Acute Kidney Injury In Sepsis Research Articles

A multicenter clinical study of critically ill patients with sepsis complicated with acute kidney injury in Beijing: incidence, clinical characteristics and outcomes

To investigate the epidemiological characteristics and prognosis of critically ill patients with sepsis combined with acute kidney injury (AKI) in intensive care unit (ICU) in Beijing, and to analyze the risk factors associated with in-hospital mortality among these critically ill patients. Data were collected from the Beijing AKI Trial (BAKIT) database, including 9 049 patients consecutively admitted to 30 ICUs in 28 tertiary hospitals in Beijing from March 1 to August 31, 2012. Patients were divided into non-AKI and non-sepsis group, AKI and non-sepsis group, non-AKI and sepsis group, AKI and sepsis group. Clinical data recorded included demographic characteristics, primary reasons for ICU admission, comorbidities, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II(APACHE II) within 24 hours of ICU admission, physiological and laboratory indexes, treatment in the ICU, AKI staging based on the Kidney Disease: Improving Global Outcomes (KDIGO), as well as the prognostic indicators including length of stay in ICU, length of stay in hospital, ICU and in-hospital mortality. The primary endpoint was discharge or in-hospital death. Multivariate Logistic regression analysis was used to investigate the risk factors for hospital death in ICU patients. Kaplan-Meier survival curve was drawn to analyze the cumulative survival of ICU patients during hospitalization. A total of 3 107 critically ill patients were ultimately enrolled, including 1 259 cases in the non-AKI and non-sepsis group, 931 cases in the AKI and non-sepsis group, 264 cases in the non-AKI and sepsis groups, and 653 cases in the AKI and sepsis group. Compared with the other three group, patients in the AKI and sepsis group were the oldest, had the lowest mean arterial pressure (MAP), and the highest APACHE II score, SOFA score, blood urea nitrogen (BUN), and serum creatinine (SCr) levels, and they also had the highest proportion of receiving mechanical ventilation, requiring vasopressor support, and undergoing renal replacement therapy (RRT), all P < 0.01. Of these 3 107 patients, 1 584 (51.0%) were diagnosed with AKI, and the incidence of AKI in patients with sepsis was significantly higher than in those without sepsis [71.2% (653/917) vs. 42.5% (931/2 190), P < 0.01]. The highest proportion of KDIGO 0 stage was observed in the non-sepsis group (57.5%), while the highest proportion of KDIGO 3 stage was observed in the sepsis group (32.2%). Within the same KDIGO stage, the mortality of patients with sepsis was significantly higher than that of non-sepsis patients (0 stage: 17.8% vs. 3.1%, 1 stage: 36.3% vs. 7.4%, 2 stage: 42.7% vs. 17.1%, 3 stage: 54.6% vs. 28.6%, AKI: 46.1% vs. 14.2%). The ICU mortality (38.7%) and in-hospital mortality (46.1%) in the AKI and sepsis group were significantly higher than those in the other three groups. Kaplan-Meier survival curves further showed that the cumulative survival rate of patients with AKI and sepsis during hospitalization was significantly lower than that of the other three groups (53.9% vs. 96.9%, 85.8%, 82.2%, Log-Rank: χ 2 = 379.901, P < 0.001). Subgroup analysis showed that among surviving patients, length of ICU stay and total length of hospital stay were significantly longer in the AKI and sepsis group than those in the other three groups (both P < 0.01). Multivariate regression analysis showed that age, APACHE II score and SOFA score within 24 hours of ICU admission, coronary heart disease, AKI, sepsis, and AKI combined with sepsis were independent risk factors for ICU mortality in patients (all P < 0.05). After adjusting for covariates, AKI, sepsis, and sepsis combined with AKI were significantly associated with higher ICU and in-hospital mortality, with the highest ICU mortality [adjusted odds ratio (OR) = 14.82, 95% confidence interval (95%CI) was 8.10-27.12; Hosmer-Lemeshow test: P = 0.816] and in-hospital mortality (adjusted OR = 7.40, 95%CI was 4.94-11.08; Hosmer-Lemeshow test: P = 0.708) observed in patients with sepsis combined with AKI. The incidence of AKI is high in sepsis patients, and those with both AKI and sepsis have a higher disease burden, more abnormalities in physiological and laboratory indicators, and significantly increased ICU and in-hospital mortality. Among surviving patients, the length of ICU stay and total length of hospital stay are also longer in the AKI and sepsis group. Age, APACHE II score and SOFA score within 24 hours of ICU admission, coronary heart disease, AKI, and sepsis are independent risk factors for in-hospital mortality in ICU patients.

Elevated Serum KIM-1 in Sepsis Correlates with Kidney Dysfunction and the Severity of Multi-Organ Critical Illness.

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.

Early acute kidney injury in sepsis and septic shock

ABSTRACT Background: Acute kidney injury is one of the severe conditions in hospitalized patients. Acute kidney injury can develop early from admission, usually within the first 24 hours of ICU admission. In Vietnam, there have been limited studies monitoring the progression of acute kidney injury in the early stages. This study aims to investigate the incidence, severity, clinical, laboratory characteristics, and progression of acute kidney injury in patients with sepsis and septic shock within the first 48 hours. Methods: This study is a cross-sectional descriptive analysis of 101 patients who are 15 or older and have been diagnosed with severe infection and septic shock. These patients were treated in the Intensive Care Unit of Hue Central Hospital. The patient had treatment in accordance with a standardized protocol while being closely observed. Samples were collected for diagnostic testing, and the patient’s urine output and blood creatinine levels were diligently checked. Results: The prevalence of acute renal injury (AKI) was 60.40%, with stage 1 accounting for 50.82% of cases, stage 2 accounting for 22.95%, and stage 3 accounting for 26.23%. The cohort of individuals diagnosed with AKI exhibited an advanced age, with a mean age of 60.72 ± 17.41 years, and predominantly consisted of male subjects. Patients diagnosed with acute kidney injury showed a statistically significant decrease in urine output and an increased incidence of shock (p &lt; 0.05). Additionally, these patients demonstrated lower levels of Hct, blood pH, and bicarbonate while exhibiting higher levels of blood urea, blood creatinine, AST, ALT, total bilirubin, PCT, and blood lactate (p &lt; 0.05) compared to individuals without AKI. Patients with AKI had significantly elevated SOFA and APACHE II scores compared to individuals without AKI, as indicated by statistical analysis (p &lt; 0.05). Upon admission, a significant proportion of patients, precisely 81.97%, experienced the development of AKI. Furthermore, a observation was made about the prompt recovery of these patients within the initial 24 and 48 hours following admission. Conclusion: The prevalence of AKI was accounted for 60.40%. Among the cases of AKI, stage 1 accounted for 50.82%, while stage 2 and stage 3 accounted for 22.95% and 26.23%, respectively. There were observed variations in urine output and rates of shock among individuals diagnosed with AKI. Additionally, SOFA and APACHE II scores were elevated. The percentage of AKI was 81.97% of patients upon their initial hospital admission, with a significant proportion seeing early recovery within the first 24 to 48 hours.

5 Serum Procalcitonin is an Independent Predictor of Acute Kidney Injury in Sepsis

5 Serum Procalcitonin is an Independent Predictor of Acute Kidney Injury in Sepsis

Andrographolide attenuates sepsis-induced acute kidney injury by inhibiting ferroptosis through the Nrf2/FSP1 pathway

Sepsis is a systemic inflammatory response syndrome caused by infection, which causes renal dysfunction known as sepsis-associated acute kidney injury (S-AKI). Ferroptosis is a form of lipid peroxidation dependent on iron and reactive oxygen species that differs from other forms of programmed cell death at the morphological and biochemical levels. Andrographolide (AG), a natural diterpenoid lactone compound extracted from Andrographis paniculata, has been shown to have therapeutic effects in kidney disease. In this study, we investigated the novel mechanism by which AG attenuates septic acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells (HK-2) through the Nrf2/FSP1 pathway. Cecum ligation and puncture (CLP)-induced septic rats and lipopolysaccharide (LPS)-induced HK-2 cells were used for in vivo and in vitro experiments. Firstly, in septic rats and HK-2 cells, AG effectively decreased the levels of kidney injury indicators, including blood creatinine, urea nitrogen, and markers of kidney injury such as neutrophil gelatinase-associated lipid transport protein and kidney injury molecule-1 (KIM-1). In addition, AG prevented ferroptotosis, by avoiding the accumulation of iron and lipid peroxidation, and an increase in SLC7A11 and GPX4 in AG-treated HK-2 cells. Furthermore, AG attenuated mitochondrial damage, including mitochondrial swelling, outer membrane rupture, and a reduction in mitochondrial cristae in LPS-treated HK-2 cells. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly inhibited LPS-induced ferroptosis in HK-2 cells. Importantly, our results confirm that Nrf2/FSP1 is an important pathway for ferroptosis resistance. Nrf2 siRNA hindered the effect of AG in attenuating acute kidney injury and inhibiting ferroptosis. These findings demonstrate that Nrf2/FSP1-mediated HK-2 ferroptosis is associated with AG, alleviates septic acute kidney injury, and indicates a novel avenue for therapeutic interventions in the treatment of acute kidney injury in sepsis.

Serum Neutrophil Gelatinase-associated Lipocalin: A Potential Marker of Impending Acute Kidney Injury in Sepsis

Abstract Introduction: Kidney injury is an inherent component of sepsis. Serum creatinine (S. Cr) as a marker of kidney injury has certain pitfalls and may not rise until significant kidney function has been lost. This study evaluated neutrophil gelatinase-associated lipocalin (NGAL) as a marker of impending acute kidney injury (AKI) in sepsis. Materials and Methods: A hospital-based cross-sectional, observational analytic study was conducted during one calendar year among patients admitted to medicine wards/intensive care units of a tertiary care hospital in Western India. A total of 80 study participants of age above 18 years fulfilling the criteria of sepsis were recruited in the study according to the Sepsis-3 criteria. Patients below 18 years of age, pregnant women, patients with known kidney diseases, malignancies, autoimmune diseases, and exposure to nephrotoxic agents (i.e. aminoglycoside, angiotensin-converting-enzyme inhibitors, and contrast agents) within the past 2 months, and patients who failed to give consent were excluded from the study. Clinical and biochemical data were collected till Day 7. Sequential organ failure assessment (SOFA) scores were calculated on Day 1 and Day 3. NGAL levels were measured on Day 3. Results: The mean age was 48 ± 19 years, with a male preponderance (63.8%). The mean of SOFA score on Day 1 and Day 3 was 9.84 ± 3.19 and 13.75 ± 3.14, respectively. The mean serum NGAL levels on Day 3 were 436.78 ± 242.23 ng/ml. The mean serum urea on Day 7 (86.99 ± 22.88 mg/dL) was significantly higher than on Day 3 (38.64 ± 9.49 mg/dL) (P = 0.004). Similarly, the mean S. Cr on Day 7 (2.97 ± 1.45 mg/dL) was significantly higher than on Day 3 (0.82 ± 0.23 mg/dL) (P = 0.033). The estimated glomerular filtration rate (eGFR) on Day 7 (35.42 ± 18.99 mL/min/1.73 m2) was also significantly lower in comparison to Day 3 (117.67 ± 56.10 mL/min/1.73 m2) (P &lt; 0.05). Serum NGAL showed a significant positive correlation with S. Cr on Day 3 (r = 0.3257, P = 0.003), Day 7 (r = 0.5944, P &lt; 0.00001), and mean change in S. Cr (r = 0.5562, P &lt; 0.00001). Serum NGAL showed a significant negative correlation with eGFR on Day 3 (r = −0.3061, P = 0.005), Day 7 (r = −0.4362, P = 0.00005), and mean change in eGFR (r = −0.1629, P &lt; 0.0001). Receiver-operating curve analysis showed 90.9% sensitivity and 98.3% specificity of NGAL (cutoff value 152 ng/ml) to predict impending AKI. Conclusion: Traditional marker of renal dysfunction (S. Cr, eGFR) had a significant correlation with NGAL. NGAL can predict impending AKI in sepsis patients earlier than S. Cr or eGFR.

Application of multimodal ultrasonography to predicting the acute kidney injury risk of patients with sepsis: artificial intelligence approach.

The occurrence of acute kidney injury in sepsis represents a common complication in hospitalized and critically injured patients, which is usually associated with an inauspicious prognosis. Thus, additional consequences, for instance, the risk of developing chronic kidney disease, can be coupled with significantly higher mortality. To intervene in advance in high-risk patients, improve poor prognosis, and further enhance the success rate of resuscitation, a diagnostic grading standard of acute kidney injury is employed to quantify. In the article, an artificial intelligence-based multimodal ultrasound imaging technique is conceived by incorporating conventional ultrasound, ultrasonography, and shear wave elastography examination approaches. The acquired focal lesion images in the kidney lumen are mapped into a knowledge map and then injected into feature mining of a multicenter clinical dataset to accomplish risk prediction for the occurrence of acute kidney injury. The clinical decision curve demonstrated that applying the constructed model can help patients whose threshold values range between 0.017 and 0.89 probabilities. Additionally, the metrics of model sensitivity, specificity, accuracy, and area under the curve (AUC) are computed as 67.9%, 82.48%, 76.86%, and 0.692%, respectively, which confirms that multimodal ultrasonography not only improves the diagnostic sensitivity of the constructed model but also dramatically raises the risk prediction capability, thus illustrating that the predictive model possesses promising validity and accuracy metrics.

Malvidin promotes PGC-1α/Nrf2 signaling to attenuate the inflammatory response and restore mitochondrial activity in septic acute kidney injury

Acute kidney injury (AKI) in sepsis is a vital and dangerous organ failure caused by an infection-induced dysregulation of the host reaction. Malvidin possesses significant anti-inflammatory and antioxidant bioactivities. This study explored the critical roles of malvidin in sepsis AKI and the crosstalk among mitochondrial function, nucleotide-binding oligomerization-like receptor 3 (NLRP3) inflammasome and nuclear factor erythroid 2 (Nrf2) signaling pathway. First, C57BL/6 mice were administered lipopolysaccharide intraperitoneally for 6 h to create an AKI model of sepsis. Hematoxylin-eosin staining and serum biomarker assays showed that malvidin protected from AKI in sepsis. Real-time fluorescence quantitative polymerase chain reaction analysis revealed that malvidin was able to inhibit inflammatory cytokines and mediators. Western blot assays indicated that malvidin suppressed NLRP3 inflammasome activation and enhanced antioxidant properties. Additionally, human renal tubular epithelial cells were stimulated by lipopolysaccharide/adenosine triphosphate to establish an NLRP3 inflammasome activation model in vitro, and in line with findings in vivo, malvidin significantly inhibited NLRP3 inflammasome activation. Furthermore, our data indicate that malvidin restored mitochondrial quality and function, reduced reactive oxygen species production, increased mitochondrial membrane potential, enhanced mitochondrial DNA copy number, and promoted peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) nuclear translocation. Moreover, inhibitor blockade assays indicated that both PGC-1α and Nrf2 affected the inhibition of the NLRP3 inflammasome by malvidin. Finally, immunoprecipitation assays showed that malvidin promoted PGC-1α and Nrf2 interactions. Overall, malvidin alleviated lipopolysaccharide-induced sepsis AKI, improved mitochondrial function and mitochondrial biogenesis, and inhibited the NLRP3 inflammasome through the PGC-1α/Nrf2 signaling pathway, suggesting that malvidin might translate into clinical applications for sepsis AKI therapy.

Clinical Research With Large Language Models Generated Writing-Clinical Research with AI-assisted Writing (CRAW) Study.

The scientific community debates Generative Pre-trained Transformer (GPT)-3.5's article quality, authorship merit, originality, and ethical use in scientific writing. Assess GPT-3.5's ability to craft the background section of critical care clinical research questions compared to medical researchers with H-indices of 22 and 13. Observational cross-sectional study. Researchers from 20 countries from six continents evaluated the backgrounds. Researchers with a Scopus index greater than 1 were included. In this study, we generated a background section of a critical care clinical research question on "acute kidney injury in sepsis" using three different methods: researcher with H-index greater than 20, researcher with H-index greater than 10, and GPT-3.5. The three background sections were presented in a blinded survey to researchers with an H-index range between 1 and 96. First, the researchers evaluated the main components of the background using a 5-point Likert scale. Second, they were asked to identify which background was written by humans only or with large language model-generated tools. A total of 80 researchers completed the survey. The median H-index was 3 (interquartile range, 1-7.25) and most (36%) researchers were from the Critical Care specialty. When compared with researchers with an H-index of 22 and 13, GPT-3.5 was marked high on the Likert scale ranking on main background components (median 4.5 vs. 3.82 vs. 3.6 vs. 4.5, respectively; p < 0.001). The sensitivity and specificity to detect researchers writing versus GPT-3.5 writing were poor, 22.4% and 57.6%, respectively. GPT-3.5 could create background research content indistinguishable from the writing of a medical researcher. It was marked higher compared with medical researchers with an H-index of 22 and 13 in writing the background section of a critical care clinical research question.

The polarization of M2 macrophages can be adjusted to alleviate renal injury by methylprednisolone in sepsis-AKI

Acute kidney injury in sepsis patients has an extreme mortality rate in clinical. It obviously seems that immune cells, for example, macrophages are involved with this process. Macrophages, as highly important immune cells, play a significant role in the development of human kidney diseases. But the specific role of macrophages in this process is still unclear. Under different timeline points, we surprisingly found that macrophages had the most dynamic changes in acute kidney injury immune cells. Based on macrophages’ functions, they are primarily classified into M1 macrophages (pro-inflammatory) and M2 macrophages (anti-inflammatory). The polarization of M2 macrophages is closely associated with the seriousness of sepsis-induced kidney injury, but how to modulate their polarization to alleviate sepsis-associated renal damage remains unknown. We discovered that the polarization of M2 macrophages after methylprednisolone injection can significantly alleviate acute kidney injury by reducing secreted cytokine. This study suggests that the proportion of macrophage subtypes can be regulated by methylprednisolone to alleviate acute kidney injury in sepsis to provide a new sight for a clinical to provide a promising strategy for renal injury caused.

The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury.

Sepsis is a syndrome caused by an imbalance in the inflammatory response of the body caused by an infection that leads to organ dysfunction, with the kidney being one of the most commonly affected organs. Sepsis-related acute kidney injury (SAKI) is strongly linked to increased mortality and poor clinical outcomes. Early diagnosis and treatment can significantly reduce patient mortality. On the other hand, the pathogenesis of SAKI is not fully understood, and early diagnosis of SAKI is a clinical challenge. Therefore, the current review describes biomarkers of acute kidney injury in sepsis and discusses the various pathogenic mechanisms involved in the progression of acute kidney injury in sepsis to develop new clinical treatment avenues.

Furosemide Stress Test and Renal Resistive Index for Prediction of Severity of Acute Kidney Injury in Sepsis.

Introduction The furosemide stress test (FST) predicts the severity and the need for renal replacement therapy (RRT) in patients with sepsis-associated acute kidney injury(S-AKI). The renal resistive index (RRI) indicates renal vascular resistance. Objectives The primary objective was to find the correlation between FST and RRI in S-AKI. The secondary objectives were to evaluate the role of FST and RRI on the progression of S-AKI. Methods A total of 154 consenting adult patients with S-AKI were administered FST. Renal echography was performed within the first 12 hours of admission, and RRI was calculated. The patients were grouped either into progressors or non-progressors to AKI-KDIGO stage 3. Results Of the patients who had RRI at Day 1 less than 0.73, 60% recovered, 34.3% needed RRT, and 35.5% died, whereas in those who had RRI at Day 1 greater than 0.73, only 22% recovered, 46.6% required RRT, and 51.6% died. RRI value of 0.73 predicted the need for RRT with a sensitivity of 35.1%, specificity of 80.4% and accuracy of 69.1%. The highest number of patients of KDIGO stage 3 (50%), followed by stage 2 (28.1%) and stage 1 (21.9%), presented technical difficulties in measuring the RRI. Conclusion FST is an economical and easily administered test to assess renal tubular function and can predict the occurrence and progression of S-AKI. RRI is a modest marker for predicting the need for RRT or persistent AKI.

Knockdown of Small Nucleolar RNA Host Gene 14 Alleviates Sepsis-Induced Acute Kidney Injury by Targeting miR-145-5p In Vitro and In Vivo

Acute kidney injury (AKI) manly occurred after sepsis and led to severe damage of the kidney. The present study was designed to explore the underlying mechanism of long non-coding RNA (lncRNA) SNHG14 in sepsis-induced AKI in In Vitro and In Vivo. The cecal ligation and puncture (CLP) rats was used as sepsis-induced AKI model for In Vivo studies and HK-2 cells with lipopolysaccharide (LPS) administration were used as cell model for In Vitro studies. Kidney tissues were stained by Hematoxylin and Eosin (H&amp;E) for histological examination. The relative levels of SNHG14 and miR-145-5p was detected using qRT-PCR. The levels of serum cytokines, inflammatory factors, oxidative stress factors, apoptosis-related proteins were evaluated by ELISA and western blot. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Compared with the sham group, the rats in the CLP group showed injured pathological morphology of kidney, high levels of serum Scr, and BUN, elevated contents of TNF-α, IL-6 and IL-1β, malondialdehyde (MDA) and apoptosis, but low SOD level in kidney tissues. However, all these changes were reversed by shRNA-SNHG14 administration or transfection In Vivo and In Vitro. SNHG14 level was upregulated, while miR-145-5p significantly decreased in kidney tissues of CLP rats and LPS-induced HK-2 cells. The target gene of miR-145-5p was SNHG14, verifying through luciferase reporter analysis. Further, miR-145-5p knockdown transfection significantly reversed the inhibition of SNHG14 interference on the secretion of inflammatory cytokines and apoptosis in LPS-induced HK-2 cells. SNHG14 silence can alleviate AKI in sepsis by upregulating the miR-145-5p expression. SNHG14 might be used as a potential therapeutic target for sepsis-induced AKI.

Association between red cell distribution width to albumin ratio and acute kidney injury in patients with sepsis: a MIMIC population-based study.

To investigate the association between red cell distribution width (RDW) to albumin (ALB) ratio and acute kidney injury (AKI) in sepsis. This was a retrospective cohort study. Data were collected from the Medical Information Mart for Intensive Care Database IV (MIMIC-IV) from 2008 to 2019. The incidence of AKI was the primary outcome, which was defined based on the improving Global Outcomes (KDIGO). The association of RDW/ALB ratio with AKI in sepsis was assessed by multivariate logistic regression analysis using relative risk (RR) and a 95% confidence interval (CI). Subgroup group analyses were applied according to age, use of ventilation, and use of vasopressor, SAPS II, and SOFA. Of 1810 sepsis patients involved in this study, 563 (31.10%) sepsis patients developed AKI after ICU admission. The results suggested an increase in RDW/ALB was associated with a rise in the risk of AKI in sepsis (RR 1.09, 95% CI 1.02 to 1.16, P = 0.013).Based on the subgroup analysis, RDW/ALB ratio was significantly associated with the risk of AKI in sepsis patients using the treatment of ventilation (RR: 1.07, 95% CI 1.01 to 1.14, P = 0.041)) and in patients with SAPS II < 43 (RR: 1.16, 95% CI 1.04 to 1.29, P = 0.007). RDW/ALB ratio was independently associated with the risk of AKI in sepsis patients.

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.