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Injured epithelial cell states impact kidney allograft survival after T-cell-mediated rejection
T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.
- Anna Maria Pfefferkorn
- , Lorenz Jahn
- & Christian Hinze
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Article
| Open AccessLucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension
Lucerastat was well-tolerated, but did not reduce neuropathic pain, abdominal pain, or diarrhea compared with placebo. Lucerastat reduced biomarkers of Fabry Disease at 6 months, and these reductions were maintained at the 18-month interim analysis.
- Peter Nordbeck
- , Ozlem Goker-Alpan
- & Derralynn Hughes
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Article
| Open Access
Butyrophilin 2A2 promotes T cell immunoregulation via CD45 phosphatase activation and protects against murine autoimmune glomerulonephritis and pregnancy loss
Butyrophilin 2A2 is a member of the B7 costimulatory family that is expressed on antigen presenting cells and is linked to the regulation of T cells. Here the authors implicate butyrophilin 2A2 in enhancement of CD45 phosphatase activity within the immunological synapse during T cell activation, leading to expansion of regulatory T cells and reduction of proinflammatory Th17 CD4 T cells.
- Shafat Ali
- , Anders H. Berg
- & S. Ananth Karumanchi
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Article
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AI-enabled electrocardiogram alert for potassium imbalance treatment: a pragmatic randomized controlled trial
Dyskalemia is a dangerous potassium imbalance requiring rapid treatment. Here, the authors show, in a randomized trial of 14,989 patients, that real-time AI-ECG alerts increased hyperkalemia (69.1% vs. 41.6%, HR 2.23, 95% CI 1.44–3.46) but not hypokalemia treatment (HR 1.14, 95% CI 0.74–1.77).
- Chin Lin
- , Chin-Sheng Lin
- & Shih-Hua Lin
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Article
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Design of precision therapeutics for a CKD risk allele by targeting Shroom3-Rock interaction
Shroom3 genetic variants increase Shroom3 levels and promote kidney fibrosis but reduce proteinuria, complicating Shroom3 targeting for precision medicine. Here, the authors show increased fibrosis mediated by Shroom3–Rock signaling and blocking this interaction genetically or with new compounds reduces tubular Rock activation and fibrosis.
- Anand Reghuvaran
- , Ashwani Kumar
- & Madhav C. Menon
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Nucleophosmin 1 lactylation in graft kidney induces ferroptotic trigger waves that exacerbate delayed graft function
Ferroptotic propagation aggravates kidney ischemia-reperfusion injury and causes delayed graft function. Here, the authors show that inhibiting lactate shuttle and AARS1-mediated NPM1 lactylation protects graft function by blocking ferroptotic waves.
- Haitao Yu
- , Hubin Yin
- & Xinyuan Li
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Article
| Open Access
Impaired glycolysis-derived serine metabolism as a key driver of podocyte injury with senescence
Previous studies showed inhibition of glycolytic enzyme pyruvate kinase M2 disrupts podocyte function. The study shows that PGK1-serine axis regulates and drives aging and damage of podocytes.
- Hongtu Hu
- , Zijing Zhu
- & Guohua Ding
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Article
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Renal insulin-like growth factor binding-protein 7 is a critical promoter of progressive diabetic kidney disease
Previous clinical studies suggested that Insulin-like growth factor binding-protein 7 (IGFBP7) is elevated in early stages of diabetes. Here authors showed tubule and glomerular-specific IGFBP7 promotes diabetic kidney disease.
- Ju-tao Yu
- , Xiao-wei Hu
- & Xiao-ming Meng
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Article
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Risk factors for mortality in patients with kidney failure on hemodialysis identified by proteomic analysis of CRIC and PACE studies
Patients with kidney failure undergoing maintenance hemodialysis have poor long-term survival. Here the authors use affinity-based proteomics to identify circulating risk factors for mortality in patients with kidney failure on hemodialysis.
- Yue Ren
- , Mark R. Segal
- & Mark L. Unruh
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Article
| Open Access
Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment
Variants in NOS1AP can cause monogenic nephrotic syndrome. Here, the authors show that disrupting the intergenic NOS1AP splice isoform that is more prevalent in podocytes leads to monogenic kidney disease responsive to RAAS inhibition.
- Florian Buerger
- , Daanya Salmanullah
- & Amar J. Majmundar
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Article
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Finerenone versus spironolactone in patients with chronic kidney disease and type 2 diabetes: a target trial emulation
The relative benefits of finerenone vs spironolactone in CKD with T2D are unclear. Here the authors show that in >2,200 matched patients, finerenone lowers risks of cardiovascular and kidney events, death, and hyperkalemia compared with spironolactone.
- Chung-An Wang
- , Hsuan-Wen Lai
- & Vin-Cent Wu
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Article
| Open Access
Low circulating miR-190a-5p predicts progression of chronic kidney disease
Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.
- David P. Baird
- , Jinnan Zang
- & Laura Denby
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Article
| Open Access
The slit diaphragm in Drosophila exhibits a bilayered, fishnet architecture
The slit diaphragm is a key component of the glomerular filter. This study reveals that the slit diaphragm of Drosophila nephrocytes exhibits a fishnet architecture, offering insights into the molecular basis of renal filtration.
- Deborah Moser
- , Konrad Lang
- & Achilleas S. Frangakis
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| Open Access
Physiologic Homeostasis in a Living Human after Pig Kidney Xenotransplantation
Kidney shortages limit treatment options for patients with end-stage kidney disease, prompting exploration of xenotransplantation. Here, the authors show that a genetically modified pig kidney sustained essential functions in a living human for 51 days, informing future clinical strategies.
- Sul A Lee
- , Marie-Camille Lafargue
- & Leonardo V. Riella
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Microbiota-derived corisin accelerates kidney fibrosis by promoting cellular aging
Here, the authors identify the microbiota-derived corisin as a driver of diabetic kidney fibrosis via cellular aging and show that targeting corisin with a monoclonal antibody alleviates disease in mice, suggesting a potential therapeutic avenue.
- Taro Yasuma
- , Hajime Fujimoto
- & Esteban C. Gabazza
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Article
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Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury
In a model of acute kidney injury the authors show that Pannexin1 can mediate a leak of Calcium from the endoplasmic reticulum leading to mitochondrial calcium overload and pro-senescence signals, and ultimately driving fibrosis and kidney disease progression
- Liuwei Huang
- , Yanting Shen
- & Jun Wang
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The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis
Ferroptosis has been reported to contribute to the pathogenesis of acute kidney injury (AKI). Here the authors report a study with male mice showing that the long non-coding RNA RSDR suppresses renal tubular cell ferroptosis in AKI by retaining nuclear hnRNPK and activating DHODH transcription
- Bojun Li
- , Fangyou Lin
- & Fan Cheng
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Article
| Open Access
SLAMseq reveals potential transfer of RNA from liver to kidney in the mouse
Hunter et al. use RNA labelling to investigate RNA transfer between organs in mice. They show that RNA potentially moves en masse from liver to kidney and that this movement is augmented in acute liver injury, although the physiological relevance of the phenomenon is not yet known.
- Robert W. Hunter
- , Jialin Sun
- & James W. Dear
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Article
| Open Access
Exome analysis links kidney malformations to developmental disorders and reveals causal genes
The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.
- Hila Milo Rasouly
- , Sarath Babu Krishna Murthy
- & Ali G. Gharavi
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Article
| Open Access
Single urinary extracellular vesicle proteomics identifies complement receptor CD35 as a biomarker for sepsis-associated acute kidney injury
Sepsis-associated acute kidney injury (SA-AKI) leads to significant morbidity and mortality, but early diagnosis remains challenging. Here the authors use single urinary extracellular vesicle proteomics to identify complement receptor CD35 as a biomarker for sepsis-associated acute kidney injury.
- Ning Li
- , Tao-Tao Tang
- & Lin-Li Lv
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Perspective
| Open Access
Opportunities and challenges with the implementation of normothermic machine perfusion in kidney transplantation
Normothermic machine perfusion could prolong and/or improve preservation of kidneys in transplantation, but the technology has yet to reach clinical realization. Here, the authors show the hurdles, but also the solutions, for this technology to become a reality in transplantation and beyond.
- Ton J. Rabelink
- , Sarah Hosgood
- & Stefan Schneeberger
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Article
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Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice
Gasdermin E (GSDME) is abundantly expressed, but its physiological function remains unclear. Here, the authors show a non-pyroptotic function of GSDME in limiting renal inflammation during cisplatin nephrotoxicity by regulating O-GlcNAcylation and STAT3-S100A7A-RAGE signaling.
- Qingzhou Chen
- , Pengxiao Sun
- & Jing Nie
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Article
| Open Access
Developing serum proteomics based prediction models of disease progression in ADPKD
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and loss of kidney function, yet prognostic biomarkers remain limited. Here, the authors show that serum proteomics identifies protein signatures associated with disease severity, enabling improved risk prediction and stratified management.
- Hande Ö. Aydogan Balaban
- , Sita Arjune
- & Roman-Ulrich Müller
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| Open Access
Normothermic human kidney preservation drives iron accumulation and ferroptosis
Ex vivo normothermic machine perfusion has been proposed to protect donor kidneys. Here, the authors show that red blood cell-based human kidney perfusion and associated hemolysis contribute to iron accumulation, ferroptosis, and kidney injury.
- Marlon J. A. de Haan
- , Marleen E. Jacobs
- & Ton J. Rabelink
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Article
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Impact of HLA evolutionary divergence and donor-recipient molecular mismatches on antibody-mediated rejection of kidney allografts
Kidney transplants are at risk of graft failure due to immune system rejection. Here, the authors assess a broad range of clinical and immunological baseline variables in a large, unselected kidney transplant cohort, providing further insights into factors associated with antibody-mediated rejection
- Zeynep Demir
- , Marc Raynaud
- & Alexandre Loupy
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Article
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Lysosome-mediated aggregation of galactose-deficient IgA1 with transferrin receptor 1 links to IgA nephropathy
The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium leads to pathogenesis in IgA nephropathy. Here the authors report that Gd-IgA1 is internalized by mesangial cells potentially via transferrin receptor 1, forming aggregates that disrupt lysosomal function and elicit inflammation.
- Meijun Si
- , Jingpeng Fu
- & Xueqing Yu
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Article
| Open Access
Three dimensional multiscalar neurovascular nephron connectivity map of the human kidney across the lifespan
The human kidney maintains homeostasis through a complex network of up to a million nephrons. Here the authors construct a 3D neuro-nephron connectivity map of human kidneys, which reveals neuro-glomerular communities across the kidney connected via “mother glomeruli” as hub points explaining structural basis for fluid homeostasis. These networks develop after birth and decline with age and in disease states
- Liam McLaughlin
- , Bo Zhang
- & Sanjay Jain
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Article
| Open Access
Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis
How Meckel-Gruber syndrome protein TMEM67 functions in ciliogenesis and Wnt signaling simultaneously is unknown. Here the authors show that TMEM67 is proteolytically cleaved by the matrix metalloproteinase ADAMTS9 generating two functional isoforms.
- Manu Ahmed
- , Sydney Fischer
- & Sumeda Nandadasa
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Article
| Open Access
Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype
The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.
- Maximilian Reck
- , David P. Baird
- & Bryan R. Conway
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Article
| Open Access
Type I interferon drives T cell cytotoxicity by upregulation of interferon regulatory factor 7 in autoimmune kidney diseases in mice
Glomerulonephritis is a frequent complication of autoimmune diseases, and involves aberrant activation of immune cells, but the underlying insights remain unclear. Here the authors use both patient data and a mouse glomerulonephritis model to show that increased type I interferon may expand a subset of pro-inflammatory T cells for subsequent kidney pathology.
- Huiying Wang
- , Jonas Engesser
- & Nariaki Asada
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Article
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Prolonged normothermic perfusion of the kidney prior to transplantation: a historically controlled, phase 1 cohort study
Kidney transplantation usually relies on hypothermia to safely preserve the graft. Here, the authors show that keeping kidneys at 37°C, using a machine to supply them with blood, oxygen, and nutrition, is feasible for up to 24 hours, and may be useful for testing and treating them pre-transplant.
- Richard Dumbill
- , Simon Knight
- & Peter Friend
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Article
| Open Access
Myeloid EGFR deficiency accelerates recovery from AKI via macrophage efferocytosis and neutrophil apoptosis
Kidney-infiltrating myeloid cells play important roles in acute kidney injury and post-injury fibrosis. Here authors show that genomic deletion of Epidermal Growth Factor Receptor specifically in myeloid cells or in neutrophils alleviates acute kidney injury in a mouse model, via limiting the life span of these pro-inflammatory cells.
- Yu Pan
- , Shirong Cao
- & Raymond C. Harris
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Article
| Open Access
Label-free multimodal optical biopsy reveals biomolecular and morphological features of diabetic kidney tissue in 2D and 3D
Fung et al. use a multi-modal label-free 3D imaging platform to uncover morphological and biomolecular features in diabetic human kidney tissues such as glomerular volume, lipid saturation, optical redox ratio, and collagen fiber thickness.
- Anthony A. Fung
- , Zhi Li
- & Lingyan Shi
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Article
| Open Access
Trans-ancestry GWAS identifies 59 loci and improves risk prediction and fine-mapping for kidney stone disease
Kidney stone disease is increasing worldwide. Cao et al. perform a cross-ancestry GWAS meta-analysis of the condition, identifying risk loci and potential causal variants, and construct a cross-population polygenic risk score.
- Xi Cao
- , Minghui Jiang
- & Xingjie Hao
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Article
| Open Access
The integrin repertoire drives YAP-dependent epithelial:stromal interactions during injury of the kidney glomerulus
Capillary loop architecture in the kidney glomerulus depends on epithelial-stromal interactions. Here the authors show that YAP and TAZ maintain capillary loop architecture and that kidney injury leads to shifts in the integrin repertoire that affect transcriptional activity of YAP and TAZ.
- Evelyne Huynh-Cong
- , Victoria Driscoll
- & Jordan A. Kreidberg
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Article
| Open Access
Caspase 9-induced apoptosis enables efficient fetal cell ablation and disease modeling
Fetal cell ablation models are essential for congenital disease modeling and organ regeneration. Here, the authors develop a rodent inducible caspase 9 model that enables rapid, specific, and efficient cell ablation, characterize its features, and apply it to generate a novel kidney disease model.
- Kenji Matsui
- , Masahito Watanabe
- & Shuichiro Yamanaka
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Article
| Open Access
Anti-myeloperoxidase IgM B cells in anti-neutrophil cytoplasmic antibody-associated vasculitis
The etiology of autoimmune disease anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is still poorly understood. Here the authors associate anti-myeloperoxidase (MPO) IgM-expressing memory B cells, and presence of anti-MPO IgM in addition to IgG with AAV disease pathophysiology to implicate potential targets of therapy.
- CM Wortel
- , R. van de Wetering
- & HU Scherer
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Article
| Open Access
CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease
Disturbed lipid metabolism is a feature of diabetic kidney disease (DKD). Here the authors report that ceramide synthase 6 (CerS6) in podocytes contributes to the pathogenesis of diabetic kidney disease (DKD) in male mice by inducing mitochondrial DNA leakage, activating the cGAS-STING pathway and promoting inflammation.
- Zijing Zhu
- , Yun Cao
- & Zhaowei Chen
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Article
| Open Access
High-density lipoprotein nanoparticles spontaneously target to damaged renal tubules and alleviate renal fibrosis by remodeling the fibrotic niches
Effectively delivering medications to the renal tubule to delay or halt chronic kidney disease progression remains a significant unmet clinical challenge. Here, authors introduce an innovative strategy for renal tubule targeting using biomimetic high-density lipoprotein (bHDL) nanoparticles.
- Shanshan He
- , Xiaoyang Li
- & Ling Zhang
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Article
| Open Access
Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease
Apolipoprotein L1 genetic variants contribute to a subtype of proteinuric kidney disease referred to as APOL1-mediated kidney disease (AMKD). Here the authors report the discovery and characterization of potent and selective APOL1 ion channel inhibitors for the potential treatment of AMKD.
- Brandon Zimmerman
- , Leslie A. Dakin
- & Mark E. Bunnage
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Article
| Open Access
Generic residue numbering of the GAIN domain of adhesion GPCRs
Transferring information on the GAIN domain is hampered by low sequence conservation. Here, authors introduce a generic residue numbering scheme for GAIN domains to facilitate information integration as demonstrated on cancer data.
- Florian Seufert
- , Guillermo Pérez-Hernández
- & Peter W. Hildebrand
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Article
| Open Access
Development and validation of a real-time prediction model for acute kidney injury in hospitalized patients
Early prediction of Acute kidney injury (AKI) may be crucial for AKI prevention. Here the authors present a simple, real-time, interpretable, AKI prediction model for hospitalized patients, based on routinely collected electronic health records data.
- Yuhui Zhang
- , Damin Xu
- & Li Yang
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Article
| Open Access
Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids
AAVs show potential for kidney gene therapy, however, kidney gene transfer remains challenging. Here, the authors show that differing viral capsids exhibit distinct delivery to tubules and podocytes which is also dependent on injection routes, disease state and species.
- Taisuke Furusho
- , Ranjan Das
- & Hiroyuki Nakai
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Matters Arising
| Open Access
Reply to: Machine learning-driven virtual biopsy system may increase organ discards at aggressive kidney transplant centers
- Marc Raynaud
- , Gillian Divard
- & Alexandre Loupy
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Matters Arising
| Open AccessMachine learning-driven virtual biopsy system may increase organ discards at aggressive kidney transplant centers
- Emmanouil Giorgakis
- , Hailey Hardgrave
- & Allison Wells
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Article
| Open Access
Non-invasive in vivo sensing of bacterial implant infection using catalytically-optimised gold nanocluster-loaded liposomes for urinary readout
Implant-associated infections with Staphylococcus aureus pose serious clinical challenges. Here, the authors develop a biosensor based on toxin-responsive liposomes encapsulating gold nanoclusters, providing a non-invasive, colourimetric diagnostic tool for bacterial infection detection with urinary readout.
- Kaili Chen
- , Adrian Najer
- & Molly M. Stevens
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Article
| Open Access
ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice
The involvement of glomerular injury in acute kidney injury (AKI) has not been fully elucidated. Here, authors visualize impaired ATP recovery in podocytes in a murine model of ischemic AKI using intravital ATP imaging and propose accelerated mitochondrial fission as a key factor of ischemic podocyte injury.
- Masahiro Takahashi
- , Shinya Yamamoto
- & Motoko Yanagita
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Article
| Open Access
The outcomes of SGLT-2 inhibitor utilization in diabetic kidney transplant recipients
Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have demonstrated efficacy in reducing cardiovascular events and potentially improving kidney function in diabetic patients. Here, using the TriNetX platform, the authors show that SGLT-2 inhibitors reduce all-cause mortality and major adverse cardiac and kidney events in diabetic kidney transplant recipients.
- Jia-Yuh Sheu
- , Li-Yang Chang
- & Vin-Cent Wu
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Article
| Open Access
Analyzing longitudinal trait trajectories using GWAS identifies genetic variants for kidney function decline
The authors use longitudinal data from the UK Biobank to search for genetic variants associated with kidney function decline. Using a linear mixed model, they identify 13 independent variants, incl. 6 novel, and link them to genetics of kidney aging.
- Simon Wiegrebe
- , Mathias Gorski
- & Iris M. Heid
Daratumumab in systemic lupus erythematosus: a single-arm phase 2 trial