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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]

Background: Sepsis is organ dysfunction due to the host’s deleterious response to infection, and the kidneys are one of the organs damaged in common sepsis. Sepsis-associated acute kidney injury (SA-AKI) increases the mortality in patients with sepsis. Although a substantial volume of research has improved the prevention and treatment of the disease, SA-SKI is still a significant clinical concern. Purpose: Aimed to use weighted gene co-expression network analysis (WGCNA) and immunoinfiltration analysis to study SA-AKI-related diagnostic markers and potential therapeutic targets. Methods: Immunoinfiltration analysis was performed on SA-AKI expression datasets from the Gene Expression Synthesis (GEO) database. A weighted gene co-expression network analysis (WGCNA) analysis was performed on immune invasion scores as trait data, and modules associated with immune cells of interest were identified as hub modules. Screening hub geneset in the hub module using protein-protein interaction (PPI) network analysis. The hub gene was identified as a target by intersecting with significantly different genes screened by differential expression analysis and validated using two external datasets. Finally, the correlation between the target gene, SA-AKI, and immune cells was verified experimentally. Results: Green modules associated with monocytes were identified using WGCNA and immune infiltration analysis. Differential expression analysis and PPI network analysis identified two hub genes (AFM and GSTA1). Further validation using additional AKI datasets GSE30718 and GSE44925 showed that AFM was significantly downregulated in AKI samples and correlated with the development of AKI. The correlation analysis of hub genes and immune cells showed that AFM was significantly associated with monocyte infiltration and hence, selected as a critical gene. In addition, Gene single-enrichment analysis (GSEA) and PPI analyses results showed that AFM was significantly related to the occurrence and development of SA-AKI. Conclusions: AFM is inversely correlated with the recruitment of monocytes and the release of various inflammatory factors in the kidneys of AKI. AFM can be a potential biomarker and therapeutic target for monocyte infiltration in sepsis-related 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]