Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global public health crisis, progressing to hepatic cirrhosis and hepatocellular carcinoma. This study investigated the causal role of systemic iron status in MASLD progression. Methods: A two-sample Mendelian randomization (MR) design was implemented, with genetic variants serving as instrumental variables for four core systemic iron biomarkers. Outcome data for hepatic steatosis (8785 cases; 912,105 controls) and hepatic fibrosis/cirrhosis (3798 cases; 904,599 controls) were extracted from the FinnGen and UK Biobank databases. Multiple complementary MR methodologies and three instrumental variable selection strategies were applied to ensure robust causal inference. Results: Genetically predicted higher serum iron (odds ratio, OR: 1.42, 95% confidence interval, 95% CI: 1.34, 1.50), ferritin (OR: 1.84, 95% CI: 1.55, 2.18), and transferrin saturation (TfSat, OR: 1.24, 95% CI: 1.19, 1.30), together with lower total iron-binding capacity (TIBC, OR: 0.81, 95% CI: 0.77, 0.85), were significantly associated with increased hepatic steatosis risk (p < 0.00625). Similar associations were observed for hepatic fibrosis/cirrhosis: serum iron (OR: 1.66, 95% CI: 1.29, 2.14), ferritin (OR: 2.52, 95% CI: 1.52, 4.18), TfSat (OR: 1.40, 95% CI: 1.19, 1.63), and reduced TIBC (OR: 0.70, 95% CI: 0.60, 0.81). MR-Bayesian model averaging prioritized serum iron (MIP: 0.85, θ^MACE: 0.295; PP: 0.725; θ^λ: 0.344) as the top-ranked factors for steatosis and TIBC (MIP: 0.604, θ^MACE: −0.240; PP: 0.476, θ^λ: −0.358) for fibrosis/cirrhosis. Conclusions: Elevated systemic iron status causally drives MASLD onset and progression, highlighting iron homeostasis and ferroptosis as potential targets for prevention and clinical management.

BACKGROUND:This study aimed to evaluate the efficacy and safety of ferric citrate tablets in Chinese patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). METHODS:In this phase III, multicenter, randomized, open-label, non-inferiority trial, patients with hyperphosphatemia on maintenance hemodialysis were randomly assigned to receive either ferric citrate or sevelamer carbonate tablets for 12 weeks. The primary endpoint was the change in serum phosphorus levels from baseline to week 12, with a non-inferiority margin of 0.32 mmol/L. Secondary endpoints included changes in serum calcium, intact parathyroid hormone, and safety assessments. RESULTS:A total of 239 patients were randomized to the ferric citrate group (n = 119) or the sevelamer carbonate group (n = 120). The mean change in serum phosphorus levels was -0.70 ± 0.50 mmol/L in the ferric citrate group and -0.61 ± 0.59 mmol/L in the sevelamer carbonate group (least squares mean difference, -0.09 mmol/L; 95% CI, -0.24 to 0.05 mmol/L; non-inferiority margin, 0.32 mmol/L). No significant inter-group differences were found in the percentage of patients achieving target phosphorus levels (49.09% vs. 48.28%, p = 0.902). Ferric citrate significantly improved iron-related parameters and hemoglobin levels. Most treatment-emergent adverse events were mild, with gastrointestinal disorders being the most common. CONCLUSIONS:Ferric citrate tablets were non-inferior to sevelamer carbonate in reducing serum phosphorus levels in hyperphosphatemia patients on maintenance hemodialysis, with the added benefit of improving iron-related anemia and a favorable safety profile.

Prolonged infusion (extended [EI, 2–4 h] or continuous [CI, 24 h] extended) of beta-lactam antibiotics is considered to have advantages for patients with severe infection compared with intermittent bolus (IB). However, the choice of EI and CI is unclear due to the lack of direct comparison. We aimed to compare the EI and CI of beta-lactams in patients with severe infections using a network meta-analysis method. We systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang Database, and Weipu Database for randomized controlled trials (RCTs) comparing EI, CI, or IB with beta-lactams in adults with severe infections. The primary outcome was all-cause mortality. A frequentist network meta-analysis with a random-effects model was performed. Risk of bias was assessed using the Cochrane RoB 2 tool. Thirty-five RCTs (10,627 patients) were included. Risk of bias was moderate to high in most studies. For mortality, EI ranked highest (SUCRA 74.20

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 1 billion people globally, yet the role of trace elements in its progression remains poorly defined. Here, we identify “macrophage zinc trapping” (i.e., selective zinc accumulation in hepatic macrophages despite systemic zinc depletion) as a critical driver of MASLD. In a cohort of 1069 individuals with MASLD, we found that serum zinc levels were inversely correlated with the disease severity. In a mouse model of MASLD, the hepatic macrophages are marked by zinc accumulation. Macrophage-specific depletion of the zinc exporter Slc30a1 in mice recapitulates human MASLD pathology. In macrophage-specific Slc30a1-deficient mice, trapped zinc activates the Ire1α-Xbp1s pathway, which on the one hand stimulates IL-1β secretion to alter hepatocyte lipid metabolism via IL-1β signaling, and on the other hand enhances direct lipid transfer from macrophages to hepatocytes, thereby synergistically exacerbating steatosis. Notably, treatment with Ire1α inhibitors (4μ8C and STF-083010) or IL-1β blockade (clinically approved anti-IL-1β antibodies) reverse established steatosis, inflammation, and fibrosis in preclinical mouse models. This work redefines the role of zinc in MASLD, shifting the paradigm from systemic deficiency to cell-specific sequestration. It reveals that zinc accumulation in macrophages exacerbates hepatocyte lipid accumulation through both fatty acid transflux and inflammation-driven metabolic reprogramming, uncovering novel therapeutic targets and a clinically actionable biomarker.

Background:Model-informed individualized dosing of imipenem is required for critically ill patients due to high infection mortality and large pharmacokinetic (PK) variability. This study aims to externally evaluate the predictive performance of available imipenem pharmacokinetic (popPK) models to facilitate clinical application. Methods:A multicenter dataset of 152 ICU patients (201 concentrations) was used for the external validation of 9 popPK models. Model performance was investigated for prediction- and simulation-based diagnostics and Bayesian forecasting. The median relative prediction error (rPEmedian), median absolute relative prediction error (rAPEmedian), and NPDE were calculated to quantify accuracy and precision. Results:Model predictive performance exhibited heterogeneity. Priori prediction showed wide rPEmedian ranges, and only 3 models were within ± 15%. Moreover, the priori predictions of all models failed to demonstrate satisfactory performance in terms of both F20 and F50. Notably, Bayesian forecasting incorporating TDM data significantly improved accuracy, with four models demonstrating superior performance in terms of rPEmedian and F50. Predictive performance was poorer in patients with renal function impairments. Simulation diagnostics revealed systematic bias across all models. In general, the Truong et al (2025) model performed better than the other models. Conclusion:Available imipenem popPK models for adult critically ill patients were unsatisfactory in predictive performance, and the Truong et al (2025) model performed best among all models. The integration of Bayesian forecasting with therapeutic drug monitoring (TDM) data significantly improved predictive accuracy, suggesting that the synergistic use of the popPK model and TDM may optimize clinical dosing decisions and potentially improve clinical outcomes.

BackgroundThe area under the concentration‒time curve (AUC) is recognized as the therapeutic drug monitoring index of polymyxin B. The two-point method, which is based on peak and trough concentrations, is recommended for AUC estimation. However, its accuracy needs to be fully elucidated.MethodsA Monte Carlo simulation study was performed on published population pharmacokinetic (PPK) models. A series of plasma concentrations at steady state were simulated for each scenario. The performance of the two-point method was evaluated via mean absolute percent error (MAPE) and root mean square error (RMSE), with acceptable performance limits defined as ≤15% for the MAPE and ≤20% for the RMSE. Additionally, variations in infusion duration, body weight, and creatinine clearance were also investigated.ResultsIn the one-compartment model, the two-point method exhibits excellent predictive performance, characterized by both the MAPE and RMSE < 15%. For multicompartment models, prolonging the infusion duration markedly improved the accuracy of the two-point method, as demonstrated by a decrease in the average MAPE from 30.2% to 7.78% and in the average RMSE from 35.5% to 9.12% when comparing infusion durations of 0.5 h and 2 h. Body weight and creatinine clearance had limited influences on estimation accuracy in most models.ConclusionThe two-point method, which is based on peak and trough concentrations, represents a strong pharmacokinetic rationale and generate a testable hypothesis for the clinical application for estimating the AUC of polymyxin B. We suggest prolonging the infusion duration to ensure estimation accuracy in different patient settings.

Fibrosis is the common terminal pathway of abnormal tissue repair in various chronic diseases and has become a major global health challenge. Recent research has identified metabolic reprogramming as one of the key factors in the pathogenesis of fibrosis. Lactate, once considered a simple byproduct of glycolysis, has now been confirmed as a crucial metabolic messenger regulating intercellular communication and functional remodeling. The dynamic balance of intercellular lactate shuttling is essential for maintaining tissue homeostasis, and its dysregulation has been closely linked to the progression of fibrosis. Lactylation, a novel post-translational modification driven by lactate accumulation, can regulate protein function and gene expression, thereby playing a significant role in the pathogenesis of fibrosis. In this review, we summarize the latest advancements in the role of lactate and lactylation in the pathogenesis of fibrosis. By integrating the most recent research, we emphasize the importance of lactylation as a potential therapeutic target and explore the translational prospects of targeting lactate metabolism and lactylation in anti-fibrotic treatments, thereby providing novel insights for clinical intervention.

BackgroundThe latest published therapeutic drug monitoring (TDM) guidelines for vancomycin recommend changing trough-based monitoring to area under the concentration-to-time curve (AUC)-based monitoring. This study aimed to evaluate the implementation status and perceptions of vancomycin AUC-based TDM in China and to determine the challenges in performing AUC-based TDM.MethodsA nationwide cross-sectional survey was conducted in China using an online questionnaire. The questionnaire comprised a total of 25 questions with open- and closed-ended answers to collect information about the current implementation of vancomycin TDM and the participants’ perceptions of these practices. The questionnaire responses were collected via the Questionnaire Star platform and analyzed.ResultsA total of 161 questionnaires were completed by 131 hospitals and were included. Approximately 59.5% (78/131) of the surveyed hospitals conducted vancomycin TDM; however, only 10.7% (14/131) of these hospitals performed AUC-based vancomycin TDM. Of the eligible participants, 58.4% (94/161) had experience with vancomycin TDM, and only 37 participants (37/161, 23.0%) had the ability to estimate the AUC, primarily through Bayesian simulation (33/161, 20.5%). The participants considered the following challenges to implementing AUC-based monitoring: (1) the high cost of AUC-based monitoring; (2) inadequate knowledge among pharmacists and/or physicians; (3) the complexity of AUC calculations; (4) difficulty obtaining AUC software; and (5) unclear benefit of AUC-based monitoring.ConclusionThe majority of surveyed hospitals have not yet implemented AUC-based vancomycin TDM. Multiple challenges should be addressed before wide implementation of AUC-based monitoring, and guidance for trough-based monitoring is still needed.

Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end-stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.

Introduction:Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets. Methods:This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR. Results:Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions. Conclusion:The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.

Breast milk (BM) is a primary biofluid that plays a crucial role in infant development and the regulation of the immune system. As a class of rich biomolecules in BM, microRNAs (miRNAs) are regarded as active factors contributing to infant growth and development. Surprisingly, these molecules exhibit resilience in harsh conditions, providing an opportunity for infants to absorb them. In addition, many studies have shown that miRNAs in breast milk, when absorbed into the gastrointestinal system, can act as a class of functional regulators to effectively regulate gene expression. Understanding the absorption pattern of BM miRNA may facilitate the creation of formula with a more optimal miRNA balance and pave the way for novel drug delivery techniques. In this review, we initially present evidence of BM miRNA absorption. Subsequently, we compile studies that integrate both in vivo and in vitro findings to illustrate the bioavailability and biodistribution of BM miRNAs post-absorption. In addition, we evaluate the strengths and weaknesses of previous studies and discuss potential variables contributing to discrepancies in their outcomes. This literature review indicates that miRNAs can be absorbed and act as regulatory agents.

Objectives X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE.Methods X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.Results Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).Conclusion Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.

BackgroundThe pivotal role of phospholipase A2 group VII (PLA2G7) has been identified in specific human cancers, such as prostate cancer, diffuse large B cell lymphoma, and melanoma. Given PLA2G7's significant involvement in established tumors, exploring its role in other cancers is highly relevant.MethodsIn this study, we acquired and analyzed data from The Cancer Genome Atlas database, the UCSC XENA website, and other online platforms including Gene Set Cancer Analysis, cBioPortal, Tumor Immune Estimation Resource, and TISIDB to investigate PLA2G7's role in human cancers, including renal cancer. Furthermore, in vitro experiments, including immunofluorescence, western blotting, and CCK-8 assays, were conducted to elucidate PLA2G7's role in renal cancer. Finally, the relationship between PLA2G7 and various drug sensitivity was explored.ResultsOur findings demonstrate that PLA2G7 is highly expressed and may serve as a valuable candidate biomarker in pan-cancer. PLA2G7 exhibits distinct alteration frequencies across human cancers and is correlated with tumor mutation burden, tumor microenvironment, DNA stemness score, RNA stemness score, tumorigenesis, tumor immunity, and microsatellite instability in pan-cancer. Immunofluorescence and western blotting revealed a relative high level of PLA2G7 protein in renal cancer cell lines (ACHN and 786-O), predominantly localized in the cytoplasm. Treatment with a PLA2G7 gene inhibitor (darapladib) significantly decreased the viability of ACHN and 786-O cell lines. Additionally, we observed an association between PLA2G7 mRNA levels and various drug sensitivity.ConclusionsOur study suggests that PLA2G7 has the potential to serve as a valuable biomarker and therapeutic target for cancer, particularly in the context of renal cancer.

IgA nephropathy (IgAN) is an immune-mediated glomerulonephritis, posing a challenge for the long-term management. It is crucial to monitor the disease's activity over the disease course. Crescent lesions have been known as an active lesion associated with immune activity. We aimed to develop the Crescent Calculator to aid clinicians in making timely and well-informed decisions throughout the long-term disease course, such as renal biopsies and immunosuppressive therapy. 1,761 patients with biopsy-proven IgAN were recruited from four medical centers in Zhejiang Province, China. 16.9% presented crescent lesions. UPCR, URBC, eGFR and C4 were independently associated with the crescent lesions. By incorporating these variables, the Crescent Calculator was constructed to estimate the likelihood of crescent lesions. The predictor achieved AUC values of over 0.82 in two independent testing datasets. In addition, to fulfill varied clinical needs, multiple classification modes were established. The Crescent Calculator was developed to estimate the risk of crescent lesions for patients with IgAN, assisting clinicians in making timely, objective, and well-informed decisions regarding the need for renal biopsies and more appropriate use of immunosuppressive therapy in patients with IgAN.

ABSTRACT Background The 2021 clinical guidelines of the Kidney Disease: Improving Global Outcomes emphasize the importance of the histological activity index (AI) in the management of lupus nephritis (LN). Patients with LN and a high AI have poor renal outcomes and high rates of nephritic relapse. In this study we constructed prediction models for the AI in LN. Methods The study population comprised 337 patients diagnosed with LN using kidney biopsy. The participants were randomly divided into training and testing cohorts. They were further divided into high-activity (AI >2) and low-activity (AI ≤2) groups. This study developed two clinical prediction models using logistic regression and least absolute shrinkage and selection operator (LASSO) analyses with laboratory test results collected at the time of kidney biopsy. The performance of models was assessed using 5-fold cross-validation and validated in the testing cohort. A nomogram for individual assessment was constructed based on the preferable model. Results Multivariate analysis showed that higher mean arterial pressure, lower estimated glomerular filtration rate, lower complement 3 level, higher urinary erythrocytes count and anti-double-stranded DNA seropositivity were independent risk factors for high histologic activity in LN. Both models performed well in the testing cohort regarding the discriminatory ability to identify patients with an AI >2. The average area under the curve of 5-fold cross-validation was 0.855 in the logistic model and 0.896 in the LASSO model. A webtool based on the LASSO model was created for clinicians to enter baseline clinical parameters to produce a probability score of an AI >2. Conclusions The established nomogram provides a quantitative auxiliary tool for distinguishing LN patients with a high AI and helps physicians make clinical decisions in their comprehensive assessment.

Introduction: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Methods: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. Results: Eighty-one patients (age, 25.0 years; interquartile range, 20.0–40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56+CD16+ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. Conclusion: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis. Methods: Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and Trpm2-knockout mice and primary cells. RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity. Results: Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin. Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger. TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca2+ influx and subsequent up-regulation of AKT-mTOR signaling. Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor. Conclusion: Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca2+-AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.

Background: There are conflicts in guideline recommendations about the value and range of vancomycin trough concentration during therapeutic drug monitoring (TDM). This multicentre, retrospective study was conducted to explore the usefulness of trough concentration in specific patients who were critically ill and without any form of dialysis. Methods: Patient information from five centres was retrospectively collected and the 24-hour area under the curve (AUC) was estimated by a Bayesian method. Patients were categorised into four groups according to trough concentration: < 10, 10-15, 15-20 and > 20 mg/L, and the corresponding AUC was analysed. A multivariable logistic regression model was used to investigate the relationship between trough concentration and AUC. Results: Overall, 645 trough concentrations available from 416 patients were included in this study. The results indicated that the AUC was always < 400 mg/L center dot h or > 600 mg/L center dot h in the < 10 or > 20 mg/L groups, whereas the ratios of vancomycin AUC target attainment (40 0-600 mg/L center dot h) were 48.8% and 92.3% in the 10-15 mg/L and 15-20 mg/L groups, respectively. Augmented renal clearance, low daily dose and non-q12h administration were found to be independent risk factors associated with AUC target non-attainment for patients with trough concentrations of 10-15 mg/L. Conclusion: Vancomycin trough concentration is a good marker of AUC for critically ill adults without any form of dialysis. However, AUC-guided TDM may be needed for patients with trough concentrations of 10-15 mg/L, especially for those with risk factors. (c) 2023Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Ferroptosis in tubules has been implicated in the pathogenesis of acute kidney injury (AKI), whereas the regulatory mechanism remains unclear. The stimulator of interferon genes (STING) is previously recognized as a critical mediator of innate immunity via a DNA-sensing pathway and has been increasingly linked to lipid peroxidation, a hallmark of ferroptosis. Herein we investigated the role and the underlying mechanism of STING in AKI models established by ischemia/reperfusion (IR) in C57BL mice. The expression level of STING was predominantly increased in tubules of kidney after IR treatment. Besides, STING deficiency markedly alleviated IR-induced lipid peroxidation, tissue damage and renal dysfunction. Consistently, in vitro experiments demonstrated that the increase in ferroptotic cell death, lipid ROS production and the decrease in GSH peroxidase 4 (GPX4) expression in renal tubular cells subjected to ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated by genetic deficiency or pharmacological inhibition of STING, while all exacerbated by STING overexpression. Further, these detrimental effects of STING overexpression relied on the induction of ferritinophagy, i.e. autophagic degradation of ferritin, leading to iron overload. Mechanistically, STING mediated the initiation of ferritinophagy through interacting with nuclear receptor coactivator 4 (NCOA4), a fundamental receptor for the transfer of ferritin into lysosome. Collectively, STING contributes to ferroptosis during ischemic AKI through facilitating NCOA4-mediated ferritinophagy and shows the potential as a promising therapeutic choice for AKI.

Background: Vancomycin dosing is difficult in critically ill patients receiving continuous renal replacement therapy (CRRT). Previous population pharmacokinetic (PopPK) models seldom consider the effect of residual diuresis, a significant factor of elimination, and thus have poor external utility. This study aimed to build a PopPK model of vancomycin that incorporates daily urine volume to better describe the elimination of vancomycin in these patients.Methods: We performed a multicenter retrospective study that included critically ill patients who received intermittent intravenous vancomycin and CRRT. The PopPK model was developed using the NONMEM program. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulation was performed to explore the optimal dosage regimen with a target area under the curve of ≥400 mg/L h and 400–600 mg/L h.Results: Overall, 113 observations available from 71 patients were included in the PopPK model. The pharmacokinetics could be well illustrated by a one-compartment model with first-order elimination, with the 24-h urine volume as a significant covariate of clearance. The final typical clearance was 1.05 L/h, and the mean volume of distribution was 69.0 L. For patients with anuria or oliguria, a maintenance dosage regimen of 750 mg q12h is recommended.Conclusion: Vancomycin pharmacokinetics in critically ill patients receiving CRRT were well described by the developed PopPK model, which incorporates 24-h urine volume as a covariate. This study will help to better understand vancomycin elimination and benefit precision dosing in these patients.