Acute kidney injury (AKI) arises from diverse insults that trigger distinct immune responses, and an integrative framework for intercellular communication is now emerging. Extracellular vesicles (EVs), membrane-enclosed particles carrying proteins, microRNAs, lipids, and metabolites, mediate crosstalk between renal parenchymal cells and immune effectors to shape inflammation and repair. This review examines three dimensions of EV biology in AKI. This review examines three dimensions of EV biology in AKI, applying the term ‘EV’ throughout in accordance with MISEV2023 guidance unless the cited primary study has experimentally established subtype origin. First, we outline the molecular basis of EV-mediated immune signaling by contrasting vesicular communication with soluble cytokine and cell-contact pathways, highlighting cargo stability, tissue tropism, and multi-signal integration as distinguishing features. Second, we describe how EV composition shifts after injury: tubular epithelial cells, podocytes, and endothelial vesicles become enriched in damage-associated patterns and pro-inflammatory microRNAs, whereas immune cell-derived EVs propagate or resolve inflammation depending on polarization and disease phase. Third, we compare vesicular signaling across four AKI etiologies (allograft rejection, sepsis, nephrotoxicity, and ischemia-reperfusion), noting that EV cargo, cellular origin, and immune targets differ markedly by insult type and evolve through early, peak, and reparative phases. Advances in single-vesicle proteomics, intravital imaging, and kidney organoid systems now enable functional dissection of EV heterogeneity at unprecedented resolution. Key gaps remain: the limited mechanistic definition of dendritic cell- and T cell-derived EVs in non-transplant settings, the underdeveloped vesicular framework for renal ischemia-reperfusion, and the absence of standardized clinical assays. Addressing these limitations is essential for translating mechanistic insights into etiology-stratified diagnostics and stage-matched immunomodulatory interventions.

Proteolysis-targeting chimeras (PROTACs) represent a revolutionary therapeutic modality that hijacks the ubiquitin–proteasome system (UPS) to achieve selective degradation of pathogenic proteins. Unlike conventional inhibitors, PROTACs can eliminate previously "undruggable" targets, offering unique advantages such as high potency and the potential to overcome drug resistance. Despite advances in the treatment of kidney diseases, a common limitation is the lack of effective therapies that can precisely target the core protein drivers of renal pathology. This review aims to systematically elucidate the theoretical rationale for applying PROTAC technology to address key challenges in nephrology, comprehensively summarize its preclinical progress across a range of kidney diseases, and thoroughly analyze the core obstacles from molecular design to clinical translation. With its innovative strategy of mechanistically eliminating disease-causing proteins, PROTAC technology holds the potential to revolutionize the treatment of kidney disease and usher in a new era of precision medicine.

SIGNIFICANCE:The aging of the global population is linked to an increase in age-related diseases. The kidneys undergo both structural and functional declines with age, and aging is a significant risk factor for kidney diseases. Mitochondrial dysfunction is recognized as a crucial factor affecting kidney aging. Although the importance of disrupted mitochondrial homeostasis in renal aging has gained increasing attention, the associations and causal mechanisms have not been systematically summarized. RECENT ADVANCES:Mitochondria are highly dynamic organelles that operate in various functions, including cell metabolism, redox regulation, cell division, and cell death, and are closely associated with both cell senescence and kidney diseases. Furthermore, aging is also associated with mitochondrial redox dysfunction, abnormal calcium homeostasis, impaired quality control (QC), and increased mitochondrial DNA (mtDNA) leakages. Mitochondrial dysfunction and cellular senescence may sustain a vicious cycle in renal injury. Several types of drugs show promising potential in alleviating renal injury by modulating mitochondria-related aging phenotypes. CRITICAL ISSUES:Dysregulated redox status, mitochondrial metabolic reprogramming, mtDNA abnormalities, impaired mitochondrial QC, and mitochondrial calcium overload are the factors that establish a self-perpetuating vicious cycle that promotes renal aging. In addition, the roles of mitochondria-associated senescence in both acute kidney injury and chronic kidney disease are examined and summarized, with potential differences and promising interventions targeting mitochondrial dysfunction and cell senescence also highlighted. FUTURE DIRECTIONS:Clinically available interventions specifically aimed at addressing mitochondrial aging remain underdeveloped and require further clinical trials. Future research should also focus on creating drugs that can precisely target mitochondrial senescence to prevent the progression of age-related kidney diseases. Antioxid. Redox Signal. 44, 464-487.

Cyclin-dependent kinase 12 (CDK12) has been identified as a susceptibility locus for kidney function, but its role in chronic kidney disease (CKD) remains unclear. We generated tubule-specific CDK12 knockdown and overexpression mice and establish CKD models via adenine-induced and unilateral ureteral obstruction. We assessed renal injury, lipid metabolism, and transcriptional alterations using histology, functional assays, full-length transcriptome sequencing, and mechanistic rescue experiments. We detected significant reduction of CDK12 expression in renal tubular epithelial cells in human patients and experimental chronic kidney disease models. We find tubule-specific CDK12 knockdown exacerbates renal dysfunction, fibrosis, and lipid accumulation, whereas CDK12 overexpression confers protection. Mechanistically, CDK12 deficiency induces intronic polyadenylation of NCEH1 (neutral cholesterol ester hydrolase 1), resulting in reduced NCEH1 expression and cholesteryl ester accumulation. Restoring NCEH1 partially rescues lipid dysregulation and renal injury, identifying it as a key downstream effector. This study reveals that CDK12 protects against CKD progression by suppressing NCEH1 intronic polyadenylation and maintaining lipid homeostasis. The CDK12-NCEH1 axis represents a previously unrecognised mechanism linking transcriptional regulation to renal lipotoxicity and fibrosis, and may provide a potential therapeutic target.

BACKGROUND:The mechanisms underlying immune microenvironment remodeling remain unclear for patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aims to identify the key features that change following the combination therapy in patients with uHCC. METHODS:Single-cell transcriptomic profiling was conducted on uHCC samples from the control group, pre-treatment group, and post-treatment group. The Cancer Genome Atlas (TCGA) database was obtained for prognostic analysis. Enriched genes and pathways were identified, and the association and underlying mechanisms of the identified sub-cluster of cells were elucidated in relation to other cellular components. RESULTS:A total of 82,687 cells were obtained from seven patients with uHCC. In the pre-treatment group, the CancerCells_1 was associated with epithelial-mesenchymal transition, indicating a poor prognosis, as evidenced by data from 370 HCC patients in TCGA database. In the post-treatment group, a high proportion of macrophages_FOLR2 was observed corresponding to an elevated interferon response signature score and a diminished pro-angiogenic signature score. The exhaustion of CD8+ effector T cell (CD8Teff) was mitigated by downregulating the notable expression of BHLHE40 and CXCL13. Following treatment, there was an increase in liver sinusoidal endothelial cell (LSEC), while both angiogenesis and TGF-β pathway scores were reduced. Notable changes were observed in the interactions across different cells, particularly concerning the key signatures of LGALS9_HAVCR2, CSF1_CSF1R, and VEGFB_FLT1. CONCLUSION:After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.

Background and Purpose Tubulointerstitial fibrosis (TIF) is a pathological hallmark of chronic kidney disease (CKD) without effective therapy. Neutrophil extracellular traps (NETs) are complex web-like structures released by activated neutrophils, but their functional contribution to CKD-TIF remains largely unknown. Here, we uncovered a novel pathological role of NETs in driving TIF development.Experimental Approach NETs levels were evaluated in human kidney biopsies and serum samples. Peptidylarginine deiminase 4 (PAD4) knockout mice were subjected to unilateral ureteral obstruction and adenine-induced nephropathy models. The underlying mechanisms were elucidated by RNA sequencing, transmission electron microscopy, molecular docking and co-immunoprecipitation. The PAD4 inhibitor GSK484 was administered to evaluate the role of NETs in TIF.Key Results NETs markedly accumulated in kidneys of CKD patients and murine models, positively correlating with renal dysfunction and fibrosis progression. PAD4 knockout suppressed NETs formation and attenuated TIF. Mechanistically, transcriptomic analyses displayed pronounced activation of autophagy-related pathways in NETs-stimulated fibroblasts, whereas autophagy inhibition suppressed fibroblast activation. NETs components interacted with the transmembrane receptor coiled-coil domain-containing protein 25 (CCDC25), triggering dissociation of Yes-associated protein 1 (YAP1) from its receptor. This molecular rearrangement facilitates YAP1 nuclear translocation, subsequently enhancing autophagic activity in fibroblasts and promoting their phenotypic transition into myofibroblasts. Therapeutic administration of the PAD4 inhibitor GSK484 significantly attenuated renal fibrosis in vivo.Conclusions and Implications Our study provides the first evidence that NETs exacerbate CKD-TIF by enhancing fibroblast autophagy via the CCDC25-YAP1 axis, highlighting the NETs inhibitor GSK484 as a promising therapeutic candidate.

Diabetes has become a significant global public health challenge, and prediabetes (preD), as the earliest detectable stage of glucose metabolism disorder, constitutes a critical window for disease intervention. Currently, China has not established diagnostic criteria for HbA1c in preD, and there is limited understanding of the molecular mechanisms at the critical transition points during disease progression. This study employs a refined stratification strategy for HbA1c at intervals of 0.3%, integrating the Dynamic Network Biomarker (DNB) theory with high-throughput proteomics technology, combined with longitudinal cohort validation and machine learning methods, to systematically depict the disease progression characteristics, spanning from a healthy physiological state through the prediabetic stage and ultimately to the onset of type 2 diabetes (T2D). This cross-sectional cohort consisted of 110 subjects, divided into three groups: healthy controls (20), prediabetic (50), and type 2 diabetic (40). Of these, 28 went on to complete a 2-year longitudinal follow-up assessment. The results indicate that the HbA1c range of 6.0-6.2% (D stage) meets the three criteria of the DNB theory (high inter-molecular coherence, decoupling from external networks, and enhanced volatility), suggesting that this stage may represent a critical state for the transition from preD to T2D. A total of 37 core DNB proteins were identified through proteomics analysis, with the majority of functional annotations focused on biological processes involving extracellular matrix remodeling, inflammatory response, and insulin signaling pathways. In the longitudinal follow-up validation, the predictive efficacy of the ADAM10 protein for clinical outcomes was significant (AUC = 0.768), outperforming traditional indicators like HbA1c, demonstrating its potential value as a novel biomarker. There are several limitations in the present investigation. With the relatively small number of subjects, the short follow-up period, and the single center, single ethnic study design, the findings have limited generalizability. Additionally, the lack of functional validation of some of the important molecular targets is a methodological limitation that should be recognized. Therefore, the identified critical transition window and the clinical predictive value of DNB molecules need to be further validated through large-scale, multi-center, long-term cohort studies to obtain more reliable evidence-based medical evidence, providing a scientific basis for the precise diagnosis and early intervention of preD in the Chinese population.

Acute kidney injury (AKI) remains a major clinical challenge due to the lack of effective interventions. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show therapeutic promise for AKI, their exact mechanisms are largely to be understood. Human umbilical cord-derived MSC-EVs were isolated, characterized, and tested in a murine bilateral renal ischemia reperfusion injury (bIRI) model and in hypoxia/reoxygenation (H/R) treated tubular epithelial cells in vitro. Integrated transcriptomic, miRNA, and biochemical analyses were performed to elucidate the metabolic pathways and molecular mechanisms underlying the renoprotective effects of MSC-EVs. MSC-EVs preferentially targeted injured kidneys and significantly improved renal function, ameliorated tubular injury, and suppressed inflammation in IRI-AKI. RNA sequencing and targeted metabolomics revealed substantial dysregulation of steroid metabolism after IRI, marked by activation of the cholesterol 25-hydroxylase (CH25H)/25-hydroxycholesterol (25HC) axis. Importantly, accumulated 25HC induced lipid peroxidation and ferroptosis in tubular epithelial cells. MSC-EVs treatment reversed these pathological changes by downregulating CH25H, lowering 25HC levels, and restoring redox homeostasis. miRNA profiling further identified miR-26b-5p as a key MSC-EVs cargo that directly targets the 3′UTR of CH25H mRNA to repress its expression. Notably, inhibiting miR-26b-5p within EVs abrogated their ability to suppress CH25H/25HC-driven ferroptosis, thereby demonstrating its essential role in the metabolic and cytoprotective actions of MSC-EVs. Our findings unveil the CH25H/25HC axis as a key metabolic checkpoint governing tubular ferroptosis in ischemic AKI. MSC-EVs deliver miR-26b-5p to suppress this axis, thereby rectifying oxysterol metabolism and preventing ferroptosis.

Background: Inherited Kidney Disease (IKD) significantly contributes to CKD in children, adolescents, and adults. However, large-scale research on the prevalence of IKD in a Chinese population is currently lacking. To address this gap, we use exome sequencing (ES) to thoroughly investigate the prevalence and disease spectrum of IKD in a Chinese population. Methods: ES was conducted on 290 patients with kidney disease of unknown etiology from two centers. Genetic test results were interpreted following the American College of Medical Genetics and Genomics (ACMG) guidelines and the criteria for Variants of Uncertain Significance (VUS). Clinical data were integrated to establish a definitive diagnosis. Results: 290 patients from 261 families were included in this study. Diagnostic variants were identified in 82 families, yielding a diagnostic rate of 31% (82/261). Six genes ( PKD1 , PKD2 , COL4A3 , COL4A4 , COL4A5 , and UMOD ) accounted for 50% (41/82) of diagnosed cases. Ciliopathies were the most common subtype, followed by tubulopathies, collagenopathies, and podocytopathies. The diagnostic rate was higher in the age groups of ≤20 years and ≥41 years, at 63% and 39%, respectively. Among 51 biopsied patients, glomerular lesions (34/51) were the most common pathological type, followed by tubulointerstitial lesions (11/51). Of the 14 genetic diagnoses, 12 (86%) were consistent with histopathologic findings. Conclusions: A molecular genetic diagnosis was achieved in 31% of selected Chinese families. Genetic and clinical diagnosis complement each other, highlighting the application value of genetic testing in the diagnosis of IKD.

IntroductionCardiovascular disease (CVD) is the leading cause of death in patients receiving dialysis, and accurate risk prediction at dialysis initiation remains limited. We developed and validated a machine learning model integrating CT-derived body composition features to predict CVD-related mortality in initial dialysis patients.MethodsPatients initiating dialysis between 2014 and 2020 from three tertiary hospitals were used for model training and internal validation, with patients from a fourth center for external validation. Clinical characteristics and laboratory variables were collected, and body composition parameters were assessed using opportunistic CT scans. Feature selection was performed using univariable logistic regression and LASSO regression. Eight machine learning algorithms were trained, and model performance was assessed using discrimination, calibration, and decision curve analysis. Model interpretability was evaluated using Shapley Additive Explanations (SHAP), and a web-based risk calculator was developed.ResultsAmong 1051 incident dialysis patients, 645 were assigned to the training and internal validation cohorts and 406 to the external validation cohort. Eight key predictors were identified, including age, diabetes, CVD, history of cardiac intervention, dialysis modality, skeletal muscle density, hemoglobin, and serum creatinine. CatBoost demonstrated the best performance, with an area under the receiver operating characteristic curve of 0.843 in internal validation and 0.799 in external validation, along with good calibration and clinical net benefit. SHAP analysis identified CVD, skeletal muscle density, and hemoglobin as major contributors.DiscussionAn explainable machine learning model incorporating CT-derived body composition features accurately predicts CVD-related mortality in initial dialysis patients. This model may facilitate early risk stratification and targeted prevention strategies at dialysis initiation.

The plasma protein corona (PC) critically influences the in vivo fate of nanomedicines, yet its composition and impact on extracellular vesicles (EVs) remain poorly defined. Using a biomimetic circulation system, we characterized PC formation and modulation on two clinically relevant EV types: mesenchymal stromal cell-derived EVs (MSC-EVs) and HEK293F-derived EVs (293F-EVs). Under dynamic flow, both EV types acquired stable coronas, resulting in increased particle size and decreased surface charge. Proteomic profiling revealed a shared corona signature enriched in immunoglobulins, complements, and other plasma components. Functionally, PC formation enhanced macrophage uptake and triggered inflammatory activation, primarily via interactions between corona-bound immunoglobulins or complement C3 and their respective receptors. To disrupt this process, we developed a charge-shielding strategy using positively charged chitosan oligosaccharide (COS) to inhibit PC assembly. COS coating effectively neutralized EV surface charge and reduced opsonin adsorption and non-specific macrophage clearance, thereby reshaping EV biodistribution-limiting hepatic sequestration and enhancing delivery to extrahepatic organs. In a murine sepsis model, COS-modified MSC-EVs further improved renal and pulmonary outcomes and markedly increased survival. Collectively, these findings elucidate the molecular architecture and immunological impact of the EV-associated plasma PC and introduce a promising anti-corona strategy for engineering stealthier and more effective EV-based nanotherapeutics.

ABSTRACT Background Electroacupuncture (EA) treatment has been utilized for recovery from neuromuscular‐related diseases and may play a significant role in the treatment of sarcopenia. This interventional, randomized controlled clinical study aims to explore the efficacy of EA treatment in maintenance haemodialysis (MHD) patients with sarcopenia. Methods Thirty‐six participants with sarcopenia undergoing MHD were randomly divided into the control group and the EA group. The participants in the EA group received a total of 24 treatments, each lasting 30 min, and were administered three times per week. Participants in the control group were instructed to continue their current lifestyle and treatment plans. The assessments were conducted at baseline and after 8 weeks. Statistical analysis was performed using two‐way analysis of covariance (ANCOVA) adjusted according to gender and baseline values. Repeated measures analysis of variance (ANOVA) was used to assess EA effects, reporting main effects and the time × group interaction with partial eta squared (η2p) effect sizes. The primary outcome was 6‐m gait speed; the secondary outcomes were skeletal muscle mass index (SMI) and handgrip strength. Fasting blood samples were collected, and serum metabolomics using the liquid chromatography–mass spectrometry method was employed to reveal metabolic changes. Results One participant from the EA group dropped out, and 35 participants were included in the analysis, aged (59.06 ± 11.69) years, including 22 men and 13 women. After intervention, the 6‐m gait speed of the EA group increased (Δ = 0.10 ± 0.08; p < 0.001), whereas that of the control group decreased (Δ = −0.06 ± 0.09; p = 0.018). The handgrip strength of the EA group increased (Δ = 0.68 ± 0.98; p = 0.011), whereas that of the control group decreased (Δ = −0.76 ± 1.19; p = 0.015). The SMI in the EA group increased (Δ = 0.19 ± 0.22; p = 0.003), although there was no significant difference in the control group. No serious adverse events were observed during the EA treatment. The results of serum metabolomics indicated that a total of 127 differentially expressed metabolites were identified (p < 0.05, VIP > 1), including 35 up‐regulated metabolites and 92 down‐regulated metabolites. KEGG pathway enrichment analysis showed that glycerophospholipid metabolism, linoleic acid metabolism and other pathways related to lipid metabolism were significantly changed. Conclusions EA treatment was an effective therapy for sarcopenia in patients undergoing MHD. Its therapeutic effect may be related to the positive regulation of systemic metabolism (including amino acid and lipid profiles).

BACKGROUND:Renal interstitial inflammation (RII) is a frequent pathological feature in IgA nephropathy (IgAN), but its prognostic value remains uncertain. This study investigated the effect of RII on renal outcomes and developed a machine learning-based model incorporating RII for individualized prognosis. MATERIALS AND METHODS:We retrospectively analyzed 540 IgAN patients diagnosed by renal biopsy at Zhongda Hospital and the First People's Hospital of Huai'an (2012 - 2023). The endpoint was a ≥ 50% decline in eGFR or end-stage renal disease, with follow-up to June 2024. Predictors included demographics, clinical/laboratory parameters (blood tests, serum biochemistry, 24-hour urine protein), and histopathology (Oxford MEST-C and RII scores). Variable selection used random forest, extreme gradient boosting, artificial neural networks, and LASSO regression. A logistic regression model and nomogram were developed and validated internally and externally. RESULTS:Of 540 patients (mean age 40.8 years; 50.6% male), 273 were in the derivation, 117 in the internal validation, and 150 in the external validation cohort. Patients with progression had lower baseline serum albumin (p = 0.023), lower estimated glomerular filtration rate (eGFR) (p < 0.001), and higher systolic blood pressure (SBP) and proteinuria (all p < 0.001). In multivariate analysis, RIIS1 (odds ratio (OR) 4.16, 95% CI 0.91 - 24.51, p = 0.048) and RIIS2 (OR 6.80, 95% CI 0.98 - 54.49, p = 0.039) independently predicted adverse outcomes. Use of renin-angiotensin-aldosterone system inhibitors was protective (OR 0.34, p = 0.026), while higher SBP increased risk (OR 1.04, p < 0.001). The nomogram achieved C-indices of 0.91, 0.90, and 0.92 in the derivation, internal, and external validation cohorts, respectively. CONCLUSION:RII is an independent predictor of renal progression in IgAN. The developed model and nomogram may assist in individualized risk stratification.

BACKGROUND:Renal fibrosis (RF) is a progressive pathological process driven by chronic inflammation and Th17/Treg imbalance. Asiaticoside (AS), a triterpenoid compound from Centella asiatica (L.) Urb., exhibits anti-inflammatory and antifibrotic activities, though its molecular mechanism remains unclear. OBJECTIVE:This study aimed to investigate whether AS alleviates RF by targeting Signal transducer and activator of transcription 3 (STAT3) through a "bind to destabilize" mechanism to restore Th17/Treg homeostasis. METHODS:An integrated approach combining network pharmacology, transcriptomics, and multimodal experimental validation was applied. UUO mice were treated with AS (10, 50, 100mg/kg/d) for 10 days. Histopathology, RNA‑seq, flow cytometry, immunofluorescence, Luminex, qPCR, DARTS‑LC‑MS/MS, molecular docking/dynamics simulations and SPR were performed. Pharmacological interventions using Stattic (STAT3 inhibitor) and Colivelin (STAT3 agonist) were included to functionally validate the role of STAT3. RESULTS:Network pharmacology identified STAT3 as the core target, with Th17 differentiation as the key pathway. AS treatment significantly attenuated RF, improved renal function, and rebalanced Th17/Treg ratios in UUO mice, accompanied by reduced IL-17A and elevated IL-10. Transcriptomic analysis revealed enriched Th17 cell differentiation genes, validated by qPCR. DARTS-LC-MS/MS confirmed direct binding of AS to STAT3 and identified a peptide derived from the SH2 domain (residues 582-602), indicating conformational destabilization. SPR showed high affinity binding to both human and murine STAT3. Molecular docking and dynamics simulations demonstrated a "local anchoring-allosteric effect" mode within the SH2 domain. qPCR analysis showed that AS significantly inhibited the mRNA expression of both IL-17A and total STAT3 in the renal tissues of UUO mice. Immunofluorescence revealed reduced STAT3 and p-STAT3 expression in kidneys. STAT3 inhibitor Stattic mimicked AS's antifibrotic and Th17 suppressive effects, whereas agonist Colivelin exacerbated fibrosis and was partially rescued by AS. CONCLUSION:AS alleviates RF via a novel "bind to destabilize" allosteric degradation mechanism that directly targets the STAT3 SH2 domain. This interaction induces conformational instability, suppresses STAT3 activation and transcriptional activity, restores Th17/Treg homeostasis, and ultimately mitigates renal inflammation and fibrosis. Collectively, these findings establish a new therapeutic strategy for STAT3-driven fibrotic diseases.

This paper reviews recent advances in the precise management of prediabetes, adopting an integrative perspective that synergizes multi-omics, radiomics, and pharmacological insights from both traditional Chinese and Western medicine. In multi-omics research, genomics aids in early warning for high-risk populations among the Chinese; metagenomics reveals associations between intestinal microbiota characteristics and disease onset; metabolomics provides biomarkers, and the integration of multiple omics has identified novel prevention and treatment targets. Radiomics can assist in diagnosis and treatment, with integrated diagnostic models combining traditional Chinese and Western medicine expected to enhance diagnostic efficacy, while other imaging examinations can aid in early diagnosis, disease assessment, and treatment evaluation. In pharmacology, both traditional Chinese and Western drugs have their respective advantages and disadvantages, and their combined use can improve prevention and treatment outcomes. Integrated traditional Chinese and Western medicine treatment is theoretically supported, enabling the formulation of precise strategies, and clinical cases have confirmed its effectiveness. However, challenges remain in technological integration, standardization, and cost-effectiveness. In the future, with the development of technology, theory, artificial intelligence, and strengthened international cooperation, greater breakthroughs are anticipated.

Autosomal dominant tubulointerstitial kidney disease -UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male UmodH36Y/+ mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male UmodH36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.

KEY POINTS:A molecular genetic diagnosis was achieved in 31.4% of Chinese families. This study has firstly identified six genes as the principal causative genes underlying CKD in Chinese patients. BACKGROUND:Inherited kidney disease (IKD) significantly contributes to CKD in children, adolescents, and adults. However, large-scale research on the prevalence of IKD in a Chinese population is currently lacking. To address this gap, we use exome sequencing to thoroughly investigate the prevalence and disease spectrum of IKD in a Chinese population. METHODS:Exome sequencing was conducted on 290 patients with kidney disease of unknown etiology from two centers. Genetic test results were interpreted following the American College of Medical Genetics and Genomics guidelines and the criteria for variants of uncertain significance. Clinical data were integrated to establish a definitive diagnosis. RESULTS:A total of 290 patients from 261 families were included in this study. Diagnostic variants were identified in 82 families, yielding a diagnostic rate of 31% (82/261). Six genes ( PKD1 , PKD2 , COL4A3 , COL4A4 , COL4A5 , and UMOD ) accounted for 50% (41/82) of diagnosed cases. Ciliopathies were the most common subtype, followed by tubulopathies, collagenopathies, and podocytopathies. The diagnostic rate was higher in the age groups 20 years or younger and 41 years or older, at 63% and 39%, respectively. Among 51 biopsied patients, glomerular lesions (34/51) were the most common pathological type, followed by tubulointerstitial lesions (11/51). Of the 14 genetic diagnoses, 12 (86%) were consistent with histopathologic findings. CONCLUSIONS:A molecular genetic diagnosis was achieved in 31% of selected Chinese families. Genetic and clinical diagnosis complement each other, highlighting the application value of genetic testing in the diagnosis of IKD.

IntroductionVascular calcification (VC) is a prevalent and life-threatening complication of chronic kidney disease (CKD), yet the mechanisms by which hyperphosphatemia drives VC remain incompletely understood. This study investigates the role of endothelial cells (ECs)-derived exosomal microRNAs in mediating osteogenic differentiation of vascular smooth muscle cells (VSMCs) under high phosphate (HP) conditions.MethodsA CKD-VC mouse model was established using a HP and high-adenine diet. Exosomes (Exos) were isolated from ECs cultured under normal or HP conditions. The effects of Exos on calcification of VSMCs were evaluated using in vitro co-culture systems and in vivo administration. miRNA sequencing, dual-luciferase reporter assays, and loss/gain of function experiments were performed to identify key exosomal miRNAs and their downstream targets. Western blotting, qRT-PCR, and histological analyses were used to assess molecular and pathological changes.ResultsHP-stimulated ECs released Exos (HP-Exos) that were internalized by VSMCs and significantly promoted VC in both in vitro and in vivo models. miRNA sequencing identified miR-299-3p as significantly upregulated in HP-Exos. Functional studies demonstrated that exosomal miR-299-3p directly targeted membrane-associated RING-CH3 (MARCH3), leading to activation of the p-JAK2/STAT5 signaling pathway. This cascade subsequently upregulated osteogenic markers and downregulated contractile marker, thereby promoting osteogenic differentiation of VSMCs. Knockdown of miR-299-3p in vivo attenuated VC in CKD mice.DiscussionThese findings reveal a previously unrecognized mechanism by which HP drives CKD-VC through ECs-derived exosomal miR-299-3p. The miR-299-3p/MARCH3/p-JAK2/STAT5 signaling axis represents a critical regulatory pathway in VC pathogenesis and offers a potential therapeutic target for this life-threatening complication of CKD.

Introduction:Iron deficiency is prevalent in chronic kidney disease (CKD), particularly among patients with anemia. However, the prognostic value of routinely measured iron biomarkers, ferritin and transferrin saturation (TSAT), in non-dialysis-dependent (NDD) CKD remains incompletely defined. Methods:We conducted a multicenter retrospective cohort study using data from the China Renal Data System. Eligible hospitalized adults had anemia and NDD-CKD with baseline serum ferritin or TSAT measurements. Iron deficiency was defined as ferritin ≤100 ng/mL and/or TSAT ≤20%. The primary outcomes were CKD progression and all-cause mortality. Associations were assessed using multivariable Cox proportional hazards models; Fine and Gray competing risk models and prespecified subgroup analyses evaluated robustness. Results:Among 40,667 patients with anemic CKD, 38,307 had ferritin measurements, and 9,210 had TSAT measurements. Of these, 11,116 (29.02%) had ferritin ≤100 ng/mL and 3,295 (35.78%) had TSAT ≤20%. During follow-up, CKD progression occurred in 8,756 (22.86%) patients in the ferritin cohort and 2,459 (26.70%) in the TSAT cohort. In multivariable analyses, ferritin ≤100 ng/mL was associated with a modestly lower risk of CKD progression than levels greater than 100 ng/mL (adjusted hazard ratio [aHR], 0.95; 95% confidence interval [CI], 0.90-0.99), with similar results in competing risk analyses. TSAT ≤20% was not associated with CKD progression (aHR, 1.04; 95% CI, 0.95-1.13). For all-cause mortality, ferritin ≤100 ng/mL was not independently associated with risk (aHR, 0.99; 95% CI, 0.93-1.06), whereas TSAT ≤20% was associated with higher risk (aHR, 1.19; 95% CI, 1.06-1.36). CRP-stratified analyses indicated that ferritin ≤100 ng/mL was associated with lower CKD progression risk only among patients with CRP ≤10 mg/L, suggesting that the prognostic association of ferritin varied by inflammatory status. Conclusion:In Chinese adults with anemia and NDD-CKD, ferritin and TSAT showed divergent prognostic associations. TSAT ≤20% identified higher mortality risk, whereas ferritin ≤100 ng/mL was associated with a modestly lower observed risk of CKD progression in an inflammation-dependent pattern. These findings support routine, context-aware assessment of iron indices, particularly TSAT, in anemic NDD-CKD.