Progression Of Acute Kidney Injury Research Articles

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

The inhibitory impact of Schisandrin on inflammation and oxidative stress alleviates LPS-induced acute kidney injury.

Inflammation and oxidative stress (OS) are the major pathogenic characteristics of acute kidney injury (AKI). Studies have shown that Schisandrin (Sch) could regulate inflammatory disease. However, the function and mechanism of Sch in AKI progression are still unknown. Here, we investigated Sch's potential effects and mechanism on mice's renal damage and macrophages induced by lipopolysaccharide (LPS). Sch decreased LPS-induced inflammatory factor production while increasing the activity of related antioxidant enzymes in macrophages and mouse kidney tissues. Hematoxylin and eosin staining revealed that Sch may have the ability to profoundly inhibit inflammatory cell invasion and tissue damage caused by LPS in renal tissue. Furthermore, Western blot and immunohistochemical studies showed that Sch exerted its effects mainly through up-regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and inhibition of Toll-like receptor 4‒mitogen-activated protein kinases/nuclear factor-kappa B pathways. Collectively, this study illustrates that Sch suppresses LPS-stimulated AKI by descending inflammation and OS, illuminating prospective AKI treatment options.

#1373 Effect of Astragalus membranaceus normalized acute kidney injury-induced renal conditions corelated with serum carnosine

Abstract Background and Aims Astragalus membranaceus (AM) exhibits various pharmacological effects against several diseases, including chronic kidney disease (CKD) (see http://nccih.nih.gov/health/astragalus). We have previously investigated the correlation between AM and acute kidney injury (AKI), which is an important factor causing CKD pathogenesis or progression. Recently, we demonstrated that old mice showed lethality in response to 20 mg/kg cis-diamminedichloroplatinum (CDDP), which is a general dose used to generate AKI in young mice. AKI also occurred in response to a reduced dose of cisplatin, which was completely reversible in young mice. The administration of AM to mice (20 mg/kg) significantly improved AKI pathology, especially in old mice treated with a reduced dose of cisplatin, thereby demonstrating the therapeutic effect of AM against age-dependent AKI pathogenicity. More recently, we found that serum carnosine levels correlated with renal conditions in AM. Here, we examined the effects associated with serum carnosine levels to prevent AKI and delay CKD progression [1]. Methods Female C57BL/6 mice (52 weeks old) were orally administered either an AM powder mixed with sterilized 0.5% methylcellulose 400 (w/v) (AM group) or only 0.5% methylcellulose 400 (control). Four hours after the most recent dose (20 mg/kg of AM twice a day), 0.5 mg/ml CDDP (reduced dose: 10 mg/kg or 0.9% NaCl for the CG) was injected intraperitoneally into old mice. Subsequently, we measured the blood serum urea nitrogen (BUN) and creatinine (CRE) levels, which are biomarkers of AKI, and assessed histochemical changes in kidney sections stained with anti-CD3 and anti-CD68 antibodies 20 h and 3 d after CDDP injection (n = 6 per group). Thereafter, serum carnosine levels in the samples collected from each sample (n = 6 per group) were determined using a carnosine ELISA kit (Novus, NBP2-75013). Data were analyzed statistically using PRISM software, and statistical significance was set at P = 0.05. Results Higher susceptibility to a half CDDP dose in old mice was indicated by increased BUN levels and the histological damage caused to renal tubule epithelial cells and glomeruli; however, no pathological change was observed in younger mice. Histochemical analysis of old mice showed a significant increase in the number of CD3-positive cells following AKI induction; however, AM pretreatment ameliorated these inflammatory conditions. Our recent findings suggest that a correlation exists between the effects of AM and serum carnosine levels. Fig. 1 shows that different serum carnosine levels were observed in old control mice (white box), probably because of age-dependent pathogenesis. However, serum carnosine was concentrated to lower levels after AM administration (orange box), suggesting an age-dependent AM effect. Moreover, owing to the effect of AM on CDDP-AKI, serum carnosine levels changed transiently but significantly in old mice (blue and yellow boxes) within 20 h; this indicates that age-dependent renal conditions were improved by the AM effect and correlated with serum carnosine levels. Conclusion AM administration normalizes the renal pathology caused by age-dependent susceptibility to CDDP-AKI; this is particularly true for older mice, wherein serum carnosine is downregulated but concentrated. Serum carnosine can be effective in preventing AKI pathology in old mice, regardless of the AM effects. We believe that AM can prevent age-dependent accumulation of AKI pathology, thereby facilitating CKD progression.

#1914 Comprehensive single-cell sequencing and lipidomics identify diverse injury states and cholesterol dynamics of the PTs in AKI-to-CKD transition

Abstract Background and Aims The underlying cellular events and metabolic dysfunction of acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is still largely unclear. Previous studies have suggested lipids and metabolites have a profound impact on acute and chronic inflammation. One of the main sites of renal lipid accumulation is the proximal tubule cells (PTs). Here we demonstrated the injury states and cholesterol dynamics of PTs and its potential function in AKI to CKD in unilateral ischemia-reperfusion injury (UIR) mice model. Method We employed single-cell combinatorial indexing lipidomics to analyze 15 mouse kidneys from a mouse model of failed repaired UIR at five time points. We identified cell types through unsupervised clustering analysis. Differential gene expression, enrichment analysis and main function scoring were applied to define functional heterogeneity and injury states of PTs. Next, pseudotime analysis of differentiation transitions was performed to create the diverse PT lineages. Finally, using SCENIC analysis, we identified the key transcription factors that drive the differentiation of PTs. Results We identified 13 main cell clusters and the dynamic changes in the process of AKI to CKD transition were analysed. A remarkable decrease in PTs after injury at day 1 followed with a recovery at day 3 post AKI were observed. Spatiotemporal profiling of the main cell types showed that the most injured areas in the acute stages of kidney injury are primarily concentrated in the outer stripe, specifically the region where the proximal straight tubules (PSTs) are located. In order to gain a higher resolution of the dynamics of PST subtypes during AKI to CKD, we performed sub-clustering analysis specifically on PSTs, partitioning them into 10 subclusters. Single-cell analysis identified maladaptive PSTs (PST-5) with the highest apoptosis and ferroptosis scores. Notably, pseudotime analysis revealed that PST-5 differentiated from PST-4, which has the highest lipid metabolism score. Indeed, among all the cells in the kidney, the PTs exhibited the most active metabolic reprogramming due to their differentiation and redifferentiation early after AKI. Lipid omics profiling reveals an abnormal elevation of the cholesterol metabolites 27-hydroxycholesterol (27-OH) and 25-hydroxycholesterol (25-OH) following AKI. Interestingly, the PST-4-specific expression of Cyp7b1 served as a key enzyme regulating the concentration of 27-OH. This gene has been found to be significantly absent after AKI. Moreover, the binding of 27HC, a natural ligand, to endogenous estrogen receptor alpha (ERα) leads to the upregulation of heme oxygenase 1 (Hmox1), thereby promoting ferroptosis. Finally, SCENIC analysis revealed that Cyp7b1-mediated accumulation of 27-HC is dependent on the transcription factor Atf3. Conclusion Our results indicate that Cyp7b1 deficiency confers ferroptosis, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27-HC secretion, leading to the progression of AKI. These findings suggest that the Cyp7b1/Hmox1/Atf3/27-HC axis may serve as a potential therapeutic target for preventing the development of CKD.

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 < 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 < 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 < 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.

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis.

The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell-cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression.

Kidney Doppler Ultrasonography in Critical Care Nephrology.

Color pulsed-wave Doppler ultrasound (CPWD-US) emerges as a pivotal tool in intensive care units (ICUs) for diagnosing acute kidney injury (AKI) swiftly and non-invasively. Its bedside accessibility allows for rapid assessments, making it a primary imaging modality for AKI characterization. Furthermore, CPWD-US serves as a guiding instrument for key diagnostic-interventional procedures such as renal needle biopsy and percutaneous nephrostomy, while also facilitating therapy response monitoring and AKI progression tracking. This review shifts focus towards the integration of renal ultrasound into ICU workflows, offering contemporary insights into its utilization through a diagnostic-standard-oriented approach. By presenting a flow chart, this review aims to provide practical guidance on the appropriate use of point-of-care ultrasound (POC-US) in critical care scenarios, enhancing diagnostic precision, patient management, and safety, albeit amidst a backdrop of limited evidence regarding long-term outcomes.

Furosemide stress test to predict acute kidney injury progression in critically ill children.

Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI); however, pediatric studies are limited. Children 3months to 18years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7days of admission underwent FST (intravenous furosemide 1mg/kg). Urine output was measured hourly for the next 6h; a value > 2ml/kg within the first 2h was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and proenkephalin (PENK) were also evaluated. Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7days of admission and underwent FST. Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive group) developed stage 3 AKI within 7days of FST, nine (17.6%) of whom (seven from non-responsive group) required kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84-1.0) and 0.96 ± 0.03 (95% CI 0.9-1.0), respectively. FST outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the diagnostic accuracy. Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need in critically ill children. Further research is required to identify the best FST cut-off in children.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Incidence, Risk Factors, and Consequences of Acute Kidney Injury in Patients Undergoing Esophageal Cancer Surgery: A Historical Cohort

Background: Limited data exist on postoperative acute kidney injury (AKI) in patients who have undergone esophageal cancer surgery. The purpose of this study was to evaluate the incidence, risk factors, and consequences of postoperative acute kidney after esophagectomy. Methods: This was a retrospective cohort study. The study was conducted in a tertiary specialized cancer center in Italy. All patients undergoing elective esophageal cancer surgery between 2016 and 2021 were included in the study. AKI was defined according to Kidney Disease Improving Global Outcomes criteria (both serum creatinine and urine output), within 48 h after surgery. Preoperative and intraoperative data were registered. We also collected data concerning progression of AKI, need for renal replacement therapy, mortality, and medical (pulmonary, cardiovascular, septic) and surgical complications within 30 days from surgery, as well as length of hospital stay. Results: Incidence of postoperative AKI was 32%. The independent risk factors were body mass index and the use of an invasive surgical approach. Persistent AKI accounted for 15% of the cases and it was associated with increased risk of major cardiovascular events (odds ratio 4.14, 95% CI 1.05–15.8, p-value 0.036), pulmonary complications (OR 3.67, 95% CI 1.04–14.9, p-value 0.050), and increased length of hospital stay (AME 7.2, 0.5–13.9, p-value 0.035). Conclusions: Postoperative AKI is common after esophageal cancer surgery. BMI and a totally invasive surgical approach are independent risk factors. Persistent AKI lasting more than 48 h increased the risk for any cardiovascular or pulmonary complications, with prolonged length of hospital stay.

Valsartan Mitigates the Progression of Methotrexate-Induced Acute Kidney Injury in Rats via the Attenuation of Renal Inflammation and Oxidative Stress.

Methotrexate (MTX) is a folic acid antagonist, commonly administered for the treatment of a variety of cancers. However, methotrexate toxicity including bone marrow suppression and hepatic and renal toxicity limits its use. Angiotensin AT1 receptor blockers including Valsartan (Val) possess the ability to ameliorate MTX-induced toxicity through various mechanisms. In this study, we explored the potential reno-protective effects of Val against MTX-induced acute kidney injury in rats. Twenty-four Wistar rats were randomly segregated into 3 groups. Group 1 served as the control group and received an oral dose of 1mL/kg of normal saline. Group 2 received a single dose of 20 mg/kg of MTX intraperitoneally (IP) for 5 days. Group 3 received a single IP dose of 20 mg/kg of MTX followed by an oral dose of 10 mg/kg of Valsartan for 5 days. At the end of the experiment, the levels of serum kidney biomarkers, inflammatory and oxidative stress markers were accessed. Furthermore, the effect of MTX on kidney tissue histology was examined. Our results showed that MTX treatment increased the level of serum kidney and inflammatory biomarkers and decreased the level of antioxidants SOD and GSH while increasing the lipid peroxidation contents. Furthermore, MTX treatment caused structural changes to kidney histology. However, the administration of Val significantly prevented these changes. Valsartan possesses nephroprotective potential and might serve as a potential therapeutic strategy against MTX-induced kidney injury.

The dynamics and outcomes of AKI progression during the COVID-19 pandemic.

Acute kidney injury (AKI) associated with COVID-19 is associated with poor prognosis. This study assessed the hitherto uninvestigated impact of COVID-19 on the progression and clinical outcomes of patients with AKI. Data from 576 patients with AKI admitted between 13/3/20 and 13/5/20 were studied. Increasingly complex analyses, from logistic regressions to competing-risk and multi-state models, have revealed insights into AKI progression dynamics associated with PCR-confirmed COVID-19 acquisition and death. Meta-analyses of case fatality ratios among patients with AKI were also conducted. The overall case-fatality ratio was 0.33 [95% CI (0.20-0.36)]; higher in COVID-19 positive (COVID+) patients 0.52 [95% CI (0.46-0.58)] than in their negative (COVID-) counterparts 0.16 [95% CI (0.12-0.20)]. In AKI Stage-3 patients, that was 0.71 [95% CI (0.64-0.79)] among COVID+ patients with 45% dead within 14 days and 0.35 [95% CI (0.25-0.44)] in the COVID- group and 28% died within 14 days. Among patients diagnosed with AKI Stage-1 within 24 h, the probability of progression to AKI Stage-3 on day 7 post admission was 0.22 [95% CI (0.17-0.27)] among COVID+ patients, and 0.06 [95% CI (0.03, 0.09)] among those who tested negative. The probability of discharge by day 7 was 0.71 [95% CI (0.66, 0.75)] in COVID- patients, and 0.27 [95% CI (0.21, 0.32)] in COVID+ patients. By day 14, in AKI Stage-3 COVID+ patients, that was 0.35 [95% CI (0.25, 0.44)] with little change by day 10, that is, 0.38 [95% CI (0.29, 0.47)]. These results are consistent with either a rapid progression in severity, prolonged hospital care, or high case fatality ratio among AKI Stage-3 patients, significantly exacerbated by COVID-19 infection.

Discovery and verification of mmu_Circ_26986/hsa_Circ_0072463 as a potential biomarker and intervention target for sepsis-associated acute kidney injury

Approximately 60% of septic patients developed acute kidney injury (AKI). The mortality rate of septic AKI (SA-AKI) is two to three times higher than that of septic without AKI (SA-non-AKI). The actual functions and mechanisms of CircRNAs in the pathophysiology of SA-AKI remain incompletely understood. Herein, we observed that the mmu_Circ_26986 could be induced by lipopolysaccharide (LPS) and cecum ligation and puncture (CLP) in BUMPT cell line and C57BL/6 mouse kidney, respectively. Functionally, mmu_Circ_26986 suppressed BUMPT cell apoptosis induced by LPS. Mechanistically, mmu_Circ_26986 sponged miRNA-29b-1-5p to upregulate the expression of PAK7. Overexpression of mmu_Circ_26986 ameliorated the progression of CLP-stimulated AKI through miRNA-29b-1-5p/PAK7 axis. In addition, we found that hsa_Circ_0072463, homologous to mmu_Circ_26986, suppressed LPS-induced HK-2 cells apoptosis via regulation of miRNA-29b-1-5p/PAK7 axis. Furthermore, sepsis patients with AKI had a higher level of hsa_Circ_0072463 compared to those without AKI. The sensitivity, specificity and AUC of hsa_Circ_0072463 were 78.8%, 87.9% and 0.866, respectively. Spearman's test indicated a noticeable positive correlation between plasma hsa_Circ_0072463 and serum creatinine in sepsis patients (r = 0.725). In summary, this study reveals that the mmu_Circ_26986/hsa_Circ_0072463 miRNA-29b-1-5p/PAK7 axis mediates septic AKI, and hsa_Circ_0072463 is a potential diagnostic marker for septic AKI.

WTAP-mediated N6-methyladenosine modification promotes the inflammation, mitochondrial damage and ferroptosis of kidney tubular epithelial cells in acute kidney injury by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways.

Acute kidney injury (AKI) is a serious complication of sepsis patients, but the pathogenic mechanisms underlying AKI are still largely unclear. In this view, the roles of the key component of N6-methyladenosine (m6A)-wilms tumor 1 associated protein (WTAP) in AKI progression were investigated. AKI mice model was established by using cecal ligation and puncture (CLP). AKI cell model was established by treating HK-2 cells with LPS. Cell apoptosis was analyzed by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and flow cytometry analysis. Cell viability was analyzed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The concentrations of inflammatory factors were examined with ELISA kits. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and Fe2+ levels were detected with related kits. Gene expression was detected by western blot assay or quantitative real-time polymerase chain reaction (qRT-PCR) assay. The relation between WTAP and lamin B1 (LMNB1) was verified by Methylated RNA Immunoprecipitation (meRIP) assay, RIP assay, dual-luciferase reporter assay and Actinomycin D assay. CLP induced significant pathological changes in kidney tissues in mice and promoted inflammation, mitochondrial damage and ferroptosis. LMNB1 level was induced in HK-2 cells by LPS. LMNB1 knockdown promoted LPS-mediated HK-2 cell viability and inhibited LPS-mediated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis. Then, WTAP was demonstrated to promote LMNB1 expression by m6A Methylation modification. Moreover, WTAP knockdown repressed LPS-treated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis, while LMNB1 overexpression reversed the effects. Additionally, WTAP affected the pathways of NF-κB and JAK2/STAT3 by LMNB1. WTAP-mediated m6A promoted the inflammation, mitochondrial damage and ferroptosis in LPS-induced HK-2 cells by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways.

Effectiveness and safety of empagliflozin: final results from the EMPRISE study.

Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases. We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure. We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD -2.08 [95% CI (-3.26, -0.90]), HHF (HR 0.50 [0.44, 0.56]; RD -5.35 [-6.22, -4.49]), MACE (HR 0.73 [0.62, 0.86]; RD -6.37 [-8.98, -3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD -10.36 [-12.63, -8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD -2.39 [-3.08, -1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD -2.46 [-3.32, -1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD -9.49 [-16.97, -2.10]); and similar risks of other safety events. Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer.

Identification and validation of ferroptosis-related gene SLC2A1 as a novel prognostic biomarker in AKI.

Emerging evidence reveals the key role of ferroptosis in the pathophysiological process of acute kidney injury (AKI). Our study aimed to investigate the potential ferroptosis-related gene in AKI through bioinformatics and experimental validation. The AKI single-cell sequencing dataset was retrieved from the GEO database and ferroptosis-related genes were extracted from the GENECARD website. The potential differentially expressed ferroptosis-related genes of AKI were selected. Functional enrichment analysis was performed. Machine learning algorithms were used to identify key ferroptosis-related genes associated with AKI. A multi-factor Cox regression analysis was used to construct a risk score model. The accuracy of the risk score model was validated using receiver operating characteristic (ROC) curve analysis. We extensively explored the immune landscape of AKI using CIBERSORT tool. Finally, expressions of ferroptosis DEGs were validated in vivo and in vitro by Western blot, ICH and transfection experiments. Three hub genes (BAP1, MDM4, SLC2A1) were identified and validated by constructing drug regulatory network and subsequent screening using experimentally determined interactions. The risk mode showed the low-risk group had significantly better prognosis compared to high-risk group. The risk score was independently associated with overall survival. The ROC curve analysis showed that the prognosis model had good predictive ability. Additionally, CIBERSORT immune infiltration analysis suggest that the hub gene may influence cell recruitment and infiltration in AKI. Validation experiments revealed that SLC2A1 functions by regulating ferroptosis. In summary, our study not only identifies SLC2A1 as diagnostic biomarker for AKI, but also sheds light on the role of it in AKI progression, providing novel insights for the clinical diagnosis and treatment of AKI.

Arachidonic acid metabolism as a therapeutic target in AKI-to-CKD transition.

Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A2 into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum.

Recent Advances in Nanomaterials for the Treatment of Acute Kidney Injury.

Acute kidney injury (AKI) is a serious clinical syndrome with high morbidity, elevated mortality, and poor prognosis, commonly considered a "sword of Damocles" for hospitalized patients, especially those in intensive care units. Oxidative stress, inflammation, and apoptosis, caused by the excessive production of reactive oxygen species (ROS), play a key role in AKI progression. Hence, the investigation of effective and safe antioxidants and inflammatory regulators to scavenge overexpressed ROS and regulate excessive inflammation has become a promising therapeutic option. However, the unique physiological structure and complex pathological alterations in the kidneys render traditional therapies ineffective, impeding the residence and efficacy of most antioxidant and anti-inflammatory small molecule drugs within the renal milieu. Recently, nanotherapeutic interventions have emerged as a promising and prospective strategy for AKI, overcoming traditional treatment dilemmas through alterations in size, shape, charge, and surface modifications. This Review succinctly summarizes the latest advancements in nanotherapeutic approaches for AKI, encompassing nanozymes, ROS scavenger nanomaterials, MSC-EVs, and nanomaterials loaded with antioxidants and inflammatory regulator. Following this, strategies aimed at enhancing biocompatibility and kidney targeting are introduced. Furthermore, a brief discussion on the current challenges and future prospects in this research field is presented, providing a comprehensive overview of the evolving landscape of nanotherapeutic interventions for AKI.

Advances in understanding of dendritic cell in the pathogenesis of acute kidney injury.

Acute kidney injury (AKI) is characterized by a rapid decline in renal function and is associated with a high morbidity and mortality rate. At present, the underlying mechanisms of AKI remain incompletely understood. Immune disorder is a prominent feature of AKI, and dendritic cells (DCs) play a pivotal role in orchestrating both innate and adaptive immune responses, including the induction of protective proinflammatory and tolerogenic immune reactions. Emerging evidence suggests that DCs play a critical role in the initiation and development of AKI. This paper aimed to conduct a comprehensive review and analysis of the role of DCs in the progression of AKI and elucidate the underlying molecular mechanism. The ultimate objective was to offer valuable insights and guidance for the treatment of AKI.

Bilateral Renal Ischemia-Reperfusion Model for Acute Kidney Injury in Mice.

Acute kidney injury (AKI) is defined as a rapid decline in renal function, in which persistent kidney dysfunction gradually progresses to chronic kidney disease (CKD) due to the irreversible loss of nephrons and their maladaptive repair. In recent years, the incidence of AKI has been increasing concerning diverse etiologies, including volume depletion, sepsis, nephrotoxicity, muscle injury, and major trauma, in which ischemia-reperfusion injury (IRI)accounts for most episodes. Development of the IRI model in mice is induced by surgical clamping of the renal pedicles, which provides powerful and controllable tools for preclinical models of AKI. Importantly, the IRI model is deployed at different stages of the AKI development, especially in the processes of AKI to CKD. Despite the IRI model being widely practiced in many laboratories, a series of variables still influence the results of this model. Here, we describe the procedure of IRI model development to provide a repeatable and reliable method for researchers to explore the underlying pathogenesis in the development of AKI and the progression of AKI to CKD.