Background: Early external validation studies demonstrated the robust and consistent predictive performance of the International IgA Nephropathy Prediction Tool (IIgAN-PT) across diverse ethnic populations. However, emerging evidence suggests that, in contemporary cohorts of patients with IgA nephropathy, the IIgAN-PT increasingly tends to overestimate the risk of adverse renal outcomes. Subclassification of segmental glomerulosclerosis (S lesions) in the Oxford Classification system (MEST-C) could identify high-risk IgAN patients, with evidence that different S subclassifications respond differently to treatment. Our study aimed to evaluate the predictive performance of the IIgAN-PT in a contemporary Chinese external validation cohort and to optimize its prognostic accuracy by incorporating the most severe and prevalent pathological subclassification of S lesions, NOS+Adh+, into the original model. Methods: A total of 746 Chinese patients were included with biopsy-proven IgAN in this study. Major adverse kidney events (MAKEs) were defined as death from any cause, initiation of renal replacement therapy, or a 50% decline in eGFR. This study evaluated the discrimination and model fit of three predictive models. The performance of the original and modified IIgAN-PT models was compared and evaluated through reclassification, survival analysis, calibration, decision curve analyses and subgroup analyses. Results: In the study cohort, the median follow-up duration was 4.2 years, during which 77 patients experienced MAKEs. The discriminative ability of the three original models was relatively limited. In contrast, the modified IIgAN-PT incorporating the NOS+Adh+ subtype of S subclassification demonstrated improved global performance for predicting 5-year risk, achieving a C-index of 0.808 (95% CI, 0.756-0.861). Kaplan-Meier survival curves showed clear risk stratification, particularly between low- and intermediate-risk categories. Reclassification analyses (continuous NRI and IDI) and decision curve analysis further supported enhanced predictive performance, while calibration curves corrected the original model's risk overestimation. The modified model maintained stable performance across clinically relevant subgroups, including patients with hypertension, proteinuria, or receiving immunosuppression. Conclusions: This study further confirms the independent and clinically relevant prognostic value of the S pathological subclassification. The modified IIgAN-PT model, incorporating the NOS+Adh+ subtype of S subclassification, demonstrated consistent performance in individualized risk assessment for patients with IgA nephropathy.

BACKGROUND AND HYPOTHESIS:Evidence from the VALIGA Immunoglobulin A (IgA) nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S). Our study aimed to validate and explore the clinical significance of S subclassification in an Asian population. METHODS:A total of 746 patients with IgAN were retrospectively included. The chi-squared automatic interaction detection method was used to identify subgroups of S lesions associated with proteinuria, eGFR, and major adverse kidney events (MAKE). Kaplan-Meier analysis was performed to assess differences in MAKE. Hazard ratios for S1 lesions with respect to MAKE were estimated using Cox proportional hazards regression models. Propensity score analysis was used to evaluate whether immunosuppressive therapy was associated with a favorable outcome within subgroups. RESULTS:Among 746 patients, S1 lesions were present in 80% of individuals, with segmental capillary occlusion by matrix (not otherwise specified (NOS), 69%), simple capsular adhesion without capillary occlusion (Adh, 63%), and podocyte hypertrophy (PH, 16%) being the top three subtypes. All three lesion types were associated with proteinuria, and NOS was also correlated with eGFR. Patients in the S1 with NOS+Adh+ subgroup had the worst prognosis. Moreover, immunosuppressive therapy was associated with better outcomes in S1 patients with NOS+Adh+. Subgroup analysis showed that the effect of NOS+Adh+ lesions on MAKE was significantly influenced by systolic blood pressure (SBP). Patients with NOS+Adh+ lesions and SBP >130 mmHg had a significantly increased risk of MAKE. CONCLUSION:Our study validated the clinical value of S subclassification in IgAN in an Asian population. Patients with NOS+Adh+ lesions have more severe proteinuria and renal function damage. Their overall renal prognosis is significantly worse; however, they can benefit from a treatment strategy that combines renin-angiotensin system inhibitors with immunosuppressants. In addition, controlling SBP to below 130 mmHg seems to be an appropriate range.

Diabetic kidney disease (DKD) lacks specific biomarkers reflecting the interplay between mitochondrial dysfunction and immune microenvironment remodeling. To address this, we integrated multi-dataset transcriptomics (GEO, MitoCarta 3.0, GeneCards) with Weighted Gene Co-expression Network Analysis, protein-protein interaction networks, and machine learning algorithms to identify key diagnostic genes. Single-nucleus RNA sequencing was utilized to map cell-type distributions. Subsequently, a single-center cohort of 70 biopsy-confirmed DKD patients was enrolled for validation of the key hub gene, HDAC6. We identified four hub genes: EGF (downregulated), HDAC6, TPM1, and VCAM1 (upregulated). All genes exhibited robust diagnostic efficacy, and single-nucleus analysis revealed distinct renal cell-type enrichment patterns. Clinically, high renal HDAC6 expression correlated with severe interstitial inflammation, elevated complement C3 and cystatin C, and reduced urinary ammonium (a clinical proxy for proximal tubular mitochondrial dysfunction). Crucially, high HDAC6 served as an independent risk factor for both renal endpoints and cardiorenal composite events. In conclusion, EGF, HDAC6, TPM1, and VCAM1 are key regulators in DKD. Specifically, intrarenal HDAC6 quantification serves as a precise histological metric for prognostic stratification and underscores its potential as a therapeutic target for DKD intervention.

Introduction: To investigate the correlation between body composition-related indicators and urinary protein levels and proteinuria remission in patients with primary membranous nephropathy (PMN). Methods: This retrospective study enrolled patients with PMN who were diagnosed by renal biopsy, exhibiting a baseline urinary protein of ≥3.5 g/day between July 2020 and May 2025. Body composition was assessed at enrollment using bioelectrical impedance analysis before any treatment. The predictors included percentage of body fat (PBF), fat mass index (FMI), and adipose tissue index (ATI). The relationship between body composition measures and proteinuria remission was studied by Kaplan-Meier analysis and Cox regression. Results: This study included 115 patients with PMN, of whom 75 (65.2%) were men, with a median age of 53.0 years. Significant differences in body composition-related indices, including PBF, FMI, and ATI, were observed between patients who achieved complete remission (CR) of proteinuria and those who did not (all p < 0.05). Univariate and multivariate Cox regression analyses demonstrated that PBF, FMI, and ATI were independently associated with proteinuria remission. Among these indices, FMI, which is less influenced by fluid overload, was independently and strongly associated with proteinuria remission (HR = 0.858; 95% CI: 0.757–0.972; p = 0.016). Compared with non-obese patients, obese individuals (defined as FMI >6 kg/m2 in men and >9 kg/m2 in women) had higher baseline proteinuria levels. In sex-stratified analysis, non-obese men were 3.586 (95% CI: 1.387–9.270; p = 0.008) times more likely to achieve CR than obese men. Conclusion: FMI was positively correlated with baseline proteinuria in patients with PMN and independently predicted a lower likelihood of CR of proteinuria.

Cardiovascular disease (CVD) leads global mortality. Insulin resistance (IR) and physical activity (PA) are key cardiometabolic factors, yet their combined impact remains unclear. This study explores the independent and combined links of IR and PA to CVD incidence across diverse populations. This prospective analysis involved the China Health and Retirement Longitudinal Study (CHARLS). The estimated glucose disposal rate (eGDR) was calculated via waist circumference, hypertension status, and Glycated Hemoglobin A1c (HbA1c). PA was divided into ≥ 600 MET-minutes/week and < 600 MET-minutes/week. The main outcomes were new CVD cases (self-reported). Lower eGDR and insufficient PA were independently tied to higher CVD incidence (eGDR: HR = 0.930, 95

Kidney tubulointerstitial disease culminates in renal fibrosis, which is a key determinant of subsequent end-stage renal disease. Krüppel-like factor 4 (KLF4), one of the Yamanaka transcription factors, controls various essential cellular functions, and has been implicated in kidney diseases. However, evidence regarding the role of KLF4 in renal fibrosis specifically within tubular epithelial cells and fibroblasts remains limited. In our study, we observed significant induction of KLF4 protein in tubular and interstitial myofibroblasts from mouse and human fibrotic kidneys. Mice with epithelium or fibroblast-specific deletion of KLF4 showed reduced extracellular matrix (ECM) deposition and downregulation of Hippo signaling components in both fibrotic models. Gain- and loss-of-function experiments supported that KLF4 signaling was responsible for TGF-β1-induced ECM production in both tubular cells and fibroblasts. Mechanistically, KLF4 protein can interact with YAP protein, promote YAP activation and drive the expression of downstream signaling proteins, whereas inhibition of the Hippo signaling suppresses KLF4-mediated ECM deposition in both epithelial cells and fibroblasts. Interestingly, KLF4's action in tubular cells may play a more significant role in fibrogenesis compared to its role in fibroblasts. Finally, inhibition of KLF4 signaling with Kenpaullone dramatically improved ECM deposition in fibrotic nephropathy models. Inhibiting KLF4/YAP signaling dramatically improve kidney fibrogenesis, suggesting that targeting this signaling pathway may shine light on therapeutic strategies to mitigate kidney fibrosis in patients with chronic kidney diseases.

Background:Anti-glomerular basement membrane (anti-GBM) disease is not a distinct, isolated entity but rather a condition that frequently overlaps with other autoimmune serological profiles. Most notably, it can coexist with antineutrophil cytoplasmic antibodies (ANCA), alongside a diverse spectrum of additional autoantibodies. Despite the occurrence of such antibody overlap in a subset of patients, their specific clinical manifestations and prognostic implications remain poorly defined and largely elusive. Methods:This study retrospectively enrolled patients diagnosed with anti-GBM disease at the First Affiliated Hospital with Nanjing Medical University between January 2017 and January 2024. Based on serological profiles, enrolled patients were stratified into three cohorts: the classic anti-GBM group (anti-GBM antibodies positive alone), the ANCA-anti-GBM double-positive group, and the anti-GBM-non-ANCA autoantibody overlap group. Clinical, pathological, treatment, and outcome characteristics were systematically compared across the three groups. Additionally, landmark analysis was conducted to assess prognostic discrepancies across distinct time intervals. Results:A total of 67 patients with anti-GBM disease were enrolled in this study, with 30, 18, and 19 cases allocated to the classic anti-GBM group, ANCA-anti-GBM double-positive group, and anti-GBM-non-ANCA autoantibody overlap group, respectively. The ANCA-anti-GBM double-positive group presented with the highest mean age at onset among the three cohorts. A statistically significant difference was detected in baseline anti-GBM antibody titers across the groups (median: 141.20 vs. 104.25 vs. 181.70; interquartile range: 102.90-257.70 vs. 52.15-137.07 vs. 121.05-555.40; p = 0.044). By contrast, no significant differences were noted in terms of other clinical characteristics, renal pathological findings, and therapeutic regimens. Although the overall survival rates showed no statistical discrepancy among the three groups, distinct trends were observed in early survival outcomes: the ANCA-anti-GBM double-positive group had the poorest early survival, followed by the anti-GBM-non-ANCA autoantibody overlap group, while the classic anti-GBM group exhibited the most favorable early survival profile. Conclusion:This study identifies the distinct phenotypic traits of anti-GBM disease with concurrent other autoimmune antibodies, underscoring that sole reliance on anti-GBM antibody titers is inappropriate for prognostic judgment and treatment decision-making. For patients with anti-GBM disease overlapping with non-ANCA autoantibodies, intensive treatment regimens may be justified to achieve more favorable clinical prognosis.

N-glycosylation, as a common post-translational modification with complex structures, plays key roles in protein folding, cellular recognition and signaling pathways. State-of-the-art mass spectrometry-based N-glycoproteomics has enabled deep N-glycoproteome characterization of various human organs. However, a comprehensive N-glycoproteome landscape of human organs remains lacking. Here we present a systematic human N-glycoproteome atlas spanning 74 subjects across 18 organs/tissues with identification of 57,884 N-glycan structure-level and 23,863 monosaccharide composition-level intact N-glycopeptides on 7543 N-glycosites of 5062 N-glycoproteins. Tissue-specific N-glycosylation patterns and crosstalk between sialylation and fucosylation are observed. An organ classifier using multiple machine learning models on our N-glycopeptide dataset is trained. This atlas, complemented by a unified multi-software analysis framework, provides insights into organ-specific glycobiology and establishes a fundamental reference for understanding physiological N-glycosylation characteristics of human tissues.

Acute kidney injury (AKI) is highly prevalent worldwide but lacks specific treatments. Mitochondrial dysfunction plays a central role in its pathogenesis, making mitochondrial protection a promising therapeutic strategy. Miro1 is a key regulator of mitochondrial dynamics, yet its involvement in AKI remains unexplored. In this study, we found that Miro1 expression was significantly downregulated in renal tubular cells from AKI patients and in multiple murine AKI models. Functional studies demonstrated that Miro1 loss aggravated tubular cell injury and mitochondrial dysfunction, whereas Miro1 overexpression exerted protective effects. Mechanistically, we identified Sirt6 as a novel interacting partner of Miro1. Sirt6 directly deacetylated Miro1 at lysine residue K182, which inhibited its ubiquitin-proteasome degradation and maintained Miro1 protein stability. Disruption of Sirt6 activity led to enhanced Miro1 downregulation and increased tubular cell apoptosis, while Sirt6 activation reversed these detrimental effects in a deacetylase-dependent manner. Reciprocal rescue experiments further confirmed that Miro1 serves as a critical downstream effector of Sirt6. Collectively, our findings uncover the Sirt6-Miro1 axis as a previously unrecognized protective mechanism in AKI, wherein Sirt6 stabilizes Miro1 via deacetylation to preserve mitochondrial homeostasis and alleviate kidney injury. This axis may represent a novel therapeutic target for AKI intervention.

Background:Lupus nephritis (LN) is among the most serious organ manifestations of systemic lupus erythematosus (SLE), contributing significantly to morbidity and long-term renal outcomes. The development of noninvasive biomarkers capable of distinguishing active LN from non-renal SLE is of considerable clinical importance. Although renal biopsy remains the diagnostic gold standard, its invasive nature limits its utility for serial monitoring. In recent years, urine has emerged as a promising noninvasive medium for detecting renal inflammation and assessing disease activity. Methods:This study investigated whether RNA signatures within urinary extracellular vesicles (EVs) could serve as diagnostic biomarkers for LN. Urinary EVs were isolated from 27 patients with active LN and 13 with LN in remission. RNA sequencing was conducted, and four candidate transcripts were prioritized using three independent machine learning algorithms. These candidates were subsequently validated in an independent cohort comprising 143 urine samples using TaqMan-based quantitative PCR with reverse transcription (RT-qPCR). Results:Among the identified candidates, LINC01127, RUNDC3A-AS1, and LRRN3 emerged as potential diagnostic biomarkers for LN. Notably, RUNDC3A-AS1 and LRRN3 demonstrated robust discriminatory capacity between proliferative (class III/IV) and non-proliferative (class V) forms of LN. Conclusions:Our findings identify urinary extracellular vesicle RNAs-particularly LINC01127, RUNDC3A-AS1, and LRRN3-as novel, noninvasive biomarkers with potential clinical utility for the diagnosis and subclassification of LN.

PURPOSE:The aim of this prospective study was to investigate the feasibility of rapid renal MRF-based quantitative mapping for noninvasive assessment of renal functional and microstructural characteristics in patients with chronic kidney disease (CKD). METHODS:Participants with CKD who consented to renal MRF examination were prospectively enrolled from June 2023 to January 2024. T1 and T2 values of the renal cortex and medulla in both kidneys were derived from manually delineated ROIs and compared across CKD groups. Spearman correlation coefficients, following normality testing, were used to examine associations between MRF-derived metrics and serum creatinine (Scr) and measured glomerular filtration rate (mGFR). For participants who underwent renal biopsy, two-way ANOVA was used to compare MRF-derived metrics of biopsied kidney with histopathologic findings. RESULTS:Fifty-two participants (median age, 49 years [IQR, 39-59 years]) were included, of whom 42 underwent renal biopsy. Higher CKD stages were associated with increased cortical T1 values (P < .001 for the left kidney, P < .0001 for the right kidney, at one-way ANOVA) and higher medullary T2 values (P < .001 for the left kidney, P < .01 for the right kidney, at one-way ANOVA). Scr and mGFR were well correlated with cortical-medullary T1 difference (△T1) of the left kidney (r = -0.543, P = .0004; r = 0.657, P < .0001, respectively). Renal MRF-derived cortical T1, △T1, and whole-kidney T1 showed difference between the low-grade and high-grade renal fibrosis groups (15 % and 20 % fibrosis thresholds, P = .040; 15 % and 30 % fibrosis thresholds, P = .046; and 20 % fibrosis threshold, P = .0264, at two-way ANOVA). CONCLUSION:MR Fingerprinting quantitation correlated well with the renal functional and pathological findings, and demonstrated promise for characterizing CKD status.

BackgroundPrimary Membranous Nephropathy (PMN) is characterized by dysregulated immune responses, with B cells playing critical roles in disease pathogenesis. However, the immunopathogenic mechanisms underlying B cell involvement in PMN remain elusive.MethodsWe employed single-cell RNA sequencing on peripheral blood mononuclear cell samples (PBMC) obtained from 6 patients with PMN and 3 healthy controls (NC) to explore the transformation of B cells and their interaction with immune cells.ResultsCompared with NC, the most significant alterations were in plasma cells and regulatory B (Breg) cells in PMN patients. Within plasma cells, Subcluster 0 was increased in PMN patients and exhibited enhanced autoimmunity. Breg subset B10 cells were elevated in PMN patients and displayed increased immune regulatory capacity, marked by enhanced cytokine and interleukin-10 production. B cell activating factor (BAFF) and galectin-9, which were secreted by CD14 monocyte, as potential regulators of plasma and Breg cells activity. Additionally, serum galectin-9 levels increased in PMN patients and showed a correlation with proteinuria and renal function in PMN.ConclusionsWe reveal novel insights into the heterogeneity and functional diversity of B cells in patients with PMN. And revealed distinct roles for subgroup 0 plasma cells and B10 Breg cells in the pathogenesis of PMN. Furthermore, targeting B cells, such as galectin-9, presents promising opportunities for modulating the immune response in patients with PMN.

Clinically, acute kidney injury (AKI) stems from a diverse array of causes including ischemia, exposure to nephrotoxic agents, or sepsis. Renal tubular cells are particularly vulnerable and often sustain the most significant damage during AKI. This raises the question of whether there exists a common pathophysiological mechanism or pathway in renal tubular cells that underlies the development of AKI. We observed that tubular Galectin-3 is significantly up-regulated in four AKI mouse models and its tissue expression shows a positive correlation with tubular injury in human kidneys affected by AKI. The urinary Galectin-3 levels were markedly elevated in a cohort of patients with AKI and these levels correlated with the severity of kidney dysfunction. Based on predictions from bioinformatic analysis and JASPAR database, ChIP-PCR and luciferase-reporter assays demonstrated the direct binding of the transcription factor KLF4 to a specific sequence in the Galectin-3 gene promoter. Furthermore, mice with proximal tubular-specific deletion of KLF4 exhibited reduced kidney injury and inflammation, along with lower Galectin-3 expression in both cisplatin and ischemia-reperfusion-induced AKI. Targeting the KLF4/Galectin-3 axis with Kenpaullone and GB1107 confirmed protective effects against cisplatin-induced cell death and acute kidney injury, respectively. Our study highlights the KLF4/Galectin-3 pathway as a key mediator in the pathogenesis of AKI. Disrupting this signaling pathway may provide a promising therapeutic approach for the treatment of AKI.

Introduction:This study assessed the safety and efficacy of B cell- and anti-PLA2R antibody-targeted low-dose rituximab therapy in patients with idiopathic membranous nephropathy (IMN). Methods:This was a multicenter, investigator-initiated, open-label, prospective cohort study. Patients were recruited from 10 hospitals in the east coastal region of China between November 1st, 2019 and June 15th, 2023. Enrolled patients were assigned to individualized rituximab therapy (guided by peripheral B cells and anti-PLA2R antibody levels) or standard rituximab therapy (1,000 mg × 2 or 375 mg/m² × 3-4): the individualized group (n = 78) and the standard group (n = 62). Odds ratios (ORs) and 95% confidence intervals (CIs) for response were estimated using multivariate logistic regression models, adjusting for key confounders, with inverse probability of treatment weighting (IPTW) applied to balance demographic and clinical characteristics. The primary outcome was a composite of complete or partial remission of proteinuria. Results:A total of 140 patients were included in the sta tistical analysis, which was completed on June 10th, 2024. After IPTW, baseline characteristics were well balanced between the two groups. Patients were followed every 2 months for 1 year after the first rituximab injection. At 12 months, 57 of 78 patients (73.1%) in the individualized therapy group and 40 of 62 patients (64.5%) in the standard therapy group achieved complete or partial remission [the adjusted risk difference and 95% CI were 0.1 (-0.05 to 0.26); p = 0.001 for noninferiority]. In the weighted cohort, 74.1% in the individualized group and 70.5% in the standard group achieved remission (p = 0.5). The median (interquartile range) total rituximab dose per patient at 1 year was 800 mg (600-1,100 mg), with a total cost of RMB 16,227.5 (13,148-23,536) per unit utility in the individualized group, which was markedly lower than in the standard group. Anti-PLA2R autoantibody negativity at 6 months post-treatment predicted a higher probability of remission. The frequency of adverse events differed significantly between groups (6.4% vs. 12.9%, P = 0.02). Discussion:B cell- and anti-PLA2R antibody-targeted rituximab therapy may be a cost-effective and safe alternative for patients with IMN. Randomized controlled trials with larger samples are needed to confirm these findings. Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=42793, identifier ChiCTR1900026382.

BackgroundHemodialysis (HD) patients are at high risk of vascular calcification (VC) and cardiovascular disease (CVD). The coexistence of sarcopenia and malnutrition, known as malnutrition-sarcopenia syndrome (MSS), may further exacerbate these risks. This study aimed to investigate the prevalence of MSS in HD patients and its association with abdominal aortic calcification (AAC) and major adverse cardiovascular events (MACE).MethodsThis prospective cohort study enrolled 462 maintenance HD patients, who were subsequently stratified into four groups: no sarcopenia-no malnutrition, sarcopenia alone, malnutrition alone, and MSS. Sarcopenia was diagnosed based on the 2019 Asian Working Group for Sarcopenia (AWGS) criteria, and malnutrition was assessed using the Geriatric Nutritional Risk Index (GNRI). AAC was evaluated using lateral abdominal radiographs and scored according to Kauppila’s semiquantitative scoring system. The primary outcome was MACE during a 3-year follow-up period. Multivariable logistic regression and mediation analyses were employed to determine associations and potential mechanisms.ResultsThe prevalence of sarcopenia and malnutrition was 46.3 and 32.0%, respectively, with 18.2% of patients having MSS. MSS was independently associated with increased AAC (OR: 2.157, 95% CI: 1.064–4.373, p = 0.033) and MACE risk (OR: 2.235, 95% CI: 1.192–4.194, p = 0.012). Mediation analysis revealed that AAC severity partially mediated the relationship between MSS and MACE, accounting for 26.7% of the total effect.ConclusionMSS is prevalent in HD patients and is associated with more severe VC and higher cardiovascular risk. Comprehensive nutritional assessment and targeted interventions are needed to address sarcopenia and malnutrition in HD patients to improve their cardiovascular outcomes.

Background:Membranous nephropathy (MN) is a frequent cause of nephrotic syndrome in adults with variable response to rituximab (RTX) therapy. While traditional markers like proteinuria and anti-phospholipase A2 receptor (PLA2R) antibodies exhibit predictive value, their limitations necessitate more robust biomarkers. Methods:We prospectively analysed 149 MN patients receiving RTX over 12 months. Inflammatory indices such as neutrophil:lymphocyte ratio (NLR), monocyte:lymphocyte ratio (MLR) and systemic inflammation response index (SIRI) together with B cell levels were measured alongside conventional markers at baseline, 3 months and 6 months. Predictive models for 6- and 12-month remission (complete/partial) were developed using multivariate regression and receiver operating characteristics (ROC) analysis. Results:Non-responders exhibited persistently elevated inflammatory markers (NLR, MLR, SIRI) throughout the entire observation period. Among the three, only SIRI can independently predict the remission of MN. At 3 months, SIRI ≤1.25 {odds ratio [OR] 3.68 [95% confidence interval (CI) 1.39-9.72]} and B cell proportion ≤0.2% [OR 2.90 (95% CI 1.00-8.35)] independently predicted 6-month response. Incorporating these two newly added indicators into the traditional variable model, which includes the levels of proteinuria, albumin and anti-PLA2R antibody at 3 months, markedly enhances prediction accuracy [area under the curve (AUC) 0.86 versus 0.81]. By 6 months, only SIRI ≤0.9 [OR 4.84 (95% CI 1.43-16.40)] and albumin change [OR 1.11 (95% CI 1.03-1.19)] predicted 12-month prognosis, as B cell and anti-PLA2R antibody levels lost significance. The prediction model incorporating SIRI also had better performance (AUC 0.82 versus 0.79). Conclusions:B lymphocyte levels constitute a robust predictive biomarker for assessing short-term therapeutic response in patients with MN receiving RTX therapy. Furthermore, SIRI emerges as a valuable prognostic indicator capable of predicting both short-term efficacy and long-term renal outcomes. These findings suggest that concurrent monitoring of B lymphocyte levels and SIRI values warrants integration into standardized monitoring frameworks within clinical management protocols.

Reliable non-invasive biomarkers for early detection of diabetic nephropathy (DN), a leading cause of chronic kidney disease, remain limited. In this study, we isolate urinary extracellular vesicles (uEVs) using wheat germ agglutinin (WGA)-conjugated magnetic beads and identify cytoskeleton-associated protein 4 (CKAP4) as a potential diagnostic biomarker for DN. Proteomic profiling and flow cytometry show that CKAP4 levels are significantly higher in uEVs from DN patients than in those from diabetic, non-diabetic renal disease (NDRD) and healthy control groups. Receiver operating characteristic (ROC) analysis demonstrates excellent diagnostic performance, with area under the curve (AUC) values of 0.9998 (sensitivity = 98.77%, specificity = 100%) for DN versus controls, and 0.9859 (sensitivity = 95.72%, specificity = 99.24%) for DN versus diabetes mellitus. CKAP4 levels, elevated even at early-stage DN, positively correlate with glomerulosclerosis, increasing with the severity of interstitial fibrosis and tubular atrophy (IFTA). Mechanistically, CKAP4-containing EVs derived from high glucose-treated podocytes promote vascular calcification in vascular smooth muscle cells via YAP signalling. These findings identify CKAP4 in podocyte-derived uEVs as a robust non-invasive biomarker for early DN detection and provide new insights into the vascular pathology associated with the disease.

BACKGROUND:Calciphylaxis, also termed calcific uremic arteriolopathy (CUA) in patients with end-stage kidney disease (ESKD), is a rare and fatal condition characterized by cutaneous ischemic necrosis. METHODS:Three patients with calciphylaxis and metastatic pulmonary calcification (MPC) were treated with human amnion-derived mesenchymal stem cells (hAMSCs). Effects were evaluated using the Visual Analogue Scale (VAS), modified Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), wound quality of life questionnaire (Wound-QoL), and histological analysis. MPC was assessed by high-resolution CT (HRCT) and 99ᵐTc-methylene diphosphonate (99ᵐTc-MDP) bone scans.99ᵐTc-labeled macroaggregated albumin (99ᵐTc-MAA) pulmonary perfusion imaging was conducted for the first time in patients with MPC. RESULTS:Three patients exhibited wound healing and improvement in skin symptoms. Two months before CUA, asymptomatic MPC was detected in Patient 1, who was treated with hAMSCs for 15 months. The condition progressed to chest pain and dyspnea. HRCT and 99ᵐTc-MDP bone scans showed worsening calcification, particularly in the upper and mid-thoracic lobes.99ᵐTc-MAA pulmonary perfusion imaging revealed impaired or absent blood perfusion in the areas of metastatic calcification. Patient 1 died from respiratory failure. Patients 2 and 3 had asymptomatic MPC at calciphylaxis diagnosis. After 2 months of treatment, Patient 2, showed no significant imaging improvement and passed away 6 months after discontinuing hAMSC treatment. Patient 3 has shown no significant progression of pulmonary lesions and continues hAMSC therapy. CONCLUSION:We reported personalized early, noninvasive diagnosis and regenerative treatments for calciphylaxis patients with MPC. Although the current hAMSC treatment regimen is effective for skin lesions, its impact on MPC requires further investigation.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a leading cause of end-stage renal disease globally. Although mesangial IgA deposition defines its pathology, this alone does not predict disease progression. Current biomarkers lack specificity for forecasting outcomes or guiding early intervention. Recent advances have highlighted the potential of exosome-derived tRNA-derived small RNAs (tsRNAs) as novel diagnostic tools and mediators of disease processes, but their role in IgAN remains insufficiently explored. In this study, serum exosomes were isolated from patients with progressive or non-progressive IgAN and healthy controls. tsRNA expression profiles were obtained using small RNA sequencing and validated by qRT-PCR. Bioinformatic analyses were conducted to identify target pathways. Functional effects of candidate tsRNAs were evaluated using luciferase reporter assays, tsRNA mimic/antago transfections, and co-culture of B cell-derived exosomes with collecting duct epithelial cells (CDECs). Among 566 identified exosomal tsRNAs, tRNA-Pro-TGG was significantly upregulated in patients with progressive IgAN. It was enriched in B lymphocytes and correlated with serum soluble TNFR1 levels. Functional assays revealed that exosomal tRNA-Pro-TGG suppressed MAPK translation and activated proinflammatory responses in CDECs, including increased secretion of TNF-α, IL-6, and CCL2. ROC analysis demonstrated its robust diagnostic power for distinguishing progressive from non-progressive disease (AUC = 0.9618). This study identifies exosomal tRNA-Pro-TGG as a novel, non-invasive biomarker for IgAN progression and implicates it as a mediator of immune-driven renal inflammation. These findings offer valuable insights into IgAN pathogenesis and support the potential clinical utility of tsRNA-based diagnostics in nephrology.