Sepsis-associated acute kidney injury in patients with chronic kidney disease: Patient characteristics, prevalence, timing, trajectory, treatment and associated outcomes.

AIM: The features and outcomes of sepsis-associated acute kidney injury (SA-AKI) may be affected by chronic kidney disease (CKD). Accordingly, we aimed to compare SA-AKI in patients with or without CKD. METHODS: Retrospective cohort study in 12 intensive care units (ICU). We studied the prevalence, patient characteristics, timing, trajectory, treatment and outcomes of SA-AKI with and without CKD. RESULTS: Of 84 240 admissions, 7255 (8.6%) involved patients with CKD. SA-AKI was more common in patients with CKD (21% vs 14%; p < .001). CKD patients were older (70 vs. 60 years; p < .001), had a higher median Charlson co-morbidity index (5 vs. 3; p < .001) and acute physiology and chronic health evaluation (APACHE) III score (78 vs. 60; p < .001) and were more likely to receive renal replacement therapy (RRT) (25% vs. 17%; p < .001). They had less complete return to baseline function at ICU discharge (48% vs. 60%; p < .001), higher major adverse kidney events at day 30 (MAKE-30) (38% vs. 27%; p < .001), and higher hospital and 90-day mortality (21% vs. 13%; p < .001, and 27% vs. 16%; p < .001, respectively). After adjustment for patient characteristics and severity of illness, however, CKD was not an independent risk factor for increased 90-day mortality (OR 0.88; 95% CI 0.76-1.02; p = .08) or MAKE-30 (OR 0.98; 95% CI 0.80-1.09; p = .4). CONCLUSION: SA-AKI is more common in patients with CKD. Such patients are older, more co-morbid, have higher disease severity, receive different ICU therapies and have different trajectories of renal recovery and greater unadjusted mortality. However, after adjustment day-90 mortality and MAKE-30 risk were not increased by CKD.

Predictive models of sepsis-associated acute kidney injury based on machine learning: a scoping review.

BACKGROUND: With the development of artificial intelligence, the application of machine learning to develop predictive models for sepsis-associated acute kidney injury has made potential breakthroughs in early identification, grading, diagnosis, and prognosis determination. METHODS: Here, we conducted a systematic search of the PubMed, Cochrane Library, Embase (Ovid), Web of Science, and Scopus databases on April 28, 2023, and screened relevant literature. Then, we comprehensively extracted relevant data related to machine learning algorithms, predictors, and predicted objectives. We subsequently performed a critical evaluation of research quality, data aggregation, and analyses. RESULTS: We screened 25 studies on predictive models for sepsis-associated acute kidney injury from a total of originally identified 2898 studies. The most commonly used machine learning algorithm is traditional logistic regression, followed by eXtreme gradient boosting. We categorized these predictive models into early identification models (60%), prognostic prediction models (32%), and subtype identification models (8%) according to their predictive purpose. The five most commonly used predictors were serum creatinine levels, lactate levels, age, blood urea nitrogen concentration, and diabetes mellitus. In addition, a single data source, insufficient assessment of clinical utility, lack of model bias assessment, and hyperparameter adjustment may be the main reasons for the low quality of the current research. CONCLUSIONS: However, studies on the nondeath prognostic outcomes, the long-term clinical outcomes, and the subtype identification models are insufficient. Additionally, the poor quality of the research and the insufficient practicality of the model are problems that need to be addressed urgently.

miR-16-5p aggravates sepsis-associated acute kidney injury by inducing apoptosis.

Sepsis-associated acute kidney injury (S-AKI) is a common disease in pediatric intensive care units (ICU) with high morbidity and mortality. The newly discovered results indicate that microRNAs (miRNAs) play an important role in the diagnosis and treatment of S-AKI and can be used as markers for early diagnosis. In this study, the expression level of miR-16-5p was found to be significantly upregulated about 20-fold in S-AKI patients, and it also increased by 1.9 times in the renal tissue of S-AKI mice. Receiver operating characteristic (ROC) curve analysis showed that miR-16-5p had the highest predictive accuracy in the diagnosis of S-AKI (AUC = 0.9188). In vitro, the expression level of miR-16-5p in HK-2 cells treated with 10 µg/mL lipopolysaccharide (LPS) increased by more than 2 times. In addition, LPS-exposed renal tissue and HK-2 cells lead to upregulation of inflammatory cytokines IL-6, IL-1ß, TNF-a, and kidney damage molecules kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL). However, inhibition of miR-16-5p significantly mitigated LPS expose-mediated kidney injury and inflammation. Furthermore, LPS-exposed HK-2 cells increased more than 1.7-fold the expression levels of Bax and caspase-3, decreased 3.2-fold the expression level of B-cell lymphoma-2 (Bcl-2), and significantly promoted the occurrence of apoptosis. MiR-16-5p mimic further increased LPS-induced apoptosis in HK-2 cells. Nevertheless, inhibition of miR-16-5p significantly attenuated this effect. In summary, up-regulation of miR-16-5p expression can significantly aggravate renal injury and apoptosis in S-AKI, which also proves that miR-16-5p can be used as a potential biomarker to promote early identification of S-AKI.

Cell-free DNA predicts all-cause mortality of sepsis-induced acute kidney injury.

Background Sepsis-induced acute kidney injury (S-AKI) is a common complication in critically ill patients. Therefore, reliable biomarkers for predicting S-AKI outcomes are necessary. Serum cell-free DNA (cfDNA) is a circulating extracellular DNA fragment used as a noninvasive screening tool for many diseases, including sepsis. This study aimed to investigate the prognostic value of cfDNA in S-AKI patients and its relationship with some other parameters.Methods A total of 89 S-AKI patients admitted to the intensive care unit (ICU) from June 2021 to December 2021 were enrolled in this study. The patients were categorized into the low cfDNA group (< 855 ng/ml) and high cfDNA group (≥ 855 ng/ml) and were followed up for three months. CfDNA was extracted from serum and quantified using Quant-iT PicoGreen dsDNA Reagent.Results Overall survival was significantly lower in the high cfDNA group than in the low cfDNA group (Log-Rank p = 0.012). Univariate Cox proportional hazard model showed that cfDNA was significantly associated with all-cause mortality (HR [hazard ratio] 2.505, 95% CI [95% confidence interval] 1.184-5.298, p = 0.016). Also, serum cfDNA was a significant risk factor for all-cause mortality after adjusting for covariates (HR 2.191, 95% CI 1.017-4.721, p = 0.045). Moreover, cfDNA was positively correlated with several baseline parameters, including serum creatine, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and International Normalized Ratio.Conclusion High serum cfDNA level is associated with higher mortality among the S-AKI population, indicating that cfDNA is a valuable biomarker for S-AKI prognosis.

TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway.

OBJECTIVE: This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. METHODS: The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. RESULTS: Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (p < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. CONCLUSION: TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Acute Kidney Injury in Sepsis.

Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological factors contribute to its presentation and perpetuation, including macrocirculatory and microcirculatory changes, mitochondrial dysfunction, and metabolic reprogramming. Recovery from acute kidney injury (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair and tubular cell regeneration, while maladaptive repair increases the risk of progression to chronic kidney disease. Fundamental management strategies include early sepsis recognition and prompt treatment, through the administration of adequate antimicrobial agents, fluid resuscitation, and vasoactive agents as needed. In septic patients, organ-specific support is often required, particularly renal replacement therapy (RRT) in the setting of severe AKI, although ongoing debates persist regarding the ideal timing of initiation and dosing of RRT. A comprehensive approach integrating early recognition, targeted interventions, and close monitoring is essential to mitigate the burden of SA-AKI and improve patient outcomes in critical care settings.

Sepsis-Associated Acute Kidney Injury: Where Are We Now?

Worldwide, sepsis is a well-recognized cause of death. Acute kidney injury (AKI) may be related to sepsis in up to 70% of AKI cases. Sepsis-associated AKI (SA-AKI) is defined as the presence of AKI according to the Kidney Disease: Improving Global Outcomes criteria in the context of sepsis. SA-AKI is categorized into early, which presents during the first 48 h of sepsis, and late, presenting between 48 h and 7 days of sepsis. SA-AKI is associated with a worse prognosis among patients with sepsis. However, there are different SA-AKI phenotypes as well as different pathophysiological pathways of SA-AKI. The aim of this review is to provide an updated synopsis of the pathogenetic mechanisms underlying the development of SA-AKI as well as to analyze its different phenotypes and prognosis. In addition, potential novel diagnostic and prognostic biomarkers as well as therapeutic approaches are discussed. A plethora of mechanisms are implicated in the pathogenesis of SA-AKI, including inflammation and metabolic reprogramming during sepsis; various types of cell death such as apoptosis, necroptosis, pyroptosis and ferroptosis; autophagy and efferocytosis; and hemodynamic changes (macrovascular and microvascular dysfunction). Apart from urine output and serum creatinine levels, which have been incorporated in the definition of AKI, several serum and urinary diagnostic and prognostic biomarkers have also been developed, comprising, among others, interleukins 6, 8 and 18, osteoprotegerin, galectin-3, presepsin, cystatin C, NGAL, proenkephalin A, CCL-14, TIMP-2 and L-FABP as well as biomarkers stemming from multi-omics technologies and machine learning algorithms. Interestingly, the presence of long non-coding RNAs (lncRNAs) as well as microRNAs (miRNAs), such as PlncRNA-1, miR-22-3p, miR-526b, LncRNA NKILA, miR-140-5p and miR-214, which are implicated in the pathogenesis of SA-AKI, may also serve as potential therapeutic targets. The combination of omics technologies represents an innovative holistic approach toward providing a more integrated view of the molecular and physiological events underlying SA-AKI as well as for deciphering unique and specific phenotypes. Although more evidence is still necessary, it is expected that the incorporation of integrative omics may be useful not only for the early diagnosis and risk prognosis of SA-AKI, but also for the development of potential therapeutic targets that could revolutionize the management of SA-AKI in a personalized manner.

Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI. METHODS: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk. RESULTS: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr. CONCLUSIONS: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.

Mesenchymal stem cells protect against sepsis-associated acute kidney injury by inducing Gal-9/Tim-3 to remodel immune homeostasis.

OBJECTIVE: The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI). METHODS: Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 106 cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery. RESULTS: After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells. CONCLUSION: Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI.

The association between lactate dehydrogenase to serum albumin ratio and the 28-day mortality in patients with sepsis-associated acute kidney injury in intensive care: a retrospective cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model.

INTRODUCTION: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. METHODS: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. RESULTS: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. CONCLUSION: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Sepsis and Acute Kidney Injury: A Review Focusing on the Bidirectional Interplay.

Although sepsis and acute kidney injury (AKI) have a bidirectional interplay, the pathophysiological mechanisms between AKI and sepsis are not clarified and worthy of a comprehensive and updated review. The primary pathophysiology of sepsis-associated AKI (SA-AKI) includes inflammatory cascade, macrovascular and microvascular dysfunction, cell cycle arrest, and apoptosis. The pathophysiology of sepsis following AKI contains fluid overload, hyperinflammatory state, immunosuppression, and infection associated with kidney replacement therapy and catheter cannulation. The preventive strategies for SA-AKI are non-specific, mainly focusing on infection control and preventing further kidney insults. On the other hand, the preventive strategies for sepsis following AKI might focus on decreasing some metabolites, cytokines, or molecules harmful to our immunity, supplementing vitamin D3 for its immunomodulation effect, and avoiding fluid overload and unnecessary catheter cannulation. To date, several limitations persistently prohibit the understanding of the bidirectional pathophysiologies. Conducting studies, such as the Kidney Precision Medicine Project, to investigate human kidney tissue and establishing parameters or scores better to determine the occurrence timing of sepsis and AKI and the definition of SA-AKI might be the prospects to unveil the mystery and improve the prognoses of AKI patients.

Circ-BNIP3L knockdown alleviates LPS-induced renal tubular epithelial cell injury during sepsis-associated acute kidney injury by miR-370-3p/MYD88 axis.

Sepsis-associated acute kidney injury (SA-AKI) is a frequent complication of the critically ill patient with high morbidity and mortality. Thus, the goal of this study was to investigate the role of circular RNA BCL2 Interacting Protein 3 Like (circ-BNIP3L) in the pathophysiological mechanism of SA-AKI. The SA-AKI cell model was established by using lipopolysaccharide (LPS)-induced HK-2 cells in vitro. Cell survival was analyzed using cell counting kit-8 (CCK-8) assay, EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry and Western blot, respectively. Levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were detected using ELISA analysis. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were examined using commercial kits. Levels of genes and proteins were detected by qRT-PCR and Western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to identify the target relationship between miR-370-3p and circ-BNIP3L or MYD88 (myeloid differentiation primary response 88). Circ-BNIP3L was highly expressed in SA-AKI patients and LPS-induced HK-2 cells. Silencing of circ-BNIP3L attenuated LPS-induced growth inhibition, inflammation, and oxidative stress in HK-2 cells. Mechanistically, circ-BNIP3L competitively bound to miR-370-3p to up-regulate the expression of its target MYD88. Moreover, miR-370-3p inhibition reversed the beneficial effects of circ-BNIP3L knockdown on LPS-stimulated HK-2 cells. Meanwhile, miR-370-3p overexpression abolished LPS-induced injury in HK-2 cells, which was counteracted by MYD88 up-regulation. Circ-BNIP3L knockdown alleviated LPS-induced renal tubular epithelial cell injury by miR-370-3p/MYD88 axis, opening up a completely new avenue for the treatment of sepsis-associated AKI.

Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment.

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of the critically ill patient and is associated with unacceptable morbidity and mortality. Prevention of S-AKI is difficult because by the time patients seek medical attention, most have already developed acute kidney injury. Thus, early recognition is crucial to provide supportive treatment and limit further insults. Current diagnostic criteria for acute kidney injury has limited early detection; however, novel biomarkers of kidney stress and damage have been recently validated for risk prediction and early diagnosis of acute kidney injury in the setting of sepsis. Recent evidence shows that microvascular dysfunction, inflammation, and metabolic reprogramming are 3 fundamental mechanisms that may play a role in the development of S-AKI. However, more mechanistic studies are needed to better understand the convoluted pathophysiology of S-AKI and to translate these findings into potential treatment strategies and add to the promising pharmacologic approaches being developed and tested in clinical trials.

SAP130 released by ferroptosis tubular epithelial cells promotes macrophage polarization via Mincle signaling in sepsis acute kidney injury.

The pathological mechanism of sepsis-associated acute kidney injury (SA-AKI) is complex and involves tubular epithelial cell (TEC) death and immune cell activation. However, the interaction between tubular cell death and macrophage-mediated inflammation remains unclear. In this study, we uncovered that TEC ferroptosis was activated in SA-AKI. Increased levels of ferroptotic markers, including ferroptosis-related proteins, lipid peroxidation, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), and mitochondrial damage, were observed in the kidney tissue of cecum ligation and puncture (CLP) and Lipopolysaccharide (LPS)-induced SA-AKI mouse models, which were subsequently suppressed by Ferrostatin-1 (Fer-1). In vitro experiments showed that Fer-1 inhibits LPS-induced mitochondrial damage, Fe2+ accumulation, and cytosolic ROS production. Moreover, it was found that TEC ferroptosis induced by promoted macrophage-inducible C-type lectin (Mincle) and its downstream expression and M1 polarization, which was mediated by the release of spliceosome-associated protein 130 (SAP130), an endogenous ligand of Mincle, from TEC. It was confirmed in vitro that the supernatant from LPS-stimulated TECs promoted Mincle expression and M1 polarization in macrophages. Further experiments revealed that M1 macrophages aggravated TEC ferroptosis, which was offset by neutralizing SAP130 or inhibiting Mincle expression. In addition, neutralizing the circulatory SAP130 blunted kidney ferroptosis and Mincle expression, as well as macrophage infiltration in the kidney of SA-AKI mice. In conclusion, the release of SAP130 from ferroptotic TECs promoted M1 macrophage polarization by triggering Mincle/syk/NF-κB signaling, and M1 macrophages, in turn, aggravated TEC ferroptosis.

Effect of propofol versus midazolam on short-term outcomes in patients with sepsis-associated acute kidney injury.

Background: Propofol and midazolam are commonly used sedative drugs in mechanically ventilated patients in the Intensive Care Unit (ICU). However, there is still a lack of relevant studies exploring the influence of midazolam and propofol on the prognosis of patients with Sepsis-associated Acute Kidney Injury (S-AKI). Patients and methods: A statistical analysis was conducted on 3,745 patients with S-AKI in the Medical Information Mart for Intensive Care IV database. The patients' baseline characteristics were grouped based on the use of either propofol or midazolam as sedatives. Cox proportional hazards models, logistic regression models, and subgroup analyses were used to compare the effects of propofol and midazolam on the short-term prognosis of S-AKI patients, including 30-day mortality, ICU mortality, and duration of mechanical ventilation. Results: In the statistical analysis, a total of 3,745 patients were included, with 649 patients using midazolam and 3,096 patients using propofol. In terms of the 30-day mortality, compared to patients using midazolam, S-AKI patients using propofol had a lower ICU mortality (hazard ratio = 0.62, 95% confidence interval: 0.52-0.74, p < 0.001), lower 30-day mortality (hazard ratio = 0.56, 95% confidence interval: 0.47-0.67, p < 0.001), and shorter mechanical ventilation time (odds ratio = 0.72, 95% confidence interval: 0.59-0.88, p < 0.001). Kaplan-Meier curves showed lower survival probabilities in the midazolam group (p < 0.001). Subgroup analyses showed that propofol was strongly protective of short-term prognosis in older, male, smaller SOFA score CCI score, no heart failure, and comorbid chronic kidney disease patients with S-AKI. Conclusion: Compared to midazolam, propofol was considered a protective factor for short-term mortality risk and ICU mortality risk in S-AKI patients. Additionally, S-AKI patients using propofol had a lower risk of requiring prolonged mechanical ventilation. Overall, propofol may be more beneficial for the short-term prognosis of S-AKI patients compared to midazolam.

Association between acetaminophen and risk of mortality in patients with sepsis-associated acute kidney injury: A retrospective cohort study from the MIMIC-IV database.

The occurrence of sepsis-associated acute kidney injury (SA-AKI) predicts a worse prognosis. We aimed to assess the impact of acetaminophen use on short-term mortality in patients with SA-AKI. A total of 6563 patients diagnosed with SA-AKI from the 2008 to 2019 Medical Information Mart for Intensive Care IV (MIMIC-IV) database were enrolled in this retrospective cohort study. The Cox regression model was utilized to analyze the associations of acetaminophen with 30-day mortality and in-hospital mortality. Additional propensity score matching (PSM) analysis was performed regarding patients with acetaminophen use versus those without. Of these patients, 30-day mortality occurred in 1421 (21.65%) patients and in-hospital mortality in 1246 (18.99%) patients. Patients who used acetaminophen were associated with a reduced risk of 30-day mortality (hazard ratio (HR) = 0.80, 95% confidence interval (CI): 0.71-0.90) and in-hospital mortality (HR = 0.72, 95% CI: 0.63-0.82). The PSM analysis demonstrated that acetaminophen use was still related to a reduced risk of 30-day mortality and in-hospital mortality. Subgroup analysis showed that the relationships between acetaminophen and 30-day mortality and in-hospital mortality were consistent across subgroups (p < 0.05). The use of acetaminophen has an association with lower short-term mortality in patients with SA-AKI.

Echinocystic acid inhibits sepsis-associated renal inflammation and apoptosis by targeting protein tyrosine phosphatase 1B.

Thefruits of Gleditsia sinensis Lam. have been utilized to treat inflammatory diseases in China. Echinocystic acid (EA), one pentacyclic triterpenoid isolated from thefruits of G. sinensis, exhibits an anti-inflammatory effect. However, its anti-sepsis activity and mechanism of action, especially the protective effect against sepsis-associated acute kidney injury (SA-AKI), are not investigated yet. This study is to explore the efficacy and potential mechanism of EA on SA-AKI. EA elevated the function of multiple organs and effectively reduced the increased inflammation and apoptosis of kidney tissue and HK-2 cells. DARTS, CETSA, and molecular docking experiments revealed that EA could directly bind to protein tyrosine phosphatase 1B (PTP1B), a widespread prototype non-receptor tyrosine phosphatase. Collectively, EA can alleviate murine SA-AKI though restraining inflammation and apoptosis and may be a potential natural drug for remedying SA-AKI.

VX-702 Ameliorates the Severity of Sepsis-Associated Acute Kidney Injury by Downregulating Inflammatory Factors in Macrophages.

Purpose: Sepsis-associated acute kidney injury (S-AKI) contributes to high mortality, but it is lack of specific treatments. We aimed to investigate the underlying mechanism of S-AKI and to identify target drugs to alleviate AKI. Methods: We establish a stable mouse model of S-AKI by Pseudomonas aeruginosa incision infection. Based on high-throughput sequencing and bioinformatics analysis, we investigated the underlying mechanism and selected the target drug (VX-702) for S-AKI. An in vitro model established by co-cultured of kidney tubular epithelial cell line (TCMK-1) cells with lipopolysaccharide (LPS)-induced leukemic monocyte/macrophage cells (RAW264.7), we explored the effect of VX-702 on S-AKI. Results: The data showed interleukin (IL)-6 and IL-1ß were the hub genes, and the mitogen-activated protein kinase (MAPK) signaling pathway was the main pathway involved in S-AKI. Administration of VX-702 by oral gavage decreased the elevated concentrations of IL-6, IL-1ß, serum creatinine, and blood urea nitrogen in mice with S-AKI. Moreover, VX-702 reduced the number of apoptotic cells in damaged kidney tissues. Cell viability was decreased, and the number of apoptotic cells was increased in TCMK-1 cells co-cultured with LPS-induced RAW264.7 cells compared to LPS-induced TCMK-1 cells. VX-702 treatment reversed this effect. VX-702 treatment reduced the levels of phosphorylated p38 MAPK and proinflammatory cytokines in RAW264.7 cells and the supernatant. VX-702 could bind IL-6, IL-1ß and MAPK, and affect the binding of IL-1ß and its receptor, as demonstrated by molecular docking. Conclusion: VX-702 ameliorated S-AKI by inhibiting the release of proinflammatory cytokines from macrophages, indicating its potential as a novel therapeutic for S-AKI treatment.

Non-Canonical STING-PERK Pathway Modulation of Cellular Senescence and Therapeutic Response in Sepsis-Associated Acute Kidney Injury.

Abstract-This study explored the role of the non-canonical STING-PERK signaling pathway in sepsis-associated acute kidney injury (SA-AKI). Gene expression data from the GEO database and serum STING protein levels in patients with SA-AKI were analyzed. An LPS-induced mouse model and an in vitro model using HK-2 cells were used to investigate the role of STING in SA-AKI. STING expression was suppressed using shRNA silencing technology and the STING inhibitor C176. Kidney function, inflammatory markers, apoptosis, and senescence were measured. The role of the STING-PERK pathway was investigated by silencing PERK in HK-2 cells and administering the PERK inhibitor GSK2606414. STING mRNA expression and serum STING protein levels were significantly higher in patients with SA-AKI. Suppressing STING expression improved kidney function, reduced inflammation, and inhibited apoptosis and senescence. Silencing PERK or administering GSK2606414 suppressed the inflammatory response, cell apoptosis, and senescence, suggesting that PERK is a downstream effector in the STING signaling pathway. The STING-PERK signaling pathway exacerbates cell senescence and apoptosis in SA-AKI. Inhibiting this pathway could provide potential therapeutic targets for SA-AKI treatment.