Drawing of Human KidneyUnderstanding and categorizing the various types of tubulointerstitial responses in acute kidney injury (AKI) may lead to the development of new treatments for the condition, according to Yale School of Medicine researchers who published a review in The Journal of Clinical Investigation on March 17 The kidneys perform many filtration and excretion functions to keep the body in balance AKI is a condition in which the kidneys are unable to filter waste from the blood ultimately leading to long-term kidney damage if not addressed It is one of the most common conditions for which nephrologists are consulted in hospitals and AKI care has remained mostly the same for the past century researchers categorized AKI tubular epithelial cell injury into four buckets: ischemic “We are only just starting to think about how immune cells are impacting kidneys after injury, and grouping the injuries helps us better delineate the pathways,” said Megan Baker, MD a postdoctoral fellow and first author on the paper “Taking a step back and looking at the literature in a critical way Using imaging mass cytometry (IMC) on human kidney tissues from the Yale Kidney Biobank the Cantley Laboratory characterizes protein-level changes in tubular and other cells in the kidney following AKI and investigates how changes in cell-cell spatial relationships in AKI can inform future therapeutic targets Baker has led an IMC-based project focused on analyzing ischemic and primary immune-mediated forms of AKI By categorizing the injury into these four buckets we are thinking about how the immune system affects both unique and shared pathways–and hope to identify targets for much more effective therapies in all types of AKI “About eight years ago, I became very interested in translating our research in mouse models of kidney injury to better understand AKI in our patients,” said Lloyd G. Cantley, MD Long Professor of Medicine (Nephrology) and professor of Cellular and Molecular Physiology “Postdoc Nikil Singh developed the tools to use IMC to analyze biobanked human kidney biopsies and now Megan has brought this to a level where we're able to compare normal kidney biopsies to AKI biopsies at a cellular level.” which provides a framework and guideline for researchers and clinicians to use in thinking about how AKI happens in individual patients will assist with research and potential treatments “There has been a bit of ‘one size fits all' thinking about how we would develop therapies for AKI the injury mechanisms for different types of AKI can be quite different So we need to develop therapies that are specific for the type of injury involved and then provide those to the right patients at the right time," said Cantley The researchers found that in many cases the immune system guides what happens to the kidney after it is injured They believe they will be able to identify the pathways by which certain immune cells help repair the kidney while other immune cells can harm it and that only works for patients with kidney injury due to acute interstitial nephritis But the treatment is nonspecific,” Baker said “By categorizing the injury into these four buckets we are thinking about how the immune system affects both unique and shared pathways–and hope to identify targets for much more effective therapies in all types of AKI.” Prioritizing the types of therapy or the immune system's ability to repair the kidney could lead to new insights into improving the outcome of AKI Yale’s Section of Nephrology is committed to excellence in patient care, research, and education with the goal for both their faculty and trainees to be national and international leaders in the field of academic nephrology. To learn more about their mission and work, visit Nephrology. set against the backdrop of the historic Toji Temple and the blooming cherry blossoms Their senses of style reflect what they love most about each other, and offer some insight into their well-balanced partnership. “Koichi’s style is consistently classic and refined, which I admire. He prioritizes quality pieces and understands how to dress his body type,” Aki says. “Despite being reserved, Koichi’s passion for life is infectious. He embraces each day as a chance for discovery, and I’ve found our time together incredibly inspiring.” Koichi, meanwhile, praises Aki as a true individual in fashion and beyond. “Aki’s style is refreshingly her own. She ignores fleeting trends and dresses solely for herself, which I deeply respect. Her look is a unique, classic, and wholly individual expression,” he says. “Aki is incredibly confident and authentic. She knows who she is and embraces it—a rare and valuable trait.” Below, Aki and Koichi bring Vogue to Kyoto for Dior’s pre-fall 2025 show. Courtesy of Aki & Koichi1/14Courtesy of Aki & Koichi2/14Lunch at Kyoyamoto for a traditional Kyoto-style meal. So oishi!! Courtesy of Aki & Koichi3/14What a treat! We felt so pampered and loved thanks to the amazing team. Courtesy of Aki & Koichi4/14We feel so cool in these looks :) Thank you Dior. Courtesy of Aki & Koichi5/14Arriving at the show! Ready for our closeup. There was an error; please refresh the page or try again There are no events matching your selection Discover the people who built one of the largest and most sophisticated canal systems in the New World prior to the coming of Europeans This National Historic Landmark and museum highlights how these engineers and farmers thrived in the Sonoran Desert for millennia S'edav Va'aki has long been a special place The Museum will be closed starting May 19th for some summer renovations Pueblo Grande Museum and Archaeo​logical Park has been renamed to S'edav Va'aki Museum Please visit us to learn more about this change and how it enriches our understanding of the prehistory of Arizona Thank you for your continued support and we look forward to sharing with you Phoenix's rich cultural history ​The City of Phoenix acknowledges it is located within Native Land SVmuseum@phoenix.gov Subscribe to the monthly Phoenix resident newsletter for updates Contact Form • Phone Directory Do you require an accommodation to participate in a City program, service, or activity? 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Metrics details This study explored the relationship between acute kidney injury (AKI) and chronic kidney disease (CKD) focusing on autophagy-related genes and their immune infiltration during the transition from AKI to CKD We performed weighted correlation network analysis (WGCNA) using two microarray datasets (GSE139061 and GSE66494) in the GEO database and identified autophagy signatures by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and XGBoost were used to construct the diagnostic model and the diagnostic performance of GSE30718 (AKI) and GSE37171 (CKD) was used as validation cohorts to evaluate its diagnostic performance The study identified 14 autophagy candidate genes among which ATP6V1C1 and COPA were identified as key biomarkers that were able to effectively distinguish between AKI and CKD Immune cell infiltration and GSEA analysis revealed immune dysregulation in AKI and these genes were associated with inflammation and immune pathways Single-cell analysis showed that ATP6V1C1 and COPA were specifically expressed in AKI and CKD drug prediction and molecular docking analysis proposed SZ(+)-(S)-202-791 and PDE4 inhibitor 16 as potential therapeutic agents this study provides new insights into the relationship between AKI and CKD and lays a foundation for the development of new treatment strategies plays an important role in the development and progression of renal diseases the specific mechanism of autophagy during the transition from AKI to CKD has not yet been elucidated These studies show how effective bioinformatics is in understanding AKI and CKD mechanisms.No research has reported on the progression from AKI to CKD Since AKI significantly contributes to CKD it is essential to further investigate their relationship The roles of autophagy-related genes (ARGs) and pathways in the progression from AKI to CKD remain largely unexplored This study aimed to identify key biomarkers associated with autophagy in the AKI-CKD context and analyze their interrelationships with immune cell infiltration and related immune pathways We analyzed microarray data and clinical information for AKI WGCNA identified co-expressed gene modules associated with AKI and XGBoost—were used to find predictive genes and evaluate their expression differences between AKI and CKD We developed predictive model for AKI-CKD patients and used the ImmuCellAI algorithm to analyze immune cell composition in AKI versus controls we predicted microRNAs and transcription factors influencing regulatory networks around these genes Our findings enhance the understanding of autophagy in AKI-CKD pathogenesis The correlation between module characteristic genes and clinical phenotypes was calculated using the module eigengene to represent the overall expression level of each module allowing for the identification of key modules significantly associated with the disease phenotype To assess and compare the expression levels of the final hub gene in the AKI and CKD groups with the control group a boxplot was created using The Sangerbox online platform “Total Points” represents the cumulative scores of all genes while “Points” indicates the score of the candidate gene The model’s performance was evaluated using calibration curves that compare observed and predicted probabilities the ROC curve for each hub gene was analyzed with the sangerbox The diagnostic performance of autophagy candidate genes for AKI and CKD was determined by the significance of the AUC value with values close to 1 indicating high model accuracy sapiens,” “Official Gene Symbol,” and “TRRUST.” Following the prediction of miRNAs we conducted an enrichment analysis to elucidate the associated regulatory mechanisms Targeted searches using candidate genes were made possible by the scRNA-seq or snRNA-seq format chosen for the datasets related to AKI and CKD Bar graphs are used for the results visualization This resource enables scientists to investigate protein distribution and functionality by providing data on expression levels and subcellular localization our primary focus was placed on examining both the expression patterns and cellular distribution of ATP6V1C1 and COPA thereby establishing fundamental data for exploring its physiological and pathological roles except for those generated with R 4.4.1 software D) Genes that are significantly up- and down-regulated in acute kidney AKI and CKD are shown in red and green in the graphs E) Heatmap of the top 40 differentially expressed genes in AKI and CKD conditions where blue denotes lowly expressed genes and red denotes highly expressed genes including the number of up-regulated and down-regulated genes The vertical coordinate shows the fold change of differential genes while the horizontal coordinate shows the number of differential genes The DEGs identified in AKI using WGCNA B) The soft threshold of β = 14 was selected based on scale independence and average connectivity (C) A hierarchical clustering dendrogram of AKI and control samples (D) An adjacency heatmap of characteristic genes (E) Co-expression modules are represented in different colors below the gene tree (F) A correlation heatmap depicting the association between module genes and AKI with the “magenta” module displaying the highest correlation The upper left triangle uses color to denote the correlation coefficient while the lower right triangle uses color to indicate the p-value (G) A graph showing the correlation of “magenta” module genes and AKI Functional enrichment analysis of autophagy-related genes (A) Differential genes in CKD were identified by Limma modular genes in AKI were identified by WGCNA and the intersection of the autophagy gene set included 14 genes as shown in the Venny diagram (B–D) GO analysis covers biological processes with the vertical axis indicating GO terms and the horizontal axis indicating the proportion of genes involved in the corresponding GO process The size of the circle corresponds to the number of genes and the shade of the color indicates the p-value different colors indicate different important pathways and their related genes (F) The GeneMANIA website was used to identify functionally similar genes and to build a PPI network 20 functionally similar genes are located in the outer circle while 14 hub genes are located in the inner circle The color of the nodes correlates with protein function while the line color represents the type of protein interaction.” Three machine learning algorithms identify key diagnostic genes from autophagy-related genes B) Key genes identified by the LASSO regression with a total of 5 genes considered suitable for diagnosis (C) Forest plot showing the results of multifactorial analysis of COX based on 5 key genes (D) Validation of the diagnostic efficacy of the key genes by ROC (E) Risk score heatmap depicting the high- and low-risk differential expression profiles of the 5 genes in the training cohort (F) The results of the Random Forest algorithm are demonstrated by scoring (G) Results of the XGBOOST algorithm are shown by scoring (H) Key genes obtained through the overlap of the three algorithms are shown as Venny plots B) Differential expression of candidate genes was validated in the validation sets of AKI and CKD (C) Nomogram construction of the diagnostic model (D) Calibration curve of the diagnostic model (E–H) Diagnostic efficacy of candidate genes in the model validated by ROC curve Immune infiltration analysis of AKI and CKD versus controls (A D) Superimposed bar graphs showing the proportions of the 24 immune cell types in all samples E) Correlation heatmap of the 24 immune cell types and numbers in the graph represent correlation coefficients F) Comparison of the proportions of immune cells in AKI and CKD and controls Significance is indicated by *p < 0.05; p < 0.01; *p < 0.001 GSEA analyzed the immune-related pathways of ATP6V1C1 and COPA in AKI and CKD. Results indicated that ATP6V1C1 was elevated in AKI but decreased in CKD, while COPA showed reduced immune enrichment in both conditions (Fig. 8A-D). This implies that these proteins may differentially regulate immune cell infiltration and affect the progression from AKI to CKD. GSEA immune pathway analysis of candidate genes C) GSEA analysis of candidate genes in AKI D) GSEA analysis of candidate genes in CKD The top box represents the enrichment score of the pathway the middlebox represents the immune pathway associated with the candidate gene and the bottom box represents the expression level of the candidate gene Construction of miRNA-mRNA-TF network by candidate genes and functional enrichment analysis of miRNAs (A) miRNA-mRNA-TF network constructed based on 2 candidate genes blue squares represent predicted miRNAs and green circles represent predicted TFs (B) Pathway analysis of predicted miRNAs through online platforms is shown in the heatmap Differential expression of candidate genes in single cells (A) Cellular compartmentalization of ATP6V1C1 in the single-cell dataset (B) Expression distribution of ATP6V1C1 in normal tissues (C) Distribution of ATP6V1C1 expression in AKI tissues (D) Expression distribution of ATP6V1C1 in CKD tissues (E) Multiple histograms demonstrating the differences in cellular expression of ATP6V1C1 in normal tissues (F) Cellular fractionation of COPA in the single-cell dataset (G) Distribution of COPA expression in normal tissues (H) Distribution of COPA expression in AKI tissues (I) Distribution of COPA expression in CKD tissues (J) Multiple sets of bar graphs demonstrating the differences in cellular expression of COPA in normal tissues Expression and localization of ATP6V1C1 and COPA B) RNA and protein expression levels of ATP6V1C1 and COPA in human tissues D) Immunohistochemical analysis of ATP6V1C1 and COPA proteins in kidney F) Immunofluorescence localization analysis of ATP6V1C1 and COPA in different cell lines Green: ATP6V1C1 and COPA proteins; blue: nuclei; red: microtubules Prediction and molecular docking of therapeutic drugs for candidate genes (A) Prediction of targeting drugs for candidate genes through an online platform visualized using Cytoscape software Blue squares represent candidate genes and orange squares represent drugs (B) Molecular docking of ligand-protein and receptor drug crystals and their visualization the molecular mechanisms linking AKI to CKD remain unclear it is essential to explore the relationship between the two conditions we examined the autophagy-related biomarkers ATP6V1C1 and COPA and investigated their potential roles in the progression from AKI to CKD utilizing data from various public databases enrichment analysis revealed that crossover genes were linked to autophagy-related pathways such as “RNA methylation,” “RNA modification,” “vesicle RNA methylation,” “vesicle,” “cytoplasmic vesicle,” and “endocytosis.” Functional enrichment analysis of predicted miRNAs associated with autophagy-related genes indicated a focus on pathways including “Apoptosis,” “PI3K.AKT.mTOR signaling,” “Interactions,” and “TGF-beta signaling” The mTOR signaling pathway is vital for regulating cell growth inhibiting mTOR and protecting the kidneys leading to excessive proliferation of renal cells showing that autophagy-related genes ATP6V1C1 and COPA are up-regulated in AKI and down-regulated in CKD Single-cell analysis also reveals lower ATP6V1C1 and COPA expression in CKD fibroblasts indicating that these miRNAs modulate autophagy via the mTOR pathway influencing the transition from AKI to CKD Our research indicates that ATP6V1C1 may activate the mTOR signaling pathway through V-ATPase thereby inhibiting autophagy and facilitating the progression from AKI to CKD Targeting ATP6V1C1 may thus serve as a promising biomarker Based on our prior enrichment function studies we propose that mutations in the COPA gene may disrupt Golgi to ER retrograde translocation inhibiting the STING pathway and enhancing autophagy which could significantly influence the transition from AKI to CKD the high expression of ATP6V1C1 and COPA during AKI may impede the repair of renal tubular epithelial cells by inhibiting autophagy whereas their low expression in CKD may enhance autophagosome formation worsening fibrosis and facilitating the transition from AKI to CKD the immune response activates many naive T cells (e.g. CD8_naive and CD4_naive) and pro-inflammatory cells (e.g. while a decline in macrophages may suggest their adaptation or dysfunction in the inflammatory environment the altered immune cell composition indicates chronic adaptation reflecting a complex imbalance of cell gains and losses as well as a link between reductions in specific cells (e.g. Th2 and effector memory cells) and immunosuppression KIM-1 and NGAL are promising biomarkers for the progression from AKI to CKD; however we found that TP6V1C1 and COPA were up-regulated in AKI and down-regulated in CKD as determined by transcriptome sequencing of renal biopsies.This dynamic change suggests a more specific and sensitive predictive ability for these biomarkers The study indicates that the autophagy-related genes ATP6V1C1 and COPA may serve as biomarkers for the early detection of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) Targeting autophagy could emerge as a novel treatment strategy for both conditions as changes in immune cell composition correspond to disease stages Future research should validate these conclusions and investigate potential therapies The datasets analyzed during the current study are available in public databases such as GEO (https://www.ncbi.nlm.nih.gov/geo/) Increased risk of death and de Novo chronic kidney disease following reversible acute kidney injury[J] Acute kidney injury: medical causes and Pathogenesis[J] Acute kidney injury and chronic kidney disease as interconnected syndromes[J] Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure[J] Therapies targeting epigenetic alterations in acute kidney Injury-to-Chronic kidney disease Transition[J] Autophagy plays a critical role in kidney tubule maintenance Autophagy in proximal tubules protects against acute kidney injury[J] Autophagy and its therapeutic potential in diabetic nephropathy[J] The mTOR pathway is highly activated in diabetic nephropathy and Rapamycin has a strong therapeutic potential[J] Data driven analysis reveals prognostic genes and immunological targets in human sepsis-associated acute kidney injury[J] Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis[J] Combined plasma Olink proteomics and transcriptomics identifies CXCL1 and TNFRSF12A as potential predictive and diagnostic inflammatory markers for acute kidney Injury[J] The STAT1/HMGB1/NF-kappaB pathway in chronic inflammation and kidney injury after cisplatin exposure[J] Novel biomarkers related to oxidative stress and immunity in chronic kidney disease[J] Identification and validation of immune and cuproptosis - related genes for diabetic nephropathy by WGCNA and machine learning[J] interaction-friendly clinical bioinformatics analysis platform[J] NCBI GEO: archive for functional genomics data sets–update[J] Limma powers differential expression analyses for RNA-sequencing and microarray studies[J] The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses[J] WGCNA: an R package for weighted correlation network analysis[J] KEGG: Kyoto encyclopedia of genes and genomes[J] The genemania prediction server: biological network integration for gene prioritization and predicting gene function[J] Regularization paths for generalized linear models via coordinate Descent[J] Classification and Regression by randomForest[C] & XGBoost: A Scalable Tree Boosting System[J] Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining Can nomograms be superior to other prediction tools?[J] ImmuCellAI-mouse: a tool for comprehensive prediction of mouse immune cell abundance and immune microenvironment depiction[J] Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles[J] MiRNet 2.0: network-based visual analytics for MiRNA functional analysis and systems biology[J] A reference tissue atlas for the human kidney[J] A single-cell type transcriptomics map of human tissues[J] DGIdb 2.0: mining clinically relevant drug-gene interactions[J] The HDOCK server for integrated protein-protein docking[J] RCSB Protein Data Bank: Sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education[J] Highly accurate protein structure prediction with AlphaFold[J] Ligand Docking and binding site analysis with PyMOL and Autodock/Vina[J] From AKI to CKD: maladaptive repair and the underlying Mechanisms[J] A clinical score to predict acute renal failure after cardiac surgery[J] and the incidence and consequences of acute kidney injury: a cohort study[J] Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis[J] Mitochondria ROS and mitophagy in acute kidney injury[J] TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy[J] Mitochondrial dysfunction and the AKI-to-CKD transition[J] The ATPase subunit of ATP6V1C1 inhibits autophagy and enhances radiotherapy resistance in esophageal squamous cell carcinoma[J] Identification and validation of autophagy-related genes in Kawasaki disease[J] Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function[J] Analysis of pulmonary features and treatment approaches in the COPA syndrome[J] COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis[J] STING operation at the ER/Golgi Interface[J] New autophagy reporter mice reveal dynamics of proximal tubular autophagy[J] Cellular and molecular pathways of renal repair after acute kidney injury[J] Autophagy in acute kidney injury and repair[J] Autophagy induces prosenescent changes in proximal tubular S3 Segments[J] lymphocyte and platelet ratio as a predictor of postoperative acute kidney injury in major abdominal surgery[J] IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background[J] Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction[J] Transition from acute kidney injury to chronic kidney disease: mechanisms KIM-1-mediated phagocytosis reduces acute injury to the kidney[J] Kidney injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury[J] Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more[J] Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes[J] Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: a meta-analysis[J] Specific commensal bacterium critically regulates gut microbiota osteoimmunomodulatory actions during normal postpubertal skeletal growth and Maturation[J] Identification of neutrophil gelatinase-associated Lipocalin as a novel early urinary biomarker for ischemic renal injury[J] Download references Q L: Conceptualization.YJ W: Conceptualization The authors declare no competing interests This study does not involve human and animal experiments and does not require ethical approval Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Below is the link to the electronic supplementary material Download citation DOI: https://doi.org/10.1038/s41598-025-97269-9 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology 62.7% relative reduction in mortality at day 30 for patients treated with Auxora versus placebo in subset of patients in CARDEA with AKI LA JOLLA, Calif., March 4, 2025 /PRNewswire/ -- CalciMedica Inc. ("CalciMedica" or the "Company") (Nasdaq: CALC) a clinical-stage biopharmaceutical company focused on developing novel calcium release-activated calcium (CRAC) channel inhibition therapies for acute and chronic inflammatory and immunologic illnesses today announced that Sudarshan Hebbar delivered a plenary presentation at the 30th International Acute Kidney Injury and Continuous Renal Replacement Therapy Conference (AKI & CRRT) on March 3 The presentation outlined the role of CRAC channels in acute kidney injury (AKI) pathophysiology and included new data highlighting the potential of CalciMedica's lead product candidate CalciMedica is currently conducting a Phase 2 trial of Auxora in patients with Stage 2 or Stage 3 AKI and acute hypoxemic respiratory failure The new data presented were based on a post-hoc analysis from the previously completed Phase 2 CARDEA trial of Auxora in severe COVID-19 pneumonia The study included 38 patients who enrolled with AKI defined as an estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73 m² in addition to moderate or severe respiratory failure This reduction in mortality in the patient subset with AKI exceeded that of the entire study population a 56.3% (p = 0.017) relative reduction versus placebo in mortality at day 30 was observed with an absolute reduction of 9.9% versus placebo Hebbar also summarized previously disclosed data supporting the role of CRAC channel inhibition as a potential therapeutic mechanism in AKI the biological rationale for CRAC channel inhibition as a potential therapeutic mechanism for AKI is compelling," said Sudarshan Hebbar "The post-hoc analysis from CARDEA is especially relevant given that the 62.7% relative reduction in mortality was observed in patients with both kidney failure and respiratory failure which mirrors the intended patient population for our ongoing Phase 2 KOURAGE study." The presentation is now available on the Medical Events & Presentations section of CalciMedica's IR website at https://ir.calcimedica.com/news-events/medical-events-publications The forward-looking statements contained herein are made as of the date hereof and CalciMedica undertakes no obligation to update them after this date Contact InformationArgot PartnersSarah Sutton/Kevin Murphy[email protected](212) 600-1902 ("CalciMedica" or the "Company") (Nasdaq: CALC) a clinical-stage biopharmaceutical company focused on developing novel calcium.. Health Care & Hospitals Medical Pharmaceuticals Pharmaceuticals Biotechnology Do not sell or share my personal information: DUBAI, UAE, April 24, 2025 /PRNewswire/ -- Building on an entrepreneurial spirit spanning more than four decades, Al Khayyat Investments (AKI) has inaugurated a state-of-the-art Fulfilment & Innovation Centre in Dubai Industrial City that will serve as a cornerstone for the company's continued regional expansion The 1 million sq ft facility not only quadruples AKI's fulfilment capacity but also raises the benchmark for agile sustainable supply chain operations in the UAE It already handles over half a million units per day with the capacity to scale up to one and a half million units The site also includes provisions to expand by nearly 200,000 sq ft in the near future The centre will serve more than 30,000 business customers as well as support home delivery services for consumers across the UAE who enjoy AKI's retail and e-commerce offerings The centre builds on the goals set out in the Dubai Economic Agenda (D33) to capitalise on Dubai's strategic location and advanced infrastructure to raise the city's status as a preferred destination for major international companies and investments the UAE has set out fresh plans to strengthen the country's position as a leading hub for global trade and raise the value of its logistics sector to beyond AED200 billion annually over the next seven years AKI has continuously expanded its supply chain infrastructure over more than four decades in-house capability enables AKI to meet ever-increasing customer expectations across multiple sectors including pharmaceuticals notes: "AKI was founded on a spirit of smart agility and entrepreneurial energy This new Fulfilment & Innovation Centre carries forward these values as we aspire to seize new opportunities over the coming decades Yet this facility is not just about enhancing our own operations It is a strategic investment that creates long-term value for our partners and customers while contributing to the UAE's future-focused economy it represents the power of our people driving our business forward every day." "Dubai Industrial City is proud to be the home of AKI's new fulfilment centre," says Saud Abu Alshawareb Executive Vice President – Industrial at TECOM Group PJSC "Our district's proximity to Jebel Ali Port and an Etihad Rail freight terminal enables connectivity for Al Khayyat Investments' new fulfilment centre and sets it up for long-term success Home to more than 1,100 manufacturing champions and 350 operational factories Dubai Industrial City is committed to supporting such strategically significant projects adds: "This facility is a testament to the extraordinary teams within AKI who embrace diverse thinking to push boundaries and set the benchmark in supply chain excellence The facility will truly redefine AKI's position within the UAE market ensuring swifter and more efficient distribution capabilities for our growing business ecosystem."  The centre's design reinforces how AKI is leading the way in digital transformation and sustainability within supply chain operations Cutting-edge technologies and smart processes are set to increase AKI's supply chain and fulfilment productivity With excellent connectivity to major transport and logistics networks the facility allows for unrestricted movement of cargo to and from all major ports as well as the eagerly anticipated expansions to Maktoum International Airport Photo: https://mma.prnewswire.com/media/2672446/AKI_fulfilment_centre.jpg View original content to download multimedia:https://www.prnewswire.com/news-releases/aki-sets-the-stage-for-continued-growth-with-next-generation-fulfilment-centre-302437261.html We’d like to share more about how we work and what drives our day-to-day business How we use your information depends on the product and service that you use and your relationship with us To learn more about how we handle and protect your data, visit our privacy center Read our editorial policy to learn more about our process by Bobby Corser (KATU) — The Gresham-Barlow School District has announced that Aki Mori will be the next principal of Gresham High School who is currently the principal of Raleigh Park Elementary in the Beaverton School District He previously served as principal at McKinley Elementary in Beaverton and has six years of experience as an assistant principal at the high school level we've found a leader whose comprehensive administrative expertise is matched by an exceptional talent for building bridges," said Interim Superintendent John Koch "His commitment to understanding every individual coupled with his extensive experience in K-12 education He's precisely the person to champion an inclusive environment where every student and each staff member can thrive." RELATED | Critical weeks ahead could decide the future of Portland Public Schools The selection process for the new principal was extensive extremely intelligent individual," said Cook "He has a wealth of knowledge in all areas of education He will be a pillar of this community." Mori's background includes teaching at the middle and high school levels in special education roles He holds an initial administrator's license from Concordia University a master’s degree in special education from the University of California and a bachelor’s degree in business administration from Georgetown University Mori understands the challenges of growing up in a multicultural and multilingual household and has worked to support students and families facing similar barriers Mori will officially begin his role as principal on July 1 who is currently serving as the interim principal The values we cherish are under attack by leaders who see public service as a personal platform and citizenship as a commodity Jacob Aki is the senior public affairs manager for Alaska Airlines and Hawaiian Airlines. He also works as a communications, political and public relations consultant. The opinions expressed are his own and do not reflect the views of Civil Beat, Alaska Airlines, Hawaiian Airlines, or any of the firms or clients he represents. He can be reached at jacob@jacobaki.com President Trump’s address to Congress on Tuesday was meant to serve two clear purposes: to give the American people an honest assessment of where we stand and to lay out a real plan for where we’re going It was a chance to show leadership — to unify inspire and provide a roadmap for the future What America got was something entirely different: a chaotic mix of personal grievances revisionist history and a stunning obsession with his predecessor This is not about Republican versus Democrat Trump’s address was a failure of leadership Trump mentioned Biden by name at least 13 times — more than any modern president has ever invoked their predecessor in an address to Congress If Trump really wanted to signal a clean break and a bold new direction why was he so consumed with settling old scores A confident leader lays out a vision for the future — Trump clung desperately to the past This wasn’t a roadmap for progress — it was a personal airing of grievances interrupted only by bizarre detours like an off-the-cuff pitch to the people of Greenland to consider becoming part of the United States What does Greenland have to do with inflation border security or the real struggles facing American families Americans voted for change last November — they wanted a leader who would put America first What they got was a president more interested in putting himself and his wealthy friends first Nothing made that clearer than Trump’s Gold Card program — a plan to literally sell American citizenship for $5 million While working immigrant families follow the rules and wait years for a shot at the American Dream Trump is auctioning off citizenship like it’s a VIP club membership — a fast pass for the global elite It’s not just hypocritical — it exposes the rot at the core of Trump’s vision: in his America and everyone else is left to fend for themselves That same warped logic shaped Trump’s approach to the economy With inflation squeezing families across the country he bragged about gutting environmental protections cutting clean energy investments and slashing foreign aid — as if those things will lower grocery bills As if taxing imports will magically fix inflation and revive manufacturing all at once Tariffs are just taxes on working families — driving up prices on everything from food to gas to basic household goods This wasn’t a plan for economic recovery — it was economic isolationism wrapped in patriotic slogans But the speech didn’t stop at economic malpractice Trump’s culture war was front and center — attacking diversity dismissing climate action as a “green new scam,” and pulling the United States out of global agreements our communities rely on to fight climate change and protect our future exclusion and environmental destruction — is the exact opposite of what most Americans want We understand that our strength comes from diversity from partnerships and from protecting the places we call home What made Trump’s address even more alarming was its tone Presidential addresses to Congress are supposed to be a blueprint for governance — this was a hit list of enemies It’s grievance politics at its worst — the rhetoric of a man who sees the presidency not as public service If this address is any indication of what the next four years will look like we should prepare for government by chaos — where public service becomes self-service and leadership serves only the wealthy and well-connected It’s about the kind of country we want to leave for the next generation Do we want leadership that lifts up every family — or a government that sells citizenship to billionaires while slamming the door on working people Do we want leaders who build a future together — or leaders who pit us against each other responsibility and a commitment to each other It’s about understanding that our strength comes from our diversity It’s about honoring our kuleana to care for the land and for each other knowing that the success of one is tied to the success of all We must stand firm in the values that have carried us through generations Trump’s speech wasn’t just a missed opportunity — it was a warning The values we cherish — here in Hawaiʻi and across the country — are under attack by leaders who see public service as a personal platform and citizenship as a commodity we must stand firm in the values that have carried us through generations We must demand leadership that serves all people — not just those who can afford to buy their way in We must show the rest of the country what real strength looks like: strength rooted in community Because if we allow the presidency to become nothing more than a personal soapbox — where citizenship is for sale and leadership is reduced to petty grievances — we won’t just lose a policy fight We will lose the very heart of our democracy that is something we cannot and will not allow Honolulu Civil Beat is a nonprofit organization and your donation helps us 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We want to showcase smart ideas about the future of Hawaiʻi, from the state's sharpest thinkers, to stretch our collective thinking about a problem or an issue. Email news@civilbeat.org to submit an idea Sign up for our FREE morning newsletter and face each day more informed Upadacitinib as New Treatment for Giant Cell Arteritis Filling the Gap: Creating a Prognostic Staging System for Patients Treated With Neoadjuvant Chemotherapy RFK Jr.’s Vaccine Policies Spark Alarm Among Public Health Experts Editorial Policy Advertising Contact Us eNewsletters Contribute Career Center MashupMD Blood Cancers Today Cancer Nursing Today GU Oncology Now Urban Health Today Aki’s BreadHaus and WunderBar is the biggest event in Minnesota German culinary culture in ages Brown as chestnuts, sparkling with salt, tied in pious and festive loops, clustered on a custom-built pegboard—are these the most beautiful pretzels in the world? Walk in the door to Aki’s BreadHaus and WunderBar now in its new location on Marshall in Nordeast near the river warm and fresh from the oven or warmed to order and it’s everything a pretzel ever could be: a tender bloom of soft dough in parts They’re everywhere and easy to spot once you clue in to the distinct handmade style: fat in the center with thinner crossed arms so you get both tender and crisp bits (machine-made ones these pretzels are dipped in culinary lye that bakes away leaving an outer millimeter of tensile tautness and pleasant bitterness as your animal inside roars up: This is it the march from just born to popular; today it’s spun in dough And it’s easy to see everything that’s amazing about these pretzels except this: Why is Minnesota so gonzo for pretzels And here’s a strange question: If you’re having pretzels and a beer Quick pretzel history: The first record we have of a pretzel is a fifth-century ancient manuscript owned by the Vatican It shows the familiar crossed arms of dough which were thought to represent praying and were thus a good thing to get you through a fasting day—when you could not eat meat or dairy—back when there used to be hundreds every year but which we now mainly associate with Lent Pretzels predate the nation we call Germany pretzels were the symbol of what we now call the German bakers’ guild and hung symbolically outside bakeries so people who couldn’t read would know: Pretzels Some food scholars say that as France is to baguettes It was the 2018 American Community Survey that pointed out how very many of us count a German ancestor a full 1.8 million of the 5.8 million souls here in the North Star State with those of us with Norwegian ancestors (810,300) vastly outnumbered and Irish (516,500) and Swedish (429,800) outnumbered even more the new jazz club that sounds awfully German though its menu is essentially Italian.) In a largely German state But if we call a brat and a beer and a pretzel German culinary culture—the implications Joachim “Aki” Berndt tying pretzels and a board of tied and baked gems and a bag of hard pretzels—pretzels in a bag being the shelf-stable skinny pretzel arms in a soft pretzel—that’s us every steamy winter kitchen packed with a couple parents and a dozen teenagers after cross-country practice That’s the meal you can build out of any decent small-town gas station “I was in my car breathing air,” for we take that as understood What if the question is not about why we have so few German restaurants but really: When we’re sitting in our backyards with a beer and a brat and pretzels are we all existing in a perpetual self-replenishing German quick-serve restaurant and biergarten and no one has ever noticed We might have been… at least until the rocketing success of Aki’s threw it all into view I thought about this as I pulled open the doors at Aki’s new location First things to notice: walls of North Sea blue a variety of tables and comfy seating such as couches piled with pillows I think of as generally Scandinavian I made a note to bring an interior designer here to tell me how the chic interior a lot of what you see was indeed handmade by a contemporary German spent five years of his early life as a cabinetmaker in Mönchengladbach not too far from the borders of both Belgium and the Netherlands the window-box cabinetry that allows you to see from bar to baking floor you’ll also see some of his photos of 1990s East and West Berlin as well as some charming childhood photos of the baker in lederhosen A former architectural engineer laid off during the 2009 Great Recession Berndt taught himself to bake after hunting for a local bread like the kind he grew up with in Germany One naïve neighbor told him to try one chain bakery and he discovered pumpernickel that he thought tasted like dyed white bread Someone else sent him to another chain bakery where he thought the breads all tasted like cake he purchased some flour and turned to the website Breadtopia where he bought a sourdough starter nursed along by an Iowan since 1974 (Aki’s is still at the farmers’ markets in Maple Grove and New Brighton.) After finding frequent customers and wondering if bread might be a new life path he spent a year working in bread production at a local co-op and liked what he lived where news of his pretzels was shouted through the town drowning out the quieter story of his excellent breads which are tucked into the shelves at the new Aki’s are as good as bread gets on this earthly plane I’m thinking specifically of the Bauernbrot a rye- and wheat-flour sourdough that does that thing great breads do: offers fragrance and complexity as resonant as those offered by good wine There’s a mushroomy meatiness to the bread the aroma of hazelnut and toasted marshmallow It’s elemental: earth and the wind above the earth The three-day sourdough is so moist and airy so subtle from the three days the little sour beasties took to eat everything they wanted to eat it’s like an exercise in tasting the difference between a new wine and an aged one A few of the ever-changing open-faced sandwiches from WunderBar The 100 percent rye pumpernickel is in the Danish style remarkably tangy with sour of the sourdough starter fragrant like someone handed you an apricot plucked from wine casks while you were in a windy fall meadow noticing the smoke of a distant bonfire—that sort of thing This pumpernickel is the necessary ingredient for all of you wanting to put out smørrebrød spreads your good gouda deserve bread this thick and good Aki Berndt’s favorite bread is his tangy currant rye absolutely stuffed with fruit baked so that some of the currants swell up with sweet moisture and others go black within the crust This creates a rainbow of currant flavors in every slice like a Christmas stollen for people who have no sweet tooth but do have an average Wednesday morning to humbly glorify and now it is my Sunday bread,” Berndt told me as he shaped pretzels as fast as a woodpecker pecks wood He worked on one of the half a dozen maple butcher-block bread tables that now produce the Twin Cities’ most significant German artisanal breads Breads that you can have as part of a sandwich now Welcome to the domain of Aki Berndt’s new business partner Nancy Marone It’s easy to confuse her with Berndt’s wife Nancy “Do you want to buy a German bakery?” Not exactly She’s doing something I appreciate a lot: bringing a handful of good German and Austrian wines to Berndt’s excellent breads and pretzels and making a humble little affordable restaurant who ran the long-gone Countryside Family Restaurant in Roseville for 40 years He makes a ham and cabbage soup supremely velvety and hearty with your choice of a pretzel stick or brötchen Get the warm sandwiches made with Aki’s bread and smashed in a panini press with good cheese and more—maybe gouda or the outrageously fun “pretzel quiche,” which is basically a pinched pretzel filled with egg and cheese—so rich My teenage son pushed away from his pretzel quiche “I wish this was near our house!” For less than a movie ticket he got more good food than he could finish or at least like a German baker around the year 1111 A Schwedhelm Scheurebe is a silky white German wine offering flourishes of thyme and apricot from within its well-knit delicacy Aki’s WunderBar also offers an Alsatian Gewürztraminer from Gustave Lorentz which tinkles with the sort of lively pie spice and energy you want beside a platter of good charcuterie and breads The spot opened with an Austrian sparkling rosé from outside the northern European wine strongholds Nancy Marone is unsure what people really want and is eager to find customers I’ve always heard that Minnesota buys more German wines than almost anywhere in the country except New York There’s a once-in-a-generation opportunity to go and raise our voices Longtime friends and now business partners Nancy Marone and Aki Berndt Berndt is currently brewing a WunderBier in collaboration with next-door neighbor Broken Clock Brewing Berndt says it will be a northern German–style pilsner which will be hoppier than a typical pilsner and good with… pretzels He started out in pursuit of bread—it’s Aki’s BreadHaus not Aki’s PretzelHaus—and he’s found himself clinging to the runaway stallion of the pretzels going and going As he flips and whips tray after tray of pretzels he makes a very German face of: Many things happen because I know that no matter what I write about the excellence of the Bauernbrot and currant bread what’s really going to happen at Aki’s WunderBar is that people are going to go and sit at the tables in the mornings and type out their emails with one eye on the pretzel pegboard and when bakers come out to load up fresh pretzels and that’s what Aki’s WunderBar will be famous for people are going to go for a beer and a hot pretzel just ask yourself: Are you one of the 1.8 million Minnesotans with a German ancestor Some Berlin Jews from a line of family I never met fled Germany in the 1880s though I never stopped before today to wonder: Is this why I just really really like to stand at a party near the bowl of Old Dutch pretzel sticks who likely guessed his name was famous in the wrong ways because of an unrelated sound-alike fellow German and so blended into the melting pot of Minnesota that melting pot that I didn’t realize was so very bobbing with pretzels until I stepped into a bit of new wunder by the river Dara Moskowitz Grumdahl was born in New York City little aware of her destiny—to live well in Minnesota She has six James Beard Awards out of 15 nominations Key Enterprises LLC is committed to ensuring digital accessibility for mspmag.com for people with disabilities. We are continually improving the user experience for everyone, and applying the relevant accessibility standards one of the Valley’s oldest stories is still being told The S’edav Va’aki Museum — formerly known as the Pueblo Grande Museum — sits on a preserved archaeological site more than 1,500 years old Designated as a National Historic Landmark and a Phoenix Point of Pride the museum offers a unique view into the lives of the ancient Hohokam people “You’re standing right next to the platform mound at the site of S’edav Va’aki,” said Christopher Schwartz and this is the largest and most centrally located one in the city.” Visitors can walk the grounds and explore the remnants of rooms and courtyards once part of a multi-level structure believed to reach up to 30 feet tall building an extensive canal system that forms the foundation of nearly half of Phoenix’s current irrigation infrastructure guests can learn more about Hohokam culture — from tools and pottery to farming techniques and daily life their legacy remains etched into the land beneath our feet Report a typo Global Lead Partner The NEUTRALIZE-AKI trial is evaluating the safety and efficacy of the Company’s proprietary therapeutic Selective Cytopheretic Device (SCD) in patients with acute kidney injury (AKI) in the intensive care unit (ICU) receiving continuous renal replacement therapy (CRRT) “We are pleased to welcome the 14th hospital to our trial especially as this site has been among the top CRRT programs in the country,” said Kevin Chung 70 of the planned 200 subjects have been enrolled We plan to conduct an interim analysis at the trial’s 90-day primary endpoint with the first 100 subjects we anticipate a Data Safety Monitoring Board (DSMB) recommendation on the interim results by mid-2025.” total addressable market for the SCD in adult AKI at $4.7 billion to $6.3 billion This significant market opportunity represents a highly attractive return on a clinical trial estimated to cost SeaStar Medical approximately $15 million with some of those costs already incurred,” said Eric Schlorff “AKI is one of several high-value indications for our SCD that we plan to pursue As we work to increase accessibility of our therapeutic device among those afflicted with potentially life-threatening hyperinflammation we believe that our clinical data showing reduced mortality and probable savings for the healthcare system will encourage adoption by the medical community.” Food and Drug Administration (FDA) Breakthrough Device Designation for adults with AKI which is awarded to a therapy to treat a serious or life-threatening condition with preliminary clinical evidence indicating it may demonstrate substantial improvement over available therapies on clinically significant endpoints the Centers for Medicare & Medicaid Services granted Category B coverage for certain expenses incurred by medical centers when treating Medicare or Medicaid patients enrolled in NEUTRALIZE-AKI The NEUTRALIZE-AKI (NEUTRophil and monocyte deActivation via SeLective Cytopheretic Device – a randomIZEd clinical trial in Acute Kidney Injury) is expected to enroll up to 200 adults The trial’s primary endpoint is a composite of 90-day mortality or dialysis dependency among patients treated with SCD in addition to CRRT as the standard of care compared with the control group receiving only CRRT standard of care Secondary endpoints include mortality at 28 days major adverse kidney events at Day 90 and dialysis dependency at one year The study will also include subgroup analyses to explore the effectiveness of SCD therapy in AKI patients with sepsis and acute respiratory distress syndrome Acute Kidney Injury (AKI) and Hyperinflammation AKI is characterized by a sudden and temporary loss of kidney function and can be caused by a variety of conditions such as COVID-19 which is the overproduction or overactivity of inflammatory effector cells and other molecules that can be toxic Damage resulting from hyperinflammation in AKI can progress to other organs and potentially to multi-organ dysfunction or even failure that could result in worse outcomes these patients may face complications including chronic kidney disease or end-stage renal disease requiring dialysis Hyperinflammation may also contribute to added healthcare costs such as prolonged ICU stays and increased reliance on dialysis and mechanical ventilation The Selective Cytopheretic Device (SCD) is a patented cell-directed extracorporeal device that employs immunomodulating technology to selectively target proinflammatory neutrophils and monocytes during CRRT and reduces the hyperinflammatory milieu including the cytokine storm Unlike pathogen removal and other blood-purification tools the SCD is integrated with CRRT hemofiltration systems to selectively target and transition proinflammatory monocytes to a reparative state and promote activated neutrophils to be less inflammatory This unique immunomodulation approach may promote long-term organ recovery and eliminate the need for future renal replacement treatment (RRT) The SCD has been awarded FDA Breakthrough Device Designation in four indications: is being commercialized following FDA approval for children with AKI and sepsis or septic condition weighing 10 kilograms or more who are being treated in the ICU with RRT QUELIMMUNE was approved in February 2024 under a Humanitarian Device Exemption (HDE) application having met the applicable criteria with clinical results showing safety and probable clinical benefit in a limited population of critically ill children with AKI who have few treatment options This press release contains certain forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995 Words such as “believe,” “project,” “expect,” “anticipate,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” “will be,” “will continue,” “will likely result,” and similar expressions are intended to identify such forward-looking statements Forward-looking statements are predictions projections and other statements about future events that are based on current expectations and assumptions and are subject to significant risks and uncertainties that could cause the actual results to differ materially from the expected results Most of these factors are outside SeaStar Medical’s control and are difficult to predict Factors that may cause actual future events to differ materially from the expected results include but are not limited to: (i) the risk that SeaStar Medical may not be able to obtain regulatory approval of its SCD product candidates; (ii) the risk that SeaStar Medical may not be able to raise sufficient capital to fund its operations including current or future clinical trials; (iii) the risk that SeaStar Medical and its current and future collaborators are unable to successfully develop and commercialize its products or services or experience significant delays in doing so including failure to achieve approval of its products by applicable federal and state regulators (iv) the risk that SeaStar Medical may never achieve or sustain profitability; (v) the risk that SeaStar Medical may not be able to access funding under existing agreements; (vi) the risk that third-parties suppliers and manufacturers are not able to fully and timely meet their obligations (vii) the risk of product liability or regulatory lawsuits or proceedings relating to SeaStar Medical’s products and services (viii) the risk that SeaStar Medical is unable to secure or protect its intellectual property and (ix) other risks and uncertainties indicated from time to time in SeaStar Medical’s Annual Report on Form 10-K including those under the “Risk Factors” section therein and in SeaStar Medical’s other filings with the SEC The foregoing list of factors is not exhaustive Forward-looking statements speak only as of the date they are made Readers are cautioned not to put undue reliance on forward-looking statements and SeaStar Medical assumes no obligation and does not intend to update or revise these forward-looking statements Alliance Advisors IRJody Cain(310) 691-7100Jcain@allianceadvisors.com Metrics details Acute Kidney Injury (AKI) is a common condition with significant impact on morbidity This study explores the epidemiology of AKI In a retrospective study we evaluated patients admitted to hospital from 2016 to 2019 excluding those with pre-existing chronic kidney disease (CKD) stages 4–5 Data were extracted from hospital databases with AKI defined by changes in serum creatinine (sCr) according to KDIGO criteria AKI was classified as “de novo” or as AKI on CKD in the subgroup of patients with available pre-hospital eGFR and had significantly higher mortality (17.7% vs AKI was associated with in-hospital mortality (HR 1.23 Considering the 34,285 patients (39% of the total cohort) with pre-hospital eGFR AKI occurred in 17.3% patients without previous CKD and in 31.1% of patients with previous CKD These patients presented higher incidence of ICU admission and mortality 17.6% of AKI patients had persistent kidney dysfunction at discharge often requiring extended hospitalization and ICU care The substantial impact of AKI on both short- and potentially long-term health emphasizes the importance of early detection and structured follow-up to enhance outcomes and reduce CKD progression risk there is an urgent need for new studies to accurately assess the actual incidence of AKI This would provide hospitals and policymakers with the necessary data to develop integrated healthcare strategies aimed at reducing AKI-related costs This study aimed to assess in-hospital incidence of AKI using a standardized epidemiologic model paving the way for improved AKI recognition and biomarker discovery to better understand the progression from AKI to CKD We performed a retrospective observational study in patients aged ≥ 18 years hospitalized at the Policlinico Universitario “San Martino” Genova (Italy) and at the Azienda Ospedaliera Universitaria “Maggiore della Carità” Patients were included at the time of first hospital admission All subjects with chronic kidney disease (CKD) stage 4 and 5 identified by the ICD- 9-CM (International Classification of Disease Clinical Modification) diagnosis codes reported on the Hospital Discharge Form (HDF) and/or in regular outpatient clinic pre-dialysis follow-up were not included in the research algorithm Both institutional review boards approved the study protocol (Genova: N Registro CER Liguria: 515/2020; Novara: Protocollo 530/CE CE 220/19 NOV-AKI Study) and waived the need for informed consent The study was performed in accordance with the Declaration of Helsinki The values of sCr were collected at different time points: hospital admission peak and nadir levels during hospitalization Only patients with at least two sCr determinations were admitted to the study AKI incidence was then determined based on changes in sCr calculated as the ratio of peak sCr to the lowest sCr during hospitalization (peak sCr/lowest sCr) Urine output was not considered due to the retrospective nature of the study and to the limited collected data outside the Intensive Care Unit (ICU) we were unable to determine which patients required dialysis during hospitalization considering their low baseline creatinine levels—potentially influenced by dialysis—were classified within the AKI stage 3 group we also collected sCr and estimated Glomerular Filtration Rate (eGFR by using CKD-EPI Formula) performed from day 7 to 180 before hospitalization to identify pre-existing CKD defined as eGFR < 60 ml/min/1.73 m2 in the subgroup of patients with available pre-hospital eGFR we differentiated and compared patients with “de novo” AKI defined as an AKI episode in absence of pre-existing CKD and AKI on CKD defined as AKI that developed in patients with pre-existing CKD AKI persistence or recovery were defined by calculating the ratio between sCr at discharge and the lowest sCr during hospitalization (discharge sCr/lowest sCr): since the inclusion in the KDIGO criteria requires a discharge sCr/lowest sCr ≥ 1.5 we considered patients with persistent AKI accordingly patients with a ratio < 1.5 were classified as recovery AKI The following outcomes were considered: a) incident in-hospital AKI; b) overall mortality; c) length of hospital stay (LOS); d) type of hospital discharge (protected vs at home); e) persistence or recovery AKI at hospital discharge Normally distributed variables are presented as mean ± 1SD and compared using an independent or paired t-test as appropriate Logarithmically transformed values of skewed variables were used for the statistical analysis Comparisons between groups were made by analysis of variance Comparisons of proportions were made using the χ2-test or Fisher’s exact test when appropriate Univariate and multivariate logistic regression analyses were used to describe the relationship between all available clinical variables of biological relevance and the presence of AKI Odds ratios and 95% confidence intervals were calculated by exponentiation of logistic regression coefficients Time-to-event analyses were performed using: (i) the Kaplan–Meier method for survival curves estimation and log-rank test to compare them; (ii) univariate and multivariate Cox regression models: risk was reported as hazard ratios (HR) along with their 95% confidence intervals (CI) Covariates included all available clinical variables with biological plausibility The time variable was defined as the interval time between the baseline date and the date of endpoint occurrence or the last available follow-up Power analysis showed that the number of individuals in the database (n = 87,087) represented a sample largely sufficient to avoid b error also after stratification by AKI Statistical calculations were performed by STATA package The null hypothesis was rejected for values of p < 0.05 we found that patients experiencing AKI showed higher sCr levels (1.55 ± 1.53 vs 1 ± 1 mg/dl p < 0.001) and lower eGFR (81.6 ± 16 vs 91 ± 15 ml/min p < 0.001) when compared with the No-AKI group AKI incidence was significantly higher in patients admitted to ICU (47%) and emergency wards (25%) compared with general internal medicine and surgery units (10.4% and 16% The in-hospital mortality rate was significantly higher in the AKI group compared to the No-AKI group (Table 3) we observed that a higher number of AKI patients were admitted to ICU compared to low- and medium-intensity care settings These patients also experienced a significantly longer LOS compared to No-AKI patients AKI patients still exhibited elevated sCr levels and required a higher number of protected follow-up to ensure the continuity of care Kaplan–Meier curves of 90-day survival according to AKI development AKI stage distribution according to age quartiles Kaplan–Meier curve of 90-day survival according to AKI stages Pre-hospitalization sCr levels were available in 34,285 patients These patients were analyzed to compare the clinical characteristics and outcomes of de novo AKI and AKI superimposed on pre-existing CKD 24,588 patients (71.8%) had no previous CKD while 9697 patients (28.2%) presented with CKD before hospital admission AKI on CKD patients were older, prevalently males and with a higher prevalence of diabetes and HF (Table 7) Kaplan–Meier curves of 90-day survival in accordance with the presence of pre-existing CKD This analysis was restricted to patients with available pre-hospitalization eGFR (n = 34,285) There was no significant difference in sex distribution between these two groups patients with persistent AKI were slightly but significantly younger and a lower prevalence of CKD compared to those who recovered patients who recovered from AKI had significantly higher sCr levels compared to those with persistent AKI with a higher incidence of stages 2–3 AKI in the persistent AKI group (persistent severe AKI) This supports the reliability of using sCr changes alone to define AKI This highlights the need for further research on AKI in non-critically ill patients an area currently underexplored in global AKI research in accordance with this selection strategy that excluded stages 4–5 CKD only patients with mild forms of CKD were included to ensure accuracy in estimating pre-hospitalization kidney function we focused on comparing the characteristics and outcomes of de-novo AKI and AKI on CKD exclusively within the subgroup of patients with available pre-hospitalization eGFR our findings confirmed that individuals with pre-existing mild CKD exhibited a higher incidence of AKI and presented with elevated sCr at admission They also developed more severe forms of AKI highlighting the role of even mild CKD as an additional risk factor for AKI and its complications our data pertains to a general hospital population where ICU admissions represent a small minority these patients should receive specialized nephrological follow-up to optimize post-AKI care creating biobanks to preserve plasma and urine samples for biomarker discovery would be a key step forward in improving AKI management and outcomes the impact of AKI on mortality during hospitalization and CKD progression after discharge will likely worsen The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury Long-term remote organ consequences following acute kidney injury Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis Acute Kidney Injury: Gateway to Chronic Kidney Disease The Economic Consequences of Acute Kidney Injury Esposito, P. et al. Recognition patterns of acute kidney injury in hospitalized patients. Clin. Kidney J. https://doi.org/10.1093/ckj/sfae231 (2024) Acute kidney injury in elderly patients: Narrative review on incidence Incidence and Outcomes in Acute Kidney Injury Acute Renal Failure in the Medical Intensive Care Unit: Predisposing Acute kidney injury in the critically ill: an updated review on pathophysiology and management Spectrum of acute renal failure in the intensive care unit: The PICARD experience Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: A multinational cross-sectional study Global epidemiology and outcomes of acute kidney injury Challenges in the Care of Patients with AKI Receiving Outpatient Dialysis: AKINow Recovery Workgroup Report A comprehensive description of kidney disease progression after acute kidney injury from a prospective Association of an Acute Kidney Injury Follow-up Clinic With Patient Outcomes and Care Processes: A Cohort Study International Classification of Diseases - 9th revision - Clinical Modification 2007. https://www.salute.gov.it/portale/documentazione/p6_2_2_1.jsp?lingua=italiano&id=2251 Changes of Acute Kidney Injury Epidemiology during the COVID-19 Pandemic: A Retrospective Cohort Study A prospective cohort study of acute kidney injury and kidney outcomes AKI: An increasingly recognized risk factor for CKD development and progression The link between acute kidney injury and chronic kidney disease Epidemiology and Outcomes in Community-Acquired Versus Hospital-Acquired AKI Community-acquired acute kidney injury: A challenge and opportunity for primary care in kidney health Saraiva, I. E. et al. Risk Factors and Outcomes Associated With the Development of Persistent Acute Kidney Injury in Non-Renal Solid Organ Transplant Recipients: Systematic Review and Meta-Analysis. Clin. Transplant. https://doi.org/10.1111/ctr.15444 (2024) Update on persistent acute kidney injury in critical illnesses Transient and Persistent Acute Kidney Injury and the Risk of Hospital Mortality in Critically Ill Patients Distribution of Acute and Chronic Kidney Disease Across Clinical Phenotypes for Sepsis Renal Functional Reserve and Renal Recovery after Acute Kidney Injury Persistent decrease of renal functional reserve in patients after cardiac surgery-associated acute kidney injury despite clinical recovery Chronic kidney disease and the global public health agenda: An international consensus Franzin, R. et al. Targeting Premature Renal Aging: From Molecular Mechanisms of Cellular Senescence to Senolytic Trials. Front. Pharmacol. https://doi.org/10.3389/fphar.2021.630419 (2021) Serum creatinine changes associated with critical illness and detection of persistent renal dysfunction after AKI Reduced production of creatinine limits its use as marker of kidney injury in sepsis Biomarkers of acute kidney injury: From discovery to the future of clinical practice Esposito, P. et al. Renal Outcomes of Dialysis-Dependent Acute Kidney Injury in Noncritically Ill Patients: A Retrospective Study. Blood Purif https://doi.org/10.1159/000517707 (2022) Acute Kidney Injury in the Outpatient Setting Associates with Risk of End-Stage Renal Disease and Death in Patients with CKD AKI!Now Initiative: Recommendations for Awareness Kashani, K. B. et al. Digital health and acute kidney injury: consensus report of the 27th Acute Disease Quality Initiative workgroup. Nat. Rev. Nephrol. https://doi.org/10.1038/s41581-023-00744-7 (2023) Download references Authors are members of the AKI and Extracorporeal Blood Purification Therapies of the Italian Society of Nephrology (SIN); VC is vice-chair of the ERAKI Working Group of the European Renal Association (ERA) Department of Internal Medicine and and Medical Specialties (DIMI) Nephrology and Kidney Transplantation Unit Department of Translational Medicine (DIMET) Alessandro Domenico Quercia & Erika Naso Department of Precision and Regenerative Medicine and Ionian Area Department of Cardiac Thoracic Vascular Sciences and Public Health Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico The AKI and Extracorporeal Blood Purification Therapies Project Group Giuseppe Castellano & Vincenzo Cantaluppi or interpretation of data: all the authors All the authors give their agreement for all aspects of the work and ensure the accuracy and integrity of any part of the work Download citation DOI: https://doi.org/10.1038/s41598-025-96236-8 Sign up for the Nature Briefing newsletter — what matters in science Metrics details Acute kidney injury (AKI) is in rapid prevalence nowadays the underlying mechanisms have not been clarified Several reports showed a cluster of differentiation-44 (CD44) its role in AKI has not been clearly clarified we found CD44 increased in renal tubules in AKI mice Gene ablation of CD44 improved mitochondrial biogenesis and fatty acid oxidation (FAO) function further protecting against tubular cell death and kidney injury ectopic CD44 impaired mitochondrial homeostasis and exacerbated tubular cell apoptosis to aggravate AKI progression we found that CD44 induces mitogen-activated protein kinase (MAPK) and NF-κB p65 signaling Lipidomics also showed that CD44 interfered with multiple aspects of lipid metabolism We deeply investigated NF-κB p65 inhibited the transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) resulting in mitochondrial dysfunction and cell apoptosis CD44 also facilitated iron intake to assist cell ferroptosis our study provided a new mechanism for AKI and demonstrated that targeted inhibition on CD44 could be a promising therapeutic strategy to resist AKI to clarify the underlying mechanisms of AKI could provide new insight to find a targeted therapy approach the role of CD44 in mitochondrial function and lipid metabolism in AKI has not been investigated in detail the underlying mechanisms have not been elucidated whether PGC-1α is regulated by NF-κB p65 and its association with CD44 have not been demonstrated we found that CD44 was upregulated in TECs in IRI mice CD44 further promoted the MAPK/NF-κB p65 pathway to silence transcription of PGC-1α This highly contributed to mitochondrial dysfunction and induced TEC apoptosis and AKI Our finding provided a new mechanism and implicated an important therapeutic strategy of targeted inhibition of CD44 to treat AKI I Co-localization of CD44 and TOMM20 in tubules Frozen renal sections were subjected to immunostaining of CD44 (red) and TOMM20 (green) J Co-localization of CD44 and cleaved caspase 3 in IRI group Frozen kidney sections were subjected to immunostaining of CD44 (red) and cleaved caspase 3 (green) their expression showed a positive correlation These results suggested that CD44 possibly triggered tubular cell apoptosis and is associated with the inhibition of mitochondrial function A Experimental design: Wild-type mice and CD44 conventional knockout mice were subjected to IRI or sham Scr was expressed as milligrams per deciliter **P < 0.01 versus wild-type mice upon sham group; ##P < 0.01 versus wild-type mice upon IRI group (n = 5) BUN was expressed as milligrams per deciliter ***P < 0.001 versus wild-type mice upon sham group; ##P < 0.01 versus wild-type mice upon IRI group (n = 5) D and E Representative western blot of CD44 (D) and graphical presentations (E) of protein expressional levels are shown **P < 0.01 versus wild-type mice upon sham group; ###P < 0.001 versus wild-type mice upon IRI group (n = 5) F Representative micrographs show the expression of CD44 in different groups Frozen kidney sections were stained with an antibody against CD44 G GO analysis shows CD44 is involved with several important pathways H GSEA shows that negative regulation of apoptosis was enriched in CD44 knockout mice versus wild-type mice upon IRI normalized enrichment score; FDR q-value < 0.25 I–L Representative western blot (I) and graphical presentations of J BAX and L cleaved caspase 3 protein expressional levels are shown ***P < 0.001 versus wild-type mice upon sham group; #P < 0.05 ###P < 0.001 versus wild-type mice upon IRI group (n = 5) M Representative micrographs show TUNEL assay in different groups Frozen kidney sections were subjected to TUNEL assay Parrafin sections were performed by immunohistochemistry staining of NGAL N and O Representative western blot of NGAL (N) and graphical presentations (O) of protein expressional levels are shown ***P < 0.001 versus wild-type mice upon sham group; ###P < 0.001 versus wild-type mice upon IRI group (n = 5) These results further demonstrated that CD44 contributed to AKI by inducing tubular cell apoptosis A Representative heatmap gene expression of RNA sequencing analysis shows that CD44 is involved with MAPK and NF-κB signaling pathway B and C GSEA shows that negative regulation of MAPK and NF-κB pathway was enriched in CD44 knockout mice versus wild-type mice upon IRI D Representative micrographs show the expression of p-ERK1/2 and p-p38 in different groups Paraffin sections were stained with antibodies against p-ERK1/2 and p-p38 E and F Representative western blot (E) and graphical presentations of p-p38/p38 and p-ERK1/2/ERK1/2 protein levels are shown G Co-localization of CD44 and p65 in 2 groups Frozen kidney sections were subjected to immunostaining of CD44 (red) and p65 (green) H and I Representative western blot (H) and graphical presentations of p-p65 large amounts of lipid accumulated in the IRI-affected kidney These results further suggest that CD44 plays a role in mitochondrial dysfunction and lipid metabolism abnormality in renal tubular cells These results further suggested CD44 induced MAPK-NF-κB p65 signaling to aggravate AKI A Experimental design: Green arrow indicated the injection of pcDNA3 plasmid or p-HA-CD44 overexpression plasmid Mice were subjected to IRI surgery or sham surgery *P < 0.05 versus sham group; #P < 0.05 versus IRI group injected with pcDNA3 (n = 5) **P < 0.01 versus sham group; #P < 0.05 versus IRI group injected with pcDNA3 (n = 5) D and E Representative western blot of CD44 (D) and graphical presentations (E) of protein levels are shown F Representative micrographs show the expression of CD44 Frozen kidney sections were subjected to TUNEL assay or stained with an antibody against CD44 G–J Representative western blot (G) and graphical presentations of H BCL2 and J cleaved caspase 3 protein expression levels are shown **P < 0.01 versus sham group; #P < 0.05 ###P < 0.001 versus IRI group injected with pcDNA3 (n = 5) K and L Representative western blot of NGAL (K) and graphical presentations (L) of protein levels are shown **P < 0.01 versus sham group; ##P < 0.01 versus IRI group injected with pcDNA3 (n = 5) M Representative micrographs show renal tubular morphologic injury and the expression of KIM-1 in different groups Paraffin sections were subjected to PAS staining and were stained with an antibody against KIM-1 A Representative micrographs show the expression of p-ERK1/2 and p-p38 in different groups B and C Representative western blot (B) and graphical presentations of p-ERK1/2/ERK1/2 and p-p38/p38 protein levels are shown ***P < 0.001 versus sham group; ##P < 0.01 D Co-localization of CD44 and p65 in CD44 overexpression mice upon IRI Frozen renal sections were subjected to immunostaining of CD44 (red) and p65 (green) E and F Representative western blot (E) and graphical presentations of p-p65 G Co-localization of CD44 and PGC-1α in CD44 overexpression mice upon IRI Frozen renal sections were subjected to immunostaining of CD44 (red) and PGC-1α (green) H and I Representative western blot (H) and graphical presentations of PGC-1α and CPT1a protein expression levels are shown ***P < 0.001 versus sham group; #P < 0.05 ##P < 0.01 versus IRI group injected with pcDNA3 (n = 5) J Representative micrographs show the expression of perilipin 2 and LDs via Oil Red O staining in different groups Frozen kidney sections were subjected to Oil Red O staining or stained with an antibody against perilipin 2 These results further demonstrated that CD44 aggravated AKI through disrupting mitochondrial function and lipid metabolism A and B HKC-8 was transfected with Ctrl-shR or CD44-shR and then were incubated in basal culture medium in a 1% O2 environment for 24 h and then were reoxygenated in normal O2 for 6 h Representative western blot (A) and graphical presentations of p-p38/p38 and p-p65 protein expression levels are shown **P < 0.01 versus Crtl-shR group; ##P < 0.01 ###P < 0.001 versus H/R with Crtl-shR group (n = 3) C Representative micrographs show the expression of p-p65 and MitoSox staining in different groups Cells cultured on coverslips were stained with an antibody against p-p65 or were stained with MitoSox D Graphic presentation shows the relative mRNA levels of PGC-1α in different groups as indicated **P < 0.01 versus Crtl-shR group; ##P < 0.01 versus H/R with Crtl-shR group (n = 3) E and F Representative western blot (E) and graphical representations of PGC-1α and PPARα protein expression levels are shown **P < 0.01 versus Crtl-shR group; #P < 0.05 ##P < 0.01 versus H/R with Crtl-shR group (n = 3) G Representative micrographs show Nile Red staining and TUNEL assay in different groups Cells cultured on coverships were stained with Nile Red or TUNEL assay H Co-localization of CD44 and cleaved caspase 3 in HKC-8 after H/R treatment Cells cultured on coverships were subjected to immunostaining of CD44 (red) and cleaved caspase 3 (green) I and J Representative western blot (I) and graphical representations of BCL2 and cleaved caspase 3 protein expression levels are shown **P < 0.01 versus Crtl-shR group; #P < 0.05 versus H/R with Crtl-shR group (n = 3) K and L HKC-8 was transfected with pcDNA3 or p-HA-CD44 overexpression plasmid and then were incubated in basal culture medium in a 1% O2 environment for 24 h and then were reoxygenated in normal O2 for 6 h Representative western blot (K) and graphical representations of CD44 p-p38/p38 and p-p65 protein expression levels are shown ***P < 0.001 versus pcDNA3 group; #P < 0.05 ##P < 0.01 versus H/R with pcDNA3 group (n = 3) M and N Representative western blot (M) and graphical presentations of PGC-1α ***P < 0.001 versus pcDNA3 group; #P < 0.05 versus H/R with pcDNA3 group (n = 3) O Representative micrographs show MitoSox staining in different groups Cells cultured on coverships were stained with MitoSox P and Q Representative western blot (P) and graphical representations of BCL2 **P < 0.01 versus pcDNA3 group; #P < 0.05; ##P < 0.01 versus H/R with pcDNA3 group (n = 3) These results further suggested that CD44 promoted mitochondrial dysfunction and tubular cell apoptosis by inducing MAPK-NF-κB p65 signaling A and B HKC-8 was transfected with pcDNA3 or p-Flag-p65 overexpression plasmid for 24 h Representative western blot (A) and graphical presentations of PGC-1α ***P < 0.001 versus pcDNA3 groups (n = 3) C Quantitative PCR result showing relative mRNA level of PGC-1α D Representative ChIP assay results showing the binding of p65 to PGC-1α gene promoter region HKC-8 cells were transfected with pcDNA3 or p-Flag-p65 for 24 h Cell lysates were precipitated with an antibody against p65 and ChIP assay was performed for PGC-1α gene promoters Total diluted lysate was used as total genomic input DNA PD98059 or PDTC at 1 h before transfection with pcDNA3 or p-HA-CD44 plasmid for 24 h Representative western blot (E) and graphical presentations of F p-p38/p38 and I PGC-1α protein expression levels are shown ##P < 0.01 versus pHA-CD44 group; ††P < 0.01 †††P < 0.001 versus pHA-CD44 group; φφφP < 0.001 versus pHA-CD44 group (n = 3) J The heatmap exhibiting differentiated lipids of lipidomics sequencing between H/R with Crtl-shR group and H/R with CD44-shR group HKC-8 cells were then treated with MAPK p38 signaling inhibitor SB203580, MAPK ERK1/2 signaling inhibitor PD98059, and NF-κB signaling inhibitor pyrrolidine dithiocarbamate (PDTC) before transfection with CD44 expression plasmid. As shown in Fig. 8E–I ectopic CD44 activated phosphorylated activation of ERK1/2 Co-treatment with SB203580 or PD98059 could suppress NF-κB p65 phosphorylation and reverse the expression of PGC-1α PD98059 showed more effects in CD44-overexpressed cells suggesting ERK1/2 signaling is more significant in signaling transduction of CD44 These results further suggest CD44 inhibited PGC-1α through ERK1/2/NF-κB p65 pathway CD44 knockdown decreased triglyceride and diglyceride contents which are accumulated during FAO dysfunction CD44 knockdown restored the content of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) the main membrane phospholipids with peroxidation of polyunsaturated fatty acids (PUFAs) which is oxidized and degraded during the progress of ferroptosis suggesting the role of CD44 in ferroptosis CD44 knockdown also regulated the contents of sphingomyelin (SM) and dihexosylceramides (Hex2cer) suggesting CD44 affects the whole processes of lipid metabolism A HKC-8 was transfected with Ctrl-shR or CD44-shR plasmid and then treated with 5 μM erastin for 24 h Representative micrographs show the Fe2+ content via FerroOrange staining in different groups B and C Quantitative results of QPCR showing relative (B) GPX4 and (C) ACSL4 mRNA levels among different groups **P < 0.01 versus Ctrl-shR group; #P < 0.05 versus erastin with ctrl-shR (n = 3) D HKC-8 was transfected with pcDNA3 or pHA-CD44 overexpression plasmid and then treated with 5 μM erastin for 24 h E and F Quantitative result of QPCR showing relative (E) GPX4 and (F) ACSL4 mRNA levels among different groups ***P < 0.001 versus pcDNA3 group; #P < 0.05 versus erastin with pcDNA3 (n = 3) G Representative micrographs show the Fe2+ content via FerroOrange staining in different groups H and I Quantitative result of QPCR showing relative H GPX4 and I ACSL4 mRNA level among different groups ***P < 0.001 versus Ctrl-shR group; ##P < 0.01 ###P < 0.001 versus H/R with ctrl-shR (n = 3) J Quantitative result showing MDA content among different groups ***P < 0.001 versus Ctrl-shR group; #P < 0.05 versus H/R with ctrl-shR (n = 3) K and L Quantitative result of QPCR showing relative (K) GPX4 and (L) ACSL4 mRNA levels among different groups ***P < 0.001 versus pcDNA3 group; #P < 0.05 versus H/R with pcDNA3 (n = 3) M Quantitative result showing MDA content among different groups N Representative micrographs show the Fe2+ content via FerroOrange staining in different groups O Quantitative result showing total iron content in kidney tissue among different groups P and Q Quantitative result of QPCR showing relative P GPX4 and Q ACSL4 mRNA levels among different groups ##P < 0.01 versus wild-type mice upon IRI group (n = 5) R Quantitative result showing MDA content in kidney tissue among different groups **P < 0.01 versus wild-type mice upon sham group; #P < 0.05 versus wild-type mice upon IRI group (n = 5) S Quantitative result showing total iron content in kidney tissue among different groups ***P < 0.001 versus sham group; ##P < 0.01 versus IRI group injected with pcDNA3 (n = 5) T and U Quantitative result of QPCR showing relative S GPX4 and T ACSL4 mRNA level among different groups ***P < 0.001 versus sham group; #P < 0.05 versus IRI group injected with pcDNA3 (n = 5) V Quantitative result showing MDA content in kidney tissue among different groups ***P < 0.001 versus sham group; ###P < 0.001 versus IRI group injected with pcDNA3 (n = 5) CD44 plays an important role in the pathogenesis of AKI Through the activation of MAPK and NF-κB p65 CD44 inhibits PGC-1α transcription and subsequent binding of PGC-1α and PPARα This leads to FAO deficiency and loss of mitochondrial biogenesis causing lipid accumulation and mitochondrial dysfunction Bax migrates to the outer membrane of mitochondria and drives high permeability in mitochondria resulting in the release of cytochrome c into cytoplasm Cytochrome c then binds with apoptosis-protease-activating factor 1 (APAF1) inducing the activation cascade of caspases which finally drives tubular cellular apoptosis and initiates AKI CD44 also facilitates endolysosomes to uptake Fe3+ and endosomal transferring to Fe2+ Fe2+ promotes the production of ROS to aggravate lipid peroxidation Some Fe2+ can also transfer into mitochondria via open channels such as mitochondrial permeability transition pore Fe2+ could also assist mitochondrial ROS production via Fenton reaction The release of mitochondrial ROS further exaggerates the production of lipid peroxidation which promotes ferroptosis in tubular cells and assists AKI progression Mitochondria are the organelles to supply energy in eukaryotic cells mitochondrial dysfunction plays a key role in renal tubular cell injury the underlying mechanisms of TEC apoptosis and mitochondrial dysfunction still remain unclear We thought that this lies in that CD44 has no effect on converting Cu2+ into Cu+ which leads to cuproptosis by disulfide bond formation one would not expect cuproptosis to only result from increased Cu2+ accumulation the role of CD44 in lipid metabolism is worthy to be studied in the future Although CD44 promotes the import of iron and copper we believe that the CD44-mediated overload of iron and copper mainly promotes cellular apoptosis via ROS-induced mitochondrial dysfunction and lipid peroxidation Reports have shown the mRNA and protein levels of PGC-1α are both downregulated in TECs in AKI mice contributing to mitochondrial dysfunction and FAO deficiency the molecular mechanism requires further investigation our study showed that the aberrant expression of CD44 plays a significant role in mitochondrial dysfunction and FAO defects which further contributes to tubular cell apoptosis in IRI This effect is mediated by p-ERK1/2- and p-p38-induced activation of NF-κB p65 which subsequently results in the transcriptional silence of PGC-1α our study provides a new mechanism and a prospective therapeutic strategy for AKI bilateral renal pedicles were clipped for 30 min by microaneurysm clamps at 37.8 °C during the ischemia period Mice were euthanized 24 h after IRI surgery Some mice were injected with pcDNA3 or p-HA-CD44 overexpression plasmid via the tail vein 3 days before IRI surgery 50% glycerol at the dose of 7.5 ml/kg is administered by a single intramuscular injection Mice were euthanized 3 days after glycerol injection mice were intraperitoneally injected with cisplatin at the dose of 20 mg/kg Mice were euthanized 3 days after cisplatin injection Serum and kidney tissues were collected for the following analyses The levels of Scr and BUN were measured with an AU480 Automatic biochemical analyzer (Beckman Coulter CA) and were expressed as milligrams per 100 ml control-shRNA or CD44-shRNA (5′-ATTTGAATATAACCTGCCG-3′) was transfected by Lipofectamine 2000 reagent (Invitrogen Cells were incubated with erastin (HY-15763; MCE) (5 μM) SB203580 (HY-10256; MCE) (10 μM) or PDTC (HY-18738; MCE) (20 μM) The H/R was performed with routine protocol HKC-8 cells were incubated in basal culture medium in a 1% O2 environment for 24 h and then were reoxygenated in normal O2 for 6 h Protein expression was analyzed by western blot analysis The primary antibodies were as follows: anti-BAX (SC-7480; Santa Cruz Biotechnology) anti-ERK1/2 (4695; Cell Signaling Technology) anti-JNK (9252; Cell Signaling Technology) anti-p-ERK1/2 (4370; Cell Signaling Technology) anti-p-JNK (4668; Cell Signaling Technology) anti-p65 (8242; Cell Signaling Technology) anti-α-tubulin (RM2007; Ray Antibody Biotech anti-β-actin (RM2001; Beijing Ray Antibody Biotech) Antibodies used were as follows: anti-KIM-1 (BA3537; Boster) Immunofluorescence staining was performed with routine protocol [2] Frozen kidney sections (3 μm) and cells cultured on coverslips were fixed with 4% paraformaldehyde All primary antibodies used were as follows: rabbit anti-CD44 (A00052; Boster) rabbit anti-Cleaved caspase 3 (25128-1-AP; Proteintech) rabbit anti-Perilipin 2 (A20843; Abclonal) rabbit anti-p65 (8242; Cell Signaling Technology) mouse anti-PGC-1α (66368-1-Ig; Proteintech) mouse anti-TOMM20 (66777-1-Ig; Proteintech) Kidney tissues were fixed in 1.25% glutaraldehyde in phosphate buffer Ultrathin sections (60 nm) were prepared by a routine procedure The mitochondria and lipid droplets were observed under an electron microscope (JEOL JEM-1010 Cells cultured on coverslips were stained with Nile red according to the manufacturer’s instructions Cells were fixed with 4% paraformaldehyde for 10 min at room temperature and then were stained by Nile red (1 μg/ml) dissolved in DAPI after washed by PBS Frozen kidney sections (3 μm) or cells cultured on coverslips were assessed by TUNEL assay (G3250; Promega) according to the manufacturer’s instruction Cells were stained by FerroOrange (F374; dojindo) (1 μM) for 30 min Frozen kidney sections (3 μm) or cells cultured on coverslips were assessed by MitoSOX Red (40778ES50; Yeasen) Lipid peroxidation assays were performed using a lipid peroxidation (MDA) assay kit (S0131; Beyotime) according to the manufacturer’s instructions Fe3+) were measured using an iron assay kit (G4301; Servicebio) and Cu2+ was measured using a copper assay kit (BC5565; Solarbio) The sequences of the primer pairs used in quantitative real-time PCR are described in Supplementary Table 1 ChIP was performed using the Simple ChIP Plus (Magnetic Bead) Kit (9005 according to the manufacturer’s instructions HKC-8 cells were transfected with p65 overexpression plasmid (pFlag-p65) for 24 h The antibody against p65 (A00284-1; Boster) and H3 was added and incubated overnight at 4 °C followed by incubation with ChIP-Grade Protein G Magnetic Beads for 2 h purified DNA was amplified as a template by PCR The sequences of human PGC-1α primers were as follows: forward 5′-TGACAGCCCAGCCTACTTT-3′ and reverse 5′-TTTTCAACTCCAATCCACA-3 Statistical analysis was performed by a researcher who was blinded Statistical analysis was carried out by SPSS 25.0 (SPSS Inc. Independent sample t-test was used to compare the mean of the two groups Comparison between groups was made via one-way ANOVA analysis of variance followed by the least significant difference when the variance between groups was homogeneous or the Dunnett T3 test when the variance between groups was not homogeneous Bivariate correlation analysis was performed using Pearson correlation analysis P value < 0.05 was considered as significant RNA Sequencing data produced in this study has been uploaded to the NCBI GEO database (accession number: GSE252060) Lipidomics Sequencing data in this study has been upload in MetaboLights database (accession number: MTBLS10954) The data used to support the findings of this study are available from the corresponding author upon request Sirtuin 6 is a key contributor to gender differences in acute kidney injury Oligosaccharides ameliorate acute kidney injury by alleviating cluster of differentiation 44-mediated immune responses in renal tubular cells Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice The membrane receptor CD44: novel insights into metabolism Hyaluronan in wound healing: rediscovering a major player A druggable copper-signalling pathway that drives inflammation CD44 regulates epigenetic plasticity by mediating iron endocytosis β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis CD44 impacts glomerular parietal epithelial cell changes in the aged mouse kidney Natural products for kidney disease treatment: focus on targeting mitochondrial dysfunction Tubular epithelial NF-κB activity regulates ischemic AKI NF-κB p65 attenuates cardiomyocyte PGC-1α expression in hypoxia Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis Klotho retards renal fibrosis through targeting mitochondrial dysfunction and cellular senescence in renal tubular cells Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility CD44-deficiency attenuates the immunologic responses to LPS and delays the onset of endotoxic shock-induced renal inflammation and dysfunction Protection against renal ischemia reperfusion injury by CD44 disruption CD44 expression in renal ischemia-reperfusion injury in rats Secreted-Osteopontin Contributes to Brown Adipogenesis In Vitro via a CD44-Dependent Pathway Horm Metab Res = Hormon Stoffwechselforsch = Hormon Metab Hyaluronidase inhibitor sHA2.75 alleviates ischemia-reperfusion-induced acute kidney injury An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis The role of mitochondria in iron overload-induced damage Iron and copper: critical executioners of ferroptosis Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice Oxalate-induced apoptosis through ERS-ROS-NF-κB signalling pathway in renal tubular epithelial cell The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression Nuclear factor-kappaB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes The p65 subunit of NF-kappaB binds to PGC-1alpha linking inflammation and metabolic disturbances in cardiac cells MAPK/ERK signaling pathway in hepatocellular carcinoma Ojeoksan ameliorates cisplatin-induced acute kidney injury in mice by downregulating MAPK and NF-κB pathways Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages Annexin A2 plays a key role in protecting against cisplatin-induced AKI through β-catenin/TFEB pathway Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease Download references This work was supported by National Natural Science Foundation of China Grant 82225010 These authors contributed equally: Jiewu Huang National Clinical Research Center for Kidney Disease State Key Laboratory of Organ Failure Research Guangdong Provincial Institute of Nephrology Guangdong Provincial Key Laboratory of Renal Failure Research Huadu District People’s Hospital of Guangzhou PM contributed to the analysis and interpretation of the data and WS prepared the materials involved in this study and SZ conceived this study and participated in its design and coordination All authors read and approved the final manuscript The animal experiments were approved by the Ethics Committee on Use and Care of Animals of Southern Medical University Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41419-025-07438-x Metrics details This study is designed to assess the effect of root extract of P ginseng on kidney tissue injury attributed to cisplatin and its molecular mechanism involved in this process in the AKI rat model Twenty-four male Wistar rats were randomly allocated into 4 experimental groups including: the control group The duration of the investigation was 7 days and all rats except the control group received a single dose of 10 mg/kg cisplatin on the 4th day Our findings exhibited a significant reduction in blood concentration of creatinine in extract groups compared to the cisplatin group severe renal histopathological alterations were observed compared to the control group significantly less tissue damage was observed than in the cisplatin group Ginseng extract 200 showed minimal tissue damage as compared to extract 100 and NF-κB decreased significantly in extract groups compared to the cisplatin group Our findings displayed amelioration of cisplatin-induced AKI and dose-dependent decrease of the NF-κB gene expression and cell death-inducing genes by administration of P the exact renoprotective mechanism of ginseng is still unknown the present investigation was designed to assess the protective effect of root extract P ginseng on kidney tissue injury by altering the expression of genes involved in the cell death process in cisplatin-treated animals HPLC and UV spectrophotometer were used to identify the active components within ginseng root extract the concentrations of the genistein and total phenol in ginseng extract were 0.04 mg/g and 2.02 ± 0.03 mg garlic acid/g The results of serum biochemical parameters of control and treated groups Cisplatin administration significantly increased the serum levels of urea and creatinine and decreased albumin and total protein serum levels in the cisplatin group compared to the control group * Significant compared to the control group (p˂0.05) # Significant compared to the cisplatin group (p˂0.05) The results of gene expression of control and treated groups and NF-κB expressions in both extract-treated groups and cisplatin group compared to the control group they were reduced significantly in extract-treated groups compared to the cisplatin group The results of the histological index in the studied groups Cisplatin significantly increased tissue damage and the ginseng extract 200 treated group showed a significant decrease in tissue damage index compared to the cisplatin group (p < 0.05) All experimental protocols were approved by the Ethics Committee of Ardabil University of Medical Sciences in accordance with the guidelines of the Helsinki ethical code regarding experiments performed on animals (Code: IR Anesthetization of the animals was done using IP injection of ketamine (100 mg/kg) and xylazine (10 mg/kg) after an overnight fast (10–12 h) then blood samples were taken directly from the heart and separated serum was maintained at − 70 °C until analysis The kidneys were then instantly removed and stored at − 70 °C for RNA extraction 10% formaldehyde was used to fixation of a part of the kidney After obtaining permission from the Ardabil University of Medical Sciences (Code: IR.ARUMS.AEC.1401.012) White ginseng root (herbarium code: 2(IMPHM)) was purchased from the Academic Center for Education For preparation of hydro-alcoholic root extract of ginseng using an electric grinder and then mixed powdered ginseng root with 70% ethanol in a ratio of 1:4 it was placed for 72 h in a shaking incubator in 40 °C (LSI-3016R the mixture was filtered and was dried at 50 °C High-performance liquid chromatography (HPLC) and UV spectrophotometer were also performed to identify the bioactive compounds of ginseng root extract the acquired extract was kept at − 70 °C until use after fixation in 10% neutral buffered formalin and hematoxylin-eosin staining (H&E) randomly 12 areas were selected in each sample The semi-quantitative histological index was calculated using a scale of 0–3: (0) none The evaluated damages included cell detachment SPSS version 19 software and GraphPad Prism 8.0.1 software were applied for statistical analysis Statistically significant differences between experimental groups were estimated using one-way ANOVA All values were stated as means ± SD and p-values of less than 0.05 were considered as significant our results showed that the administration of P ginseng extract ameliorated cisplatin-induced AKI and decreased the expression of NF-κB and cell death-inducing genes in a dose-dependent manner The data used and analyzed during the current study are available 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Impact of peroxisome proliferator activated receptor agonist drugs in a model of nephrotoxicity in rats Cisplatin nephrotoxicity as a model of chronic kidney disease Cisplatin-induced rodent model of kidney injury: characteristics and challenges Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy The mechanism of drug nephrotoxicity and the methods for preventing kidney damage SIS3 alleviates cisplatin-induced acute kidney injury by regulating the lncRNA Arid2-IR-transferrin receptor pathway P53 in kidney injury and repair: mechanism and therapeutic potentials Epithelial cell cycle behaviour in the injured kidney Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21 Cell cycle arrest as a therapeutic target of acute kidney injury NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification Discovery and validation of cell 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constituent thymoquinone against kidney injury: An aspect on pharmacological insights Antioxidant and anti-inflammatory potential of pomegranate rind extract to ameliorate cisplatin-induced acute kidney injury Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities Nephroprotective activity of Aframomum melegueta seeds extract against diclofenac-induced acute kidney injury: A mechanistic study the main active components of Panax ginseng Nephroprotective effects of anthocyanin from the fruits of Panax ginseng (GFA) on cisplatin-induced acute kidney injury in mice Brief introduction of Panax ginseng CA Meyer Panax ginseng and its ginsenosides: Potential candidates for the prevention and treatment of chemotherapy-induced side effects Protective effect of Panax ginseng against serum biochemical changes and apoptosis in kidney of rats treated with gentamicin sulphate Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model Cisplatin-induced renal toxicity via tumor necrosis factor-α oxidative stress and nitric oxide in rats: protective effect of ginseng Panax ginseng protects against global ischemia injury in rat hippocampus Ginseng: a promising neuroprotective strategy in stroke The MIQE Guidelines: M inimum I nformation for Publication of Q uantitative Real-Time PCR Experiments (Oxford University Press Protective effects of natural products against drug-induced nephrotoxicity: A review in recent years Clinical characteristics of hospitalized patients with drug-induced acute kidney injury and associated risk factors: A case-control study Natural products: potential treatments for cisplatin-induced nephrotoxicity A review of neuroprotective effects and mechanisms of ginsenosides from Panax ginseng in treating ischemic stroke Effects of genistein on common kidney diseases Protective effect of genistein in a rat model of ischemic acute kidney injury Preventive effect of fermented black ginseng against cisplatin-induced nephrotoxicity in rats Ginseng® alleviates malathion-induced hepatorenal injury through modulation of the biochemical and anti-inflammatory markers in male rats Grape seed extract protects against amiodarone-induced nephrotoxicity and ultrastructural alterations associated with the inhibition of biomarkers of inflammation and oxidative stress in rats The potential protective effects of citrus bergamot extract against amikacin-induced nephrotoxicity in male albino rats Protective effects of ethanolic extract of Alhagi maurorum roots on renal failure induced by acetaminophen in mice leaves extract loaded gold nanoparticles against cisplatin-induced acute kidney injury Genome and evolution of the shade-requiring medicinal herb Panax ginseng DNA damage response in cisplatin-induced nephrotoxicity N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation Renoprotective effect of the isoflavonoid biochanin A against cisplatin induced acute kidney injury in mice: effect on inflammatory burden and p53 apoptosis Acquired resistance to rechallenge injury after acute kidney injury in rats is associated with cell cycle arrest in proximal tubule cells Serial measurement of cell-cycle arrest biomarkers [TIMP-2]·[IGFBP7] and risk for progression to death or severe acute kidney injury in patients with septic shock Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice D-Limonene alleviates acute kidney injury following gentamicin administration in rats: role of NF-κB pathway Maslinic Acid attenuates Ischemia/Reperfusion-Induced Acute kidney Injury by suppressing inflammation and apoptosis through inhibiting NF-κB and MAPK signaling pathway Curcumin attenuates inflammation and cell apoptosis through regulating NF-κB and JAK2/STAT3 signaling pathway against acute kidney injury Casticin elicits inflammasome-induced pyroptosis through activating PKR/JNK/NF-κB signal in 5–8F cells Downregulation of TIMP2 attenuates sepsis-induced AKI through the NF-κb pathway Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation Cisplatin nephrotoxicity: new insights and therapeutic implications Acute nephrotoxicity of cisplatin: molecular mechanisms Silymarin ameliorates cisplatin-induced nephrotoxicity by downregulating TNF-α and NF-kB and by upregulating IL-10 Combination of red ginseng and velvet antler extracts prevents skin damage by enhancing the antioxidant defense system and inhibiting MAPK/AP-1/NF-κB and caspase signaling pathways in UVB-irradiated HaCaT keratinocytes and SKH-1 hairless mice Download references We are grateful to the Faculty of Medicine This study is financially supported by the Ardabil University of Medical Sciences Reza Alipanah-Moghadam and Vahideh Aghamohammadi contributed equally to this work contributed to the conception and design of the study and the study protocol conducted data analysis and all authors helped with data interpretation wrote this manuscript with input from all co-authors All authors read and approved the final version of the manuscript Download citation DOI: https://doi.org/10.1038/s41598-025-87447-0 Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research Metrics details Elevated intra-abdominal pressure can engender a spectrum of adverse physiological repercussions in patients but further research is needed to ascertain whether elevated intra-abdominal pressure exerts significant effects on renal function The study used MIMIC-IV database to identify critical patients with IAP monitoring Patients were categorized into Low-IAP and High-IAP groups based on the results of the restricted cubic splines curve The primary outcome of the study was the occurrence of AKI within 72 h of ICU admission and secondary outcomes including the rate of CRRT utilization and 28-day all-cause mortality Cox proportional hazards regression analysis was employed to clarify the relationship between IAP and AKI A total of 1746 patients were included in our study Restricted cubic spline analysis demonstrated an increased risk of AKI with higher IAP Multivariable Cox proportional hazards analysis uncovered a notable correlation between elevated IAP and AKI incidence (HR: 1.40(1.14–1.71)) patients with elevated IAP remained significantly related with AKI (HR: 1.23(1.01–1.52)) The Kaplan–Meier survival curves indicated a significant superior 28-day survival rate for Low-IAP group (the log-rank test p-value was 0.001) and the cumulative risk curve showed a higher demand for CRRT in the High-IAP group (the log-rank test p-value was 0.0028) Augmented intra-abdominal pressure (above 16 mmHg) is significantly associated with a higher incidence of acute kidney injury (AKI) in critically ill patients along with an increased need for continuous renal replacement therapy (CRRT) and a higher 28-day mortality rate diligent monitoring of intra-abdominal pressure and associated organ dysfunction is crucial for managing high-risk patients effectively This approach is essential for improving outcomes and mitigating the adverse effects of IAH and ACS in the ICU setting may be one of the significant complications caused by elevated intra-abdominal pressure This study aims to explore the relationship between intra-abdominal pressure and the occurrence of AKI Approval for database access was granted by the Institutional Review Boards of MIT and Beth Israel Deaconess Medical Center Given the anonymized nature of the database and its standardized data this study was exempt from separate ethics approval in accordance with the principles outlined in the Declaration of Helsinki regarding patient populations the Medical Information Mart for Intensive Care database; ICU AKI is defined by either an absolute increase in Scr exceeding 0.3 mg/dL (26.5 μmol/L) or a relative increase by more than 50% from baseline within 48 h and it also can be diagnosed when urine output is less than 0.5 mL/kg/h (in adults) for 6 h or longer Secondary outcomes comprised the 28-day mortality rate utilization of CRRT within 72 h and one-week Continuous variables are expressed as means (standard deviations) while categorical variables are presented as total counts and percentages Group comparisons were conducted using the X2 test or Fisher’s exact test for categorical variables and Student’s t-test or the Mann–Whitney U test for continuous variables Certain models were adjusted for specific variables Both clinical and prognostic variables were included in the multivariable models: Crude model: Unadjusted; Adjusted model 1: Adjusted for demographic variables including age and weight; Adjusted model 2: Adjusted for all variables red blood cell (RBC) count and creatinine(Cr) The cumulative risk curves depict the incidence of AKI within 72 h and the utilization of CRRT within 72 h for both the Low-IAP and High-IAP groups Kaplan–Meier curves illustrate the 28-day mortality rates for patients in both groups Subgroup analyses were conducted by stratifying the study population based on age Statistical analyses were conducted using the R programming language (version 4.3.3) Statistical significance was defined as p < 0.05 (a) Restricted cubic spline for AKI within the first 72 h of ICU admission Intra-abdominal pressure; (b) the cumulative risk curve for AKI within the first 72 h of ICU admission the area under the curve (AUC) for IAP did not meet the desired threshold of adequacy (AUC for occurrence of AKI within 72 h: 0.550 and we identified the optimal threshold to be 14.5 mmHg using the Youden index method The multivariate Cox regression analyses revealed a significant detrimental effect of elevated IAP on AKI occurrence (Table2) No adjustments were made for any confounding factors in crude model (HR: 1.40(1.14–1.71) adjustments were made for demographic parameters (HR: 1.27(1.04–1.6) adjustments were made for all potential influencing factors (HR: 1.23 (1.01–1.52) (a) The cumulative risk curve for CRRT utilization within the first 72 h of ICU admission Continuous renal replacement therapy; (b) Kaplan–Meier survival analysis curves for 28-day all-cause mortality Forest plots of hazard ratios for the incidence of acute kidney injury (AKI) in different subgroups investigated the potential link between elevated IAP and the risk of AKI Our findings indicate a significant association between increased IAP and the likelihood of developing AKI Even after adjusting for potential confounders with the high IAP group exhibiting a hazard ratio (HR) of 1.23 (95% CI: 1.01–1.52) compared to the normal IAP group analysis using RCS revealed a nonlinear relationship between elevated IAP and the incidence of AKI These results underscore the importance of vigilant monitoring and management of intra-abdominal pressure Despite the prevalence of IAH and AKI in this cohort the AUC for IAP in predicting early AKI was only 0.499 (95% CI: 0.325–0.673) with a p-value of 0.992 Our study further explores this relationship through careful adjustment for related confounders the high IAP group showed a HR of 1.23 (1.01–1.52) with a p-value of less than 0.05 indicating that elevated IAP is an independent risk factor for AKI representing a 1.23-fold increased risk of the outcome in the high IAP group compared to the low IAP group These findings emphasize the need for vigilant monitoring and management of intra-abdominal pressure to mitigate the risk of AKI in critically ill patients we utilized restricted cubic spline regression to assess the nonlinear association between IAP and AKI The results of the RCS model revealed a nonlinear escalation in the risk of AKI as IAP increased (nonlinear P = 0.002) the associated risk curve for AKI stabilizes we observed that a significant elevation in intra-abdominal pressure (IAP > 16 mmHg) appears to be necessary to substantially increase the risk of AKI occurrence heightened IAP can adversely affect renal function through both indirect systemic effects and direct renal impacts underscoring the complex interdependencies between increased abdominal pressure and renal health This study presents several notable advantages it is pioneering in utilizing data from the MIMIC database to investigate the correlation between IAP and AKI The large sample size employed exceeds those of previous observational studies lending greater reliability to the findings we accounted for potential confounding factors enhancing the robustness of our conclusions this study advances our understanding by exploring the nonlinear relationship between IAP and the incidence of AKI using RCS regression thereby providing a more nuanced analysis of how variations in IAP influence AKI risk and although we employed the multivariable regression method to minimize the influence of confounding factors and enhance the robustness of our results these findings need to be validated through further prospective cohort studies patients who did not undergo intra-abdominal pressure measurement were excluded from the study our study population may inherently consist of individuals considered at potential risk for intra-abdominal hypertension which could introduce a degree of selection bias relying on a single measurement may not adequately capture the relationship between its fluctuations over time and the incidence of AKI A more comprehensive approach that accounts for the dynamic changes in IAP may provide deeper insights into its impact on AKI our research indicated that mildly elevated IAP within the range of 12–16 mmHg does not substantially raise the risk of AKI development higher IAP levels are associated with increased rates of AKI This data can be found here: MIMIC-IV v2.2 (physionet.org) The Medical Information Mart for Intensive Care database Prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study and outcomes of intra-abdominal hypertension in critically ill patients-a prospective multicenter study (IROI Study) Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome Analysis of intra-abdominal hypertension in severe burned patients: the Vall d’Hebron experience Intra-abdominal hypertension and increased acute kidney injury risk: a systematic review and meta-analysis Intra-abdominal hypertension among medical septic patients associated with worsening kidney outcomes (IAH-WK study) How to explain glomerular filtration rate decrease in intra-abdominal hypertension? Intra-abdominal pressure as a predictor of acute kidney injury in postoperative abdominal surgery Role of intra-abdominal pressure in early acute kidney injury: a prospective cohort study in critically ill obstetric patients Intra-abdominal hypertension does not predict renal recovery or in-hospital mortality in critically ill patients with acute kidney injury a freely accessible electronic health record dataset Cardiac surgery-associated acute kidney injury: risk factors A practical guide to multiple imputation of missing data in nephrology Controversies in acute kidney injury: conclusions from a kidney disease: improving Global Outcomes (KDIGO) Conference Semi-parametric regression model for survival data: graphical visualization with R Intra-abdominal hypertension and postoperative kidney dysfunction in cardiac surgery patients Blood flow dependence of postglomerular fluid transfer and glomerulotubular balance Renal dysfunction associated with intra-abdominal hypertension and the abdominal compartment syndrome Effect of increased renal venous pressure on renal function Importance of venous congestion for worsening of renal function in advanced decompensated heart failure High intra-abdominal pressure increases plasma catecholamine concentrations during pneumoperitoneum for laparoscopic procedures Systemic inflammatory response secondary to abdominal compartment syndrome: stage for multiple organ failure Amplified cytokine response and lung injury by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory model of ischemia-reperfusion Download references This work was sponsored by grants from Zhejiang Provincial Clinical Research Center for Critical Care Medicine These authors contributed equally: ShengHui Miao and Mingkun Yang Department of Second Clinical Medical College Shenghui Miao and Mingkun Yang co-led this study Shenghui Miao extracted data from the MIMIC-IV database Wen Li assisted with data processing and statistical analysis Shenghui Miao and Mingkun Yang drafted the initial manuscript Jing Yan provided feedback and approved the final manuscript All authors reviewed and approved the final manuscript Use of the database was approved by the Institutional Review Boards of MIT and Beth Israel Deaconess Medical Center As the database is anonymized and contains standardized data this study did not require separate ethics approval per the Declaration of Helsinki this manuscript is exempt from the requirement for ethical approval statement and informed consent The participants in the study have all passed the official ethics test and are qualified to access the database Download citation DOI: https://doi.org/10.1038/s41598-024-84831-0 Aki Hamada Architects presents Floating Wood, a furniture series that applies digital fabrication and embraces natural imperfections. The project transforms real tree trunks into table legs through 3D scanning and printing to preserve their natural shapes while allowing them to rotate freely The result is a collection of tables that resemble a floating grove Each table leg is made from cellulose acetate, a biodegradable material derived from wood fiber and cotton which naturally decomposes when buried or submerged The plasticizer is food-safe and also used in space food supporting the eco-friendly approach of the design team tree-like legs are oak tabletops marked with insect-made patterns repurposing wood that would typically be discarded Floating Wood brings a fresh take on traditional craft by using digital tools to shape organic forms. Tokyo-based Aki Hamada Architects teams up with Boolean for 3D printing and Yutaro Matsumoto for wood production combining their expertise to transform real tree trunks into unique furniture pieces The process starts with scanning the trunks and customizing their shapes through 3D printing aiming to preserve their natural feel as much as possible The use of insect-related bio-fabrication adds an unexpected quality The project challenges conventional mass production showing how digital design can integrate imperfections instead of erasing them.  this furniture series applies digital fabrication and embraces natural imperfections the project transforms real tree trunks into table legs this collection of tables that resembles a floating grove each table leg is made from cellulose acetate this biodegradable material is derived from wood fiber and cotton the plasticizer is food-safe and also used in space food the tabletops are marked with insect-made patterns Floating Wood brings a fresh take on traditional craft name: Floating Wood designer: Aki Hamada Architects | @aki_hamada_architects Yanning Hou 3D print: Boolean (Toki Hamasaki) wood furniture: Yutaro Matsumoto photographer: Yuuki Tanaka AXOR presents three bathroom concepts that are not merely places of function but destinations in themselves — sanctuaries of style He received his BA in Communications from Temple University working in print and online on a variety of topics and in newsrooms including CNBC and Fox Digital Now the Online Content Editor for Healio Nephrology he is focused on producing quality health care content for people involved in the specialty Carter enjoys spending time learning about new topics and discussing them with family and friends Connect with him on LinkedIn here “Patients with dialysis-requiring AKI consistently report that being able to stop dialysis is one of the most important patient-centered outcomes to them There is compelling data that even some individuals with stage 4 chronic kidney disease may experience enough renal recovery to allow them to come off dialysis,” Kathleen Liu professor of medicine and anesthesia at the University of California and chair of the ASN Kidney Health Guidance Oversight Committee there are a lack of best practices and guidance for nephrologists about how to optimize care for these patients to maximize the likelihood that they will come off dialysis.” recommendations were developed by a team of kidney professionals for patients with AKI requiring dialysis (AKI-D) at risk for dialysis dependence The group included adult and pediatric nephrologists pharmacists and advanced practice nurses — all familiar with AKI-D-specific considerations based on current evidence the panel formulated key clinical questions conducted a structured evidence review and reached a consensus using a modified Delphi process Researchers also accounted for patient input the guidance serves as a resource for an interdisciplinary approach to dialysis care providing recommendations without replacing clinical judgment “A key aspect of AKI-D care is the potential for multiple transitions of care and handoffs between care settings and the nephrology community should work toward improving communication at these critical junctures through more standardized means,” according to the authors and treatment decisions should be tailored to patient preferences the guidance outlines several practice points for providers: Patient education and transition of care Blood pressure and volume management Anemia and mineral bone disease management One of the key challenges to care is “oftentimes patients transition from dialysis in-hospital to the outpatient setting and have an entirely new set of providers unfamiliar with their prior course,” Liu said The guidance pinpoints “what information should be handed off to the outpatient care team It also addresses management issues related to dialysis that the outpatient care team may need to customize or modify for the AKI-D patient.” In addition to clinical practice recommendations the guidance identifies key areas for future research and policy initiatives to enhance the management of AKI-D including preventing dialysis-related hypotension; strategizing methods to wean patients off dialysis during recovery; and improving interoperability between hospital and outpatient electronic health records The researchers emphasized the need for further studies legislation and improved communication between care settings the guidance lays the foundation for more effective optimizing care to promote renal recovery should be the top priority of the nephrology care team because renal recovery is likely for many patients and patients consistently report that coming off dialysis is a top priority,” she said patients and their multidisciplinary team should include nephrologists nutritionists and nurses — all working together.” American Society of Nephrology releases kidney health guidance on the outpatient management of patients with dialysis-requiring acute kidney injury. https://www.asn-online.org/about/press/releases/ASN_PR_20250227_finalakiguidance2.2.pdf Get the latest news and education delivered to your inbox The email address associated with your Healio account is: If you would like to edit or change the email address that your subscriptions and alerts are sent to You'll receive reminders to complete your saved activities from Healio CME According to On3's Pete Nakos Ogunbiyi has committed and signed with Deion Sanders and the Colorado Buffaloes He will have one year of eligibility remaining in Boulder The Buffaloes are coming off of a season in which they narrowly missed out on the Big 12 Championship Game with a loss to Kansas One of the main issues with the Buffaloes this season was their inability to protect the quarterback 123 out of 133 teams in the nation in sacks allowed with 39 The 6-foot-4, 330-pound Kempner (TX) native played in three games this season vs. McNeese, Missouri and New Mexico State. Ogunbiyi had been with the Aggies since 2020 and earning the team's most improved offensive player award He would go on to play in eight games with four starts in 2021 He started in four of his six appearances before having his season cut short due to injury Ogunbiyi came to College Station as a consensus four-star recruit 34 player in Texas per the 247 Composite ranking He was part of an Aggies offensive line class that included tackle Chris Morris You can follow us for future coverage by subscribing to our newsletter here. Also, be sure to like us on Facebook @AllAggiesOnSI & follow us on Twitter at @TAMUAggiesSI Texas A&M Aggies To Receive Visit From Georgia Bulldogs Transfer Former Colorado Buffaloes Edge Rusher Commits To Texas A&M Aggies Texas A&M Aggies' Myles Garrett Reaches Major Career Milestone WATCH: Texas A&M Transfer Micah Hudson Already Getting Offseason Reps In Texas A&M Aggies Transfer DL Commits to SEC Program The content on this site is for entertainment and educational purposes only Betting and gambling content is intended for individuals 21+ and is based on individual commentators' opinions and not that of Sports Illustrated or its affiliates All picks and predictions are suggestions only and not a guarantee of success or profit If you or someone you know has a gambling problem crisis counseling and referral services can be accessed by calling 1-800-GAMBLER Mild and reversible AKI was tied to an increased risk for probable dementia and mild cognitive impairment in older adults with high cardiovascular risk director of the clinical vascular physiology laboratory at the University of Colorado Anschutz Medical Camp division of renal diseases and hypertension in Aurora “CKD is associated with high risk of mild cognitive impairment and dementia It is also well accepted that acute cognitive dysfunction and delirium can occur with severe AKI as a result of uremic encephalopathy.” Researchers conducted a retrospective cohort study of 8,148 U.S adults at high risk for cardiovascular disease and who were enrolled in the Systolic Blood Pressure Intervention Trial between 2010 and 2013 The goal was to determine whether AKI increased the risk of cognitive decline Patients with baseline systolic blood pressure between 130 mmm Hg and 180 mm Hg with a blood pressure goal of less than 120 mm Hg were placed in the intensive treatment group and those with a goal of 140 mm Hg were counted as the standard treatment group and researchers incorporated all major antihypertensive medication classes to achieve desired blood pressure goals The incidence rates of mild cognitive impairment probable dementia and its composite were higher among 270 patients who had an AKI event the researchers found a link between AKI and probable dementia (HR = 1.72; 95% CI 1.07-2.75) and the composite outcome of probable dementia and mild cognitive impairment (HR = 1.43; 95% CI “These results suggest that cognitive function should be monitored following AKI in this patient population,” the researchers wrote “Further research is needed to continue to elucidate the mechanisms by which AKI may increase susceptibility to cognitive impairment.” Metrics details acute kidney injury (AKI) is the most common cause of morbidity and mortality Hospital-acquired acute kidney injury (HAAKI) is AKI developing after 48 h We aimed to study the development of AKI and its associated risk factors We conducted a longitudinal observational study Inclusion criteria were patients > 18 years of age admitted to ICU The primary outcome was the development of AKI as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria A total of 273 patients were included in the study The median acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores were 12(8–18) and 5(3–7) Diabetes mellitus (23.44%) and hypertension (23.81%) were predominant comorbidities The risk factors associated with AKI were serum chloride level The hospital mortality was significantly higher in patients with AKI (43.18%) as compared with no AKI (14.41%) 7 (15.90%) patients required renal replacement therapy (RRT) during hospitalisation The length of ICU stay was higher in patients with AKI 8(5–13) compared to no AKI 5(3–8) Among survivors none of the patients were on RRT.Patients admitted with normal kidney function can develop AKI careful monitoring of ICU patients is necessary We aimed to evaluate the proportion of ICU patients developing AKI and survival rates of AKI patients after hospital discharge over six months in a longitudinal study Methodology- A prospective observational study was conducted in a tertiary care hospital from 5th September 2018 to 16th October 2023 Institutional ethics committee approval was obtained (IEC205/2018 dated 28th August 2018 All the procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975 Strengthening the reporting of observational studies in epidemiology (STROBE) guidelines were followed (Strobe checklist) The written informed consent was obtained from the legally acceptable representative (LAR) The inclusion criteria were patient’s ≥ 18 yrs Patients presenting with AKI or had chronic kidney disease were excluded Pregnant patients and terminally ill patients were excluded Diagnosis of HAAKI was made based on the admission creatinine and using KDIGO guidelines Baseline and demographic characteristics were collected Acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores were calculated and ventilator parameters (noninvasive or invasive) were collected for the first seven days of ICU admission patients were followed up till the hospital discharge At 6 months from discharge telephonic follow up was done Survival outcome in the AKI patients was collected Continuous variables presented as mean (standard deviation SD) or median (interquartile range IQR) as applicable Categorical data presented as percentages (%) Clinical characteristics compared between AKI and no AKI using independent ‘t test’ or ‘Mann Whitney U’ test as applicable A generalized linear mixed model analysis was performed to assess the clinical factors associated with the development of AKI over 7 days APACHE II score were considered in the regression model for adjusted analysis Risk factors associated with the hospital mortality were analysed Estimation of survival probabilities was done using Kaplan-Meier and log-rank test The p-value < 0.05 was considered statistically significant Statistical analysis was done using STATA 15.0 A total of 273 patients were included in the analysis The mean age was 45.80(standard deviation SD 17.39) yrs. 11(25%) and 5(11.36%) patients developed stage 1 Total 7 patients (15.90%) required renal replacement therapy Comparison of baseline characteristics of the patients with AKI and no AKI is presented in Table 1 Mean age of the AKI patients was significantly higher than no AKI group (p < 0.01) Presence of any comorbidities was significantly associated with the development of AKI (p = 0.027) Diabetes mellitus and ischemic heart disease (IHD) were significantly associated with the development of AKI Patients of AKI had significantly higher median APACHE II 16 (12–23) score higher requirement of vasopressors on day1 Postoperative status and sepsis were not significantly associated with the development of AKI Readmissions were significantly associated with the development of AKI Total 44(16.11%) patients developed AKI. Overall, the mortality rate was 19.05%. The mortality was significantly higher in AKI (43.18%) as compared to no AKI group (14.41%). The length of ICU stay was significantly higher in AKI group (8 Vs. 5 median days, p = 0.001). Factors associated with the development of AKI are presented in Table 2 Patient with increased serum chloride [1.06 (1.03 requiring invasive ventilation [2.583(1.708 midazlam and pantoprazole were found to be protective Kaplan-Meier graph showing comparison of survival probabilities between patients with AKI and no AKI Among the patients who were alive none was requiring renal replacement therapy In our study mortality at the end of six months was 23% We observed lower mortality in follow up patients possibly due to less severe AKI and none of the patients were requiring RRT This indicates although PEEP is beneficial in improving oxygenation one need to check its effects on kidney We could not find any evidence showing fentanyl or dexmedetomidine as a possible risk factor for AKI We observed patients who were on invasive ventilator support were on sedatives Hence invasive ventilation was a possible risk factor for AKI Among patients who were on midazolam we observed lesser renal impairment (p = 0.031) The patients who received midazolam were predominantly neurological patients who presented with neurotrauma or had presented with seizures Antiepileptic effect of midazolam was possibly renal protective We did not find any association with use of paralytics like vecuronium and AKI The strengths of our study are this is one of the study that showed the longitudinal data of patients who developed HAAKI and also included follow up of these patients We observed several risk factors associated with HAAKI We studied various medications which are routinely used in ICU patients The findings of this study will help the clinicians in identifying patients at risk of developing HAAKI AKI was diagnosed based on the serum creatinine only The measurement of hourly urine output requires intensive monitoring of the patient and is associated with errors we used change in the serum creatinine to diagnose AKI We did not study the effect of antifungals (Amphotericin B) as only 5(1.83%) patients received this drug The future studies should focus on early diagnosis of AKI using a specific biomarker The results of the study showed possible modifiable risk factors like monitoring of serum chloride levels fluid balance and early weaning thereby reducing the effect of PEEP and sedation Findings of this study need to be validated in a larger cohort The proportion of patients developing AKI was 16.11% Risk factors associated with AKI were high serum chloride level Mortality was higher (43.18%) in AKI patients As AKI is associated with the higher mortality vigilant monitoring for risk factors is necessary in ICU patients Data will be available on reasonable request from the principal investigator Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study Mortality and predictors of acute kidney injury in adults: a hospital-based prospective observational study The pathophysiology of sepsis-associated AKI A prospective international multicenter study of AKI in the intensive care unit Accurate and interpretable prediction of ICU-acquired AKI Epidemiology and outcomes in community-acquired versus hospital-acquired AKI Clinical characteristics and outcomes of community-acquired versus hospital-acquired acute kidney injury: a meta-analysis Clinical spectrum of hospital acquired renal failure: a study from tertiary care hospital Hospital-acquired acute kidney injury in medical and intensive care unit: a comparative study Sepsis-associated acute kidney injury in the intensive care unit: incidence Acute renal failure in critically ill patients: a multinational Long-term survival and dialysis dependency following acute kidney injury in intensive care: extended follow-up of a randomized controlled trial Serum chloride levels in critical illness—the hidden story Acute kidney Injury in critical illness Study Group Effect of hyperchloremia on acute kidney injury in critically ill septic patients: a retrospective cohort study Hyperchloremia is not associated with AKI or death in septic shock patients: results of a post hoc analysis of the HYPER2S trial Balanced crystalloids versus saline in critically ill adults Effects of chloride content of intravenous crystalloid solutions in critically ill adult patients: a meta-analysis with trial sequential analysis of randomized trials Mhanna, A. et al. Balanced crystalloids versus isotonic saline in pediatric sepsis: a comprehensive systematic review and meta-analysis. Proc. (Bayl Univ. Med. Cent). 37 (2), 295–302. https://doi.org/10.1080/08998280.2024.2301904 (2024) Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study Is colistin-associated acute kidney injury clinically important in adults Colistin population pharmacokinetics after application of a loading dose of 9 MU colistin methanesulfonate in critically ill patients Impact of dexamethasone in severe COVID-19-induced acute kidney injury: a multicenter cohort study Acute kidney injury in critical COVID-19: a multicenter cohort analysis in seven large hospitals in Belgium Acute kidney injury (AKI) in patients with Covid-19 infection is associated with ventilatory management with elevated positive end-expiratory pressure (PEEP) Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis Sedation and renal impairment in critically ill patients: a post hoc analysis of a randomized trial Fluid overload is an independent risk factor for acute kidney injury in critically ill patients: results of a cohort study Cumulative fluid accumulation is associated with the development of acute kidney injury and non-recovery of renal function: a retrospective analysis and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Comparison of two fluid-management strategies in acute lung injury Acute interstitial nephritis due to pantoprazole Protective effect of pantoprazole against sepsis-induced acute lung and kidney injury in rats Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series Download references We would like to thank all staffs who helped in completing this project SS -Helped in statistical analysis and writing the manuscript All the authors have approved the final draft IEC approval was obtained from the respective hospitals Consent was obtained from the legally acceptable representative (LAR) Download citation DOI: https://doi.org/10.1038/s41598-024-79533-6 Metrics details Acute kidney injury (AKI) has been noticed after both COVID-19 vaccination and infection affecting risk-benefit evaluations and vaccine hesitancy We conducted a large-scale N3C cohort study to compare AKI incidence following COVID-19 vaccination and infection Participants from December 2020 to August 2023 were divided into two groups based on their initially observed COVID-19 antigen exposure: COVID-19 vaccination group (n = 2,953,219) and COVID-19 infection group (n = 3,616,802) AKI was defined by diagnostic codes and serum creatinine changes within a 30 day follow-up window after exposure The absolute risk of AKI was 0.66% in the vaccination group versus 4.88% in the infection group COVID-19 infection was associated with a significantly higher risk of AKI than COVID-19 vaccination (aHR = 10.31 Our study reveals that COVID-19 vaccination is associated with a significant lower AKI risk compared to COVID-19 infection vaccination is deemed acceptable under the hypothesis that an individual faces a higher risk of developing diseases from COVID-19 infection compared to that from COVID-19 vaccination this hypothesis has not been extensively tested on a large scale with accurate calculation and explored the association between AKI incidence and two types of COVID-19 antigen and other predefined risk factors The N3C Data Enclave is managed under the authority of the NIH Data transferred to the National Center for Advancing Translational Sciences (NCATS) from N3C is conducted under a Johns Hopkins University Reliance Protocol (IRB00249128) or individual site agreements with NIH Data usage of this study was authorized by N3C (DUR-22361BD) and had been reviewed and approved by the Medical School Institutional Review Board (IRB) at the University of Michigan (HUM00192962) Notes: Adults included in the study were categorized in two groups based on their initial exposure to COVID-19 antigens in the period over December 2020 – August 2023 The vaccination group: those whose first recorded COVID-19 vaccination preceded any infection formed the vaccine group; The infection group: those whose first documented COVID-19 infection occurred prior to any vaccination The index event established as the initial instance of either vaccination or infection Follow-up period: Patients were followed from the index date to 30 days (primary analysis) and 60/90 days (secondary analysis) Censored at the end of 30 days without AKI outcomes or death within 30 days (primary analysis) Selection period: 1 year before index date Patients who had AKI within 30 days before the index date were excluded to eliminate suspected non-onset events.Abbreviation: AKI acute kidney injury Notes: Adults included in the study were categorized into two groups based on their initial exposure to COVID-19 antigens (vaccines or pathogens) over December 2020 – August 2023 The vaccine group: Firstly those who received COVID-19 vaccines were included after excluding any preceded infection or follow-up period infection people younger than 18 years old or had ESKD history the vaccine group formed; The infection group: Those who were confirmed withCOVID-19 infection after 2020-12-11 were included after excluding any preceded vaccination or follow-up period vaccination Abbreviation: ESKD end stage kidney disease the lowest serum creatinine value during the follow-up period was considered as the baseline value We assessed each patient’s history of previous AKI and other comorbidities within 1 year prior to the index date using the N3C data The demographic characteristics and AKI incidence in both groups were compared using Chi-square tests for categorical variables and t-tests for continuous variables Time-to-event data were analyzed using the Kaplan-Meier (KM) method and Cox proportional hazards model adjusted for demographic factors and comorbidity status was utilized to evaluate the hazard ratio of AKI incidence following COVID-19 infection compared to COVID-19 vaccination (2) Extended follow-up period: We extended the follow-up period from 30 days to 60 and 90 days after the index date (3) AKI measurement methods: We included different AKI measurements These dimensions aimed to assess the consistency of results between two groups across different temporal phases extended time-to-event periods and AKI measurement methods We further assessed AKI incidence by different strains (Alpha Delta and Omicron) in the infection group and by different types of vaccines (mRNA vaccines and viral vector vaccines) in the vaccination group All analyses were conducted within the N3C enclave using SQL Notes: Adults included in the study were categorized in two groups based on their initial exposure to COVID-19 antigens in the period over December 2020 to August 2023 The vaccination group: those whose first recorded COVID-19 vaccination preceded any infection formed the vaccination group; The infection group: those whose first documented COVID-19 infection occurred prior to any vaccination Patients were followed from the index date to 30 days to observe AKI incidence The probability of developing AKI in the infection group was significantly higher than that in the vaccination group from day 0 to day 30(Log-Rank test In the univariate analysis of AKI incidence using the Cox proportional hazards model(Table 2) COVID-19 infection demonstrated a 7.55-fold higher hazard of AKI incidence compared to COVID-19 vaccination (HR In the multivariable analysis adjusting for demographics the COVID-19 infection remained a significantly higher risk factor with an adjusted hazard ratio (aHR) of 10.31 (95% CI P < 0.001) compared to the COVID-19 vaccination The multivariable analysis also demonstrated significantly higher risks of AKI in older age groups (age group of 65-90: aHR, 11.43; 95% CI, 11.14–11.72, P < 0.001) and among individuals with a previous AKI history (aHR, 3.17; 95% CI, 3.12-3.23, P < 0.001) (Table 2) P < 0.001) and cardiovascular disease (aHR P < 0.001) were associated with an increased hazard of developing AKI P < 0.001) exhibited higher hazards of AKI Individuals who did not identify themselves as Hispanic or Latino had a lower hazard (aHR as did those with no ethnicity information (aHR compared to individuals who identified themselves as Hispanic or Latino In a retrospective observational cohort study with a large-scale population we observed a substantial disparity in AKI incidence between the COVID-19 vaccination group and the COVID-19 infection group The infection group exhibited a significantly higher risk of AKI compared to the vaccination group Further investigation into this aspect is crucial further helping to address vaccine hesitancy our study contributes to a comprehensive safety profile of COVID-19 vaccines While our study adopted an observational cohort study for comparison our research included secondary analysis and time-to-event analysis We observed a consistently stable time-to-event curve within 30 days after COVID-19 vaccination It is possible for events to occur beyond the 30 day follow-up period or vary with different strains and AKI measurement methods extended studies over 60 and 90 days follow-up periods various strains and AKI measurement consistently demonstrated this low-risk pattern in line with our primary findings We calculated the crude rates and found statistical differences between vaccine types suggesting that the viral vector vaccine has a higher crude incidence rate of AKI than the mRNA vaccine Our results are consistent with a previous study that found higher AKI reporting rates for viral vector vaccines compared to mRNA vaccines after COVID-19 vaccination11 our findings show associations instead of causality Further studies are needed to investigate the biological link between AKI and vaccine types The process of COVID-19 vaccines may activate antigen-presenting cells (APCs) leading to strong CD4+ and CD8 + T-cell responses and significant inflammatory cytokine release This may trigger a cytokine storm and future lead to AKI but the conclusion was made among critically ill patients which was a totally different study population from ours Activation of the coagulation system can result in microthrombi formation impairing renal blood flow and causing ischemic damage the renin-angiotensin system may become dysregulated exacerbating renal injury through altered blood pressure regulation and inflammatory pathways these factors contribute to the multifaceted pathogenesis of COVID-19 related AKI We also found that the factor of previous AKI history increased the risk of AKI This could be attributed to potential lingering effects on renal resilience the persistence or progression of underlying conditions and the sensitization to subsequent insults We observed that minority races and ethnicities had lower risk of AKI But this might be underestimated by residual confounding factors such as socioeconomic factors the inherent weaknesses of EHR data pose challenges missing or incomplete records about COVID-19 vaccination and infection in N3C Despite the extensive data available in N3C it represents only a portion of the country rather than its entirety limiting the generalizability of our findings Our study design is retrospective and observational introducing potential biases due to unmeasured confounders and lacking the ability to establish causal relationships between outcomes and exposures our findings need to be interpreted with caution the novelty of our research is also embedded in the above limitations The N3C dataset provides the largest ever EHR dataset related to COVID-19 for an unparalleled opportunity to investigate the vaccine adverse events and compare them with the occurrences of the diseases or symptoms following infections COVID-19 pandemic made the majority of people worldwide infected; however the massive COVID-19 vaccination campaign significantly reduced the severity of the disease The simultaneous comparison of an adverse event such as the AKI provides us a unique angle to investigate the risk of a health outcome such as AKI following vaccination or natural infection This work significantly supports our addressing of the vaccine hesitancy issue promoting the wider usage of vaccination for the benefit of public health our retrospective cohort study reveals a significant difference in AKI incidence between individuals who received the COVID-19 vaccination and those who had COVID-19 infection individuals who received the COVID-19 vaccination experienced a significantly lower risk of AKI incidence compared to those who had COVID-19 infection The N3C Publication committee confirmed that this manuscript msid:1834.309 is in accordance with N3C data use and attribution policies; however this content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the N3C program All data of this study is available in the N3C Data Enclave for researchers with an approved protocol and data use request from an institutional review board. Data access is governed by the National Institutes of Health. More information on the enclave and instructions for data access can be found at https://covid.cd2h.org/for-researchers Real-world effectiveness of seasonal influenza vaccination and age as effect modifier: a systematic review meta-analysis and meta-regression of test-negative design studies Our World in Data. Coronavirus (COVID-19) Vaccinations. https://ourworldindata.org/covid-vaccinations (2023) A global database of COVID-19 vaccinations COVID-19: talk of ‘vaccine hesitancy’ lets governments off the hook acute interstitial nephritis in SARS-CoV-2 infection and vaccination CDC. Vaccine Adverse Event Reporting System (VAERS). https://vaers.hhs.gov/ (2023) Acute kidney injury after COVID-19 vaccines: a real-world study Adverse events of acute nephrotoxicity reported to EudraVigilance and VAERS after COVID-19 vaccination Distinct glomerular disease association after vaccination with BNT162b2 and mRNA-1273: a VigiBase analysis ANCA-associated vasculitis following Pfizer-BioNTech COVID-19 vaccine Minimal change disease following the Pfizer-BioNTech COVID-19 vaccine Minimal change disease with severe acute kidney injury following the oxford-AstraZeneca COVID-19 Vaccine: a case report ANCA glomerulonephritis after the moderna COVID-19 vaccination New-onset nephrotic syndrome after janssen COVID-19 vaccination: a case report and literature review An additional case of minimal change disease following the Pfizer-BioNTech COVID-19 vaccine Relapse of minimal change disease following the Pfizer-BioNTech COVID-19 vaccine Minimal change disease following the moderna mRNA-1273 SARS-CoV-2 vaccine Relapse of primary membranous nephropathy after inactivated SARS-CoV-2 virus vaccination AKI in hospitalized patients with COVID-19 Geographic and temporal trends in COVID-associated acute kidney injury in the national COVID cohort collaborative Characterization of acute kidney injury in critically ill patients with severe coronavirus disease 2019 The national COVID cohort collaborative (N3C): rationale NCATS. National COVID Cohort Collaborative. https://covid.cd2h.org (2023) Antigen presentation of mRNA-based and virus-vectored SARS-CoV-2 vaccines Observational health data sciences and informatics (OHDSI): opportunities for observational researchers Using big data to emulate a target trial when a randomized trial is not available Performance and limitations of administrative data in the identification of AKI CDC. COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#variant-proportions (2023) Understanding vaccine safety information from the vaccine adverse event reporting system Global covid-19 vaccine rollout and safety surveillance-how to keep pace Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine Safety and efficacy of NVX-CoV2373 covid-19 vaccine A comprehensive analysis of the efficacy and safety of COVID-19 vaccines Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis Systems vaccinology of the BNT162b2 mRNA vaccine in humans Cytotoxic T-lymphocyte elicited vaccine against SARS-CoV-2 employing immunoinformatics framework Self controlled case series methods: an alternative to standard epidemiological study designs New insights into kidney disease after COVID-19 infection and vaccination: histopathological and clinical findings New insights into the mucosal immune pathogenesis of IgA nephropathy from the perspective of COVID-19 vaccination COVID-19 variants in critically Ill patients: a comparison of the delta and Omicron variant profiles Pathophysiology of COVID-19-associated acute kidney injury Early versus late acute kidney injury among patients with COVID-19-a multicenter study from Wuhan Download references We gratefully acknowledge the following core contributors to N3C: Adam B Details of contributions available at covid.cd2h.org/core-contributors Hershey Medical Center — UL1TR002014: Penn State Clinical and Translational Science Institute • Rush University Medical Center — UL1TR002389: The Institute for Translational Medicine (ITM) • Rutgers The State University of New Jersey — UL1TR003017: New Jersey Alliance for Clinical and Translational Science • Stony Brook University — U24TR002306 • The Alliance at the University of Puerto Rico Kenneth and Dianne Wright Center for Clinical and Translational Research • Wake Forest University Health Sciences — UL1TR001420: Wake Forest Clinical and Translational Science Institute • Washington University in St Davis — UL1TR001860: UCDavis Health Clinical and Translational Science Center • University of California Irvine — UL1TR001414: The UC Irvine Institute for Clinical and Translational Science (ICTS) • University of California Los Angeles — UL1TR001881: UCLA Clinical Translational Science Institute • University of California San Diego — UL1TR001442: Altman Clinical and Translational Research Institute • University of California San Francisco — UL1TR001872: UCSF Clinical and Translational Science Institute NYU Langone Health Clinical Science Core Department of Respiratory and Critical Care Medicine and NHC Key Laboratory of Immunological Diseases Center for Computational Medicine and Bioinformatics was responsible for cohort data generation and Y.Han were responsible for data analysis and writing the first version of the manuscript and Y.He initiated the project and provided the original project design played roles in developing research questions and ways to address the questions YHe served as the vaccine adverse event domain expert All authors participated in result interpretation Download citation DOI: https://doi.org/10.1038/s41541-024-00964-3 have teamed up to protect citizens from extreme heat and replenish Sierra Leone’s tropical rainforests Yvonne Aki-Sawyerr and Eugenia Kargbo photographed by Kristin-Lee Moolman in Freetown, Sierra LeoneByArielle SamuelsonMarch 18, 2025This story is part of the National Geographic 33.A decade ago just as Sierra Leone’s Ebola epidemic was ending Yvonne Aki-Sawyerr saw the effects of another catastrophe: The tropical rainforests encircling the country’s capital “I just suddenly noticed the level of deforestation,” she says coupled with rising temperatures that regularly exceeded 100 degrees Fahrenheit offered irrefutable evidence of the growing climate crisis Aki-Sawyerr had already decided to run for mayor She soon realized what a daunting mission she’d undertaken One of the most climate-vulnerable countries in the world severely restricting its ability to adapt to a crisis primarily caused by wealthy nations burning fossil fuels who campaigned against the blood diamond trade and co-founded a charity that helped women and children displaced by the country’s civil war offers another way of thinking: “Things that aren’t right don’t need to stay that way,” she says Aki-Sawyerr recalls a ritual that was once common in her country: A newborn’s umbilical cord was buried with a freshly planted tree, symbolically tying each person to the land. She believes in the power of customs that connect us to our world. And she’s hoping future generations can rediscover them. “There’s so many traditions that we have around trees that are lost,” she says. “Just bringing that tradition back is something very powerful.” LA JOLLA, Calif., Feb. 19, 2025 /PRNewswire/ -- CalciMedica Inc. ("CalciMedica" or the "Company") (Nasdaq: CALC) today announced a plenary presentation at the 30th International Acute Kidney Injury and Continuous Renal Replacement Therapy Conference (AKI & CRRT) being held March 3-6 Details for the presentation are as follows: Presentation Title: The Role of ORAI-1 in AKI Session Title: Plenary 2: Bench to Bedside: Translating Discoveries to Clinical Care Contact InformationArgot PartnersSarah Sutton/Kevin Murphy[email protected](212) 600-1902 Trade Show News Metrics details Kidneys are at risk from drug-induced toxicity with a significant proportion of acute kidney injury (AKI) linked to medications Existing cytoprotective drugs for cisplatin-AKI carry side effects prompting a search for better biological therapies Mesenchymal Stem Cells (MSCs) are under consideration given their regenerative properties yet their clinical application has not achieved their full potential mainly due to variability in the source of MSC tested translating treatments from rodent models to humans remains challenging due to a lack of standardized dosing and understanding potential differential responses to cisplatin between animal strains we performed a time-course analysis of the effect of cisplatin across different mouse strains and evaluated gender related differences to create a robust preclinical model that could then be used to explore the therapeutic efficacy of different sources of MSCs for their ability to reverse AKI Our data indicated that different mouse strains produce differential responses to the same cisplatin dosing regimen we did not observe any gender-related bias towards cisplatin nephrotoxicity our time-course analysis identified that cisplatin-induced inflammation was driven by a strong CXCL1 response which was used as a putative biomarker to evaluate the comparative therapeutic efficacy of different MSC sources in reversing AKI Our data indicates that UC-MSCs have a stronger anti-inflammatory effect compared to BM-MSCs and AD-MSCs our data underscores the importance of using an optimized preclinical model of cisplatin-AKI to test different therapies We identified CXCL1 as a potential biomarker of cisplatin-AKI and identified the superior efficacy of UC-MSCs in mitigating cisplatin-AKI which may restrict their universal usage for preventing cisplatin-AKI These constraints have therefore spearheaded the need to look for alternative therapies for treating cisplatin related nephrotoxicity growth/proliferative and angiogenic properties which collectively could have implications in the development of a targeted therapy for cisplatin-AKI To improve the translatability of preclinical mice models of cisplatin-AKI it is important to understand: (i) the effect of different dosing regimens and (iii) the heterogeneity in the temporal profile of the functional and molecular responses between different strains of mice this will increase the likelihood of identifying and validating novel therapeutic targets for increased translatability into patients we looked at the dose-dependent responses to cisplatin in two different mouse strains and performed a transcriptome based time-course analysis of the molecular signature in male and female C57BL/6 mice during the progression of cisplatin-AKI to generate a robust and reproducible preclinical model that could then be used to investigate the ability of different sources of MSCs to function as a rescue therapy to reverse AKI MSCs from passage 4–6 were used in this study USA (Catalogue: CRL-2190) and cultured in Keratinocyte Serum-free media (K-SFM) from Invitrogen (GIBCO) using additives 0.05 mg/mL Bovine Pituitary Extract (BPE) and 5 ng/ml human recombinant Epidermal Growth Factor (EGF) HK-2 cells were co-cultured with MSCs (in a trans well system) from different sources (n = 3 donors) in a ratio of 10:1 in serum-free media containing cisplatin at a concentration of 100 μM in saline (Sigma-Aldrich) for 24 h we used a colorimetric Cell Death Detection ELISAPLUS (Roche Switzerland) according to the manufacturer’s guidelines and absorbance was measured at 405 nm Cellular ROS was measured using DCFDA (ThermoFisher USA) and fluorescence intensity was monitored at Ex/Em = 485/535 nm All animal experiments were performed according to the Institutional Animal Care and Use Committee (IACUC) at Stanford University CD1 and C57BL/6 mice aged 6–8 weeks were acquired from Charles River Laboratories AKI was induced by a single intra-peritoneal injection of cisplatin (Sigma Aldrich USA) in 0.5% saline at two different doses: 15 mg/kg and 20 mg/kg AKI was defined by measurement of serum Creatinine > 0.3 mg/dL and 1.5-fold increase in BUN for two consecutive days A single dose of MSCs (1 × 106 cells/animal) was administered via tail vein injection at Day 3 following cisplatin injection (20 mg/kg) Animals were sacrificed on Day 5 or Day 7 based on experiments Serum blood urea nitrogen (BUN) and creatinine were assayed spectrophotometrically at the Stanford diagnostic facility Total RNA was extracted using an RNAeasy kit (Qiagen Germany) and RT-qPCR for gene expression analysis was performed using an iTaq Universal One-Step RT-qPCR Kit by SYBR GREEN method Primers were procured from Integrated DNA Technologies (Table S2) and GAPDH was used as an internal control Renal tissue was fixed in 10% neutral-buffered formalin and processed for light microscopy examination Histopathological changes were analyzed by a pathologist following hematoxylin and eosin (H&E) staining ROIs were defined as 1mm2 areas of renal parenchyma To compare time-dependent variables among multiple groups a mixed ANOVA was used followed by Sidak’s post hoc correction for evaluating pairwise comparisons between groups A p-value (adjusted p-value for non-parametric and mixed ANOVA) P ≤ 0.05 was considered statistically significant Efficacy for the different MSC-sources was calculated as percentage differences compared to untreated samples (Table S1) doses in the range of 16–25 mg/kg were shown to induce moderate to severe AKI in > 50% of cases in mice following a single injection with no related mortality for modeling cisplatin induced AKI we chose two different sub-lethal concentrations of cisplatin at 15 mg/kg and 20 mg/kg to test in our studies Time-course effect of cisplatin dosing in two different mouse strains Panel showing changes in C57BL/6 renal functional parameters (b) Creatinine and (c) Phosphorous following intra-peritoneal (IP) injection of two different doses of cisplatin over 7 days Panel showing changes in CD1 renal functional parameters (e) Creatinine and (f) Phosphorous following systemic injection of two different doses of cisplatin over 7 days Statistical analysis: (a–f) Results expressed as mean ± SD (n = 5 biological replicates) Statistical significance was determined using a mixed ANOVA followed by Sidak’s post hoc correction for evaluating multiple pairwise comparison Time-course analysis of cisplatin-AKI on male and female mice a Temporal profile of mean gene expression intensity in C57BL/6 male and female mice over a period of 5 Days following cisplatin dose with strong overlap between C57BL/6 male and female mice at Day 2 and Day 3 (Red: male; Brown: female) b PCA analysis of variance in gene expression data for C57BL/6 male and female mice at Day 2 and Day 3 following cisplatin injection (c) Venn diagram showing overlap of DEG [log(FC) > 1.5 FDR < 0.05] between C57BL/6 male and female mouse at Day 2 and Day 3 d Unsupervised hierarchical clustering of conserved DEGS from C57BL/6 male and female mouse at Day 2 and Day 3 identified n = 9 modules with a positive Pearson correlation (R) > 0.1 Heatmap visualization of temporal change in gene expression across each module Modules were sorted into upregulated and downregulated based on their basal gene expression at Day 0 Top GO biological pathways for each module sorted by pvalue (p < 0.05) a–d All experiments were performed with male (n = 4 biological replicates) and female (n = 4 biological replicates) Six of the modules (m1–m6) showed an upregulation of conserved DEGs compared to healthy animals at Day 0 and three modules (m7–m9) showed a downregulation of conserved DEGs compared to healthy animals at Day 0 GO analysis of genes in each module (Supplementary dataset S2) identified biological pathways related to DNA damage repair (response to γ radiation G2 DNA damage checkpoint) and cell death (apoptotic process downregulation of glucocorticoid signaling) as upregulated at Day 2 while cytokine signaling (Neutrophil and monocyte chemotaxis TNFα and IL-1 response,) was upregulated at Day 3 and remain upregulated into Day 5 following cisplatin administration pathways related to epithelial cell damage (epithelial cell morphogenesis) and renal function (calcium ion hemostasis transmembrane transport) were downregulated at Day 2 while pathways related to aberrant angiogenic signals associated with fibrosis (VEGF signaling MAPK kinase signaling) were upregulated at Day 3 the time-course analysis indicates that Day 3 following cisplatin administration to be the time point when the inflammatory milieu is most evident The effect of different sources of MSCs on renal function and inflammation following cisplatin-AKI a Heatmap showing correlation of cytokines in the “Inflammation” module with the early kidney injury biomarker NGAL (Lcn2) at Day 3 which was the fixed timepoint of evaluation (b) Variation in Pearson correlation coefficient (R) for inflammatory cytokines w.r.t NGAL (Lcn2) over a period of 5 days Changes in serum (c) BUN and (d) creatinine following cisplatin-AKI w/ and w/o treatment with different MSCs Changes in mRNA expression level for early tubular injury biomarker (e) NGAL and (f) KIM-1 (Havrc1) following cisplatin-AKI w/ and w/o treatment with different MSCs Changes in mRNA expression level of pro-inflammatory cytokines (g) Tnfα and (h) Cxcl1 following cisplatin AKI w/ and w/o treatment with different MSCs i Changes in Myleoperoxidase (MPO) enzyme activity following cisplatin AKI w/ and w/o treatment with different MSCs j Changes in mRNA expression level of caspase in kidney tissue following cisplatin AKI w/ and w/o treatment with different MSCs Statistical analysis: c–j Results are expressed as min to max data distribution with IQR range and median (n = 4 biological replicates) Statistical significance was determined using a non-parametric Kruskal–Wallis test followed by 2-stage linear step-up procedure of Benjamini and Yekutieli for evaluating pairwise comparisons between the groups The effect of different sources of MSCs on renal tubular damage following cisplatin-AKI a Representative H&E stained images of tubular cast formation following cisplatin-AKI and treatment with different sources of MSCs b Quantification of tubular cast formation under the above-mentioned conditions Changes in (c) apoptosis and (d) cellular ROS in HK-2 renal epithelial cells following cisplatin treatment w/ and w/o MSC therapy in our in vitro cellular model of AKI Statistical analysis: b Results are expressed as min to max data distribution with IQR range and median (n = 4 biological replicates) d Results are expressed as min to max data distribution with IQR range and median (atleast n = 6 biological replicates) *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 and ****P ≤ 0.0001 we explored the dose-dependent responses to cisplatin in two different mouse strains and assessed gender and time-dependent heterogeneity in the molecular responses to cisplatin-AKI we then investigated the ability of MSCs from different sources to rescue cisplatin-AKI we undertook bulk transcriptomic studies of the whole kidney tissue and thus could not accurately assess the temporal damage pattern to the different cell types and hence this needs to be further evaluated in future studies work is still ongoing to develop novel and sensitive biomarkers for early AKI Clinical and experimental studies have shown that AKI can generate a strong inflammatory response there is less consensus in using inflammatory cytokines (TNFα IL6 and IL18) as biomarkers for identifying AKI since such signals are also known to be involved in conditions of systemic stress our time-course analysis suggests that when using a sub-lethal dose of cisplatin which does not carry risk of systemic toxicity CXCL1 may be a strong potential candidate biomarker to predict and monitor different stages of cisplatin-AKI out of four clinicals trials listed on ClinicalTrials.gov while only one trial (NCT04194671) uses UC-MSCs which likely contributes to the discrepancy noted in MSC efficacy observed in clinical trials our results underscore the importance of cell source selection as an important variable when considering how to translate MSCs into patients a broader protein biomarker screen should be conducted to prevent a potential positive bias in biomarker identification future studies should explore the differential effectiveness of MSCs from different sources in other models of kidney injury (i.e. ischemia–reperfusion) in order to prevent any model selection bias for the development of MSCs as a cell therapy for AKI our study aims to negate the effect of sampling bias by including both male and female sex in our study future studies can also focus on exploring the effect of cisplatin-AKI and MSC therapy in animals of different ages in order to prevent potential negative sampling bias Future studies will also aim to evaluate potential cell-free options in the form of extracellular vesicles derived from MSCs that can overcome immunogenicity issues associated with cell therapies although intravenous delivery is the most common technique used to administer MSCs into patients this method results in a majority of cells getting trapped in the lung requiring higher doses to ensure enough cells can then reach target organs Future work will thus explore whether the regenerative potential of MSCs can be enhanced using precision delivery approaches (i.e. via locoregional intraarterial administration of MSCs directly into the kidney) our study highlights the importance for the development of an optimized preclinical model for understanding the pathophysiology of cisplatin-AKI Our data shows the critical role which the chemokine CXCL1 plays in cisplatin-induced kidney inflammation while also providing an opportunity for the evaluation of therapeutic interventions based on this our comparative analysis of different sources of MSCs revealed distinct anti-inflammatory properties with UC-MSCs exhibiting superior efficacy in mitigating cisplatin-AKI compared to BM-MSCs and AD-MSCs our findings are of interest as there are currently no approved therapies available to treat AKI of any etiology; the ability to mitigate AKI severity is relevant given that prolonged AKI can lead to future chronic kidney dysfunction The authors declare that all data supporting the findings of this study are available within the article and its supplementary material files The transcriptomics data has been deposited in GEO data set identifier GSE263678 Neutrophil gelatinase associated lipocalin Spectrum of acute renal failure in the intensive care unit: the PICARD experience Cisplatin in cancer therapy: molecular mechanisms of action Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin Kher V, Srisawat N, Noiri E, Benghanem Gharbi M, Shetty MS, Yang L, et al. Prevention and therapy of acute kidney injury in the developing world. Kidney Int Rep. 2017;2(4):544–58. https://doi.org/10.1016/j.ekir.2017.03.015 Acute kidney injury is associated with increased healthcare utilization and mortality after primary total knee arthroplasty Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity French National Network of Pharmacovigilance Centres: the drugs that mostly frequently induce acute kidney injury: a case-noncase study of a pharmacovigilance database Effect of rosiglitazone on cisplatin-induced nephrotoxicity editor Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases Current understanding of the administration of mesenchymal stem cells in acute kidney injury to chronic kidney disease transition: a review with a focus on preclinical models Cisplatin and AKI: an ongoing battle with new perspectives—a narrative review Characterization of different sources of human MSCs expanded in serum-free conditions with quantification of chondrogenic induction in 3D Comparison of mesenchymal stem cell markers in multiple human adult stem cells Comparison of mesenchymal stem cell surface markers from bone marrow aspirates and adipose stromal vascular fraction sites Integrated transcriptome-proteome analyses of human stem cells reveal source-dependent differences in their regenerative signature Developing better mouse models to study cisplatin-induced kidney injury DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources A randomised multicentre phase II study with cisplatin/docetaxel vs oxaliplatin/docetaxel as first-line therapy in patients with advanced or metastatic non-small cell lung cancer Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury HSP70-mediated NLRP3 inflammasome suppression underlies reversal of acute kidney injury following extracellular vesicle and focused ultrasound combination therapy Reversing acute kidney injury using pulsed focused ultrasound and MSC therapy: a role for HSP-mediated PI3K/AKT signaling Incidences and range of spontaneous findings in the lymphoid and haemopoietic system of control Charles River CD-1 mice (Crl: CD-1(ICR) BR) used in chronic toxicity studies Drug discovery oncology in a mouse: concepts The origins and uses of mouse outbred stocks Use of C57BL/6N mice on the variety of immunological researches Mouse model of ischemic acute kidney injury: technical notes and tricks Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding C57BL/6 and 129/Sv mice: genetic difference to renal ischemia-reperfusion Mesenchymal stem cells therapy for acute kidney injury: a systematic review with meta-analysis based on rat model Human adipose-derived mesenchymal stem cells repair cisplatin-induced acute kidney injury through antiapoptotic pathways Precise quantitative evaluation of pharmacokinetics of cisplatin using a radio-platinum tracer in tumor-bearing mice Spatio-temporal transcriptomic analysis reveals distinct nephrotoxicity DNA damage and regeneration response after cisplatin Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group KDIGO clinical practice guideline for acute kidney injury Biomarker-guided risk assessment for acute kidney injury: time for clinical implementation NGAL: a biomarker of acute kidney injury and other systemic conditions Chemokine-induced macrophage polarization in inflammatory conditions power and effect size revisited: simplified and practical approaches in pre-clinical Differential dynamics of the mammalian mRNA and protein expression response to misfolding stress Download references The authors thank Novogene (China) for mRNA NGS sequencing; Histotech-laboratory Inc for histology slide preparation and H&E staining; Stanford diagnostic laboratory for help with serum BUN and creatinine analysis This work was supported by NIH Grant DK129598 Interventional Radiology Innovation at Stanford (IRIS) Editing: R.P and S.R; All authors read and approved the final manuscript unless otherwise stated in a credit line to the data Download citation DOI: https://doi.org/10.1186/s12967-024-05439-6 Metrics details and inflammation are considered to be central in the pathogenesis of sepsis-induced acute kidney injury (AKI) we hypothesized that extracorporeal removal of inflammatory cytokines by hemoadsorption (HA) therapy may mitigate renal injury associated with sepsis-induced AKI we investigated renal microcirculatory oxygenation and perfusion and kidney function in a rat model of septic AKI elicited by endotoxin infusion Three groups of rats were investigated on extracorporeal circulation: HA only Endotoxin infusion reduced cortex microcirculatory oxygenation and raised creatinine and lactate levels measured by two independent techniques (phosphorescence (µPO2) and spectrophotometry/Doppler (µHbO2sat and \(\mu \text{RBCv}\))) lactate and creatinine levels were restored in the LPS + HA group A reduced amount of injured tubular cells was found in histological analysis of the kidneys This experimental study demonstrated an improvement in multiple determinants of kidney oxygenation and systemic blood perfusion by HA in a clinically relevant rat model of septic AKI Further studies are needed to optimize and support the clinical use of HA as a renal protective strategy we undertook this present study to investigate in a clinically relevant fully instrumented rat model of sepsis AKI to test the effect of extracorporeal HA therapy on the microcirculatory oxygenation and perfusion of the kidney as responsible mechanisms responsible for acute kidney injury In this hypothesis-driven experimental study we hypothesized that the measurement of renal microcirculatory oxygenation and renal function would elucidate the mechanism by which HA may mitigate injury in a rat sepsis AKI model This study was approved by the National Committee of Animal Experimentation (AVD1010020231687 approval date: 26–05-2023) and the Animal Welfare Body of the Erasmus Medical Centre Care and handling were performed in accordance with the institutional and ARRIVE guidelines 24 male Wistar albino rats (Mean ± SD bodyweight of 411 ± 21 gr) g) were used in 3 groups (Charles River The Netherlands) with eight animals per group All rats were anesthetized with an intraperitoneal injection of a mixture of ketamine (90 mg/kg) dexmedetomidine (0,5 mg/kg) and atropine (0,05 mg/kg) Fluid maintenance was achieved by infusion of 20 ml/kg/h Ringer Acetate (RA) throughout experiments Anesthesia was maintained with ketamine (50 mg/kg/h) and dexmedetomidine (12,5μgr/kg/h) in 5 ml/kg/h Ringer acetate solution The depth of anesthesia was controlled with pinch stimulation and the end-tidal 40–45 mmHg of CO2 was maintained with a small animal capnograph A heating pad was used to control the animal’s body temperature at 37 ± 0.5 °C The arterial catheters primed with heparinized saline in the right carotid artery were used for hemodynamic measurements and the right femoral artery was used for taking blood samples HA was driven by a mini pump at a blood flow rate of 0.8–1.0 ml/min from the internal jugular to the right femoral vein the extracorporeal circuit was primed with heparinized 4% albumin solution (20 Units/ml) Miniature CytoSorb hemoadsorbers (volume 0.5 ml) were provided by the manufacturer (Cytosorbents Corporation USA) and attached to the extracorporeal circuit the left kidney was exposed and fixed in a Lucide cap A perivascular ultrasonic transient time flow probe (type 0.7 RB; Transonic Systems Inc. USA) was placed around the left renal artery and connected to a flow meter to continuously assess renal blood flow (RBF) The second light guide (Oxygen To See (O2C Germany) was used at each time point to measure renal microcirculatory Hb saturation (µHbO2sat) and renal microcirculatory red blood cell velocity (µRBCv) A total of 24 rats were randomized into the three experimental groups All three experimental groups had an extracorporeal circuit attached; the first group received only a Cytosorb hemoadsorber (HA group) the second group received LPS infusion (lipopolysaccharide (LPS); Sigma and in the third group received both LPS and hemadsorber (LPS + HA) 10 mg/kg LPS infusion at 30 min used by a syringe pump (Harvard 33 syringe pump; Harvard Apparatus extra-corporeal circulation was initiated and continued for 3 h in each group and arterial blood gas measurements were recorded 3 ml of blood was withdrawn from the arterial line for further plasma assessments of cytokines The left kidney was harvested and stored in a 4% neutral formaldehyde solution for immunohistochemical analysis Animals were euthanized with 1 ml/kg of 20% pentobarbital sodium injection (Euthasol Arterial blood samples (0.1 ml) were drawn from the femoral artery at four time points: baseline (T0) and every hour of extracorporeal circulation at T1 renal vein blood samples were obtained to calculate renal vein oxygen content and consumption The samples were used to determine blood gas values and electrolyte concentrations (Siemens RP500 Gas Analyzer) A second technique to measure microcirculatory oxygen availability based on a completely different measurement principle measures microcirculatory Hb sat by use of reflectance spectrophotometry (Oxygen to See System (O2C This technique illuminates tissue with white light and analyzes the spectrum of reflected white light from which it calculates µHbO2sat placed next to the phosphorimeter light guide on the kidney cortex surface also houses a micro laser Doppler flowmeter allowing renal cortex microcirculatory red blood cell velocity (µRBCv) to be measured Arterial oxygen content (AOC) was calculated by the following equation: (1.31 × hemoglobin x SaO2) + (0.003 × PaO2) where SaO2 is arterial oxygen saturation and PaO2 is the arterial partial pressure of oxygen Renal venous oxygen content (RVOC) was calculated as (1.31 × hemoglobin x SrvO2) + (0.003 × PrvO2) where SrvO2 is renal venous oxygen saturation and PrvO2 is renal vein partial pressure of oxygen Renal oxygen consumption was calculated as VO2ren (ml/min) = RBF (AOC-RVOC) C-reactive protein (CRP) and kidney damage marker neutrophil gelatinase-associated lipocalin (NGAL) were determined by enzyme-linked immunosorbent assay (ELISA) (Rat TNF-α ELISA kit Plasma creatinine was determined as a measure of renal function using an ELISA kit (item no: 502330 Data analysis and presentation were performed using GraphPad Prism 8 (GraphPad Software Shapiro Wilk normality test was used for the Gaussian distribution of data Two-way ANOVA for repeated measurements with a Tukey multiple comparison test was used for comparative analysis of inter-and intragroup variations The repeated-measures analysis of variance (One-way ANOVA with a Tukey multiple comparison test) was used for comparative analysis between the groups if baseline values differed distinctively Statistical analysis of histological results (values are reported mean ± SE) was performed by Kruskal–Wallis test with Dunn’s posttest was used Extracorporeal circulation reduced mean arterial pressure and renal blood flow in all three groups (Panel A–C) Heart rate remains more or less unchanged (Panel B) Values are represented as Mean ± SD.*p < 0.05 vs T0 Improvement of kidney microcirculatory oxygenation and perfusion Renal cortical microvascular oxygen pressure (cortical μPO2) (Panel A) microvascular hemoglobin O2 saturation (μHbO2sat ) (Panel B) and microvascular red blood cell velocity (μRBCv)(Panel C) during the experiments Improved metabolic function following Cytosorb HA therapy Renal oxygen consumption (VO2ren) at T3 (Panel A) and plasma lactate values during experiments (Panel B) Inflammatory cytokines; tumor necrosis alpha (TNF-α) c-reactive protein (CRP) in plasma (Panel A-B-C) Improved plasma creatinine following HA therapy and neutrophil gelatinase-associated lipocalin (NGAL) levels The histological damage score revealed that renal tubular damage was much lower in the LPS + HA group than with LPS alone (Fig. 5). Representative renal histological images (Panel A-B-C with X 4 magnification-bar = 250μm and D-E-F with X 20 magnification-bar = 50μm) and tubular damage score is the first study that demonstrates that extracorporeal HA therapy in the setting of sepsis-induced AKI improves renal function This novel experimental study demonstrated that extracorporeal HA therapy successfully improved renal microcirculatory oxygenation Results showed that concomitant to these microcirculatory improvements HA therapy also effectively mitigated renal tubular injury and improved kidney function as judged by lowered creatine levels in this rat model of septic AKI These facts should be taken into consideration when investigating the mechanisms underlying the benefits of extracorporeal HA therapy This study has some technical limitations which would need to be addressed in future studies we could not demonstrate that HA therapy effectively reduced cytokine levels Although TNF-α levels increased upon LPS administration we could not find a change when using HA therapy may have suffered from technical shortcomings because we did not have enough plasma sample volume to perform the required dilution needed to be within the range of the sensitivity of the IL-6 kit This possibly meant that the IL-6 levels exceeded the sensitivity range of the kit it would have been interesting to be able to measure the impact of HA on medullary oxygenation while being precise in measuring the cortical region of the kidney is unable to measure renal medullary oxygenation An immunohistochemical analysis of the kidney section using pimonidazole may provide additional information concerning hypoxic areas in the different kidney regions our study showed that extracorporeal HA therapy was effective in improving renal microcirculatory oxygenation and function and mitigating renal injury associated with septic AKI in rats The present novel experimental model can be an effective platform to further optimize HA therapy as a renal protective strategy in septic patients The data that support the findings of this study are available from the corresponding author and so are not publicly available Data are however available from the authors upon reasonable request and with permission of Cytosorbent Corporation Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup Zhou, X. Reducing Oxygen Demand to Alleviate Acute Kidney Injury. Front. Biosci. https://doi.org/10.31083/j.fbl2803062 (2023) Evolution of altered tubular metabolism and mitochondrial function in sepsis-associated acute kidney injury Effects of fluid and norepinephrine resuscitation in a sheep model of endotoxin shock and acute kidney injury Differences between cytokine effects in the microcirculation of the rat Immunoregulatory mechanism of acute kidney injury in sepsis: a narrative review CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study Improved Survival beyond 28 Days up to 1 Year after CytoSorb Treatment for Refractory Septic Shock: A Propensity-Weighted Retrospective Survival Analysis Sublingual microcirculatory evaluation of extracorporeal hemoadsorption with cytosorb® in abdominal sepsis: a case report Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation and function in a rat model of endotoxemia Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats Guerci, P. et al. Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats. Anesth. Analg. https://doi.org/10.1213/ANE.0000000000003918 (2018) A LED-based phosphorimeter for measurement of microcirculatory oxygen pressure Divergent Effects of Hypertonic Fluid Resuscitation on Renal Pathophysiological and Structural Parameters in Rat Model of Lower Body Ischemia/Reperfusion-Induced Sterile Inflammation The central role of renal microcirculatory dysfunction in the pathogenesis of acute kidney injury Sepsis-induced acute kidney injury: A disease of the microcirculation Role of hemoperfusion with cytosorb associated with continuous kidney replacement therapy on renal outcome in critically iii children with septic shock and arterial stiffness during hemodialysis and their clinical implications in intradialytic hypotension Pulmonary complications associated with veno-arterial extra-corporeal membrane oxygenation: a comprehensive review The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology haemodynamics and microcirculation in patients with sepsis/septic shock undergoing continuous renal replacement therapy and blood purification with cytosorb Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis ovine fab for injection (CytoFab) in severe sepsis Download references This study was partially supported by Cytosorbents Europe We would like to thank Myrthe van de Grint for her support and contribution to this work Laboratory of Translational Intensive Care Department of Medical Technical Innovation & Development (MIO) and L.M: conducting histology and data analysis C.I: supervising and writing the final version and review of the manuscript and services related to clinical microcirculation All other authors declare that they have no conflict of interest Download citation DOI: https://doi.org/10.1038/s41598-024-79997-6 There was the Fort Collins High School alumnus But still storming the court right alongside the current students and fans The Fort Collins boys basketball team shot past Rocky Mountain 54-44 on Tuesday night in the first city rivalry game of a winter season that will be full of them Well, the first-year Lambkins coach (and program's all-time assists leader) briefly but earnestly joined the party with a spirted home student section that showed up in force on a snowy foggy night and rushed the court after a thrilling win Never seen Coach with energy like that," Fort Collins senior Marcus Burkett said I guess we gave him a good reason," fellow senior Marcel Herrera said The Lambkins trailed by as many as 11 early and some non-conference struggles looked like they may continue into the new year the home team caught fire with five second-half 3-pointers outscoring the Lobos by 15 in the final two quarters after trailing by five at halftime A parade of Fort Collins players backed up the long-distance shooting with nine clutch free throws in the final minutes as Rocky fouled to extend its hopes 1-0 league) quickly took the party from the floor to the locker room where the raucous celebration could easily be heard from the gym hallway "I was just caught up in the excitement for our kids," Palmer said of the postgame fun "I've seen how hard they worked and just happy to see it pay off with a win like that." so we had fun sharing the love with everybody," Burkett said Thanks to a new league and schedule format this year this was more than just a landmark win for Palmer and his team It was an exhilarating start to two months full of Fort Collins-area rivalry boys and girls basketball doubleheaders revampedThe four large Fort Collins city schools are all part of a newly realigned Northern Conference this season on the hardwood That brings major tangible impacts for local hoops Gone is the larger Front Range League stretching down to Broomfield and Boulder which often meant city teams would play each other just once each in conference play for the past decade Not to mention Windsor in a separate conference completely smaller league with more local teams also creates greater standardized scheduling allowing for many more boys and girls doubleheaders More packed houses and rowdy student sections with fans coaches and players who know each other well "We love the extra energy in the gyms for these local games," said Rocky Mountain girls head coach Justin Vallejo "The girls absolutely feed off it as competitors and we'll get to do that a lot this year." It all began Tuesday night at Fort Collins High School as the Lambkins hosted Rocky Mountain in the first of nearly 20 local double bills over the next two months The Coloradoan will have Rivalry Night coverage each Tuesday (and some Fridays) throughout the winter furious finishes and star performances from our local hoopers on the big city stage as Rocky Mountain jumped all over Fort Collins and cruised to a 58-41 crosstown road win Rocky Mountain girls MVP: Kenna WagnerThe Lobos senior point guard was in total control on offense and smelled blood in the water on defense Wagner had 16 points and led a strong "hustle" game as the Lobos dominated defensively and on the glass She found driving lanes and then set teammates up for good looks before swiping the ball right back with quick hands on some lax Lambkin passes Wagner also finished with at least five assists and five steals She's the focal point for this surging Rocky squad that has won six straight since a 1-3 start Every Lambkin who hit the floor had an impact in this one an absolute all-around team effort that included some disruptive defense But it was the 3-point shot that really lit the fuse in a decisive second half Four different Fort Collins players combined to make seven total 3-pointers Spiro Palmer (Aki's son) spearheaded a second-half run with another and Herrera also hit a pair of impressive pull-up triples Here are all of the remaining girls and boys basketball doubleheaders this winter featuring Fort Collins city teams This story has been updated with additional information and postgame context Chris Abshire covers high school and community sports for the Coloradoan © 2025 Mashup Media, LLC, a Formedics Property. All Rights Reserved. The “Our Roots Say That We’re Sisters” podcast series features women students staff and alumnae of color who have exhibited leadership positive impact or social change in their personal or professional roles especially those who remain unsung “sheroes.”  This month’s podcast highlights the story of Aki Alvarez a Marquette senior studying international business and information systems and a demonstrator who has countered anti-LGBTQ+ protests Associated with Marquette’s campus mural project richness and complexity of our campus and provides a way for campus community members to see themselves and their potential elevated It also makes visible the interconnected nature of the experiences and struggles of many women of color.   For more information about the Our Roots project, contact Dr. Jacki Black at jacqueline.black@marquette.edu Take part in Baccalaureate Mass, May 10  A prayer for the president French Mass at St. Joan of Arc Chapel, May 1  DENVER, Dec. 03, 2024 (GLOBE NEWSWIRE) -- SeaStar Medical Holding Corporation (Nasdaq: ICU) a commercial-stage medical device company developing proprietary solutions to reduce the consequences of hyperinflammation on vital organs announces the activation of Sentara Norfolk General Hospital in Norfolk Virginia as its thirteenth active site in its NEUTRALIZE-AKI pivotal trial The Company also reports the enrollment of nine critically ill adult acute kidney injury (AKI) patients in the trial during November bringing total trial enrollment to 65 subjects The NEUTRALIZE-AKI trial is evaluating the safety and efficacy of the Company’s proprietary therapeutic Selective Cytopheretic Device (SCD) in 200 adult patients with AKI in the intensive care unit (ICU) receiving continuous renal replacement therapy (CRRT) “We are thankful for the steady pace of site activations and continued brisk enrollment with our recently activated sites already contributing,” said Kevin Chung “The rate of enrollment has increased significantly with nearly two times the number of subjects enrolled in the first two months of the fourth quarter compared with the total number for each of the previous three quarters of 2024 We are working to activate additional sites in December which will help us reach our enrollment milestones sooner.” “Previously completed pilot studies demonstrate the SCD’s ability to save the lives of critically ill patients with AKI and to eliminate dialysis dependence with additional benefits to the overall healthcare system,” said Eric Schlorff “Given the addressable adult AKI population of approximately 210,000 patients in the U.S we estimate annual peak sales of approximately $1 billion for the SCD in this indication AKI is only one of multiple high-value indications where hyperinflammation plays a role and we have preliminary evidence of effectiveness of the SCD in mitigating a variety of illnesses We plan to pursue cardiorenal syndrome as our next clinical focus.” SeaStar Medical’s SCD previously received U.S The NEUTRALIZE-AKI (NEUTRophil and monocyte deActivation via SeLective Cytopheretic Device – a randomIZEd clinical trial in Acute Kidney Injury) is expected to enroll up to 200 adults Alliance Advisors IRJody Cain(310) 691-7100Jcain@allianceadvisors.com Friday, Nov. 1, was my last day with the Free Press, and I bring to a close a career in Vermont journalism that spanned just shy of 33 years – fully half of my life I am retiring from daily journalism after nearly 40 years of reporting and editing I am truly grateful for the opportunity I’ve been given to help deliver the news vital to understanding who we are as a community I leave the newsroom in the very capable hands of a dynamic group of reporters who are laser-focused on local journalism and supported by colleagues throughout New England who are part of the USA Today Network You can expect them to continue to deliver stories big and small that matter to Vermonters The scale and character of this state allows journalists in Vermont to cover what the major stories without losing sight that we are writing about our friends and neighbors we might run into at the grocery store I thank all the readers who over the years have reached out to me and the Free Press I appreciate the criticisms because they are evidence that the readers care about the Free Press signs that they felt an ownership of the coverage we delivered into their lives I came to the Free Press in 1991 after five years working as a reporter in Tokyo then as a correspondent for a financial news wire in the very early days of digital journalism I have been a reporter on the features and business desks in charge of the opinion pages under various titles and I’ve been able to build a fulfilling career in a single newsroom that has a deep connection to the people and communities we cover That’s a rare privilege in our profession these days I’m just one more subscriber who turns to Free Press journalists to keep me informed about my community I came to Vermont for a job and by choosing to sink our family’s roots in this community Paul end of the long building along Kilburn Street next to Citizen Cider) at the beginning of August The Free Press newsroom moved to Williston in 2021 to join our colleagues in the circulation department who had set up shop at the White Cap Business Park we saw an opportunity to move our offices again and focused our search on Burlington We found our home in the heart of the South End About us | Advertise with us | Contact us Posted: 9 September 2024 | | No comments yet The study’s findings could contribute to future therapeutic strategies to prevent chronic kidney disease Researchers from University of Southern California (USC) and California Institute of Technology (Caltech) have provided novel insights into how damaged cells interact within disease-promoting microenvironments after acute kidney injury (AKI) This study could contribute to future therapeutic strategies to prevent chronic kidney disease (CKD) which affects an estimated 37 million individuals in the US and can lead to kidney failure find microenvironments associated with injury and predict cellular interactions associated with the progression to CKD Furthermore, another significant injury-associated microenvironment called ME-16 was recognised This had aggregations of tertiary lymphoid structures that are known to contribute chronic inflammation ME-16 was distributed throughout the injured organ instead of being confined to a specific region of the kidney So that the researchers could share their findings, they generated a comprehensive map of cellular, molecular and structural changes following AKI. This map is publicly available here: https://woldlab.caltech.edu/ci2-celltiles/Mouse-Kidney-Fibrosis/ This study, funded and supported by USC Broad Innovation Award, was published in Nature Communications Related topics, , , Related conditions, Related organisations, Related people, , By No comments yet , , , , , , , All subscriptions include online membership giving you access to the journal and exclusive content Comment * document.getElementById("comment").setAttribute( "id" "adcc96e61bdccaff0e95d4cc9342123d" );document.getElementById("a3f6228d48").setAttribute( "id" Write for us | Advertise with us Drug Target Review is published by: Russell Publishing Ltd.Court LodgeHogtrough HillBrasted © Russell Publishing Limited, 2010-2025. All rights reserved. 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functionalities of the website CookieTypeDurationDescriptioncf_ob_infopersistent1 minuteThis cookie is set by Cloudflare content delivery network and in conjunction with the cookie 'cf_use_ob' The popular Enka singer passed away in 2023 New Century Records released Wasurenaide — meaning “Don’t forget me” — a collection of songs by the late Enka artist Aki Yashiro Yet rather than just focusing on her music including popular tracks such as “Funauta” and “Ame no Bojo,” the Kagoshima-based company decided to try to boost sales by including two fully nude photographs of the singer when she was in her mid-20s The pictures were shot by an individual she was living with at the time all female artists will work in fear of the possibility of their dignity being trampled upon after their death.”  President Hiroshi Hayakawa said the company bought the master recording rights to several of Yashiro’s songs along with her public and private photographs around a quarter of a century ago. “There is also a purchase agreement,” he said “It’s just business.”  in 1950 and took her stage name from her hometown. After working as a bus tour guide she eventually fulfilled her dream of becoming a singer “Namida Goi,” was released two years later She was the first female Enka singer to have seven top 10 singles on the main Oricon chart Yashiro died in 2023 at the age of 73.   one preeminent healthcare provider organization is employing RPM to enhance post-discharge care for AKI survivors Rochester, Minnesota-based Mayo Clinic launched its RPM program for AKI survivors in October 2021. Recently published research reveals that the program is feasible driving interventions that can help boost kidney health and address AKI complications AKI -- in which the kidneys are unable to filter waste from the blood -- can cause fatigue, high blood pressure, chest pain, and, in some severe cases, seizures or coma. AKI prevalence rose from 80 per 1,000 patient-years in 2007 to 242 per 1,000 patient-years in 2022 The post-discharge period is especially critical for those who undergo hospitalization for AKI because, without proper management, these patients can experience poor outcomes including an increased risk of cardiovascular events progression of chronic kidney disease after AKI and long-term mortality RPM can help ensure that AKI survivors are receiving critical support that addresses post-discharge needs; however the research shows that there might be limits to what RPM can achieve in this area researcher and associate professor of medicine and pharmacy at Mayo Clinic the health system decided to launch an RPM program for AKI survivors to fill gaps in follow-up care post-discharge "We need[ed] to help them find ways to stay in their homes so they can keep working and living while still getting adequate care," she said in an interview we developed the AKI remote patient monitoring program which is one of several remote patient monitoring programs that exists and is supported by the Mayo Clinic Center for Digital Health." The AKI RPM program involves identifying potential AKI patients during hospitalization who would benefit from continued monitoring after discharge The enrolled patients receive a blood pressure cuff They measure their blood pressure and weight daily and transmit the readings to their care team in the Center for Digital Health "If there are indications that the vital signs or the symptoms that they're having are out of normal then there are escalation pathways that allow that [data] to get to the care providers to make sure that [the patients] have the resources they need," Barreto said if all of a sudden they have gained five pounds and they are newly short of breath then we might call an advanced practice provider and see if they want to do anything different with their medications or talk to a nephrologist about whether they need even more monitoring." The patients are also scheduled for routine maintenance lab tests at the clinic about once a week to monitor their kidney health Patients remain in the program for at least four weeks and a maximum of three months they either move into Mayo Clinic's chronic kidney disease care clinic or return to their primary care provider "[We try] to make sure that that transition is seamless and then they're aware of how best to care for them[selves] from a kidney perspective moving forward," Barreto said The AKI RPM program aims to improve post-discharge care for AKI survivors in numerous ways AKI patients experience electrolyte changes RPM helps care teams track these changes and intervene before they result in severe illness or death Another significant issue facing AKI patients is that they might have a buildup of fluid if they haven't fully recovered when they leave the hospital "That fluid can cause weight gain and shortness of breath," Barreto noted and you need medications to try and remove that fluid from your body they're trying to relearn how to remove that fluid from their body and sometimes they put too much urine out while they're still getting reorganized after being injured you can end up dry in the sense that you can have too little fluid circulating and that can increase your risk of having AKI again in the future." it is vital to effectively manage the utilization of diuretics -- medications that help rid the body of excess fluid -- following AKI hospitalization real-time view of diuretic use and its effects enabling clinicians to adjust the medications as needed to prevent recurrent episodes of AKI or the progression to chronic kidney disease Though the RPM program has the potential to enhance post-discharge care for AKI survivors Baretto noted several key considerations that organizations must be aware of to ensure its success including having a process in place to help identify suitable patients for the program "Many patients who have acute kidney injury also have heart disease and lung disease and are admitted to the hospital for infections and brain problems and all of these other things," she said "And so acute kidney injury is kind of a diffuse problem that affects a whole host of patients across the practice Trying to figure out exactly how to choose patients for the program [in a way] that is thoughtful and equitable and doesn't add complexity to already complex care for people the health system tasked their inpatient kidney specialists with identifying viable candidates for the program not every patient with AKI is cared for by a kidney specialist the Mayo Clinic developed screening lists that can be used across service lines to identify patients for the program equitably Another consideration was digital health literacy which is the level of access and comfort a person has with digital health tools Mayo Clinic's Center for Digital Health has created a team to address this issue The team sends new candidate packages to newly enrolled participants in the various technology-supported programs the health system offers They also contact patients directly to train them on digital health tools and answer questions we have had to be a little bit more adaptable which is expected when you open a program; you have to keep it kind of restrained until you figure out how it's going and where your gaps are and what you need to shore up," Barreto said After launching the AKI RPM program nearly three years ago Mayo Clinic researchers set out to study its feasibility and efficacy in improving post-discharge AKI support publishing their findings in the journal Kidney Medicine to share the health system and participants' experience with AKI RPM including program recruitment and the types of alerts and interventions it prompted to examine whether the program could reduce readmissions The researchers performed a cohort study with matched historical controls that included adults hospitalized at the Mayo Clinic for AKI and then discharged to their homes They included 49 patients enrolled in the AKI RPM program between October 2021 and November 2022 The historical control group included AKI survivors hospitalized from October 2018 to September 2021 82% participated in the program after hospital discharge The median duration of participation in the program was 32 days patients were able to be recruited into the program," Barreto said they went to the lab to get their blood drawn and get their laboratory monitoring completed that's a pretty good sign that the program at least among this subset of 40 or so odd people The study also shows that among the 40 patients who actively participated in the program The alerts were primarily for abnormal symptoms The leading intervention recommendation by RPM providers was diuretic adjustments "So that highlights the potential role that this remote monitoring has for these patients because there were certainly interventions that needed to be made during that timeframe," she said Another common intervention was the management of electrolyte abnormalities These study results give program leaders a sense of which areas in post-discharge AKI care need to be improved The study showed that the AKI RPM program did not reduce unplanned hospital readmissions or emergency visits within six months of discharge compared to the historical control group the risk for new worsening kidney dysfunction in the 90 days to six months after discharge did not differ between AKI RPM program participants and controls Barreto noted that there might be several reasons for these outcomes that are not connected to AKI "When you look at reasons for rehospitalization they might have very little to do with kidney health," she said and it might have nothing to do with kidney health [The study was] also a very small comparison -- better than anything else that's out there in the field but that might have contributed to an inability to see a signal." Barreto further underscored the challenges inherent in an epidemiologic study like this where researchers compare study participants to historical controls because provider behavior is outsized in patient discharge and post-discharge monitoring Barreto and her fellow researchers concluded that though advocating for integrating RPM into routine post-discharge care for AKI survivors would be premature continued research is needed to more fully understand the effect of digital health tools on patient outcomes within AKI subgroups noting that the data has "demonstrated the potential for acute kidney injury survivors' care to be affected through interventions like diuretic management emergency department referral -- all of those are sufficiently promising to continue to propel forward with AKI RPM And we certainly [will] continue to do that and we're refining aspects of the program to better meet these needs." The Mayo Clinic team also plans to continue diversifying and expanding the participant pool for the AKI RPM program the benefits of RPM might outweigh its limits "We'll continue to mature as we do more studies and build more programs but I think that what we have shown is that there is a way to connect with patients that is acceptable to them and also resource-conscious in the healthcare environment," Barreto said "And I think it will probably enable us to reach more patients and minimize the gaps in care that we currently are observing." Anuja Vaidya has covered the healthcare industry since 2012 She currently covers the virtual healthcare landscape remote patient monitoring and digital therapeutics GenAI in healthcare offers promise for tasks such as clinical documentation but clearly defined regulations and standards are .. 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Yale New Haven Health reported a March hack and data breach to HHS impacting nearly 5.6 million individuals A survey shows physician practices aim to improve patient payments and payer reimbursement rates About a fourth of federal spending goes to healthcare administration including paying medical bills to physicians Medigap premiums were higher and fewer plan options were offered in states that passed Medigap consumer protection policies Healthcare payers need to focus on broad issues like benefit design engagement and digital strategies as they tailor a better .. Nearly 1 in 3 adults with employer-sponsored health insurance received ACA no-cost coverage of preventive services threatened by .. A nonselective extracorporeal blood purifier connected to the cardiopulmonary bypass circuit during nonemergent cardiac surgery may help reduce post-surgical AKI Researchers evaluated adults undergoing nonemergent cardiac surgery to assess whether an extracorporeal blood purification reduces the risk for CSA-AKI The study assessed 343 patients undergoing nonemergent cardiac surgery and who were at high risk for AKI across two tertiary hospitals in Spain Patients enrolled in the double-blind SIRAKI02 clinical trial from 2016 to 2021 were randomly selected to receive extracorporeal blood purification or standard care 169 patients had extracorporeal blood purification and 174 had usual care The main outcome was CSA-AKI in the 7 days after randomization Follow-up data were collected through 2022 The rate of CSA-AKI was 28.4% in the extracorporeal blood purification group (95% CI 21.7%-35.8%) and 39.7% for standard care (95% CI The adjusted difference of was 10.4% (95% CI Researchers found no differences in most secondary or exploratory end points Extracorporeal blood purification was more effective in reducing CSA-AKI for patients with chronic kidney disease low left ventricular ejection fraction and lower BMI No differences were observed in adverse events tracking “The use of a nonselective [extracorporeal blood purifier] device connected to the [cardiopulmonary bypass] circuit in a nonemergent population of patients undergoing cardiac surgery was associated with a significant reduction of CSA-AKI in the first 7 days after surgery,” Pérez-Fernández and colleagues wrote especially those aged between 16 and 55 years may face higher AKI risk than female patients according to data that assessed the impact of sex and age on kidney health Golestaneh and colleagues from Yale and the Albert Einstein College of Medicine set out to understand the relationship between sex and the rate of AKI in hormonally distinct age groups across different stages of life The prospective cohort study included 132,667 patients hospitalized in the Montefiore Health System between October 2015 and January 2019 and did not include those with kidney failure or obstetric conditions There were 235,629 total hospitalizations among the cohort with women accounting for 55% of admissions Black and Hispanic patients made up 30.5% and 10.3% of hospitalizations Researchers used Kidney Disease: Improving Global Outcomes AKI criteria Boys and men had higher risk for AKI across all age groups The odds ratio for men aged 16 to 55 years was 1.7 (95% CI the study highlighted a certain protective effect for women: Those older than 55 years who were prescribed estrogen had lower AKI odds vs “Numerous studies have primarily included post-menopausal women with low estrogen levels thus masking the protective role of female sex,” Golestaneh said in the release “Our study shows that the protection afforded by female sex is highest among menstruating women is absent in prepubertal females and declines with the onset of menopause.” girls at lower risk of acute kidney injury: Study https://medicalxpress.com/news/2024-11-women-girls-acute-kidney-injury.html AKI remote patient monitoring after hospital discharge can help manage kidney health complications but the practice may not lower the risk of hospital return Researchers evaluated 40 patients on remote monitoring after discharge who were initially hospitalized at the Rochester-based Mayo Clinic with AKI and not on home dialysis following their hospital stay The 13-month program used a multidisciplinary approach that included home vital sign and symptom tracking and weekly in-center lab assessments Matching patients in a 1:3 ratio to historical controls researchers aimed to find the risk of unplanned hospital readmission or ED visits within 6 months Results showed 73% of patients had one AKI remote monitoring alert most of which were related to fluid status the risk of unplanned readmission or ED visit within 6 months post-discharge was similar compared with controls Charkviani and colleagues also found that the risk of an ED visit without hospitalization was significantly higher in the AKI remote monitoring group (HR = 1.95; 95% CI Unplanned readmission or ED visit risk was higher for patients with a baseline eGFR below 45 mL/min/1.73 m2 who had remote monitoring (HR = 2.24; 95% CI those with a baseline eGFR of at least 45 mL/min/1.73 m2 (HR = 0.69; 95% CI advocating for routine AKI remote patient monitoring program participation for AKI survivors would be premature,” the researchers wrote “Continued exploration of digital health tools is needed to understand their impact on patient outcomes and to identify specific subgroups of AKI survivors who may benefit the most from this resource,” they added Metrics details Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies we investigated the risk factors and clinical impact of AKI in patients undergoing CAR-T cell therapy This retrospective study involved hematologic patients treated with CAR-T therapy Clinical and laboratory data were collected and clinical outcomes were monitored during follow-up after CAR-T infusion AKI was defined according to KDIGO criteria The outcome measures included early mortality with a mean onset of 6 days after CAR-T infusion The risk of AKI was associated with baseline performance status (OR 8.65 p = 0.032) and the development of severe cytokine release syndrome post-therapy (OR 16.4 95%CI 1.9-138.5 Patients with AKI more frequently required intensive care severe AKI was independently associated with worse clinical outcomes patients who developed AKI post-CAR-T therapy were more likely to progress to chronic kidney disease during follow-up frail patients undergoing CAR-T therapy are at an increased risk of developing AKI which can significantly affect both short- and long-term outcomes Preventive strategies and early recognition of AKI are essential in these patients This treatment consists in collecting autologous T-cells after genetic modification and in vitro activation/expansion CRS may lead to life-threatening multiple organ dysfunction although the relationship between AKI and CRS is well-established the epidemiology of AKI in this clinical context including specific individual risk factors for developing AKI The primary objectives of our study were to determine the incidence of AKI and provide a more detailed characterization of how baseline conditions influence the risk of AKI in patients undergoing CAR-T therapy including early and overall mortality and disease-free survival acknowledging that not all AKI episodes are equivalent The severity of AKI and the patients’ overall health status may significantly affect clinical outcomes We retrospectively analyzed patients undergoing CAR-T therapy for hematological indications at our center from 2020 to 2023 We included all patients who underwent CAR-T treatment during the specified period without applying specific exclusion criteria and subsequent onset of complications and related treatments the follow-up visits were conducted based on clinical judgment The follow-up period concluded at the time of the first event (either disease recurrence or death) or at the last visit for patients still alive and free from disease (last observation on April 2024) Presence of proteinuria was evaluated by dipstick urinalysis and C-reactive protein (CRP) were measured using standard laboratory techniques The Ann Arbor staging system was used for the anatomic staging of disease16 The study protocol was approved by our institutional review board [Comitato Etico Regionale (CER) Liguria Due to the retrospective nature of the study CER Liguria waived the need of obtaining informed consent The study adhered to the principles outlined in the Helsinki Declaration Disease/tumor recurrence after CAR-T treatment was defined as any clinical or radiological evidence of disease possibly confirmed by a confirmatory biopsy Ealy mortality was defined as mortality occurring for any causes within 30 days from CAR-T infusion Overall survival (OS) was defined as the interval from CAR-T cell infusion to death for any causes (uncensored) or the last follow-up date (censored) Disease-free survival (DFS) was defined as the time from CAR-T treatment to the first event (either tumor recurrence or death AKI was subsequently classified into three stages: stage 1 (sCr increase > 0.3 mg/dl and/or 1.5 to 1.9 times the baseline creatinine) stage 2 (2 to 2.9 times the baseline creatinine) and stage 3 (3 or more times the baseline creatinine) Urine output was not considered for defining AKI due to limited available data Renal recovery was defined as a decrease in sCr to levels that no longer met the criteria for AKI when compared to baseline values Chronic kidney disease (CKD) was defined as an eGFR < 60 mL/min The primary endpoint of the study was to determine the incidence of AKI in our cohort and to identify risk factors for its development we examined clinical and biochemical factors influencing patient outcomes Characteristics of the patients were reported as mean with standard deviation (SD) or median with interquartile range (IQR) for continuous variables and as N (%) for the categorical ones; t-test and Pearson chi-square test or Fisher’s exact test were performed to compare patients with and without AKI Univariate and multivariate logistic regression analyses were used to describe the relationship between all available variables at baseline and the development of AKI Model fit was examined using the Hosmer-Lemeshow test and P ≥ 0.05 was judged as a good model fit Kaplan Meier survival analysis was used to assess DFS in patients with severe CRS (stage 4) The survival curves between groups were compared by log-rank tests The absence/presence of AKI stage 2/3 was tested as independent variable in multivariate Cox proportional hazard model analyses adjusted for the potential confounders All tests were two-sided and p-values < 0.05 were considered statistically significant All statistical analyses were performed using Stata version 14.2 (Stata Corporation) We analyzed a cohort of 48 patients (M/F: 29/19, mean age 61.4 ± 11.4 years) undergoing CAR-T therapy for diffuse large B-cell lymphoma (DLBCL) in 40 cases and mantle cell lymphoma (MCL) in 8 cases (Table 1) 18 patients (37.5%) had a history of hypertension all patients had received at least two lines of therapy and 12 patients (25%) had also undergone autologous stem cell transplantation 24 patients (50%) had Ann Arbor stage 4 disease (i.e.; extranodal disease) 19 patients (39.6%) had high IPI/MIPI scores and 8 patients (16.7%) had an ECOG performance status score ≥ 3 with an eGFR of 95 ± 19.2 mL/min; three patients (6.2%) had pre-existing CKD were elevated compared to normal laboratory ranges with a mean onset of 6 ± 3.6 days following CAR-T infusion the etiology of AKI was primarily attributed to CAR-T therapy mainly because of the close temporal association between CAR-T infusion and the increase in serum creatinine as all patients (both those who developed AKI and those who did not) underwent similar therapy immediately prior to CAR-T infusion renal ultrasounds were performed in all AKI patients except in two patients who had urinary obstruction due to a lymphomatous tumor mass a condition that was already present before CAR-T therapy and the onset of AKI A comparison of baseline characteristics between patients who developed AKI and those who did not revealed that the AKI group had worse prognostic indices and poorer performance status (Table 1) associated with lower serum albumin and magnesium levels did not differ significantly between the groups patients who developed AKI had markedly higher levels of lactate dehydrogenase (LDH) and inflammatory markers Multivariate logistic regression analysis, adjusted for general characteristics and disease stage, demonstrated that a high baseline ECOG performance status score was independently associated with an increased risk of developing AKI (Table 2) The multivariate model was significant and fitted well (Model χ2 test: P < 0.01 The most commonly administered CAR-T product was tisagenlecleucel followed by axicabtagene ciloleucel and brexucabtagene autoleucel 41 patients (85.1%) developed CRS of any grade with 9 patients (21.9%) experiencing severe CRS grade 3 or 4 The mean duration of CRS was 6.5 ± 3.9 days and 13 patients (27.1%) required admission to the intensive care unit (ICU) When comparing patients based on the development of AKI we observed a higher incidence and a longer duration of CRS in the AKI group all patients who developed AKI also had concurrent CRS while none of the patients without CRS developed AKI patients with AKI experienced more severe forms of CRS stage 3 and 4 compared to those without AKI Multivariate logistic regression analysis confirmed that severe CRS increased the risk of AKI by 16 times, independently by age, gender and disease stage (OR 16.4 95%CI 1.9-138.5, p = 0.01, Table 4) Laboratory tests revealed that patients with AKI following CAR-T treatment had significantly elevated inflammatory markers compared to those without AKI AKI patients were more frequently admitted to the ICU and required hemodynamic and ventilatory support evaluating AKI patients according to CRS severity we observed that while there were not significant differences in IL-6 elevation [peak IL-6 in CRS stage 3–4 patients 4575(4500) vs patients developing AKI in concomitance of severe CRS stage 3–4 had a significantly high need of intensive care support [seven (100%) required ICU admission and six (85%) vasopressor support] while the use of tocilizumab was similar between the patients developing AKI and those without AKI corticosteroids and anakinra were more commonly used in AKI patients we provided guidance on optimizing volume status closely monitoring electrolyte levels and acid-base balance All these measures were implemented on an individual patient basis among the fourteen patients who developed AKI four (28.5%) required kidney replacement therapy (KRT) including one patient with AKI stage 2 and three with AKI stage 3 All the patients undergoing KRT had associated CRS stage 4 The primary indications for KRT were the management of hyperinflammatory syndrome in three patients and the treatment of kidney failure in one patient who developed anuria All patients requiring KRT underwent continuous veno-venous hemodiafiltration two patients (14%) died with unrecovered AKI while the remaining twelve patients recovered kidney function within a median of 4 days (range: 4–10 days) without substantial differences in patients developing AKI in association of more severe CRS stage 3–4 [4 (5) days] compared with patients with CRS stage 1–2 [4 (6.2) days two patients experienced a second episode of AKI during their hospital stay In terms of clinical outcomes, the mean LOS following CAR-T infusion was 25.6 ± 17.6 days, with significantly longer stays observed in patients who developed AKI (Table 5) Early mortality occurred in three patients (6.2%) all included in the AKI group (p = 0.02 vs at a median follow-up of 175 days (IQR 63–389) 26 patients had disease recurrence and 18 patients had died [8 patients (57%) in the AKI group n = 16) was the most common cause of death with no significant difference between the AKI and non-AKI groups Kaplan Maier analysis of disease-free survival on the basis of (A) the presence of AKI and (B) the stages of AKI. Kaplan Maier analysis of disease-free survival on the basis of the presence of AKI and CRS stage 4 Multivariate Cox regression analysis identified age, male sex, high tumor burden, CRS stage 4, and severe AKI (HR = 18.2, 95%CI 2.6–27.3, p = 0.003) as independent risk factors for events (Table 6) after excluding patients who experienced early mortality a significantly higher number of those who developed AKI post-CAR-T infusion were diagnosed with CKD at the last follow-up visit Given the complexity of patients with hematological malignancies and their multiple comorbidities attributing an AKI episode occurring long after therapy solely to CAR-T treatment remains challenging focusing on AKI occurring immediately after CAR-T cell administration the mean time from CAR-T infusion to AKI diagnosis was 6 days These different diagnostic approaches may explain some of the observed discrepancies in clinical presentation and the impact of AKI on outcomes across different populations our study explored baseline risk factors for AKI development Previous studies have predominantly focused on the relationship between AKI and post-CAR-T infusion complications This is crucial as it may provide insights into the pathogenesis of AKI which is thought to be an expression of organic and functional alterations secondary to hyperinflammatory syndrome it may be more informative to determine if the risk of developing AKI after CAR-T cell infusion can be correlated with baseline clinical These observations are particularly significant and recognizing risk factors early can help in planning preventive strategies and evaluating candidates for CAR-T therapy CRS is the most significant complication of CAR-T treatment in terms of incidence (85.4% in our cohort) and potential harm associated with high morbidity and mortality Elevated cytokine levels can lead to kidney hypoperfusion through vasodilation which may result in intravascular volume depletion These changes can alter renal hemodynamics leading to functional damage and ultimately AKI showing that CRS was strongly and independently associated with AKI AKI was more prevalent in patients with CRS who exhibited a marked increase in inflammatory markers AKI predominantly occurred in patients with severe CRS who also presented a more complicated clinical course including a higher need for intensive care all patients requiring KRT had CRS stage 4 with the management of CRS being the primary indication for initiating KRT it cannot be excluded that the concurrent development of AKI in patients with CRS may sustain and amplify inflammatory processes AKI significantly impacted patient outcomes all three patients with early mortality experienced AKI and two of them still had AKI at the time of death while there were no significant differences in the absolute number of disease-free patients between those experiencing AKI and those who did not the difference became evident when considering OS and DFS which were significantly lower in AKI patients Multivariate analysis of clinical factors associated with outcomes showed that male sex and severe AKI were all independently and inversely associated with DFS This disparity may be partly attributed to the different size composition and settings of cohorts analyzed and heterogeneous AKI diagnostic criteria adopted in various studies we also analyzed the occurrence of adverse events a well-established outcome measure in cancer patients our results suggest that a more detailed analysis of AKI might be necessary to uncover its clinical effects While previous studies examined the effects of overall AKI we demonstrate that only the most severe forms of AKI impact patient prognosis primarily due to its retrospective design and relatively small sample size which restrict our ability to establish clear causal relationships between clinical factors no specific timepoints for AKI diagnosis and follow-up evaluations were predefined temporal correlations between the onset of complications and clinical outcomes could not be clearly recorded we did not adopt standardized protocols for AKI management and treatment making it difficult to assess the individual effects of specific interventions on patient outcomes anakinra was used to treat CRS in both patients with and without AKI complicating the evaluation of its specific impact while in our cohort the attribution of AKI to CAR-T therapy appears clinically plausible our data show that among patients eligible for CAR-T therapy those who are more fragile have a higher risk of AKI which is associated with the post-treatment inflammatory response and represents a significant complication that impacts short-term clinical management and prognosis These considerations highlight the importance of closely monitoring kidney function in patients undergoing CAR-T therapy as it may be a critical factor in their overall prognosis is needed to clarify additional factors influencing AKI risk and develop approaches to mitigate this complication in CAR-T-treated patients potentially incorporating biomarkers for detecting preclinical kidney injury Chimeric antigen receptor T cells: A race to revolutionize cancer therapy CAR-T cell therapy in hematological malignancies: Current opportunities and challenges Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma Ide-cel or standard regimens in relapsed and refractory multiple myeloma Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies Cytokine release syndrome: Current perspectives The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy: A systematic review Cytokine release syndrome with chimeric antigen receptor T cell therapy Lee, M. D. et al. Acute Kidney injury after the CAR-T therapy tisagenlecleucel. Am. J. Kidney Dis. 77, 990–992. https://doi.org/10.1053/j.ajkd.2020.08.017 (2021) Acute kidney injury following treatment with CD19-specific CAR T-cell therapy in children and young adult patients with B-cell acute lymphoblastic leukemia Systematic review of risk factors and incidence of acute kidney injury among patients treated with CAR-T cell therapies Jhaveri, K. D. & Rosner, M. H. Chimeric antigen receptor T cell therapy and the kidney: What the nephrologist needs to know. Clin. J. Am. Soc. Nephrol. 13, 796–798. https://doi.org/10.2215/CJN.12871117 (2018) A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation Report of the Committee on Hodgkin’s disease staging classification ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Toxicity and response criteria of the Eastern Cooperative Oncology Group International Non-Hodgkin’s Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin’s lymphoma A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma and management of acute kidney injury: A KDIGO summary (Part 1) A new equation to estimate glomerular filtration rate Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-cell lymphoma Incidence and risk factors for acute kidney injury after chimeric antigen receptor T-cell therapy Acute kidney injury after CAR-T cell therapy: Low incidence and rapid recovery Transient acute kidney injury after chimeric antigen receptor T-cell therapy in patients with hematological malignancies Outcomes of CD19-targeted chimeric antigen receptor T cell therapy for patients with reduced renal function including dialysis Performance status score: Do patients and their oncologists agree Alnefaie, A. et al. Chimeric antigen receptor t-cells: An overview of concepts, applications, limitations, and proposed solutions. Front. Bioeng. Biotechnol. 10. https://doi.org/10.3389/fbioe.2022.797440 (2022) Acute kidney injury after chimeric antigen receptor T-cell therapy for pediatric acute lymphoblastic leukemia FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome Anakinra for refractory cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T cell therapy and outcome of chimeric antigen receptor T cells in adults: An update Singbartl, K., Formeck, C. L. & Kellum, J. A. Kidney-immune system crosstalk in AKI. Semin. Nephrol. 39, 96–106. https://doi.org/10.1016/j.semnephrol.2018.10.007 (2019) Ansari, R., Caimi, P., Lee, H. J., Chen, Z. & Rashidi, A. Renal outcomes after chimeric antigen receptor T-cell therapy: A single-center perspective. Nephrol. Dial. Transplant. 37, 1777–1779. https://doi.org/10.1093/ndt/gfac048 (2022) Recognition patterns of acute kidney injury in hospitalized patients Download references Department of Internal Medicine and Medical Specialties (DIMI) Anna Maria Raiola & Emanuele Angelucci Download citation DOI: https://doi.org/10.1038/s41598-024-77720-z « Back There are no statistics available for this player Thanks for visiting The use of software that blocks ads hinders our ability to serve you the content you came here to enjoy We ask that you consider turning off your ad blocker so we can deliver you the best experience possible while you are here Metrics details Sepsis-associated acute kidney injury (SA-AKI) is a severe complication in critically ill patients with a complex pathogenesis involving in cell cycle arrest Current diagnostic strategies remain suboptimal this study aimed to evaluate pathophysiology-based biomarkers and develop an improved predictive model for SA-AKI The prospective observational study was conducted enrolling 26 healthy individuals and 96 sepsis patients from Peking University Third Hospital and patients were monitored for AKI development within 72 h sepsis patients were categorized into SA-noAKI (n = 46) and SA-AKI (n = 50) groups including tissue inhibitor of metalloproteinase-2 (TIMP-2) insulin-like growth factor-binding protein-7 (IGFBP-7) the SA-AKI group had significantly higher levels of TIMP-2 (93.55 [79.36 logistic regression identified TIMP-2×IGFBP-7 (OR = 2.71) and PCT (OR = 1.05) as independent risk factors The ROC curve of the predictive model demonstrated superior early-stage accuracy (AUC = 0.898) which remained stable during internal validation (AUC = 0.899) the nomogram exhibited that this model was characterized with excellent discrimination Ang-2 and PCT were the independent risk factors for SA-AKI and the novel model based on the three indicators provided a more accurate and sensitive strategy for the early prediction of SA-AKI it is urgent for more effective and advanced biomarkers to predict the development of SA-AKI their clinical application in SA-AKI remains limited indicating that Ang-2 may be a reliable biomarker for the detection of SA-AKI the clinical significance of endothelial markers in reflecting SA-AKI pathophysiology has not been clarified our study combines clinical data with SA-AKI biomarkers including TIMP-2 and Ang-2 to enable a comprehensive evaluation of SA-AKI This integrative approach aims to improve early prediction and risk stratification including sepsis-associated-no AKI group (SA-noAKI n = 46) and sepsis-associated-AKI group (SA-AKI This study involving human participants were approved by the Ethics Committee of Peking University Third Hospital (M2017032) The principle of the Helsinki Declaration for using human subjects was obeyed All subjects gave their informed consent to participate in this study for diagnostic and research purposes Fulfill the diagnostic criteria of sepsis-3 Patients with confirmed AKI for the first time of sample collection Patients who have received kidney transplantation Patients who have undergone hemodialysis or are in urgent need of hemodialysis upon admission Received drug treatment (including corticosteroids and contrast agents) in the preceding two weeks Known infection with human immunodeficiency virus (HIV) or a hepatitis virus the median of all available values from three months to seven days prior to enrollment was used; if pre-enrollment creatinine was not available the creatinine value at the time of enrollment was used Baseline kidney function was evaluated using the estimated glomerular filtration rate (eGFR) derived from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation Based on the clinical expertise of emergency medicine specialists and previous studies comprehensively collect clinical information related to SA-AKI Clinical data and traditional tests at admission were obtained from the hospital’s electronic system The acute physiology and chronic health assessment (APACHE) II score and sequential organ failure assessment (SOFA) score were calculated to assess the SA-AKI severity on the first day of admission C-reactive protein (CRP) and procalcitonin (PCT) were analyzed to evaluate inflammation and fibrinogen (Fib) were utilized for estimating the coagulation function observing kidney function indicators every 24 h for the first 3 days Venous blood samples were collected by trained medical professionals within 24 h of sepsis diagnosis and admission to the emergency department and storage of specimens were conducted in accordance with the industry-standard protocol for blood specimen collection and handling for clinical chemistry testing (WS/T 225–2024) The blood samples were centrifuged at 3,500 rpm for 10 min to obtain serum which were then stored at -80 °C for subsequent analysis and Ang-2 were measured using enzyme-linked immunosorbent assay (ELISA) kits following the manufacturer’s instructions and performed by experienced laboratory personnel The TIMP-2 and IGFBP-7 concentrations were multiplied to calculate the TIMP-2×IGFBP-7 product The TIMP-2 ELISA kit (DTM200) and Ang-2 ELISA kit (DANG20) were purchased from R&D Systems while the IGFBP-7 ELISA kit (ab213790) was obtained from Abcam laboratory operators were blinded to the clinical information of the patients All statistical analyses were conducted using SPSS 26.0 or R version 4.0.3 The Kolmogorov–Smirnov test was used to assess the normality of data distribution Descriptive statistics were expressed as the mean ± standard deviation (SD) or median (interquartile range Comparisons between two groups were performed using the Mann–Whitney U test or two-tailed unpaired Student’s t-test for continuous variables and the Chi-square test or Fisher’s exact test for categorical variables P value < 0.05 was considered statistically significant which accounted for less than 5% of the dataset Collinearity analysis was conducted to avoid multicollinearity among covariates Univariate and multivariate logistic regression analyses were used to develop the prediction model for SA-AKI The model’s performance was evaluated using receiver operating characteristic (ROC) curve analysis with DeLong’s test applied to compare AUC values The Youden index was used to determine the optimal cutoff value Hosmer–Lemeshow test and decision curve analysis (DCA) were utilized for evaluating its Goodness of fit and clinical utility To further validate the model’s accuracy and stability Baseline demographic and clinical features of the health and sepsis groups were presented in Supplementary Table S1 26 healthy donors aged from 66 to75 years old and 96 patients with sepsis aged from 62 to 84 years old The age and gender between two groups showed no differences Flowchart exhibiting the selection of the patients 96 of whom were remained due to the inclusion principle Patients with sepsis were further divided into SA-noAKI group (n = 46) and SA-AKI group (n = 50) according to the AKI criteria 26 healthy donors were selected as health group The concentrations of serum TIMP-2 (a) TIMP-2×IGFBP-7 (c) and Ang-2 (d) between the health TIMP-2   tissue inhibitor of metalloproteinase-2 IGFBP-7 insulin-like growth factor-binding protein 7 The ROC curves of Model 1 and Model 2 for predicting SA-AKI (a) The nomogram of the novel prediction model for SA-AKI (b)The calibration curves for the nomogram of the model The solid line represented the performance of the nomogram The diagonal dotted line represented a perfect prediction using an ideal model The closer the solid line fits to the dotted line the better predictive ability of the nomogram has TIMP-2  tissue inhibitor of metalloproteinase-2 IGFBP-7  insulin-like growth factor-binding protein 7 DCA analysis of the model for predicting SA-AKI and the X-axis indicated the threshold probability The red line represented the nomogram of Model 2 SA-AKI has emerged as one of the leading causes of mortality in emergency department patients traditional diagnostic criteria based on renal function markers Scr and urine output are hindered by their delayed response and inherent variability These limitations pose significant challenges to the timely identification and management of SA-AKI researchers have been exploring various strategies for early detection grounded in the latest consensus from the ADQI aimed to integrate clinical information and biomarkers of SA-AKI to identify key risk factors and construct a predictive model to support early recognition and clinical decision-making we incorporated novel kidney stress biomarkers TIMP-2 and IGFBP-7 The results demonstrated that a model including TIMP-2×IGFBP-7 and PCT outperformed models relying solely on conventional metrics the three biomarkers in the model each reflect distinct core pathophysiological mechanisms of SA-AKI: TIMP-2×IGFBP-7 indicates G1 cell cycle arrest Ang-2 reflects microcirculatory dysfunction and PCT captures the systemic inflammatory state These mechanisms are widely recognized as pivotal in the development of SA-AKI a combination of biomarkers based on the key pathophysiological mechanisms of SA-AKI can more accurately predict the occurrence of SA-AKI the integration of these biomarkers highlights the multifactorial and multimodal nature of SA-AKI pathophysiology providing a solid theoretical foundation for early diagnosis our data demonstrated that PCT was more specific for SA-AKI than other inflammatory markers targeting coagulation and inflammation may represent a promising direction for the diagnosis and treatment of SA-AKI we observed that TIMP-2 and IGFBP-7 were synergistically upregulated in SA-AKI and TIMP-2×IGFBP-7 emerged as an independent risk factor for SA-AKI highlighting its potential for early prediction and intervention in SA-AKI the clinical use of TIMP-2 × IGFBP-7 in the management of SA-AKI remains limited and warrants further investigation These changes result in renal microvascular thrombosis Ang-2 functions as both a risk factor and a biomarker for SA-AKI we demonstrated that Ang-2 is a valuable indicator for the early prediction of SA-AKI as its levels increase during disease progression Ang-2 alone lacks sufficient specificity for SA-AKI necessitating its combination with other biomarkers for more accurate our study demonstrated that TIMP-2×IGFBP-7 and PCT are synergistically upregulated in SA-AKI with their combined assessment exhibiting enhanced sensitivity and specificity This finding supports the development of novel predictive models for the early detection of SA-AKI and provides a foundation for clinical application These biomarkers were measured using the ELISA method and suitable for various clinical settings facilitating integration into routine clinical practice the primary samples required for detecting these biomarkers are blood and urine which are readily accessible and minimally invasive for patients predictive models incorporating these biomarkers could enable the timely identification of SA-AKI allowing for early intervention in nephrotoxic drug administration and fluid management ultimately reducing the incidence and severity of AKI our study had several limitations: Firstly but the concentration of Scr was not be accurately measured due to the inaccurate urine volume records in emergency patients as well as the susceptibility to liquid capacity the level of biomarkers was only detected for the first time at admission the relationship between the concentrations of novel biomarkers and the stage and severity of SA-AKI cannot be verified this study was a single-center study with a small sample size in emergency department only representing a small part of older patients with sepsis who had many basic diseases and lacking of an external validation the clinical performance of the combination biomarkers needs to be proven in more population Ang-2 and PCT were identified to be the 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Angiopoietin-2 as a prognostic biomarker in septic adult patients: a systemic review and meta-analysis Excess Circulating angiopoietin-2 May contribute to pulmonary vascular leak in sepsis in humans Download references We thank all participants for their contribution to the present study The study was supported by National Natural Science Foundation of China (61771022 Core Unit of National Clinical Research Center for Laboratory Medicine Author contributions conceptualization: ZQ The study has been approved by the Ethics Committee of Peking University Third Hospital (M2017032) All subjects gave their informed consent to participate in this study for diagnostic and research purposes before inclusion in this study Download citation DOI: https://doi.org/10.1038/s41598-025-92315-y