Unveiling the role of sTLR2: A novel biomarker for predicting septic-associated AKI.

BACKGROUND: Acute kidney injury (AKI) is common in septic patients and strongly associated with adverse outcomes. The pathophysiology of AKI in septic patients remains elusive, and detection of patients at risk of AKI or at risk of progression to severe and persistent AKI is critical for timely and adequate support measures, including mitigating further renal damage. Therefore, identification of biomarkers associated with septic-associated AKI that contribute to improve septic AKI is an area of intensive research. METHODS: A total of 116 consecutive patients with sepsis were categorized into two groups (AKI and non-AKI) based on the occurrence of AKI within 24 h of admission to the intensive care unit (ICU). Serum levels of soluble TLR2 (sTLR2), as well as biomarkers such as interleukin(IL)-6, IL-22, IL-10, creatinine, urea, procalcitonin, hypersensitive C-reactive protein (hs-CRP), and D-Dimer (D2), were measured within 24 h after ICU admission. Demographic and clinical characteristics including sequential organ failure assessment (SOFA) scores and acute physiology and chronic health evaluation II (APACHE II) scores were recorded. Logistic regression analysis was conducted to identify potential predictive biomarkers. Receiver operating characteristic (ROC) curve analysis was employed to determine the optimal model for predicting septic-associated AKI. RESULTS: Patients in the AKI group exhibited significantly higher serum concentrations of IL-6, IL-10, sTLR2, creatinine, urea, hs-CRP, procalcitonin, D2 and lower serum albumin concentrations as well as higher APACHE II scores compared to those in the non-AKI group. Logistic regression analysis revealed that APACHE II scores, log10-transformed sTLR2 concentration, creatinine and D2 concentration were valuable predictors of AKI among septic patients. ROC curves demonstrated that log10-transformed sTLR2 concentration exhibited comparable predictive value to creatinine in determining the incidence of sepsis-associated AKI. The model with variables of APACHE II score, Log10-transformed serum TLR2 concentration, creatinine and D2 concentration yielded the greatest area under the curve of 0.863. CONCLUSION: Elevated levels of sTLR2 in early-stage of septic patients may serve as a promising novel biomarker for predicting sepsis-associated AKI.

Development and validation of the PHM-CPA model to predict in-hospital mortality for cirrhotic patients with acute kidney injury.

BACKGROUND: The presence of acute kidney injury (AKI) significantly increases in-hospital mortality risk for cirrhotic patients. Early prognosis prediction for these patients is crucial. We aimed to develop and validate a machine learning model for in-hospital mortality prediction for cirrhotic patients with AKI. METHODS: Data from cirrhotic patients with AKI hospitalized at the First Affiliated Hospital of Zhejiang University between January 1, 2013, and December 31, 2020 were used to train and validate an extreme Gradient Boosting model to predict in-hospital mortality risk. The Boruta algorithm was used for variable selection. The optimal model was selected and named as PHM-CPA (Prediction of in-Hospital Mortality for Cirrhotic Patients with AKI). The PHM-CPA model was then externally validated in patients from eICU Collaborative Research Database (eICU-CRD) and Medical Information Mart for Intensive Care III dataset (MIMIC). The predictive performance of PHM-CPA model was compared with that of logistic regression (LR) model and 25 previously reported models. RESULTS: A total of 519 cirrhotic patients with AKI were enrolled in model training cohort, of whom 118 (23%) died during hospitalization. Fifteen variables from common laboratory tests were selected to develop the PHM-CPA model. The PHM-CPA model achieved an AUROC of 0.816 (95% CI, 0.763-0.861) in the internal validation cohort and 0.787 (95% CI, 0.745-0.830) in the external validation cohort. The PHM-CPA model consistently outperformed the LR model and 25 previously reported models. CONCLUSION: We developed and validated the PHM-CPA model, comprising readily available clinical variables, which demonstrated superior performance and calibration in predicting in-hospital mortality for cirrhotic patients with AKI.

The evolution of public attention in acute kidney injury and continuous renal replacement therapy: trends analysis from 2004 to 2024.

Background: Acute kidney injury (AKI) and the need for Continuous Renal Replacement Therapy (CRRT) are critically important health concerns. This study analyzes global and regional Internet search queries to understand public attention in AKI and CRRT over time. Methods: We used Google Trends™ to analyze search queries for AKI and CRRT from January 2004 to March 2024. The study examined global trends and detailed insights from the United States, including state-by-state breakdowns. We identified patterns, peaks of attention, and temporal trends in public attention, comparing regional variations across the US and top-ranking countries worldwide. Results: Global attention in AKI peaked in October 2022, with Portugal, Zambia, and Spain showing the highest regional attention. Within the United States, peak attention was in February 2008. Tennessee, Pennsylvania, and West Virginia were the top states that paid attention to AKI. Attention in CRRT peaked globally in March 2024. South Korea, Saudi Arabia, and Bahrain have led the global attention to CRRT. In the United States, peak attention was in April 2020. West Virginia, Tennessee, and Kentucky showed the highest state-specific attention in CRRT. Conclusions: This study reveals significant temporal and geographical variations in online search patterns for AKI and CRRT, suggesting evolving public attention to these critical health issues. This knowledge can guide the development of targeted public health initiatives, enhance medical education efforts, and help healthcare systems tailor their approach to improving awareness and outcomes in kidney health across diverse populations.

A Case of Severe Acute Kidney Injury Due to an Antibiotic-Loaded Cement Spacer for Infected Knee Arthroplasty.

The treatment for periprosthetic joint infection frequently involves the placement of a high-dose antibiotic-loaded bone cement spacer (ALCS) into the debrided joint. Typical antibiotics in the spacer include aminoglycosides and vancomycin. It has been believed that systemic absorption of intraarticular antibiotics would be low and early experience suggested that the risk of acute kidney injury (AKI) from ALCS was minimal. However, recent case reports and case series have suggested a risk of acute kidney injury due to antibiotic absorption, though confounding factors are common. We report a case of severe AKI requiring hemodialysis with extremely high systemic tobramycin levels after the placement of an ALCS with increased dosing of antibiotics after previous failure to resolve a periprosthetic joint infection with a prior ALCS. There was no concomitant use of intravenous nephrotoxic antibiotics nor other confounding factors. Despite dialysis, the patient needed urgent removal of the ALCS to control tobramycin levels with subsequent resolution of the AKI. This case highlights the potentially serious nephrotoxicity of ALCS's, the importance of antibiotic type and dosing, and the value of close monitoring after ALCS placement, especially in a patient with chronic kidney disease.

Aquaporin-1 Facilitates Macrophage M1 Polarization by Enhancing Glycolysis Through the Activation of HIF1α in Lipopolysaccharide-Induced Acute Kidney Injury.

This study aimed to investigate how aquaporin 1 (AQP1) modulates hypoxia-inducible factor-1α (HIF1α) to promote glycolysis and drive the M1 polarization of macrophages. Within 12 h post-treatment with LPS to induce acute kidney injury in rats, a significant upregulation of AQP1 and HIF1α protein levels was noted in serum and kidney tissues. This elevation corresponded with a decrease in blood glucose concentrations and an enhancement of glycolytic activity relative to the control group. Furthermore, there was a pronounced reduction in the circulating levels of the anti-inflammatory cytokine IL-10, accompanied by an upregulation in the levels of the pro-inflammatory cytokines IL-6 and TNF-α. The administration of an HIF1α inhibitor reversed these effects, which did not affect the production of AQP1 protein. In cellular assays, AQP1 knockdown mitigated the increase in HIF1α expression induced by LPS. Furthermore, the suppression of HIF1α with PX-478 led to decreased expression levels of Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), indicating that AQP1 regulates glycolysis through HIF1α. M1 polarization of macrophages was reduced by AQP1 knockdown and was further diminished by the addition of an HIF1α inhibitor. Inhibition of the glycolytic process not only weakened M1 polarization but also promoted M2 polarization, thereby reducing the release of inflammatory cytokines. These findings provide a novel perspective for developing therapeutic strategies that target AQP1 and HIF1α, potentially improving the treatment of sepsis-associated AKI.

Interdisciplinary Management of Traumatic Injuries to the Kidneys and Urinary Tract Caused by Blunt Abdominopelvic Trauma.

Purpose: Blunt abdominopelvic trauma frequently results in injuries to the urinary organs, especially in polytrauma. The urotrauma is rarely an acute life-threatening event; however, it may lead to severe complications. Methods: This review addresses the under-representation of urological trauma management in interdisciplinary medical training and its impact on patient outcomes. It compiles evidence-based recommendations and guidelines from multiple specialties, focusing on common challenges in managing these injuries. The resource is tailored for primary care physicians in radiology, trauma surgery, internal medicine, urology, and nephrology. Results: Urinary tract injuries can occur even if the patient's condition initially appears normal. An exclusion diagnosis is obligatory by contrast medium tomography of the entire urinary tract and, if suspected, an additional uroendoscopic examination. Interventional therapy by catheterisation of the urinary tract is often required. Urosurgical treatment is not commonly needed, but when there is a demand, it must be administered via an interdisciplinary approach with visceral and trauma surgery. Over 90% of life-threatening kidney injuries (usually up to grade 4-5 AAST) are presently treated by interventional radiologists. Acute kidney injury (AKI) as a complication in trauma patients may complicate clinical management and often worsens the outcome. The incidence of trauma-associated AKI in patients admitted to an intensive care unit is high. Conclusions: Patients suffering from blunt abdominopelvic trauma should ideally be referred to certified trauma centres with subspecialised or fully specialised care provided by visceral/vascular surgery, trauma surgery, interventional radiology, urology, and nephrology. This recommendation is based on the complex nature of most damage patterns.

Macroscopic hematuria-associated severe acute kidney injury triggered by kidney stone formation in a patient with thin basement membrane and no history of microscopic hematuria.

Macroscopic hematuria (MH)-associated acute kidney injury (AKI) is a rare condition that causes acute tubular damage due to severe glomerular bleeding with MH. A 66-year-old Japanese woman with no significant past medical history was referred for severe kidney injury with oliguric MH. Her prior medical checkup results showed no occult blood in her urine. Seven days earlier, she had experienced transient severe acute right lumbar back pain. On admission, her serum urea nitrogen was 147 mg/dL, serum creatinine (sCr) 18.3 mg/dL, urinary red blood cells (RBCs) > 100/hpf, urinary protein 28.8 g/gCr, with no hydronephrosis in either kidney, but two stones were found in the right kidney and right ureteropelvic junction. At the start of her hemodialysis, the patient was treated with high-dose steroids because of suspected rapidly progressive glomerulonephritis. A renal biopsy of the left kidney showed acute tubular injury with massive RBC casts filling the tubular lumen. Glomerulitis was not detected, but electron microscopy revealed diffuse glomerular thin basement membrane (TBM). Despite immediate steroid discontinuation, the patient's renal function and MH improved, and she was weaned from hemodialysis. The stones resolved 2 months after onset, but microscopic hematuria persisted for 7 months post-onset. The sCr level was fixed at 1.1 mg/dL 20 months post-onset. This is the first report of MH-AKI in a TBM without the risk of MH-AKI development, such as bleeding tendency or iron overload. In this TBM, a colic attack of the renal urinary tract induced glomerular bleeding, and intolerance to hematuria may have caused severe tubular damage.

Characterizing the relationship between social determinants of health and risk of albuminuria among children with type 1 diabetes.

In a cohort of 2303 children with type 1 diabetes (T1D), we found that non-English speaking status (HR 2.82, 95% CI 1.54-5.18) and public insurance (HR 1.48, 95% CI 1.07-2.05) were associated with an increased risk of incident albuminuria, after adjusting for T1D-related variables (age, hemoglobin A1c, diabetic ketoacidosis episodes with acute kidney injury).

GSTT1/GSTM1 deficiency aggravated cisplatin-induced acute kidney injury via ROS-triggered ferroptosis.

Introduction: Cisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatin- induced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear. Methods: To investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. Results: Here, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin. Discussion: Our study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

Critical Role of S100A9 in Sepsis-associated Acute Kidney Injury: Mechanistic Insights through Pyroptosis Pathway Modulation.

This study investigates the role of S100A9 in sepsis-associated AKI (SA-AKI) through the lens of pyroptosis, a controlled form of cell death mediated by the gasdermin protein family. Using C57BL/6 mice and S100A9 knockout mice subjected to cecal ligation and puncture (CLP), RNA sequencing and bioinformatics analyses revealed differentially expressed genes (DEGs) related to inflammation and immune responses, with notable upregulation of S100A9. Functional enrichment analyses (GO and KEGG) indicated these DEGs are involved in interferon-beta response, immune processes, and cell adhesion. Protein-protein interaction (PPI) network analyses further emphasized S100A9's pivotal role in SA-AKI.Clinical validation measured S100A9 levels in serum and urine samples from SA-AKI patients and healthy volunteers, finding elevated S100A9 levels in the former. In vivo experiments showed that S100A9 knockout mice exhibited reduced kidney injury and inflammation, indicated by lower serum creatinine, urea nitrogen, and inflammatory markers (IL-1ß and IL-18). Histopathological analyses and immunohistochemistry confirmed less renal damage and reduced expression of cleaved IL-1ß and GSDMD-N in S100A9-deficient mice. Electron microscopy and Western blotting validated that S100A9 deficiency mitigates caspase-1-dependent pyroptosis.Cellular experiments with HK-2 cells demonstrated that S100A9 knockdown alleviated LPS-induced cell damage and reduced pyroptosis markers. These findings illuminate S100A9's involvement in NLRP3 inflammasome activation and pyroptosis, suggesting potential therapeutic targets for SA-AKI. Targeting S100A9 may offer new therapeutic avenues, improving outcomes for sepsis-related kidney injury patients. Future research should aim to validate these findings in larger clinical settings.

Modern CRRT systems are associated with lower risk of hypothermia.

One risk of continuous renal replacement therapy (CRRT) is inadvertent hypothermia (IH), which is defined as a non-therapeutic core temperature decrease below normal. In continuous renal replacement therapy, heat loss will always occur from blood pumped through the dialysis circuit to cooler environment, predisposing for hypothermia. Blood flow and effluent flows are the most important parameters causing heat loss. We investigated and compared the novel TherMax warmer to previous generation technologies during CRRT in a multicenter setting. This was a prospective observational multicenter study with historic single-center controls. The study group consisted of 100 patients in eight Swedish ICUs with clinical indication for CRRT, using the PrisMax platform and TherMax warmer. Both patient and set warmer temperatures were recorded hourly for the first 24 h. The presence of treatment hours in hypothermia (< 36.0 Celsius) and the difference between set warmer temperature and measured patient temperature in the multi-center study cohort were compared to a matched single-center historic control cohort treated with the old Prismaflex platform and adjacent Barkey warmer. In the TherMax group 77/100 (77.0%) of patients, and for controls 26/86 (30.2%) of patients were free of hypothermia (Chi square, p < 0.001). The mean number of hours spent in hypothermia was (mean ± SD) 0.66 ± 1.60 and 6.92 ± 7.79 h in the TherMax and control groups, respectively (Chi square p < 0.001). In the study group the patient temperature was higher than the set temperature on the warmer with a difference of Δ0.47 ± 0.80 °C (minor difference), whereas in the control group the set temperature on the warmer was higher than the patient temperature with a difference of Δ4.55 ± 1.00 °C (over-correction). The novel TherMax warmer technology protected against hypothermia and was significantly more accurate than the Barkey warmer.

Associations between acute kidney injury and bone fractures: a retrospective cohort study.

Background: Acute kidney injury (AKI) is common. An AKI episode may disrupt the normal mineral bone balance maintained by normal kidney function, thereby modifying the risk of developing bone fractures. However, it remains unclear whether an AKI episode is associated with the risk of bone fractures. Methods: Using retrospective cohort study from an Australian Local Health District, we examined the association between an AKI episode and bone fractures using patient data between 2008 and 2017. Time-varying Cox proportional hazards and propensity-matched analysis were used to examine the association. Sensitivity analyses were undertaken to capture the impact of confirmed AKI status and AKI severity. Results: Of 123 426 included patients, 14 549 (12%) had an AKI episode and 12 505 (10%) had a bone fracture. In the unadjusted analysis, AKI was associated with bone fractures [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.88-2.11]. This association persisted in the adjusted analysis (HR 1.50, 95% CI 1.41-1.59) and propensity-matched dataset (HR 1.71, 95% CI 1.59-1.83). The sensitivity analysis yielded similar results, with the AKI patients having a higher risk of fractures compared with no AKI patients in the adjusted analysis (HR 1.34, 95% CI 1.25-1.43) and in the propensity-matched dataset (HR 1.44, 95% CI 1.33-1.55). Similar results were seen in the subsidiary sensitivity analysis excluding patients without baseline creatinine. We did not find an increased risk of bone fractures with increasing AKI severity (P = .7). Interaction tests demonstrated a significant association between sex and age category with AKI status and fractures, but not CKD stage or osteoporosis. Conclusions: AKI is associated with a greater risk of bone fractures. This could have implications for managing and screening for bone disease in patients post-AKI episode. This association should be examined in other cohorts and populations for verification.

The SIRT6/BAP1/xCT signaling axis mediates ferroptosis in cisplatin-induced AKI.

BACKGROUND: Cisplatin is extensively utilized in clinical settings for treating solid tumors; However, its use is restricted because of the kidney damage caused by side effects. Moreover, currently, no effective medications have been approved to prevent or treat acute kidney injury induced by cisplatin. Our research indicates that sirtuin 6 (SIRT6) can inhibit ferroptosis induced by cisplatin, and the use of SIRT6 agonists can alleviate acute kidney injury caused by cisplatin. METHODS: An animal model of cisplatin-induced acute kidney injury (AKI) was established, followed by RNA sequencing to identify potential differentially expressed genes (DEGs) and associated pathways. To explore the role of SIRT6 in this model, SIRT6 knockout mice were generated, and recombinant adeno-associated virus was employed to achieve SIRT6 overexpression in the mice. In vitro, cells were cultured in a cisplatin-containing medium to establish a cisplatin-induced cell model. The function of SIRT6 was further investigated by overexpressing or knocking down the gene using lentiviral plasmids. To elucidate the underlying molecular mechanisms, we employed RNA sequencing, performed bioinformatics analyses, and conducted chromatin immunoprecipitation assays. RESULTS: RNA sequencing and Western blot analyses revealed a significant reduction in SIRT6 expression in mice with cisplatin-induced acute kidney injury (AKI). Enhancing SIRT6 expression improved renal function, reduced ferroptosis, and mitigated kidney damage, whereas SIRT6 knockout exacerbated kidney injury and heightened ferroptosis. Mechanistically, RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assays demonstrated that SIRT6 inhibits ferroptosis by reducing the acetylation of histone H4K9ac at the BAP1 promoter. Furthermore, in vitro studies demonstrated that the SIRT6 agonist UBCS039 can alleviate cisplatin-induced acute kidney injury, highlighting its potential therapeutic role in mitigating cisplatin's damaging effects. However, further research is needed to fully elucidate the underlying mechanisms and to validate these findings in vivo. CONCLUSION: Our findings underscore the critical role of the SIRT6/BAP1/xCT axis in regulating ferroptosis, particularly via the downregulation of SIRT6, in the context of cisplatin-induced acute kidney injury (AKI). This suggests that SIRT6 could be a promising therapeutic target for treating cisplatin-induced AKI. However, additional research is required to explore the specific mechanisms and fully assess the therapeutic potential of SIRT6 in this context.

A Rare Encounter of Postoperative Abscess Not Linked to Staple Line in Sleeve Gastrectomy: A Case Report and Literature Review.

Sleeve gastrectomy is a common bariatric procedure known for its safety and effectiveness, but postoperative complications like abscess formation, though rare, can occur. We report the case of a 37-year-old female who presented with atypical abdominal pain following a sleeve gastrectomy. Imaging revealed an abscess located away from the staple line. Surgical exploration and culture identified Streptococcus anginosus as the causative organism. This case emphasizes the importance of vigilant postoperative monitoring and early intervention to prevent complications. Proper management, including antibiotics and surgical drainage, is crucial for patient recovery.

Desmopressin use in major cardiac surgery is associated with renal impairment: a retrospective single-center analysis.

BACKGROUND: Desmopressin acetate (1-deamino-8-d-arginine vasopressin-DDAVP) is a analogue of the antidiuretic hormone vasopressin. DDAVP is suggested to reduce bleeding after cardiac surgery using cardiopulmonary bypass. The aim of this study was to determine if DDAVP has any negative impact on renal function leading to acute kidney injury (AKI) and therefore increases the need for renal replacement therapy (RRT). METHODS: We performed a retrospective single institutional cohort analysis of 2,179 patients undergoing elective and urgent cardiac surgery with CPB from 2017 to 2021. Logistic regression analysis was used to investigate any association between DDAVP, the incidence of AKI KDIGO class 3 and the need for RRT, respectively. The model was adjusted for relevant covariates, including preexisting renal impairment, pharmacological hemodynamic support with vasopressors, complexity of the surgery and postoperative lactate. Secondary outcomes included, in hospital mortality and the need for allogenic blood transfusion. RESULTS: A total of 992 (45.5%) patients received DDAVP intraoperatively during surgery or shortly thereafter. The use of DDAVP was associated with a significant increase in in AKI KDIGO class 3 (OR 2.27; 95% CI 1.46-3.55; p < 0,001) and the need for RRT (OR 2.19; 95%CI 1.48-3.24; p < 0,001). Both findings persisted after covariate adjusting. No increased in-hospital mortality was associated with DDAVP. CONCLUSION: In cardiac surgery, the use of DDAVP was associated with an increased rate of server AKI and the requirement for RRT. Given the severity of the potential harm associated with DDAVP, an evidence-based reevaluation is needed to enable an accurate risk and benefit assessment.

Persistent Renal Dysfunction After Acute Kidney Injury Among STEMI Patients Undergoing Primary Coronary Intervention: Prevalence and Predictors.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of ST-elevation myocardial infarction (STEMI). AKI and chronic kidney disease (CKD) are highly heterogeneous, leaving a wide gap between them. Therefore, the term acute kidney disease (AKD) was implemented, describing prolonged renal injury between 7 and 90 days. We aimed to evaluate the prevalence and predictors of AKD among STEMI patients. METHODS: This retrospective observational study included 2940 consecutive patients admitted with STEMI between 2008 and 2022. Renal function was assessed upon admission and routinely thereafter. Renal outcomes were evaluated according to KDIGO criteria, with AKD defined as persistent renal injury of between 7 and 90 days. RESULTS: Two hundred and fifty-two subjects with STEMI and AKI were included; of them, 117 (46%) developed AKD. Among baseline CKD patients, higher rates of AKD were observed (60% vs. 46%). KDIGO index ≥ 2 was an independent predictor for AKD in in subjects without baseline CKD (AOR 2.63, 95% CI 1.07-6.53). In subjects with baseline CKD, older age and higher creatinine were independent predictors for AKD. Subjects with AKD had a higher 1-year mortality rate (HR 3.39, 95% CI 1.71-6.72, p < 0.01). This trend was mainly driven by the CKD subpopulation where higher mortality rates for AKD on CKD were observed (HR 5.26, 95% CI 1.83-15.1, p < 0.01). CONCLUSION: AKD is common among STEMI patients with AKI. The presence of CKD and higher KDIGO stage should prompt strict monitoring for early diagnosis, treatment, and prevention of renal function deterioration.

An early and stable mouse model of polymyxin-induced acute kidney injury.

BACKGROUND: Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. METHODS: In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. RESULTS: Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. CONCLUSION: The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.

Modified furosemide responsiveness index and biomarkers for AKI progression and prognosis: a prospective observational study.

BACKGROUND: Modified furosemide responsiveness index (mFRI) is a novel biomarker for assessing diuretic response and AKI progression in patients with early AKI. However, the comparative predictive performance of mFRI and novel renal biomarkers for adverse renal outcomes remains unclear. In a single-center prospective study, we aimed to evaluate the discriminatory abilities of mFRI and other novel renal biomarkers in predicting AKI progression and prognosis in patients with initial mild and moderate AKI (KDIGO stage 1 to 2). RESULTS: Patients with initial mild and moderate AKI within 48 h following cardiac surgery were included in this study. The mFRI, renal biomarkers (including serum or urinary neutrophil gelatinase-associated lipocalin [sNGAL or uNGAL], serum cystatin C, urinary N-acetyl-beta-D-glycosaminidase [uNAG], urinary albumin-to-creatinine ratio) and cytokines (TNF, IL-1ß, IL-2R, IL-6, IL-8, and IL-10) were measured at AKI diagnosis. The mFRI was calculated for each patient, which was defined as 2-hour urine output divided by furosemide dose and body weight. Of 1013 included patients, 154 (15.2%) experienced AKI progression, with 59 (5.8%) progressing to stage 3 and 33 (3.3%) meeting the composite outcome of hospital mortality or receipt of renal replacement therapy (RRT). The mFRI showed non-inferiority or potential superiority to renal biomarkers and cytokines in predicting AKI progression (area under the curve [AUC] 0.80, 95% confidence interval [CI] 0.77-0.82), progression to stage 3 (AUC 0.87, 95% CI 0.85-0.89), and composite outcome of death and receipt of RRT (AUC 0.85, 95% CI 0.82-0.87). Furthermore, the combination of a functional biomarker (mFRI) and a urinary injury biomarker (uNAG or uNGAL) resulted in a significant improvement in the prediction of adverse renal outcomes than either individual biomarker (all P < 0.05). Moreover, incorporating these panels into clinical model significantly enhanced its predictive capacity for adverse renal outcomes, as demonstrated by the C index, integrated discrimination improvement, and net reclassification improvement (all P < 0.05). CONCLUSIONS: As a rapid, cost-effective and easily accessible biomarker, mFRI, exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers in cardiac surgical patients with mild to moderate AKI. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04962412. Registered July 15, 2021, https://clinicaltrials.gov/ct2/show/NCT04962412?cond=NCT04962412&draw=2&rank=1 .

NRF1-induced mmu_circ_0001388/hsa_circ_0029470 confers ferroptosis resistance in ischemic acute kidney injury via the miR-193b-3p/TCF4/GPX4 axis.

AIMS: Circular RNAs (circRNAs) are critical in the progression of ischemic acute kidney injury (AKI). Nevertheless, the specific functions and regulatory pathways of mmu_circ_0001388 and hsa_circ_0029470 remain elusive. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression patterns of mmu_circ_0001388, hsa_circ_0029470, and miR-139b-3p. Protein expressions of nuclear respiratory factor 1 (NRF1), transcription factor 4 (TCF4), glutathione peroxidase 4 (GPX4), and Acyl-CoA synthetase long-chain family member 4 (ACSL4) were identified via immunoblotting. Furthermore, the functions and control mechanisms of mmu_circ_003062 and hsa_circ_0075663 were examined via diverse cell and animal studies, encompassing bioinformatics prediction, dual-luciferase reporter (DLR), chromatin immunoprecipitation (ChIP), fluorescence in situ hybridization (FISH), flow cytometry (FCM), hematoxylin and eosin (H&E) staining, dihydroethidium (DHE), TUNEL, immunohistochemistry, and transmission electron microscopy (TEM), and Fe2+ assay. KEY FINDINGS: Initially, the induction of mmu_circ_0001388 by NRF1 was observed in vitro and in vivo following ischemia/reperfusion (I/R) injury. Subsequently, knockdown or overexpression of mmu_circ_0001388 was found to either promote or inhibit ferroptosis caused by I/R in Boston University mouse proximal tubule (BUMPT) cells, respectively. From a mechanistic standpoint, mmu_circ_0001388 was found to function as a sponge for miR-193b-3p, which promoted TCF4 and subsequently enhanced GPX4, thereby suppressing ferroptosis. Finally, the overexpression of mmu_circ_0001388 was shown to ameliorate I/R-induced AKI in mice. In parallel, hsa_circ_0029470, homologous to mmu_circ_0001388, demonstrated an identical control pathway in human renal tubular epithelial (HK-2) cells. SIGNIFICANCE: The NRF1/mmu_circ_0001388, hsa_circ_0029470/miR-193b-3p/TCF4/GPX4 axis is pivotal in regulating ferroptosis induced by ischemic AKI and holds potential as a therapeutic target.