Acute Kidney Injury In Sepsis Research Articles

BAM15 treats mouse sepsis and kidney injury, linking mortality, mitochondrial DNA, tubule damage, and neutrophils.

Sepsis pathogenesis is complex and heterogeneous; hence, a precision-medicine strategy is needed. Acute kidney injury (AKI) following sepsis portends higher mortality. Overproduction of mitochondrial ROS (mtROS) is a potential mediator of sepsis and sepsis-induced AKI. BAM15, a chemical uncoupler, dissipates mitochondrial proton gradients without generating mtROS. We injected BAM15 into mice at 0, 6, or 12 hours after cecal ligation and puncture (CLP), and these mice were treated with fluids and antibiotics. BAM15 reduced mortality, even after 12 hours, when mice were ill, and BAM15 reduced kidney damage and splenic apoptosis. Serial plasma and urinary mitochondrial DNA (mtDNA) levels increased after CLP and decreased after BAM15 administration (at 0 or 6 hours). In vitro septic serum proportionately increased mtROS overproduction and mtDNA release from kidney tubule cells, which BAM15 prevented. BAM15 decreased neutrophil apoptosis and mtDNA release; neutrophil depletion counteracted BAM15 benefits. Further, mtDNA injection in vivo replicated inflammation and kidney injury, which was prevented by BAM15. A large dose of exogenous mtDNA reversed protection by BAM15. We conclude that BAM15 is an effective preventive and therapeutic candidate in experimental sepsis and that BAM15 and mtDNA, a potential drug-companion diagnostic/drug-efficacy pair for clinical sepsis, are mechanistically linked via mtROS.

Acute kidney injury biomarker olfactomedin 4 predicts furosemide responsiveness.

Acute kidney injury (AKI) is associated with increased morbidity and mortality in critically ill patients. Olfactomedin 4 (OLFM4), a secreted glycoprotein expressed in neutrophils and stressed epithelial cells, is upregulated in loop of Henle (LOH) cells following AKI. We hypothesized that urine OLFM4 (uOLFM4) will increase in patients with AKI and may predict furosemide responsiveness. Urine from critically ill children was collected prospectively and tested for uOLFM4 concentrations with a Luminex immunoassay. Severe AKI was defined by KDIGO (stage 2/3) serum creatinine criteria. Furosemide responsiveness was defined as > 3mL/kg/h of urine output in the 4h after a 1mg/kg IV furosemide dose administered as part of standard of care. Fifty-seven patients contributed 178 urine samples. Irrespective of sepsis status or AKI cause, uOLFM4 concentrations were higher in patients with AKI (221ng/mL [IQR 93-425] vs. 36ng/mL [IQR 15-115], p = 0.007). uOLFM4 concentrations were higher in patients unresponsive to furosemide (230ng/mL [IQR 102-534] vs. 42ng/mL [IQR 21-161], p = 0.04). Area under the receiver operating curve for association with furosemide responsiveness was 0.75 (95% CI, 0.60-0.90). AKI is associated with increased uOLFM4. Higher uOLFM4 is associated with a lack of response to furosemide. Further testing is warranted to determine whether uOLFM4 could identify patients most likely to benefit from earlier escalation from diuretics to kidney replacement therapy to maintain fluid balance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Evaluation of the Efficiency of TIMP-2 as a Biomarker for Acute Kidney Injury in Sepsis.

The aim of this study was to evaluate the biomarker potential of TIMP-2 in septic-induced acute kidney injury (AKI). Healthy male rats (n=56, age 8-10 weeks, body weight 250-300 g) were randomized into 3 groups: controls (intact rats, n=6), sham-operated (SO, n=24), and sepsis model (cecum ligation and perforation, CLP, n=24). Thirty minutes before and 6, 12, 24, and 48 h after surgery, blood samples were collected to measure serum creatinine, blood urea nitrogen (BUN), and TIMP-2 and the kidneys were isolated for histopathological analysis and Western blotting. The key sepsis-related genes were screened through bioinformatics analysis. In 24 and 48 h after surgery, 2 rats in the SO group reached the diagnostic criteria of AKI (increased levels of serum creatinine and BUN). In the CLP group, serum creatinine in 6 h after the surgery was slightly higher than 30 min before the surgery, but this change did not meet the diagnostic criteria for AKI. In the CLP group, BUN was normal 6 h after the surgery, but increased after 12 h. In more than 50% rats of the CLP group, serum creatinine and BUN significantly increased 12 h after operation, so this can be diagnosed as AKI. In rats of the CLP group, plasma TIMP-2 was elevated 6 h after surgery and increased with time, suggesting that plasma TIMP-2 can be used as an early marker of AKI. Histological examination of the kidneys in this group revealed destruction of the renal tubular structure, swelling of renal tubular epithelium, the disappearance of brush edge and collapse of necrotic epithelial cells, etc., and the degree of damage increased with time. Immunohistochemistry showed that TIMP-2 was expressed in rats of the CLP group at all terms of the experiment. The expression of TIMP-2 and pyroptosis-related proteins (NLRP3, IL-1β, caspase-1, and GSDMD) in the CLP group was higher than in the SO group (p<0.05) and increased with time, suggesting that pyroptosis is involved in AKI. Thus, plasma TIMP-2 is sensitive indicator for the early detection of kidney injury and can be used as an early biomarker of AKI.

Kaempferol Reverses Acute Kidney Injury in Septic Model by Inhibiting NF-κB/AKT Signaling Pathway

Sepsis is the main cause of acute kidney injury (AKI), mainly due to systemic immune dysregulation. Kaempferol (KAE) is a natural flavonoid compound with multiple biological activities including anti-inflammatory, antioxidant, and antiapoptotic properties. In this study, we constructed a sepsis-induced AKI mouse model and an LPS-induced glomerular mesangial cell (HK-2) in vitro sepsis AKI model. We found that KAE ameliorated sepsis-induced renal pathological damage, reversed renal function damage, and inhibited p-p65 and p-AKT protein expression. In addition, KAE reversed LPS-induced proliferation and inhibited apoptosis in HK-2 cells. These studies suggest that KAE reverses sepsis by inhibiting activation of the NF-κB/AKT pathway to reverse acute kidney injury.

CIRC_0114428 INFLUENCES THE PROGRESSION OF SEPTIC ACUTE KIDNEY INJURY VIA REGULATING MIR-370-3P/TIMP2 AXIS.

Background: Septic acute kidney injury (AKI) is a serious complication of sepsis, which greatly threatened the life safety of critically ill patients. Recently, circular RNA is considered to be implicated in sepsis-induced renal cell damage. However, the role of circ_0114428 in sepsis AKI is still unclear. Methods: LPS was used to establish a sepsis-related AKI cell model. The expression of circ_0114428, microRNA (miR)-370-3p, tissue inhibitor of metalloproteinase-2 (TIMP2), Proliferating cell nuclear antigen, Bax, and Bcl-2 were detected by quantitative real-time polymerase chain reaction and Western blot. Cell counting kit 8 and enzyme-linked immunosorbent assay were used to measure cell proliferation ability and the secretion of inflammatory factors (tumor necrosis factor α, interleukin 1β, and interleukin 6), respectively. Cell cycle and apoptosis rate were analyzed by flow cytometry. Caspase-3 assay kits were used to detect Caspase-3 activity. Interaction between miR-370-3p and circ_0114428 or TIMP2 was analyzed by bioinformatics analysis, a dual-luciferase reporter assay, and RNA immunoprecipitation assay. Results: Circ_0114428 was upregulated in septic AKI serum samples and LPS-induced HK2 cells. The knockdown of circ_0114428 notably promoted cell proliferation and cycle, whereas it restrained cell inflammation and apoptosis in LPS-stimulated HK2 cells. Subsequent mechanism analysis revealed that miR-370-3p was a target of circ_0114428, and miR-370-3p inhibition could rescue the effects of circ_0114428 downregulation on LPS-induced cell injury. Meanwhile, TIMP2 was a target gene of miR-370-3p. miR-370-3p mimic could attenuate LPS-induced cell injury, whereas these impacts were overturned by overexpressed TIMP2. Furthermore, circ_0114428 enhanced TIMP2 protein expression by sponging miR-370-3p. Conclusion: Our data demonstrated that circ_0114428 contributed to septic AKI progression by regulating miR-370-3p-mediated TIMP2 expression, which provided a promising target for septic AKI treatment.

Effects of three types of fresh Rehmannia glutinosa improve lipopolysaccharide-induced acute kidney injury in sepsis through the estrogen receptor pathway.

To explore the effects and mechanism of three types of fresh Rehmannia glutinosa, namely Beijing No. 3 (BJ3H), Huaizhong No. 1 (HZ1H), and Taisheng (TS) on lipopolysaccharide (LPS)-induced acute kidney injury in the sepsis (S-AKI) mice model through the estrogen receptor pathway. BALB/c mice were randomly divided into control (CON), model (LPS), astragalus injection (ASI), BJ3H, HZ1H, TS water extract groups, the estrogen receptor antagonist ICI182,780 groups were added to each group. The antagonist groups received an intraperitoneal injection of ICI 0.5 hr before administration and an intraperitoneal injection of LPS 3 days after administration. The kidney pathology, function, inflammatory factors, immune cells, levels of reactive oxygen species (ROS), apoptosis, and the protein expression levels of TLR4/NF-κB/NLRP3 signaling pathway in the mice kidneys were detected. ASI, BJ3H, HZ1H, and TS improved LPS-induced renal pathology in S-AKI mice, reduced the kidney and serum levels of inflammatory factors, positive rates of macrophages and neutrophils, levels of ROS and apoptosis, and the relative expression levels of TLR4, MyD88, NF-κB p-p65/NF-κB p65, and NLRP3 proteins in the kidney. In addition, they increased the positive rate of dendritic cells (DCs) in the mice kidneys. The overall effect of HZ1H was superior to that of ASI, BJ3H, and TS. However, after adding ICI, the regulatory effects of drugs were inhibited. The three types of fresh R. glutinosa may completely or partially affect the TLR4/NF-κB/NLRP3 signaling pathway through the estrogen receptor pathway to exert a protective effect on S-AKI.

Acute kidney injury and early fluid load in a retrospective cohort of neonatal sepsis.

Sepsis and acute kidney injury (AKI) are associated with mortality in the newborn intensive care unit (NICU). There is a paucity of studies that describe AKI and fluid overload in neonatal sepsis and their association with mortality. Retrospective study of neonates with culture positive sepsis admitted to the NICU between June 2020 and June 2021 was conducted. Primary outcome was in-hospital mortality according to AKI as defined by the neonatal modified Kidney Diseases Improving Outcomes criteria. Secondary outcomes were early fluid overload and vasopressor use. Thirty-three percent of neonates had AKI with sepsis, and 57% of cases were severe AKI. AKI was associated with mortality after adjusting for variables that were different between survivors and non-survivors (aOR 5.7 [95% CI 1.1-36], p = 0.04). Early fluid overload occurred in 27% of neonates who were at higher risk of having AKI with sepsis (OR 7.4 [95% CI 1.6-26.0], p = 0.01) and higher risk of mortality (aOR 17.8 [95% CI 2-7545], p = 0.02). AKI and early fluid overload are associated with mortality in sepsis in our retrospective cohort. Mitigating AKI and early fluid overload in sepsis might be a fruitful strategy in reducing mortality with sepsis. A higher resolution version of the Graphical abstract is available as Supplementary information.

Plasma proteomic characterization of the development of acute kidney injury in early sepsis patients

Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design (n = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis.

Factors associated with occurrence and severity of acute kidney injury in patients with Sepsis – A retrospective database study

PurposeSepsis remains the most common cause of acute kidney injury (AKI) and is associated with a high mortality. This study aims to identify laboratory, clinical and demographic factors that are associated with the different stages of AKI in sepsis. MethodsWe studied patients >18 years who met Sepsis-3 criteria between July 10, 2009 and September 7, 2019 using ordinal logistic regression to determine the factors associated with different stages of AKI. Sensitivity analyses for development of any stage vs no AKI and, separately, the factors associated with receipt of kidney replacement therapy were also done. ResultsOf 31,228 patients meeting Sepsis-3 criteria, 4684 (15%) developed AKI. Of the AKI patients, 53% were KDIGO stage 1, 9% stage 2, and 37% stage 3, with 27% of AKI patients receiving kidney replacement therapy (Stage 3b). Several comorbidities, mechanical ventilation, and pre-sepsis creatinine levels were associated with AKI occurrence and severity. Positive blood culture was associated with a higher risk (OR 1.10 [1.06, 1.15], p < 0.001), while positive respiratory, urine, and wound cultures were associated with lower risks of developing AKI and with lower severity. ConclusionPresepsis creatinine levels, mechanical ventilation, comorbidities, and positive blood cultures were associated with AKI.

Cystatin C and derived measures of renal function as risk factors for mortality and acute kidney injury in sepsis – A post-hoc analysis of the FINNAKI cohort

PurposeTo assess the association between cystatin C-derived estimates of kidney function and mortality and acute kidney injury (AKI) in sepsis. Materials and methodsPost-hoc analysis of sepsis patients in the FINNAKI-cohort (n = 802). Primary outcome was 90-day mortality. We measured plasma cystatin C and creatinine at intensive care unit (ICU) admission and estimated glomerular filtration rates (eGFRcys, eGFRcrea) and shrunken pore syndrome (SPS; defined as eGFRcys/eGFRcrea ratio < 0.7). Associations were assessed using Cox- or logistic regression. ResultsIncreased cystatin C and decreased eGFRcys were associated with mortality in unadjusted analyses and in analyses adjusted for illness severity and creatinine. Hazard ratios (HRs) in unadjusted analyses were 3.30 (95% CI; 2.12–5.13, p < 0.001) and 3.26 (95% CI; 2.12–5.02, p < 0.001) respectively. SPS was associated with mortality in an unadjusted- (HR 1.78, 95% CI; 1.33–2.37, p < 0.001) and in an adjusted analysis (HR 1.54, 95% CI; 1.07–2.22, p = 0.021). All cystatin C-derived measures were associated with mortality also after adjustment for AKI development. Cystatin C was associated with AKI in unadjusted analyses but not in analyses adjusted for creatinine. ConclusionCystatin C and derived measures of kidney function at ICU admission are associated with an increased 90-day mortality. Increased AKI incidence does not fully explain this association.

The incidence and outcome of AKI in patients with sepsis in the emergency department applying different definitions of AKI and sepsis

BackgroundSepsis is often accompanied with acute kidney injury (AKI). The incidence of AKI in patients visiting the emergency department (ED) with sepsis according to the new SOFA criteria is not exactly known, because the definition of sepsis has changed and many definitions of AKI exist. Given the important consequences of early recognition of AKI in sepsis, our aim was to assess the epidemiology of sepsis-associated AKI using different AKI definitions (RIFLE, AKIN, AKIB, delta check, and KDIGO) for the different sepsis classifications (SIRS, qSOFA, and SOFA).MethodsWe retrospectively enrolled patients with sepsis in the ED in three hospitals and applied different AKI definitions to determine the incidence of sepsis-associated AKI. In addition, the association between the different AKI definitions and persistent kidney injury, hospital length of stay, and 30-day mortality were evaluated.ResultsIn total, 2065 patients were included. The incidence of AKI was 17.7–51.1%, depending on sepsis and AKI definition. The highest incidence of AKI was found in qSOFA patients when the AKIN and KDIGO definitions were applied (51.1%). Applying the AKIN and KDIGO definitions in patients with sepsis according to the SOFA criteria, AKI was present in 37.3% of patients, and using the SIRS criteria, AKI was present in 25.4% of patients. Crude 30-day mortality, prolonged length of stay, and persistent kidney injury were comparable for patients diagnosed with AKI, regardless of the definition used.ConclusionThe incidence of AKI in patients with sepsis is highly dependent on how patients with sepsis are categorised and how AKI is defined. When AKI (any definition) was already present at the ED, 30-day mortality was high (22.2%). The diagnosis of AKI in sepsis can be considered as a sign of severe disease and helps to identify patients at high risk of adverse outcome at an early stage.

Relation between red blood cell distribution width and acute kidney injury in patients with sepsis.

ABSTRACTObjective The objective of the present study is to evaluate the association of red blood cell distribution width with acute kidney injury in sepsis.Methods This is a retrospective study of 849 critically ill patients with sepsis in intensive care unit. Demographic data, renal function, inflammation, complete blood count, and acid-base parameters were compared between acute kidney injury and non-acute kidney injury groups. Therefore, a multivariate analysis was performed to observe independent predictive factors.Results Comparatively, higher levels of C-reactive protein, lactate, red blood cell distribution width, and Simplified Acute Physiology Score 3 were found in the acute kidney injury group. The study showed a higher frequency of women, hemoglobin (Hgb) concentration, platelets, bicarbonate and PaO2/FiO2 ratio in the non-acute kidney injury group. In addition, there was an independent association of comorbidity-chronic kidney disease [OR 3.549, 95%CI: 1.627-7.743; p<0.001], urea [OR 1.047, 95%CI: 1.036-1.058; p<0.001] and RDW [OR 1.158, 95%CI: 1.045-1.283; p=0.005] with acute kidney injury in sepsis patients.Conclusion As an elective risk factor, red blood cell distribution width was independently associated with sepsis-related acute kidney injury. Thus, red blood cell distribution width acts like a predictive factor for sepsis-induced acute kidney injury in intensive care unit admission.

Paediatric Dialysis at a Tertiary Hospital in South-West Nigeria: A 4-Year Report

Introduction: Dialysis is potentially lifesaving in children with acute kidney injury (AKI) or chronic kidney disease (CKD), but availability is limited in low-income countries and lower-middle-income countries (LMICs). Methods: In the present study, we perform a 4-year study of patients who received peritoneal dialysis (PD) or haemodialysis (HD) at the Paediatric Nephrology Unit of the University College Hospital Ibadan, Nigeria. Subgroup analysis was performed on patients with sepsis or malaria AKI who underwent HD or PD for predictors of in-hospital mortality. Results: A total of 167 children aged 7 days to 18 years, median 7 (interquartile range 3–12) years, (60.5% males) were studied. In total, 129 (77.2%) had AKI, while 38 had CKD. Regarding AKI, 83 children (64.3%) received HD only, 42 underwent PD only, while 4 underwent both HD and PD. Malaria AKI was treated with HD in 43 (51.8%) or PD in 8 (10.5%), while sepsis AKI was treated with HD in 20 (21.4%) or PD in 33 (78.6%). Mortality in AKI was 16.3% overall, 10.8% in children on HD only, and 26.2% in children on PD only. Patients with sepsis AKI had higher mortality compared to patients with malaria AKI (RR 7.96 [1.70–37.37]). Subgroup analysis showed that age, diagnosis, and dialysis modality were not independent risk factors for mortality. The aetiology of CKD was glomerulonephritis in 26 (68.4%): treatment was HD in 36 and PD in 2 with mortality being 26.3%. Conclusions: PD for AKI showed relatively good outcomes in a LMIC. However, funding and support for a formal dialysis program for the management of AKI and CKD are needed.

Balanced Crystalloids versus Normal Saline in Adults with Sepsis: A Comprehensive Systematic Review and Meta-Analysis.

The crystalloid fluid of choice in sepsis remains debatable. We aimed to perform a comprehensive meta-analysis to compare the effect of balanced crystalloids (BC) vs. normal saline (NS) in adults with sepsis. A systematic search of PubMed, EMBASE, and Web of Sciences databases through 22 January 2022, was performed for studies that compared BC vs. NS in adults with sepsis. Our outcomes included mortality and acute kidney injury (AKI), need for renal replacement therapy (RRT), and ICU length of stay (LOS). Pooled risk ratio (RR) and mean difference (MD) with the corresponding 95% confidence intervals (CIs) were obtained using a random-effect model. Fifteen studies involving 20,329 patients were included. Overall, BC showed a significant reduction in the overall mortality (RR 0.88, 95% CI 0.81–0.96), 28/30-day mortality (RR 0.87, 95% CI 0.79–0.95), and AKI (RR 0.85, 95% CI 0.77–0.93) but similar 90-day mortality (RR 0.96, 95% CI 0.90–1.03), need for RRT (RR 0.91, 95% CI 0.76–1.08), and ICU LOS (MD −0.25 days, 95% CI −3.44, 2.95), were observed between the two groups. However, subgroup analysis of randomized controlled trials (RCTs) showed no statistically significant differences in overall mortality (RR 0.92, 95% CI 0.82–1.02), AKI (RR 0.71, 95% CI 0.47–1.06), and need for RRT (RR 0.71, 95% CI 0.36–1.41). Our meta-analysis demonstrates that overall BC was associated with reduced mortality and AKI in sepsis compared to NS among patients with sepsis. However, subgroup analysis of RCTs showed no significant differences in both overall mortality and AKI between the groups. There was no significant difference in the need for RRT or ICU LOS between BC and NS. Pending further data, our study supports using BC over NS for fluid resuscitation in adults with sepsis. Further large-scale RCTs are necessary to validate our findings.

Early predictive value of high density lipoprotein cholesterol for secondary acute kidney injury in sepsis patients

Objective: To investigate the changes of high density lipoprotein cholesterol (HDL-C) in sepsis patients and its early predictive value for secondary acute kidney injury (AKI) in such patients. Methods: A retrospective case series study was conducted. From June 2019 to June 2021, 232 sepsis patients who met the inclusion criteria were admitted to the Second Hospital of Hebei Medical University, including 126 males and 106 females, aged 24 to 71 years. According to whether complicating secondary AKI, the patients were divided into non-AKI group (n=158) and AKI group (n=74). Data of patients between the two groups were compared and statistically analyzed with independent sample t test or chi-square test, including the sex, age, body mass index (BMI), body temperature, heart rate, primary infection site, combined underlying diseases, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score and sepsis-related organ failure assessment (SOFA) score at admission, and the serum levels of C-reactive protein (CRP), procalcitonin, creatinine, cystatin C, and HDL-C measured at diagnosis of sepsis. The multivariate logistic regression analysis was performed on the indicators with statistically significant differences between the two groups to screen the independent risk factors for developing secondary AKI in 232 sepsis patients, and the joint prediction model was established based on the independent risk factors. The receiver operating characteristic (ROC) curve of the independent risk factors and the joint prediction model predicting secondary AKI in 232 sepsis patients were drawn, and the area under the curve (AUC), the optimal threshold, and the sensitivity and specificity under the optimal threshold were calculated. The quality of the above-mentioned AUC was compared by Delong test, and the sensitivity and specificity under the optimal threshold were compared using chi-square test. Results: The sex, age, BMI, body temperature, heart rate, primary infection site, combined underlying diseases, and CRP level of patients between the two groups were similar (P>0.05). The procalcitonin, creatinine, cystatin C, and scores of APACHE Ⅱ and SOFA of patients in AKI group were all significantly higher than those in non-AKI group (with t values of -3.21, -16.14, -12.75, -11.13, and -12.88 respectively, P<0.01), while the HDL-C level of patients in AKI group was significantly lower than that in non-AKI group (t=6.33, P<0.01). Multivariate logistic regression analysis showed that creatinine, cystatin C, and HDL-C were the independent risk factors for secondary AKI in 232 sepsis patients (with odds ratios of 2.45, 1.68, and 2.12, respectively, 95% confidence intervals of 1.38-15.35, 1.06-3.86, and 0.86-2.56, respectively, P<0.01). The AUCs of ROC curves of creatinine, cystatin C, HDL-C, and the joint prediction model for predicting secondary AKI in 232 sepsis patients were 0.69, 0.79, 0.89, and 0.93, respectively (with 95% confidence intervals of 0.61-0.76, 0.72-0.85, 0.84-0.92, and 0.89-0.96, respectively, P values all below 0.01); the optimal threshold were 389.53 μmol/L, 1.56 mg/L, 0.63 mmol/L, and 0.48, respectively; the sensitivity under the optimal threshold were 76.6%, 81.4%, 89.7%, and 95.5%, respectively; the specificity under the optimal threshold values were 78.6%, 86.7%, 88.6%, and 96.6%, respectively. The AUC quality of cystatin C was significantly better than that of creatinine (z=2.34, P<0.05), the AUC quality and sensitivity and specificity under the optimal threshold of HDL-C were all significantly better than those of cystatin C (z=3.33, with χ2 values of 6.43 and 7.87, respectively, P<0.01) and creatinine (z=5.34, with χ2 values of 6.32 and 6.41, respectively, P<0.01); the AUC quality and sensitivity and specificity under the optimal threshold of the joint prediction model were all significantly better than those of creatinine, cystatin C, and HDL-C (with z values of 6.18, 4.50, and 2.06, respectively, χ2 values of 5.31, 7.23, 3.99, 6.56, 7.34, and 4.00, respectively, P<0.05 or P<0.01). Conclusions: HDL-C level in sepsis patients with secondary AKI is significantly lower than that in patients without secondary AKI. This is an independent risk factor for secondary AKI in sepsis patients with a diagnostic value being superior to that of creatinine and cystatin C. The combination of the aforementioned three indicators would have higher predicative valuable for secondary AKI in sepsis patients.

RasGRP Exacerbates Lipopolysaccharide-Induced Acute Kidney Injury Through Regulation of ERK Activation.

BackgroundExcessive inflammatory activities are reported to be the primary cause of sepsis-induced acute kidney injury (AKI). Ras guanyl nucleotide-releasing protein (RasGRP) could prevent inflammatory response. However, its role in the regulation of inflammatory response in sepsis-associated AKI remains unclear.MethodsWild-type or RasGRP1-deficient mice were treated with lipopolysaccharide intraperitoneally in combination with D-galactosamine to establish a mouse model of sepsis-associated AKI. Serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The messenger RNA (mRNA) levels of interleukin 6, tumor necrosis factor, nitric oxide synthase 2, and interleukin 1β were measured using quantitative reverse-transcription polymerase chain reaction. The morphological change in kidney tubule was determined by hematoxylin-and-eosin staining. The protein levels of RasGRP, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK) were determined using Western blot.ResultsRasGRP1 mRNA and protein levels were significantly increased in patients with sepsis-related AKI compared to those in healthy subjects. RasGRP knockout markedly reduced inflammatory cytokines induced by AKI in sepsis when compared with wild-type mice. Additionally, RasGRP deficiency inhibited the phosphorylation of ERK1/2 without altering JNK expression. In conclusion, we demonstrate that RasGRP1 plays a pivotal role in sepsis-associated AKI. Downregulation of RasGRP1 could significantly inhibit inflammatory response by inhibiting the activation of ERK1/2 and mitogen-activated protein kinase pathway, thereby reducing AKI induced by sepsis.ConclusionsOur data suggest that RasGRP exacerbates lipopolysaccharide-induced acute kidney injury through regulating ERK activation, which reveals a potential therapeutic target for the treatment of sepsis-induced AKI.

Perioperative acute kidney injury: impact and recent update.

Acute kidney injury (AKI) is common in hospitalized patients and is a major risk factor for increased length of stay, morbidity, and mortality in postoperative patients. There are multiple barriers to reducing perioperative AKI - the etiology is multi-factorial and the diagnosis is fraught with issues. We review the recent literature on perioperative AKI and some considerations for anesthesiologists that examine the far-reaching effects of AKI on multiple organ systems. This review will discuss recent literature that addresses the epidemiology, use of novel biomarkers in risk stratification, and therapeutic modalities for AKI in burn, pediatrics, sepsis, trauma, cardiac, and liver disease, contrast-induced AKI, as well as the evidence assessing goal-directed fluid therapy. Recent studies address the use of risk stratification models and biomarkers, more sensitive than creatinine, in the preoperative identification of patients at risk for AKI. Although exciting, these scores and models need validation. There is a need for research assessing whether early AKI detection improves outcomes. Enhanced recovery after surgery utilizing goal-directed fluid therapy has not been shown to make an appreciable difference in the incidence of AKI. Reducing perioperative AKI requires a multi-pronged and possibly disease-specific approach.

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries.

The novel therapeutic target cytokine LIGHT (TNFSF14) was recently shown to play a major role in COVID-19-induced acute respiratory distress syndrome (ARDS). This study aims to investigate the associations of plasma LIGHT and another potentially targetable cytokine, interleukin-18 (IL-18), with ARDS, acute hypoxic respiratory failure (AHRF), or acute kidney injury (AKI), caused by non-COVID-19 viral or bacterial sepsis. A total of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this cohort study. Day 0 plasma LIGHT and IL-18, as well as 59 other biomarkers (cytokines, chemokines, and acute-phase reactants) were measured by sensitive bead immunoassay and associated with symptom severity. We observed significantly increased LIGHT level in both bacterial sepsis patients (p = 1.80 × 10−5) and patients with sepsis from viral infections (p = 1.78 × 10−3). In bacterial sepsis, increased LIGHT level was associated with ARDS, AKI, and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failure. IL-18 levels were highly variable across individuals and consistently correlated with Apache III scores, mortality, and AKI in both bacterial and viral sepsis. There was no correlation between LIGHT and IL-18. For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failure. The association of plasma LIGHT with AHRF suggests that targeting the pathway warrants exploration, and ongoing trials may soon elucidate whether this is beneficial. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway requires precise application.

Inhibition of Phosphoinositide 3-Kinase Gamma Protects Endothelial Cells via the Akt Signaling Pathway in Sepsis-Induced Acute Kidney Injury

Introduction: Sepsis is a primary cause of death in critically ill patients and is characterized by multiple organ dysfunction, including sepsis-induced acute kidney injury (AKI), which contributes to high mortality in sepsis. However, its pathophysiological mechanisms remain unclear. The kidney has one of the richest and most diversified endothelial cell populations in the body. This study was designed to investigate the effects of endothelial dysfunction in sepsis-induced AKI and explore possible intervention measures to offer new insight into the pathogenesis and treatment of sepsis-induced AKI. Methods: The circulating levels of endothelial adhesion molecules were detected in patients with sepsis and healthy controls to observe the role of endothelial damage in sepsis and sepsis-induced AKI. A murine sepsis model induced by cecal ligation and perforation was pretreated with a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (CZC24832), and survival, kidney damage, and renal endothelial injury were assessed by pathological examination, immunohistochemistry, quantitative polymerase chain reaction, and Western blotting. Lipopolysaccharides and CZC24832 were administered to human umbilical vein endothelial cells in vitro, and endothelial cell function and the expression of adhesion molecules were evaluated. Results: Endothelial damage was more serious in sepsis-induced AKI than that in non-AKI, and the inhibition of PI3Kγ alleviates renal endothelial injury in a murine sepsis model, protecting endothelial cell function and repairing endothelial cell injury through the Akt signaling pathway. Conclusions: In this study, endothelial cell dysfunction plays an important role in sepsis-induced AKI, and the inhibition of PI3Kγ alleviates endothelial cell injury in sepsis-induced AKI through the PI3Kγ/Akt pathway, providing novel targets for treating sepsis and related kidney injury.

Clinical and economic assessment of the therapy of acute kidney injury in sepsis with continuous combined methods of renal replacement therapy

Objective: complex assessment of clinical and economic effectiveness as well as saving of the state budget assets within the therapy of patients with sepsis/septic shock based on different technologies of blood purification.Methods. Evaluation of direct and indirect costs of the eight blood purifcation methods. The target population includes adult patients 18+ with septic acute kidney injury. The study was conducted in compliance with acting Standards on Clinical Economic Studies used in the Russian Federation.The study methods included evaluation of existing randomized clinical studies and trials with data from network meta-analyses and systematic reviews of the target technologies. The direct medical and indirect non-medical costs were calculated and analyzed in respect of cost-effectiveness and budget impact analyses.Results. Direct and indirect costs were calculated for the sorption devices oXiris (Baxter International Inc.), Toraymyxin (Toray Medical Co.), Alteco LPS Adsorber (Alteco Medical AB), Toxipak (POKARD NPF), Desepta.LPS (BIOTECH M NPP), CytoSorb (CytoSorbents Inc.), HA330 (Jafron Biomedical Co.), Desepta (BIOTECH M NPP) for two time-horizons: 1-year period and 5-years period with discounting. For both periods, the use of oXiris hemoflter results in the least economic burden for the state budget.Conclusion. The use of blood purifcation in septic patients therapy is associated with considerable direct and indirect fnancial expenses, the amount of which and consequential budget saving depend on the technology of blood purifcation applied. The actual tariff compensation policy evidently demands revising.