Sepsis-associated Acute Kidney Injury Research Articles

AFM negatively regulates the infiltration of monocytes to mediate sepsis-associated acute kidney injury.

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. Aimed to use weighted gene co-expression network analysis (WGCNA) and immunoinfiltration analysis to study SA-AKI-related diagnostic markers and potential therapeutic targets. 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. 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. 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.

Pectolinarigenin alleviated septic acute kidney injury via inhibiting Jak2/Stat3 signaling and mitochondria dysfunction

Sepsis is a systemic inflammatory response to infection, where sepsis-associated acute kidney injury (AKI) is a common morbid disease with a high morbidity and mortality, and however at present no effective therapy exists. Increasing evidence have shown that mitochondrial damage and inflammatory response are important initiating factors in pathogenesis of septic AKI. Natural flavonoid pectolinarigenin exerted anti-inflammatory properties in previous studies, while its role in septic AKI remains unknown. In the study, pectolinarigenin administration significantly ameliorated the dramatic rise of serum creatinine and blood urea nitrogen in lipopolysaccharide (LPS)- and cecal ligation/puncture (CLP)-induced septic mice, respectively. Consistently, LPS/CLP-induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by pectolinarigenin. Meanwhile, LPS/CLP triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, pectolinarigenin inhibited renal expression of IL-6, IL-1β, TNF-α, and MCP-1 to improve inflammatory response. Furthermore, pectolinarigenin upregulated Bcl-2 protein expression and suppressed apoptotic protein of BAX and cleaved caspase-3 in the kidneys of CLP-induced septic AKI. Mechanistically, LPS could induce the high expression of IL-6 and trigger the phosphorylation of Jak2 and Stat3, while pectolinarigenin remarkably reduced their corresponding levels. Notably, CLP-induced kidney injury of mice significantly reduced the expression of PGC-1α, OPA1 and increased the expression of Drp1, Cyt-C, where pectolinarigenin pretreatment significantly restored their corresponding expression in mice. In summary, pectolinarigenin improved septic AKI via inhibiting JAK2/STAT3 signaling and mitochondria dysfunction.

Use of kidney injury molecule-1 for sepsis-associated acute kidney injury staging.

Journal Article Accepted manuscript Use of kidney injury molecule-1 for sepsis-associated acute kidney injury staging Get access Luca Molinari, Luca Molinari Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Translational Medicine, Università del Piemonte Orientale, Novara, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Douglas P Landsittel, Douglas P Landsittel Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar John A Kellum, John A Kellum Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Correspondence to: John A. Kellum; E-mail: kellum@pitt.edu Search for other works by this author on: Oxford Academic PubMed Google Scholar the ProCESS and ProGReSS-AKI Investigators the ProCESS and ProGReSS-AKI Investigators Search for other works by this author on: Oxford Academic PubMed Google Scholar Nephrology Dialysis Transplantation, gfad004, https://doi.org/10.1093/ndt/gfad004 Published: 16 January 2023

Toll-like Receptor 4 in Acute Kidney Injury.

Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed.

Effects of mesencephalic astrocyte-derived neurotrophic factor on sepsis-associated acute kidney injury.

To determine the protective role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in regulating sepsis-associated acute kidney injury (S-AKI). A total of 96 mice were randomly divided into the control group, control+MANF group, S-AKI group, and S-AKI+MANF group. The S-AKI model was established by injecting lipopolysaccharide (LPS) at 10 mg/kg intraperitoneally. MANF (200 μg/kg) was administered to the control+MANF and S-AKI+MANF groups. An equal dose of normal saline was administered daily intraperitoneally in the control and S-AKI groups. Serum and kidney tissue samples were obtained for biochemical analysis. Western blotting was used to detect the protein expression of MANF in the kidney, and enzyme-linked immunosorbent assay (ELISA) was used to determine expression of MANF in the serum, pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]). Serum creatinine (SCr), and blood urea nitrogen (BUN) were examined using an automatic biochemical analyzer. In addition, the kidney tissue was observed for pathological changes by hematoxylin-eosin staining. The comparison between two groups was performed by unpaired Student's t-test, and statistics among multiple groups were carried out using Tukey's post hoc test following one-way analysis of variance (ANOVA). A P-value <0.05 was considered statistically significant. At the early stage of S-AKI, MANF in the kidney tissue was up-regulated, but with the development of the disease, it was down-regulated. Renal function was worsened in the S-AKI group, and TNF-α and IL-6 were elevated. The administration of MANF significantly alleviated the elevated levels of SCr and BUN and inhibited the expression of TNF-α and IL-6 in the kidney. The pathological changes were more extensive in the S-AKI group than in the S-AKI+MANF group. MANF treatment may significantly alleviate renal injury, reduce the inflammatory response, and alleviate or reverse kidney tissue damage. MANF may have a protective effect on S-AKI, suggesting a potential treatment for S-AKI.

Efficacy of Immature Platelet Fraction in Predicting Septic Acute Kidney Injury.

Immature platelet fraction (IPF) is a new hematological parameter. Although its value in predicting the severity and mortality of sepsis patients has been shown, no study has assessed whether IPF can predict sepsis-associated acute kidney injury (S-AKI). Thus, this study aimed to analyze the predictive value of IPF in the occurrence and mortality of S-AKI. Sepsis patients from the intensive care unit were screened and divided into S-AKI (n = 53) and non-S-AKI (n = 71) groups. IPF values were calculated by using the CDR mode of the BC-6800Plus hematology analyzer (Mindary, Shenzhen, China). Relevant data, such as serum creatinine (Scr) and uric acid (UA) levels, of the patients were obtained through the hospital information-management system. The sepsis patients with S-AKI had lower high-density lipoprotein (HDL) levels, higher IPF values, higher Scr, UA, C-reactive protein (CRP), and procalcitonin (PCT) levels, and higher SOFA and APACHE Ⅱ scores than the non-S-AKI patients (p < 0.05). IPF value was found correlated with Scr, HDL, CRP, and PCT levels and APACHE Ⅱ score but not with age, UA level, urine output in 24 hours, or SOFA score. Multivariate logistic regression analysis suggested that IPF, UA, and HDL are independent risk factors for S-AKI. The area under the curve (AUC) of IPF in the identification of S-AKI incidence was found superior to the AUC of UA and 1/HDL with a cutoff value of 12.15. However, IPF was not found associated with mortality in S-AKI. IPF can serve as a biomarker to predict S-AKI in sepsis patients.

Early Enteral Nutrition and Sepsis-Associated Acute Kidney Injury: A Propensity Score Matched Cohort Study Based on the MIMIC-III Database.

We aimed to analyze the optimal timing of enteral nutrition (EN) in the treatment of sepsis and its effect on sepsis-associated acute kidney injury (SA-AKI.). The MIMIC-III database was employed to identify patients with sepsis who had received EN. With AKI as the primary outcome variable, receiver operating characteristic (ROC) curves were utilized to calculate the optimal cut-off time of early EN (EEN). Propensity score matching (PSM) was employed to control confounding effects. Logistic regressions and propensity score-based inverse probability of treatment weighting were utilized to assess the robustness of our findings. Comparisons within the EEN group were performed. 2364 patients were included in our study. With 53 hours after intensive care units (ICU) admission as the cut-off time of EEN according to the ROC curve, 1212 patients were assigned to the EEN group and the other 1152 to the delayed EN group. The risk of SA-AKI was reduced in the EEN group (odds ratio 0.319, 95% confidence interval 0.245-0.413, p<0.001). The EEN patients received fewer volumes (mL) of intravenous fluid (IVF) during their ICU stay (3750 mL vs. 5513.23 mL, p<0.001). The mediating effect of IVF was significant (p<0.001 for the average causal mediation effect). No significant differences were found within the EEN group (0-48 hours vs. 48-53 hours), except that patients initiating EN within 48 hours spent fewer days in ICU and hospital. EEN is associated with decreased risk of SA-AKI, and this beneficial effect may be proportionally mediated by IVF volume.

LncRNA MIAT Modulates LPS-Induced Acute Kidney Injury via BECN1-Dependent Autophagy by Interacting with PTBP1.

Autophagy plays critical adaptive and nonadaptive roles in the pathogenesis of Sepsis-associated acute kidney injury (Sepsis-AKI). However, it remains unknown whether myocardial infarction associated transcript (MIAT) is involved in the process of autophagy in Sepsis-AKI. This study aimed to explore the exact association between MIAT1 and Beclin 1 (BECN1)-mediated autophagy in Sepsis-AKI in vitro. HK-2 (human renal tubular epithelial cell line) cells were stimulated by lipopolysaccharide (LPS) to construct a septic kidney injury cell model in vitro. The relative expression changes of genes or proteins in clinical samples and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell survival was detected by cell counting kit-8 (CCK-8) and flow cytometry analysis. The production of inflammatory mediators was determined using Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR assays. The interlinked relationship between polypyrimidine tract-binding protein 1 (PTBP1) and MIAT or BECN1 was validated by RNA immunoprecipitation (RIP) and RNA pull-down detections. The expression of MIAT was up-regulated in Sepsis-AKI patients and LPS-stimulated HK-2 cells. Down-regulation of MIAT strikingly lightened LPS-induced cell apoptosis and inflammation, but enhanced cell viability. Evidenced by mechanistic experiments, MIAT silencing was confirmed to activate BECN1-mediated cell autophagy by interacting with PTBP1. Furthermore, the elimination of BECN1 remarkably reversed the antiapoptotic and anti-inflammatory roles mediated by MIAT silencing. In summary, the experimental data reinforced that MIAT downregulation attenuated LPS-stimulated renal cell inflammatory injury by promoting BECN1-mediated autophagy activation through binding to PTBP1, providing some new insights into the function and mechanism of MIAT in Sepsis-associated acute kidney injury (Sepsis-AKI).

Identification of Biomarkers for the Diagnosis of Sepsis-Associated Acute Kidney Injury and Prediction of Renal Recovery in the Intensive Care Unit.

Acute kidney injury (AKI) following sepsis is associated with higher mortality; however, reliable biomarkers for AKI development and recovery remain to be elucidated. Patients with sepsis admitted to the medical intensive care unit (ICU) of Severance Hospital between June 2018 and May 2019 were prospectively analyzed. Patients were divided into those with and without AKI within 48 hours. Patients with septic AKI were subdivided into AKI-recovery and non-recovery groups based on whether their kidney injury recovered within 7 days. A total of 84 patients were enrolled. The baseline creatinine (2.9 mg/dL vs. 0.8 mg/dL vs. 1.2 mg/dL, p<0.001), Charlson Comorbidity Index (4.5 vs. 2.0 vs. 3.0, p=0.002), Sequential Organ Failure Assessment (10.0 vs. 6.5 vs. 8.0, p<0.001), and Acute Physiology and Chronic Health Evaluation II scores (32.0 vs. 21.5 vs. 30.5, p=0.004) were higher in the non-recovery AKI group compared to the non-AKI and AKI-recovery groups. The Kaplan-Meier curves revealed that non-recovery from AKI was associated with lower survival (p<0.001). High-lactate (p≤0.05) and kynurenine levels (p≤0.05) were associated with non-recovery of renal function following AKI. The areas under the curve for predicting non-recovery from AKI were 0.693 and 0.721 for lactate and kynurenine, respectively. The survival rate was lower in the high-kynurenine (p=0.040) and high-lactate (p=0.010) groups. The mortality of patients who recovered from AKI was comparable to that of patients without AKI. Lactate and kynurenine could be useful biomarkers for the diagnosis and recovery of AKI following sepsis.

The Potential Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Cardiovascular System, Respiratory System and Skin.

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and xeroderma pigmentosum). Additionally, the significance of CXCL1 is described in vascular physiology, such as the effects of CXCL1 on angiogenesis and arteriogenesis.

Identifying the molecular mechanisms of sepsis-associated acute kidney injury and predicting potential drugs.

Objective: To provide insights into the diagnosis and therapy of SA-AKI via ferroptosis genes. Methods: Based on three datasets (GSE57065, GSE30718, and GSE53771), we used weighted co-expression network analysis to identify the key regulators of SA-AKI, its potential biological functions, and constructed miRNA‒mRNA complex regulatory relationships. We also performed machine learning and in vitro cell experiments to identify ferroptosis genes that are significantly related to SA-AKI in the two datasets. The CIBERSORT algorithm evaluates the degree of infiltration of 22 types of immune cell. We compared the correlation between ferroptosis and immune cells by Pearson's correlation analysis and verified the key genes related to the immune response to reveal potential diagnostic markers. Finally, we predicted the effects of drugs and the potential therapeutic targets for septic kidney injury by pRRophetic. Results: We found 264 coDEGs involving 1800 miRNA molecules that corresponded to 210 coDEGs. The miRNA‒mRNA ceRNA interaction network was constructed to obtain the top-10 hub nodes. We obtained the top-20 ferroptosis genes, 11 of which were in the intersection. We also identified a relationship between ferroptosis genes and the immune cells in the AKI dataset, which showed that neutrophils were activated and that regulatory T cells were surpassed. Finally, we identified EHT1864 and salubrinal as potential therapeutic agents. Conclusion: This study demonstrated the roles of miR-650 and miR-296-3p genes in SA-AKI. Furthermore, we identified OLFM4, CLU, RRM2, SLC2A3, CCL5, ADAMTS1, and EPHX2 as potential biomarkers. The irregular immune response mediated by neutrophils and Treg cells is involved in the development of AKI and shows a correlation with ferroptosis genes. EHT 1864 and salubrinal have potential as drug candidates in patients with septic acute kidney injury.

Value of Central Venous Pressure Monitoring in the Patients with Sepsis-Associated Acute Kidney Injury.

Although the measurement of central venous pressure (CVP) is a common clinical tool, the role of CVP monitoring in the outcome of sepsis is controversial because threshold values of CVP are uncertain, and there are only limited data on short-term survival of patients with septic acute kidney injury (AKI). This retrospective cohort study was based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (source of the training dataset). Multivariate regression analysis was performed to clarify the relation between CVP measurement and clinical outcomes, and a univariate regression model after propensity score matching was utilized to validate our findings. A mortality prediction model for septic AKI and a risk stratification scoring approach were developed, and the emergency intensive care unit (eICU) database was used for external validation. Of the 9170 patients in the training set, 2446 (26.7%) underwent CVP measurement. No significant association was found between CVP monitoring and 28-day mortality among patients with septic AKI (odds ratio = 0.479; 95% confidence interval 0.213-1.076, P = 0.075), even after adjustments (propensity score matching; P = 0.178). Length of ICU stay and hospital stay was markedly reduced in patients undergoing CVP measurement within 3 hours (median 6.2 and 10.9 days, respectively, P < 0.001). The addition of the mean perfusion pressure initial, CVP, and the magnitude of the CVP change within 48 hours to the model significantly increased model discrimination (area under the receiver operating characteristic curve: 0.867 and 0.780, respectively, P < 0.001). These findings suggest that CVP measurement alone has little effect on the outcome of septic AKI. Nonetheless, initial CVP levels and the dynamic changes in CVP within the first 48 hours after ICU admission and the mean perfusion pressure initial can improve the accuracy of outcome prediction models.

Predictive value of the serum anion gap for 28-day in-hospital all-cause mortality in sepsis patients with acute kidney injury: a retrospective analysis of the MIMIC-IV database.

The kidney is one of the most vulnerable organs in sepsis patients, which mainly manifests as sepsis-associated acute kidney injury (SA-AKI). The case fatality rate of SA-AKI is high, and thus, predicting the risk of SA-AKI-related death is hugely significant. Anion gap (AG) is an important indicator in critical illness patients. The present study aimed to analyze the predictive value of the AG for the short-term prognosis of SA-AKI patients. SA-AKI patient data from the Medical Information Mart for Intensive Care (MIMIC-IV) database were collected retrospectively. Hospitalized septic patients who meet the inclusion criteria were included in the final analysis. All laboratory test parameters only included the data generated within the first 24 hours after the patient entered the intensive care unit (ICU) and the extreme value. Univariate and multivariate logistic regression analyses were performed to analyze the risk factors related to the death of SA-AKI patients within 28 days during hospitalization in the ICU. A total of 3,684 SA-AKI patients were included, including 3,305 patients with low AG (<18 mmol/L) and 379 patients with high AG (≥18 mmol/L). Among these patients, 497 cases (13.5%) died during hospitalization, including 376 cases (11.4%) in the low AG group and 121 cases (31.9%) in the high AG group. Multivariate logistic regression analysis showed that elevated AG increased the risk of death in SA-AKI patients within 28 days during hospitalization in the ICU (odds ratio =1.2, 95% confidence interval: 1.2-1.3). Further analysis showed that the risk of death of SA-AKI patients within 28 days during hospitalization in the ICU was increased when AG ≥14 mmol/L. The relationship between AG level and the risk of death of SA-AKI patients during hospitalization was S-shaped. In clinical practice, AG levels can serve as a valuable predictor of the death risk of SA-AKI patients during hospitalization.

Assessment of Urinary Exosomal NHE3 as a Biomarker of Acute Kidney Injury.

The diagnosis of acute kidney injury (AKI) traditionally depends on the serum creatinine (Scr) and urine output, which lack sufficient sensitivity and specificity. Using urinary exosomes as a biomarker has unique advantages. To assess whether urinary exosomal Na+/H+ exchanger isoform 3 (NHE3) protein could serve as a biomarker of AKI, we constructed four AKI rat models: cisplatin (7.5 mg/kg) injected intraperitoneally (IP), furosemide (20 mg/kg, IP) with a low-NaCl (0.03%) diet, a low-NaCl (0.03%) diet with candesartan (1 mg/kg, IP) and bilateral ischemia and reperfusion (I/R) injury for 40 min. Additionally, we assessed six sepsis-associated AKI patients and six healthy volunteers. Urinary exosomes were extracted by ultracentrifugation, and the NHE3 protein abundance was tested by immunoblotting for all the AKI rats and human subjects. The isolated cup-shaped particles with an average diameter of 70 nm and enrichment in CD63 were identified as exosomes. NHE3 abundance was six times higher in exosomes than in the whole urine. In cisplatin-induced AKI rats, urinary exosomal NHE3 was increased on day 2, one day earlier than the increases in Scr and blood urea nitrogen (BUN). In additional rats, urinary exosomal NHE3 decreased along with the decline in Scr after EPO pretreatment. In volume-depletion AKI induced by furosemide injection with a low-NaCl diet, the urinary exosomal NHE3 expression was higher than that in the control. Under a low-NaCl diet with candesartan-related AKI, the urinary exosomal NHE3 was elevated on day 5, earlier than Scr. In I/R-injury AKI, the urinary exosomal NHE3 was also raised compared with that in the control. In humans, the urinary exosomal NHE3 level was also elevated in sepsis-associated AKI patients in comparison with that in the healthy volunteers. The urinary exosomal NHE3 was increased in multiple AKI; it may be used as a diagnostic biomarker of AKI.

Scutellarin alleviates lipopolysaccharide-provoked septic nephrotoxicity via attenuation of inflammatory and oxidative events and mitochondrial dysfunction

Background Sepsis-associated acute kidney injury (AKI) is highlighted by high incidence of mortality and morbidity. Scutellarin is a flavone extracted from certain medicinal plants with anti-inflammatory and anti-oxidative properties. This research study was done to investigate the beneficial effect of scutellarin on lipopolysaccharide (LPS) murine model of AKI. Materials and methods Five groups of mice were used including control (without LPS injection), LPS group (LPS injection, 10 mg/kg), and LPS + Scutellarin25, 50, and/or 100 groups (receiving scutellarin orally at different doses of 25, 50, or 100 mg/kg before LPS injection). Results Scutellarin pretreatment effectively lowered kidney function markers (BUN, creatinine, and cystatin C), improved superoxide dismutase (SOD) besides enhancement of level, and/or gene expression for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) and also reduced oxidative stress factors including reactive oxygen species (ROS) and malondialdehyde (MDA). In addition, scutellarin reduced tissue level and/or gene expression of inflammatory markers comprising toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), and tumor necrosis factor α (TNF-α) and properly raised anti-inflammatory factor IL-10. Moreover, scutellarin enhanced mitochondrial membrane potential (MMP) and attenuated histopathological changes in renal tissue subsequent to LPS challenge. Beneficial effects of scutellarin was associated with improvement of gene expression regarding peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PGC-1α as specific markers of mitochondrial biogenesis. Conclusion These results indicate that scutellarin could protect against LPS-provoked AKI through restraining inflammation and oxidative stress and maintenance of mitochondrial health and biogenesis which is partly mediated through its regulation of Nrf2/PPAR-γ/PGC-1α/NF-kB/TLR4.

Progression of Kidney Injury with the Combination of Vancomycin and Piperacillin-Tazobactam or Cefepime in Sepsis-Associated Acute Kidney Injury.

The combination of vancomycin/piperacillin-tazobactam is associated with increases in serum creatinine compared to other antibiotic combinations in the treatment of infections for hospitalized patients. However, the available literature is limited to the study of incident acute kidney injury (AKI). The combination has not been evaluated in patients with AKI already present and the degree to which the trajectory of AKI is influenced by this combination is unknown. This was a single center, retrospective cohort study of adult patients with sepsis and AKI present on admission prescribed a combination of vancomycin with either piperacillin-tazobactam or cefepime within the first 3 days of admission. The primary outcome was maximum serum creatinine observed within days 2-7 of the hospital stay. Subsequent kidney outcomes were evaluated at one week and hospital discharge. Of 480 patients with sepsis and AKI who met inclusion criteria, 288 (60%) received vancomycin/piperacillin-tazobactam, and 192 (40%) received vancomycin/cefepime. Patients were well-matched on clinical factors, including severity of illness, stage of AKI, exposure to other nephrotoxins, and durations of antimicrobial therapy. There were no differences in AKI trajectory during the first week as assessed by maximum serum creatinine (2.1 (1.4-3.5) mg/dl vs. 2.1 (1.4-3.0) mg/dl; p=0.459) and AKI progression (24.0% vs. 23.4%; p=0.895). No differences were observed with other kidney related outcomes, including the need for dialysis (14.6% vs. 13.0%; p=0.628) or major adverse kidney events at hospital discharge (48.3% vs. 47.9%; p=0.941). In patients with sepsis and AKI, the combination of vancomycin/piperacillin-tazobactam compared to vancomycin/cefepime was not associated with higher serum creatinine values or AKI progression in the week following ICU admission.

Association between dexmedetomidine administration and outcomes in critically ill patients with sepsis-associated acute kidney injury

Study objectiveTo investigate the association between dexmedetomidine administration and outcomes in critically ill patients with sepsis-associated acute kidney injury (SA-AKI). DesignA single-center, retrospective, cohort study. SettingIntensive care unit (ICU). PatientsA total of 2192 critically ill patients with SA-AKI were included in the analysis, which identified from the Medical Information Mart for Intensive Care (MIMIC-IV) database between 2008 and 2019. InterventionsIntravenous infusion of dexmedetomidine. MeasurementsThe primary outcome was recovery of renal function. In-hospital mortality, vasopressor requirements, length of ICU and hospital stay were considered secondary outcomes. The Cox proportional hazards, logistic regression, and linear regression models were used to assess the association between dexmedetomidine and outcomes. Propensity score matching (PSM) analysis was used to match patients receiving dexmedetomidine to those without treatment. Main resultsAfter PSM, 719 matched patient pairs were derived from patients who received dexmedetomidine and those who did not. The administration of dexmedetomidine was associated with a higher rate of renal recovery [61.8% vs. 55.8%, hazard ratio (HR) 1.35; P = 0.01], reduced in-hospital mortality [28.3% vs. 41.3%, HR 0.56; P < 0.001], and prolonged intensive care unit (ICU) stay [15.8d vs 12.6d, HR 2.34; P < 0.001] and hospital stay [23.7d vs 19.7d, HR 4.47; P < 0.001]. No significant difference was found in vasopressor requirements in patients with SA-AKI. Nevertheless, results illustrated that dose receiving between 0.30 and 1.00 μg/kg/h and duration using under 48 h of dexmedetomidine was associated with improvements in renal function recovery in SA-AKI patients. ConclusionDexmedetomidine administration was associated with improvements in renal function recovery and in-hospital survival in critically ill patients with SA-AKI. The results need to be verified in further randomized controlled trials.

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

Sepsis-induced AKI: From pathogenesis to therapeutic approaches.

Sepsis is a heterogenous and highly complex clinical syndrome, which is caused by infectious or noninfectious factors. Acute kidney injury (AKI) is one of the most common and severe complication of sepsis, and it is associated with high mortality and poor outcomes. Recent evidence has identified that autophagy participates in the pathophysiology of sepsis-associated AKI. Despite the use of antibiotics, the mortality rate is still at an extremely high level in patients with sepsis. Besides traditional treatments, many natural products, including phytochemicals and their derivatives, are proved to exert protective effects through multiple mechanisms, such as regulation of autophagy, inhibition of inflammation, fibrosis, and apoptosis, etc. Accumulating evidence has also shown that many pharmacological inhibitors might have potential therapeutic effects in sepsis-induced AKI. Hence, understanding the pathophysiology of sepsis-induced AKI may help to develop novel therapeutics to attenuate the complications of sepsis and lower the mortality rate. This review updates the recent progress of underlying pathophysiological mechanisms of sepsis-associated AKI, focuses specifically on autophagy, and summarizes the potential therapeutic effects of phytochemicals and pharmacological inhibitors.

Abstract 115: Soluble (pro)renin Receptor Contributes To Endotoxin-induced Septic Shock And Aki In Mice

Sepsis associated acute kidney injury (S-AKI) is a life-threating disease with poorly defined mechanisms and limited therapeutic options. Here we examined the role of site-1 protease (S1P)-derived soluble PRR (sPRR) in the S-AKI model induced by lipopolysaccharide (LPS). Male 10-week-old B6129SF1/J mice were pretreated with a S1P inhibitor PF-429242 (PF) at 20 mg/kg/day via minipump and treated with a single s.c. injection of LPS at 10 mg/kg and monitored for 24 hours. By radiotelemetry, LPS induced fall in mean arterial pressure (MAP) (Δ mmHg: -14.98 ± 4.13 in LPS+PF group vs . -23.15 ± 1.82 in LPS+ Vehicle group; n = 6, p &lt; 0.05) and heart rate (HR) (Beats/min: -78.60 ± 20.73 in LPS+PF group vs . -133.35 ± 30.92 in LPS group, n = 6, p &lt; 0.05), which was significantly attenuated by PF treatment. In parallel, renal dysfunction as reflected by the rises in plasma creatinine and BUN along with albuminuria, urinary excretion of NGAL and Kim-1 were all improved. Similar improvement was observed for infiltration of macrophage as assessed by immunofluorescence detection of F4/80 as well as renal mRNA expression of M1 markers such as iNOS, IL-1β, IL-6, and TNFα. The results from the pharmacological study were validated using a recently generated mouse model of mutagenesis of the cleavage site of PRR (termed Mutant mice). LPS-induced hypotensive response, renal dysfunction, the markers of renal injury and inflammation and M1 activation were all improved in Mutant mice as seen with PF treatment. LPS induced a 3.35-fold increase in plasma sPRR which was attenuated by PF or in Mutant mice. By immunofluorescence, LPS-induced PRR expression was largely restricted to renal medullary intercalated dells. In cultured RAW264.7 macrophage cells, recombinant sPRR treatment at 30 nM directly promoted macrophage migration and stimulated mRNA levels of M1 markers, all of which were attenuated by losartan. Taken together, the present study suggests that (1) S1P-derived sPRR contributes to LPS-induced septic shock and AKI, and (2) within the kidney, LPS-induced sPRR originates from intercalated cells and may act in a paracrine manner to activate AT1R on macrophages to induce pro-inflammatory response.