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Chronic kidney disease (CKD) affects more than 850 million people worldwide, and progressive renal fibrosis is the most common cause of irreversible renal loss. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are nanoscale membrane-bound particles carrying bioactive proteins, lipids, and regulatory RNAs across biological barriers. Target cells are EVs that enter via membrane receptors and endocytic/fusion pathways and provide cargo delivery and modulation of downstream signaling. Engineering techniques such as genetic modification of parent cells, chemical surface functionalization, stimuli-responsive materials, and synthetic materials have improved the therapeutic potential of MSC-EVs by improving tissue targeting and antifibrotic activity. This review summarizes MSC-EV colloidal biology, biogenesis, surface properties, cargo composition, and engineered modifications for antifibrotic applications. Mechanisms that inhibit fibrosis, such as suppression of the TGF-β/Smad pathway, reversal of epithelial-mesenchymal transition, and modulation of macrophage behavior at the tissue-vesicle interface, are discussed. Effects of donor cell preconditioning and microenvironmental factors on surface properties and therapeutic potency are discussed. This paper is a paradigm shift from traditional biology to precision nanomedicine engineering using colloidal surface chemistry, biointerface dynamics, and translational manufacturing. We bridge material science with renal pathophysiology to develop a rational roadmap for future clinically available EV therapeutics targeting multifactorial renal fibrotic diseases.

Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD. CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins. Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.

Identified as a pathological hallmark of all forms of chronic kidney disease (CKD), renal fibrosis contributes to renal failure when dysregulated. In this process, renal fibroblasts act as the primary source of myofibroblasts, which play a pivotal role as the central effector cells. This study identifies a critical role for the lysine methyltransferase Suv39h1 in regulating fibroblast-myofibroblast transition (FMyT) and renal fibrosis. Fibroblast- and myofibroblast-specific gene knockout in mice was achieved using the Col1a2-CreERT2 and Postn-CreERT2 drivers. The model of renal fibrosis was established by unilateral ureteral obstruction (UUO) or streptozotocin-induced diabetic nephropathy (DN). Transcriptomic alterations were evaluated by RNA-seq. Our data indicate that the transcriptional upregulation of Su39h1 may be implicated in the process of FMyT, as evidenced by its consistent induction in both employed model systems. Suv39h1 deletion attenuated renal fibrosis in three animal models, consistent with its inhibition of FMyT in fibroblasts. Moreover, the conditional ablation of Suv39h1 within Postn-expressing mature myofibroblasts resulted in a significant abrogation of the pathological remodeling associated with renal fibrosis in mice. Notably, the targeted inhibition of the histone methyltransferase Suv39h1 by chaetocin effectively suppresses fibroblast activation in vitro and ameliorates the pathological progression of renal fibrosis in a murine model. Transcriptomic analysis revealed CXCL10 as a downstream target of Suv39h1. Furthermore, CXCL10 knockdown abolished the protective effect of Suv39h1 insufficiency on renal fibrosis. Mechanistically, CXCL10 regulated FMyT by suppressing the Hippo/YAP pathway. We identify Suv39h1-mediated regulation as a previously unrecognized facet of renal fibrogenesis.

Recent clinical trials have shown that dual GLP-1R/GCGR agonists, including mazdutide and cotadutide, provide kidney benefits in patients with type 2 diabetes and CKD, suggesting a potential contribution of GCGR activation to these renal effects. However, whether GCGR directly confers renoprotection and the underlying mechanisms remain unclear. Here, using tubule-specific GCGR loss- and gain-of-function mouse models and human kidney samples, we show that tubular GCGR signaling exerts an important renoprotective role in DKD. Tubular GCGR expression is reduced in humans and mice with DKD and correlates with worse kidney function and increased renal injury. Genetic ablation of tubular GCGR markedly exacerbates DKD and induces pronounced phospholipid accumulation within enlarged lysosomes. Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification. This defect leads to impaired phospholipid hydrolysis and protease maturation, blockade of autophagic flux, and ultimately tubular cell injury. In vivo, ATP6V1A overexpression markedly reverses GCGR deficiency-induced lysosomal dysfunction and DKD progression. Consistently, re-expression of tubular GCGR via AAV9 restores lysosomal function, reduces phospholipid accumulation, and mitigates renal injury in DKD. Together, these findings provide genetic evidence for the renoprotective role of tubular GCGR in DKD, delineate a kidney-intrinsic GCGR-ATP6V1A-lysosome axis that protects tubular integrity, and extend prior GCGR-in-kidney observations into a more concrete GCGR-lysosome mechanism.

Kidney fibrosis is the pathologic hallmark of chronic kidney disease (CKD) and is driven by fibroblast-to-myofibroblast transformation (FMT), excessive extracellular matrix accumulation, and persistent activation of transforming growth factor-β (TGFβ) signaling. Although TGFβ is a central mediator of fibrosis, its pleiotropic physiological functions have limited the development of direct anti-fibrotic therapies, highlighting the need to identify context-specific regulators of this pathway. Matrix Gla Protein (MGP) is a vitamin K-dependent extracellular protein best known for inhibiting vascular calcification; however, its role in kidney fibrosis remains unknown. Here, we demonstrate that MGP expression is markedly upregulated in fibroblasts from fibrotic kidneys in mouse models of chronic kidney injury and in human CKD samples. Using inducible global and fibroblast-specific Mgp knockout mice, we show that Mgp deficiency attenuates renal fibrosis, suppresses fibroblast activation, and preserves kidney function following folic acid nephropathy and unilateral ureteral obstruction. Mechanistically, MGP promotes FMT and amplifies TGFβ receptor/Smad3 signaling, whereas genetic or molecular inhibition of MGP blunts TGFβ-driven fibroblast activation both in vivo and in vitro. We further identify phosphorylation and γ-carboxylation as essential post-translational modifications required for the profibrotic activity of MGP. In addition, MGP interacts with bone morphogenetic protein-2 (BMP-2), reduces BMP-2 protein abundance, and counteracts BMP-2-mediated suppression of TGFβ signaling, thereby enhancing profibrotic responses. Collectively, these findings identify MGP as a previously unrecognized regulator of TGFβ-dependent fibroblast activation and kidney fibrosis, supporting MGP as a potential fibroblast-associated target for future strategies aimed at limiting CKD progression.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays critical regulatory roles in multiple signaling pathways by preventing the ubiquitin-mediated degradation of its substrates. Dysregulated expression of USP7 is implicated in tumor progression; however, its role in renal fibrosis remains unclear. In the present study, USP7 was observed to be significantly upregulated in the kidneys of patients with chronic kidney disease (CKD), which correlated with fibrotic lesions and renal dysfunction. Both genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in two mouse models of kidney fibrosis-unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury models, indicating a pro-fibrotic function of USP7. Mechanistically, intergrated proteomic sequencing and phosphoproteomic sequencing revealed that USP7 modulated the tuberous sclerosis complex 1 (TSC1)-mTOR pathway. USP7 knockdown restored TSC1 expression and inhibited mTOR activation. However, USP7 did not directly interact with TSC1; instead, it deubiquitinated and stabilized lysine-specific demethylase 5B (KDM5B), which subsequently reduced histone H3K4me3 modification at the Tsc1 promoter to repress its transcription. Conversely, the inhibition of USP7 promoted KDM5B degradation, thereby restoring TSC1 expression and suppressing mTOR-driven fibrogenesis. Thus, these findings identify USP7 as a critical promoter of renal fibrosis, acting at least in part through the KDM5B-TSC1-mTOR axis. This highlights USP7 as a potential therapeutic target for CKD.

The optimal timing of adjunctive vasopressin after norepinephrine escalation in septic shock remains uncertain. We emulated a target trial comparing ultra-early vasopressin initiation within 0-3 h with early initiation within > 3-6 h after the norepinephrine infusion rate reached 0.25 μg/kg/min or higher. We emulated a target trial using electronic health record databases (MIMIC-IV 2008-2022 and eICU-CRD 2014-2015). Adults with septic shock who reached the norepinephrine threshold before vasopressin use were eligible. We used the clone-censor-weight method to estimate cumulative incidence curves under the ultra-early and early initiation strategies and compared them via the weighted Cox model. Among 3810 eligible patients, after cloning, 744 clones adhered to the ultra-early strategy and 293 clones adhered to the early strategy. The weighted 28-day mortality risk was 48.1% under the ultra-early strategy and 53.0% under the early strategy (risk difference, - 5.0 percentage points; 95% confidence interval [CI] - 6.8 to - 3.2), with a restricted mean survival time difference of 1.58 days (95% CI 1.21-1.92) and a hazard ratio (HR) of 0.82 (95% CI 0.78-0.85). Ultra-early initiation was associated with lower renal replacement therapy (HR, 0.68; 95% CI 0.63-0.74), continuous renal replacement therapy (HR, 0.61; 95% CI 0.55-0.68), and medically treated arrhythmia (HR, 0.91; 95% CI 0.83-0.99), but not with lower acute kidney injury. Among adults with septic shock whose norepinephrine infusion reached 0.25 μg/kg/min or higher before vasopressin use, vasopressin initiation within 0-3 h was associated with lower 28-day mortality than initiation within > 3-6 h.

Intraoperative arterial hypotension commonly occurs and is associated with adverse outcomes. Evidence on causality from RCTs is sparse. This meta-analysis aimed to summarise evidence from RCTs that categorise groups based on MAP thresholds, examining the impact on mortality, acute kidney injury (AKI), and myocardial injury in patients undergoing noncardiac surgery. A systematic search of PubMed, Embase, and Web of Science was conducted for RCTs in adults undergoing noncardiac surgery that categorised groups based on MAP thresholds. The primary objective was to examine the effect of differences in achieved MAP on the primary outcome of all-cause mortality within 30 days of surgery. AKI, myocardial injury, and MAP achieved in the intervention and control arms were analysed as secondary outcomes. For each study, two groups were identified: an intervention ('higher-pressure' target) group, and a control ('lower-pressure' target) group. Exploratory analysis examined whether the difference in achieved MAP between groups modified the study outcomes. Nine RCTs comprising 14 658 patients did not demonstrate a difference in the primary outcome of all-cause mortality between intervention and control groups (RR: 1.06, 95% CI: 0.77-1.45, I2=0%). No differences were observed for secondary outcomes in 13 RCTs. Differences in intraoperative MAP between study groups were not associated with study outcomes. Higher vs lower intraoperative MAP did not affect all-cause 30-day mortality, AKI, or myocardial injury; however, only limited differences in blood pressure were achieved between study groups. Stratification by differences in achieved pressure did not alter the results. Systematic review protocol. PROSPERO (CRD420251230069).

To date, the effects of packed red blood cell (PRBC) transfusion on sepsis-associated acute kidney injury (SA-AKI) have not been reported in the literature. The objective of this study is to conduct a preliminary exploration of the association between these two factors using a target trial emulation (TTE) that allows for causal inference. The present study utilized the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, including adult sepsis patients who were admitted to the intensive care unit (ICU) for the first time between 2008 and 2022, with an ICU stay exceeding 24 h. All patients had hemoglobin levels ≤ 10 g/dL within 24 h of sepsis diagnosis. A clone-censor-weight (CCW) approach was employed for target trial emulation (TTE) to evaluate the effects of PRBC transfusion within 24 h of sepsis diagnosis on patient outcomes. The primary outcome was SA-AKI, whereas the secondary outcomes included 7-, 28-, and 90-day mortality. The primary outcome underwent competing risk analysis. The treatment effect was primarily evaluated through differences in SA-AKI risk and survival rate. The 95% confidence intervals (CIs) were calculated using the nonparametric bootstrap method with 1000 repetitions. The present study included a total of 14,869 patients. PRBC transfusion was not significantly associated with the risk of SA-AKI (risk difference: 0.67%, 95% CI: -1.32 to 2.63). However, compared with non-PRBC transfusion, PRBC transfusion significantly enhanced 7-, 28-, and 90-day survival, with significant survival differences of 2.54% (95% CI: 1.68 to 3.46), 4.86% (95% CI: 3.64 to 6.14), and 4.52% (95% CI: 3.06 to 5.97), respectively. Sensitivity analyses produced consistent results. In this study, early PRBC transfusion did not impact the risk of SA-AKI but provided potential benefits in reducing mortality, particularly among sepsis patients with hemoglobin levels ≤ 10 g/dL.

Nanoparticles show great potential for the management of acute kidney injuries (AKIs). It is well known that nanoparticle size plays a critical role in targeting renal tubules due to the pore structure and kidney filtration threshold (KFT) of the glomerulus. However, AKI can compromise the physiological barriers, which might render the established KFT (∼6 nm) and size laws under healthy conditions not applicable in AKI conditions. Reinvestigating the nanoparticle size effect on targeting injured kidneys is thus essential for developing efficacious AKI nanomedicine. Herein, using different-sized gold nanoparticles (AuNPs) ranging from 4 to 60 nm as a model of renal nanomedicine, we discovered that the KFT for AuNPs expands from ∼6 nm to ∼10-40 nm under rhabdomyolysis-induced AKI conditions. After loading curcumin, a natural antioxidant, into 5, 16, and 60 nm AuNPs to compare their efficacies against AKI, we found that 5 and 16 nm AuNPs both effectively delivered drugs into renal tubules, resulting in their equal therapeutic performance and significantly better efficacy than 60 nm ones, further validating the enlarged KFT under AKI. Our results provide valuable insights for size engineering of nanomedicine for better AKI management and enable a deeper understanding of AKI renal physiology at the nanoscale.

Polycystin-1 (PKD1) and -2 (PKD2) are causative genes for autosomal dominant polycystic kidney disease (ADPKD), which often presents with cardiovascular manifestations by mechanisms still not completely understood. PKD1 and PKD2 have been suggested to function as mechanoreceptors in endothelial cells (ECs), transducing mechanical forces exerted by the flowing blood into downstream signalling pathways. Our zebrafish functional screening of EC mechanoreceptors identified PKD1 and PKD2 as anti-apoptotic, protective factors in the zebrafish endothelium. In mice, we show that inducible EC-specific loss of PKD1, but not PKD2, led to increased atherosclerosis. To dissect the underlying mechanisms, we performed single cell RNA sequencing and identified candidate pathways regulating EC behaviour downstream from PKD1. Knockdown of PKD1 in human aortic ECs resulted in increased EC apoptosis and decreased expression of athero-protective endothelial nitric oxide synthase (eNOS), which was mediated by thrombospondin 1 (THBS1) and cellular communication network factor 1 (CCN1). By integrating in vivo and in vitro models with -omics approaches, we have identified PKD1 as a novel regulator of EC survival and protective factor against atherosclerosis development. We conclude that therapeutic targeting of this pathway may treat atherosclerosis.

Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02-1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20-2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16-0.87 years). The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. Vienna Science and Technology Fund, NIH/NIAID.