through the lens of pyroptosis, a controlled form of cell death mediated by the gasdermin protein family. Using C57BL/6 mice and S100A9 knockout mice subjected to cecal ligation and puncture (CLP), RNA sequencing and bioinformatics analyses revealed differentially expressed genes (DEGs) related to inflammation and immune responses, with notable upregulation of S100A9. Functional enrichment analyses (GO and KEGG) indicated these DEGs are involved in interferon-beta response, immune processes, and cell adhesion. Protein–protein interaction (PPI) network analyses further emphasized S100A9's pivotal role in SA-AKI.Clinical validation measured S100A9 levels in serum and urine samples from SA-AKI patients and healthy volunteers, finding elevated S100A9 levels in the former. In vivo experiments showed that S100A9 knockout mice exhibited reduced kidney injury and inflammation, indicated by lower serum creatinine, urea nitrogen, and inflammatory markers (IL-1β and IL-18). Histopathological analyses and immunohistochemistry confirmed less renal damage and reduced expression of cleaved IL-1β and GSDMD-N in S100A9-deficient mice. Electron microscopy and Western blotting validated that S100A9 deficiency mitigates caspase-1-dependent pyroptosis.Cellular experiments with HK-2 cells demonstrated that S100A9 knockdown alleviated LPS-induced cell damage and reduced pyroptosis markers. These findings illuminate S100A9’s involvement in NLRP3 inflammasome activation and pyroptosis, suggesting potential therapeutic targets for SA-AKI. Targeting S100A9 may offer new therapeutic avenues, improving outcomes for sepsis-related kidney injury patients. Future research should aim to validate these findings in larger clinical settings. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute renal injury (SA-AKI) is a common critical clinical disease. It is associated with increased mortality and increased risk of progression to chronic kidney disease. However, its pathogenesis is not fully known. We hypothesized that metabolic interactions mediate cell apoptosis and AKI. We found that phosphatidylcholine content in human renal tubular epithelial cells following lipopolysaccharide-induced injury was increased. The activity of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme in phospholipid metabolism, was increased, while the expression of miR-124-3p.1, which targets LPCAT3, was decreased. We also found that in the serum of SA-AKI patients, LPCAT3 activity was increased, and miR-124-3p.1 expression was decreased. Further experiments confirmed the specific binding of exocrine miR-124-3p.1 to LPCAT3. Our data reveal the molecular mechanisms of phospholipid metabolic disorder in early SA-AKI as well as the role of the miR-124-3p.1/LPCAT3 pathway in SA-AKI, which leads to ferroptosis. These results could provide the scientific basis for early diagnosis and renal replacement therapy in SA-AKI. • In early SA-AKI, the phospholipid metabolic disordered. • MiR-124-3p.1 can regulate LPCAT3 expression and affect lipid metabolism, which leads to ferroptosis. • These results could provide the scientific basis for early diagnosis and renal replacement therapy in SA-AKI. [ABSTRACT FROM AUTHOR]

Background: In critically ill children, sepsis-associated acute kidney injury (SA-AKI) has significant morbidity and mortality. Aim: To estimate whether early initiation of peritoneal dialysis (PD) has a better short-term outcome than standard PD. Methods: Early PD (n = 25) was defined as a need for PD in Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 AKI, while those fulfilling the criteria for stage 3 KDIGO were categorised as a standard PD group (n = 25). The primary outcome measure was the estimated glomerular filtration rate (eGFR) at discharge or at 4 weeks after initiation of PD, whichever occurred earlier. Results: A prospective cohort of 50 children (32 boys) aged 2 months to 16 years with SA-AKI who underwent PD were recruited. The most frequent indication for PD was fluid overload (40%), followed by persistent metabolic acidosis (36%). Children in the early PD group had lower creatinine and higher eGFR at discharge/4-week follow-up (p < 0.001). The duration of PD was less if it was commenced early (p < 0.04); 24 of 25 (96%) children in the early PD group were off PD within 6 days of initiation compared with 13 of 25 (52%) in the standard PD group (p < 0.001). Conclusions: Compared with standard PD, early PD in SA-AKI resulted in a favourable renal outcome, decreased duration of PD and early discontinuation of dialysis. Abbreviations : AKI: acute kidney injury; CRRT: continuous renal replacement therapy; CS-AKI: cardiac surgery-associated acute kidney injury; eGFR: estimated glomerular filtration rate; ELAIN: early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury; ESCAPE: effect of strict blood pressure control and ACE inhibition on the progression of chronic kidney disease in paediatric patients; HIC: high-income countries; ISN: international society of nephrology; KDIGO: Kidney Disease: Improving Global Outcomes; LMIC: low- to middle-income countries; PD: peritoneal dialysis; PICU: paediatric intensive care unit; RRT: renal replacement therapy; SA-AKI: sepsis-associated acute kidney injury; SYL: Saving Young Lives; SOFA: sequential (sepsis-related) organ failure assessment score; STARRT-AKI: standard versus accelerated initiation of renal replacement therapy in acute kidney injury. [ABSTRACT FROM AUTHOR]

• •The members and functions of IL-17 cytokine family are mentioned. • •IL-17 is involved in the occurrence of many inflammatory diseases, autoimmune diseases, and tumors. • •IL-17 is involved in acute renal injury caused by various reasons, such as sepsis associated acute renal injury, nephrotoxic acute renal injury, ischemia/reperfusion acute renal injury. Acute kidney injury (AKI) is a common clinical kidney disease with a high mortality rate. AKI is caused by a variety of factors, including sepsis, ischemia, and nephrotoxic drugs, and can progress to chronic kidney disease and end-stage renal disease. Numerous studies have suggested that cytokines can be used as therapeutic targets for AKI. IL-17 is a pro-inflammatory cytokine that not only participates in the host defense and the development of autoimmune diseases but also is linked to AKI due to a variety of factors. This review will give an overview of the structure, signaling pathways, and biological functions of IL-17, as well as its role in AKI, to show that IL-17 is a potential target for the prevention and treatment of AKI. [ABSTRACT FROM AUTHOR]

[Display omitted] Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening condition associated with high mortality and morbidity. However, the underlying pathogenesis of SA-AKI is still unclear. Lyn belongs to Src family kinases (SFKs), which exert numerous biological functions including modulation in receptor-mediated intracellular signaling and intercellular communication. Previous studies demonstrated that Lyn gene deletion obviously aggravates LPS-induced lung inflammation, but the role and possible mechanism of Lyn in SA-AKI have not been reported yet. Here, we found that Lyn protected against renal tubular injury in cecal ligation and puncture (CLP) induced AKI mouse model by inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation and cell apoptosis. Moreover, Lyn agonist MLR-1023 pretreatment improved renal function, inhibited STAT3 phosphorylation and decreased cell apoptosis. Thus, Lyn appears to play a crucial role in orchestrating STAT3-mediated inflammation and cell apoptosis in SA-AKI. Hence, Lyn kinase may be a promising therapeutic target for SA-AKI. [ABSTRACT FROM AUTHOR]