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PubMed2026

Anifrolumab Treatment Leads to Rapid Reduction in Urinary Biomarkers of Intrarenal Inflammation in Lupus Nephritis: Results From the Phase 2 Randomized Trial.

OBJECTIVE: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and is partially driven by type I interferon signaling. Anifrolumab, an approved treatment for patients with SLE, has been investigated in a phase 2 trial in patients with LN receiving standard therapy (TULIP-LN, ClinicalTrials.gov identifier NCT02547922). We studied the impact of anifrolumab treatment on urinary biomarker expression in patients with LN through proteomic analysis of samples from TULIP-LN. METHODS: Urine samples were collected at weeks 0, 12, and 48 from patients treated with the anifrolumab basic regimen (n = 35), intensified regimen (n = 42), or placebo (n = 35), in addition to standard therapy, and analyzed for the presence of 197 proteins. The impact of anifrolumab relative to placebo on prespecified biomarkers linked to histologic activity was assessed, and a comparison of responders versus nonresponders was conducted on proteins detected in ≥75% of samples. RESULTS: Anifrolumab treatment significantly reduced urinary CD163 and monocyte chemoattractant protein 1 expression at week 12 versus placebo, including in patients classified as proteinuric nonresponders across all regimens. By week 48, biomarker levels declined in all groups, indicating that standard therapy alone can eventually suppress intrarenal inflammation but with slower kinetics. Proteomic analyses further revealed that anifrolumab was superior to placebo in reducing the proteomic inflammatory signature, regardless of responder status. CONCLUSION: Compared with placebo, anifrolumab treatment significantly reduced urinary biomarkers of renal histologic activity in patients with LN, which may accelerate the resolution of intrarenal inflammation, potentially preventing damage accrual.

Humans↗

PubMed2026

PRDX1 as a novel urinary biomarker for bladder cancer: Development of an integrated fiber optic sensing platform.

In this study, integrated proteomic and transcriptomic analyses identified peroxiredoxin 1 (PRDX1) as a novel urinary biomarker for bladder cancer (BC). PRDX1 was significantly upregulated in BC tissues and was associated with poorer overall survival. In vitro experiments further demonstrated that PRDX1 promotes malignant phenotypes of BC cells, including proliferation, migration, and invasion. Silencing PRDX1 in BC cells significantly reduced the invasiveness and proliferation ability.To address the clinical need for rapid and non-invasive detection, we developed an innovative optical fiber biosensor based on surface plasmon resonance (SPR) technology for the quantitative detection of urinary PRDX1. The biosensor exhibited excellent analytical performance, including high sensitivity (limit of detection: 0.06 ng/mL), a wide linear range (0-25 ng/mL), rapid response (∼14 s), as well as good stability and selectivity. In clinical validation involving 97 BC patients and 30 healthy controls, the biosensor demonstrated outstanding diagnostic performance, with an area under the receiver operating characteristic curve (AUC) of 0.91 and an overall diagnostic accuracy of 86.6%, outperforming conventional enzyme-linked immunosorbent assay (ELISA). Collectively, this study not only identifies PRDX1 as a promising biomarker for non-invasive diagnosis and prognostic evaluation of BC, but also establishes an efficient SPR-based optical fiber sensing platform, providing new insights into both clinical detection and the functional role of PRDX1 in BC progression.

Humans↗

PubMed2026

Diurnal differences in the effects of heat exposure on renal function: A randomized controlled crossover trial.

High temperature is a major risk factor for kidney injury, and population exposure to nighttime heat is increasing as the climate warms. However, whether renal responses to heat exposure differ between daytime and nighttime remains unclear. Forty-one healthy adults participated in a randomized crossover experiment conducted in a controlled laboratory setting. Participants were exposed to heat (32°C during daytime; 30°C during nighttime) and thermoneutral conditions (26°C) for 8 h. Blood and urine samples were collected before and after each exposure to examine various renal biomarkers reflecting glomerular filtration function, tubular injury, and early kidney stress. Heat exposure affected both blood and urinary biomarkers of kidney function, with notable diurnal differences in renal responses. Daytime heat exposure primarily affected blood markers of glomerular filtration, increasing creatinine by 7.67% (95% CI: 4.73%-10.61%) and cystatin C by 3.05% (95% CI: 0.17%-5.93%), while reducing estimated glomerular filtration rate by 0.05% (95% CI: 0.02%-0.08%). In contrast, nighttime heat exposure predominantly elevated urinary biomarkers of early kidney stress, including insulin-like growth factor-binding protein 7 (58.40%, 95% CI: 27.66%-89.14%), kidney injury molecule-1 (47.25%, 95% CI: 18.91%-75.59%), and tissue inhibitor of metalloproteinases-2 (51.88%, 95% CI: 22.26%-81.51%). Moreover, increases in insulin-like growth factor-binding protein 7 were significantly greater at night than during the day. Sleep-related parameters, including sleep quality, duration, and heart rate variability, partially mediated nighttime heat effects on renal responses. These results indicated that heat exposure induced different diurnal patterns in renal responses.

Humans↗

PubMed2026

Systemic Platelet Activation and Respiratory Exacerbations, Pulmonary Symptoms, and Mortality among Current and Former Smokers in SPIROMICS.

RATIONALE: Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE: Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS: We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS: Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS: Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION: NCT01969344.

aspirin↗

PubMed2025

T cell subsets of urine-derived lymphocytes (UDLs) serve as an indicator of TILs and reflect immunological sex differences in bladder cancer.

BACKGROUND: Bladder cancer is unique among visceral malignancies in that urine, which can be easily obtained, has prolonged contact with bladder tumors. Urinary biomarkers offer the potential to provide insight into the host and tumor immune microenvironment to guide therapeutic strategies. We evaluated the immune cellular composition of urine (urine-derived lymphocytes (UDLs)) versus tumor (tumor-infiltrating lymphocytes (TILs)). METHODS: We employed high-dimensional flow cytometry analyses on immune cells from tumors (TILs), urine (UDLs), and peripheral blood (peripheral blood mononuclear cells) among patients with bladder cancer. We performed multiplexed immunofluorescence (mIF) of matched tumors to provide spatial context to our findings, comparing deep/invasive and superficial/urine-facing regions of matched tumors. RESULTS: Our findings suggest that the CD4+ and CD8+ T cell subsets of UDLs characterized by flow cytometry had similar phenotypic profiles to those found in TILs (cell clusters quantified by multidimensional scaling and differentiation states). Results of mIF imaging with a panel of phenotypic and functional T cell markers suggested that UDLs reflected TILs in both superficial and deep tumor sections. We also found sex-dependent patterns in TILs and UDLs, indicating the male bladder cancer tumor microenvironment is enriched in exhausted CD4+ and CD8+ T cells, while the female bladder cancer microenvironment is enriched for activated T cells. CONCLUSIONS: Assessment of UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response. UDLs may also reflect sex-based differences in antitumor immunity.

Humans↗

PubMed2025

Preliminary screening of urinary host protein biomarkers for Schistosomiasis haematobium: A proteome profiling study identifying candidate diagnostic targets in school-aged children.

Schistosomiasis is a major public health challenge and a globally neglected tropical disease. Schistosoma haematobium, the causative agent of urogenital schistosomiasis, is endemic in African countries; with school-aged children ages 7-15 years being the most vulnerable population. Current diagnostic methods rely on microscopy to identify parasite eggs in urine; which is labor-intensive, requires specialized skills, and often lacks sensitivity, especially in mild infections. To address these limitations, we explored host disease-related biomarkers as a promising avenue for advancing diagnosis and detection. We recruited 135 children ages 7-15 years from Zanzibar, a known transmission hotspot, and used data-independent acquisition (DIA) proteomics combined with machine learning to identify potential host protein biomarkers in urine samples from individuals infected with Schistosoma haematobium. Proteomic analysis identified 823 common host proteins in urine samples from the infected group. Machine learning algorithms highlighted candidate discriminative proteins; which were validated using enzyme-linked immunosorbent assays (ELISA). Machine learning emphasized SYNPO2, CD276, α2M, LCAT, and hnRNPM as the most discriminating biomarkers for Schistosoma haematobium infection. ELISA validation confirmed the differential expression trends of these proteins, while machine learning further validated LCAT and α2M, underscoring their diagnostic potential. Our study focused on host-derived proteins and identified key urinary protein biomarkers associated with Schistosoma haematobium infection, and offers new insights into host-parasite interactions and potential tools for non-invasive diagnostics. While validated in African pediatric populations from transmission hotspots, this host-protein approach inherently overcomes geographic limitations of parasite-based diagnostics; which is a critical advantage for surveillance in non-endemic regions where imported cases threaten gains toward elimination. These findings lay the groundwork for developing novel diagnostic approaches that could significantly improve the detection and surveillance of schistosomiasis, particularly in high-risk populations.

Humans↗

PubMed2026

Urinary clusterin as a biomarker of human kidney disease progression and response to the endothelin receptor antagonist atrasentan: An exploratory analysis from the SONAR trial.

The endothelin receptor antagonist atrasentan improved kidney outcomes in the SONAR trial for type 2 diabetes and chronic kidney disease (NCT01858532), though individual responses varied. To identify molecular biomarkers of atrasentan response and outcome, we conducted a nested case-control proteomics study (N = 180) within the SONAR trial population and identified urinary clusterin (uCLU) as the top candidate. Transcriptomic analyses of human kidney biopsies at tissue and single cell level from independent cohorts revealed higher CLU mRNA levels associated with worse kidney function and outcomes. An endothelin signaling activation score derived from pathway genes was reduced by atrasentan in mice with diabetic kidney disease. In the SONAR trial (N = 3,060) population, higher uCLU predicted worse outcomes, while atrasentan reduced uCLU by 42.6% over six weeks. Early uCLU changes independently predict improved kidney outcomes. In summary, uCLU is associated with kidney disease progression and response to atrasentan treatment, supporting its potential as a pharmacodynamic biomarker to target therapy.

Humans↗

PubMed2026

Urinary multi-omics reveal non-invasive diagnostic biomarkers in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy. Yet, no rapid, non-invasive biomarkers are available for diagnosis or screening. Urine represents an ideal analyte matrix due to its accessibility, low invasiveness, longitudinal sampling, and the kidney's central role in filtration. Here, we integrated proteomic, lipidomic, and metabolomic analyses of urine from ccRCC patients and controls to identify diagnostic biomarkers. Multi-omics profiling revealed urogenital metabolic dysregulation in ccRCC, including increased lipid metabolism, altered mitochondrial respiration signatures, and elevated urinary lipid content. We identified three urinary protein biomarkers: serum amyloid A1 (SAA1), haptoglobin (HP), and lipocalin 15 (LCN15). Using a parallel reaction monitoring mass spectrometry workflow, we developed a rapid and sensitive assay and combined these markers into a diagnostic UrineScore. The UrineScore achieved 0.96 in an area under the receiver operating characteristic curve analysis in the discovery cohort, and 0.95 in an independent validation cohort. Together, these results support the feasibility of multi-omics-guided urinary biomarker discovery and represent a step toward accessible diagnostic platforms for ccRCC.

Humans↗

PubMed2026

Benchmarking urinary cell transcriptomes for noninvasive differentiation of BK polyomavirus-associated nephropathy from T cell-mediated rejection.

BK polyomavirus-associated nephropathy (BKVN) adversely impacts kidney allograft survival and often mimics acute T cell-mediated rejection (TCMR), confounding diagnosis and management. To address this conundrum, we performed unbiased RNA sequencing of urinary cells matched to biopsies classified as BKVN with intragraft inflammation (BKVN-P), BKVN without inflammation (BKVN-N), TCMR, or no rejection (NR). BKVN-N displayed dominant host DNA replication, cell cycle, and repair programs, while BKVN-P samples exhibited expansive innate immune activation, antigen presentation, chemokine upregulation, and epithelial injury. Both BKVN subtypes shared signatures of T cell exhaustion and mature and tolerogenic dendritic cell activation but differed in immune orientation - Th1 predominance in BKVN-N versus Treg and CD8 enrichment in BKVN-P. Compared with TCMR samples, BKVN-P lacked robust TCR/CD28 signaling and was enriched for viral and innate modules; BKVN-N lacked alloimmune activation. B cell exhaustion characterized BKVN-N, while BKVN-P displayed robust B cell activation with metabolic downregulation. A ratiometric urinary cell biomarker, CXCL10 mRNA/CD3E mRNA, distinguished both BKVN subtypes from TCMR with diagnostic accuracy, replicated by quantitative reverse transcription PCR for clinical translation, and confirmed in an independent cohort. These findings demonstrate the utility of urinary cell transcriptomics for resolving viral injury from alloimmunity, enabling precision diagnostics and targeted immunomodulation in kidney transplantation.

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PubMed2026

Application of PathoChip to urine-derived nucleic acids for broad microbial profiling in men with suspected prostate cancer: setup of a methodological workflow and pilot feasibility study.

BACKGROUND: Urine-based liquid biopsy is an attractive non-invasive source of prostate cancer (PCa) biomarkers, but urinary microbiome studies have mainly relied on 16S rRNA sequencing or shotgun metagenomics. This pilot study optimized and evaluated a practical workflow using PathoChip - a broad-spectrum microarray designed to detect bacterial, viral, fungal, and parasitic signatures - for microbial profiling of urine sediments from men with suspected PCa, an application not previously established. METHODS: First-morning urine was collected without prostatic massage from 35 men scheduled for biopsy; 19 were diagnosed with PCa and 16 were biopsy-negative. Different urine volumes and extraction strategies were evaluated to optimize DNA/RNA recovery. A setup phase compared 25 ng versus 50 ng of urine DNA and RNA input. DNA/RNA isolated from human B cells was used as reference control. An analysis pipeline was developed to detect outlier probes and create a presence/absence matrix. Reproducibility was assessed via library yield, Pearson correlation, blank-control subtraction, outlier probe detection. Prevalence comparisons were performed between clinical groups. RESULTS: An 8 mL starting volume was chosen as consistently available from self-collected urine. Sequential DNA/RNA extraction using the AllPrep DNA/RNA Micro Kit from sediment provided the best balance between nucleic-acid recovery, purity, and clinical compatibility. Reducing the input from 50 ng to 25 ng preserved highly concordant hybridization profiles, with matched samples clustering together with strong correlations. Exploratory analysis revealed PCa- and grade-associated patterns involving Actinomycetaceae, Aerococcaceae, and Streptococcaceae, with Streptococcaceae enriched in PCa of higher grades (ISUP GG ≥ 2). Other signatures, including Mobiluncus, Prevotella, Rhodotorula, Hymenolepis, and JC polyomavirus, were broadly detected but not PCa-discriminating. CONCLUSIONS: PathoChip can be adapted to urine sediments, generating reproducible microbial profiles from limited DNA/RNA input without prostatic massage. This platform provides a quick and accessible approach to broad screening, extending beyond 16S rRNA sequencing by enabling simultaneous multi-kingdom detection. The observed PCa- and grade-associated patterns are hypothesis-generating and require validation in larger independent cohorts.

Pathochip↗

PubMed2026

Urinary Small Extracellular Vesicle DNA as a Biomarker for the Non-Invasive Diagnosis of Bladder Cancer.

Existing diagnostic technologies for bladder cancer (BC) suffer from low sensitivity, low specificity, or a lack of validation. Therefore, validated, non-invasive diagnostic biomarkers with high sensitivity and specificity for early detection of BC are needed to complement and improve upon the limitations of existing diagnostic methods. We used low-pass whole genome sequencing (LP-WGS) technology to detect copy number variations (CNVs) in small extracellular vesicle (sEV) DNA isolated from urine samples of patients. Based on these results, we constructed and validated a diagnostic model to differentiate between benign and malignant bladder lesions. We conducted a receiver operating characteristic analysis and calculated the area under the curve (AUC) to evaluate the performance of the diagnostic model. The urine sEV-DNA LP-WGS data revealed CNV differences between benign and malignant samples. The diagnostic model achieved an AUC of 0.953, a sensitivity of 86.7%, and a specificity of 100% in the training cohort and an AUC of 0.985, a sensitivity of 90%, and a specificity of 100% in the validation cohort. Even at the lowest coverage depth of 0.01X, the performance of the diagnostic model remained relatively robust. Notably, the performance of this diagnostic model surpassed that of the biomarker neuron-specific enolase (sensitivity: 85.7% vs. 64.3%; specificity: 100% vs. 87.5%) and urinary cytology (sensitivity: 100% vs. 66.7%; specificity: 100% vs. 94.1%). Our study demonstrates that urine sEV-DNA exhibits high discriminatory power in distinguishing between benign and malignant bladder lesions, making it a promising tool for auxiliary diagnosis of BC.

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PubMed2026

Label-Free Urinary Proteomics Uncovers Immune-Related Non-Invasive Biomarkers for Primary Biliary Cholangitis.

Diagnosis of primary biliary cholangitis (PBC) currently depends on invasive liver biopsy or serum markers with inadequate diagnostic performance. This study aimed to identify non-invasive urinary protein biomarkers for PBC detection. Urine specimens from biopsy-verified PBC patients and healthy controls were processed through ultracentrifugation-based protein extraction, enzymatic digestion, and HPLC-ESI-IT/MS proteomic profiling; protein quantification was completed using Spectronaut v14.8. We identified 194 differentially expressed urinary proteins (109 upregulated, 85 downregulated) and screened 10 immune-related candidates through GO and KEGG enrichment. Pearson correlation further filtered three core proteins, osteopontin (SPP1/OPN), RAMP3 and S100A8, that correlated significantly with key PBC biochemical indices (ALP, GGT, AST, ALT, IgM, p < 0.05). Elevated urinary concentrations of OPN, RAMP3 and S100A8 were validated by ELISA in an independent cohort containing 30 PBC patients and 20 healthy volunteers. In summary, urinary OPN, RAMP3 and S100A8 are markedly increased in PBC patients and hold promise as non-invasive diagnostic biomarkers for PBC; however, their diagnostic specificity against other cholestatic and autoimmune liver diseases remains to be evaluated, and further confirmation in larger multicenter cohorts with disease control groups is warranted.

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PubMed2025

Identification of Biomarkers for Right Ventricular Dysfunction in Idiopathic Dilated Cardiomyopathy Via Urinary Proteomics and Machine Learning.

BACKGROUND: Right ventricular dysfunction (RVD) is a common complication of idiopathic dilated cardiomyopathy linked to poor outcomes. However, reliable noninvasive biomarkers for RVD remain lacking. This study aimed to identify urinary proteomic markers using mass spectrometry and machine learning. METHODS: In this prospective cohort, patients with idiopathic dilated cardiomyopathy were classified by cardiac magnetic resonance imaging into groups with RVD (RV ejection fraction <45%) and without RVD groups. Baseline urine samples were profiled by data-independent acquisition mass spectrometry. Differentially expressed proteins were identified and selected by least absolute shrinkage and selection operator regression to build a diagnostic model, developed in a training set, and validated in a test set. The primary end point was a composite of cardiovascular death, heart failure rehospitalization, left ventricular assist device implantation, or heart transplantation. RESULTS: The study enrolled 147 patients with idiopathic dilated cardiomyopathy (64 with RVD, 83 without), with a median follow-up of 19.3 months. Of 3579 quantified urinary proteins, 46 were differentially expressed between groups. A 3-protein panel (RARRES1 [retinoic acid receptor responder protein 1], MVB12B [multivesicular body subunit 12B], GSK3A [glycogen synthase kinase 3 alpha]) was identified and showed excellent diagnostic accuracy (training area under the curve 0.946; validation area under the curve0.935), outperforming both NT-proBNP (N-terminal pro-brain natriuretic peptide) and tricuspid annular plane systolic excursion. The risk score derived from this panel effectively stratified patients, with the high-risk group exhibiting significantly worse outcomes than the low-risk group (hazard ratio, 3.24 [95% CI, 1.56-6.71], P=0.002). CONCLUSIONS: The urinary proteomic panel developed in this study demonstrates diagnostic and prognostic potential for identifying RVD in idiopathic dilated cardiomyopathy, providing a promising noninvasive tool for precise detection and clinical risk stratification.

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PubMed2026

A stratified urine-based molecular diagnostic and prognostic model for non-muscle-invasive bladder cancer management.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high recurrence rate requiring lifelong cystoscopic surveillance. Existing urine-based molecular assays mainly rely on mutations or methylation, which fail to capture large-scale genomic instability. Copy number variation (CNV) profiling offers complementary information on tumor evolution and aggressiveness, but its application in urinary diagnosis remains limited. We aimed to integrate CNV and DNA methylation signals from urinary DNA to establish a noninvasive and biologically informed stratified diagnostic model for NMIBC recurrence surveillance and risk stratification. METHODS: Urine samples were prospectively collected from 91 patients (75 evaluable) between June 2021 and August 2023. Shallow whole-genome sequencing (sWGS) was used to detect CNVs at chromosomal arm and focal gene levels, while ONECUT2 promoter methylation was quantified by qPCR. Diagnostic and prognostic performance was evaluated by ROC analysis, Kaplan-Meier survival, and stratified recurrence assessment. RESULTS: We evaluated a stratified diagnostic model combining CNV and ONECUT2 methylation testing in a cohort of 79 patients. CNV analysis alone showed high specificity (0.923) for NMIBC diagnosis. A combined model, using CNV as an initial screen followed by ONECUT2 methylation testing in CNV-positive cases, achieved a sensitivity of 0.783, specificity of 0.981, and a negative predictive value (NPV) of 0.911. This approach reduced the number of required ONECUT2 tests by 35% and identified a high proportion of true-negative patients (98.1%), which may help reduce unnecessary cystoscopy procedures. The model also demonstrated significant prognostic value, with the molecularly defined high-risk group showing significantly shorter recurrence-free survival (RFS) than the low-risk group (median RFS: 4.33 months vs. not reached; p < 0.001). Additional, in patients with initially negative cystoscopy after urine sample collection, the model demonstrated a predictive accuracy of 0.922 for recurrence, with molecular positivity observed a median of 9.6 months prior to clinical diagnosis. CONCLUSIONS: Integrating CNV and DNA methylation profiling from urinary DNA provides a powerful and noninvasive molecular framework for NMIBC surveillance. By combining early epigenetic changes with genomic instability signals, this approach enhances recurrence risk assessment and enables earlier detection compared with conventional cystoscopy. It offers a practical route toward personalized and adaptive post-treatment monitoring of NMIBC. TRIAL REGISTRATION: NCT04994197.

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PubMed2026

Generation of a novel Slc7a9G105R mutant mouse identifies new biomarkers for cystinuria.

INTRODUCTION: Cystinuria is a rare inherited disease characterized by increased urinary cystine levels resulting in the formation of cystine stones in the urinary tract. Mutations in the genes encoding the cystine transporter complex, SLC3A1 and SLC7A9, are the primary drivers of the disease. Current mouse models used to study cystinuria rely on gene deficiency or spontaneous mutations in mice that do not accurately reflect the pathogenic mutations found in humans. METHODS: We generated a novel Slc7a9G105R knock-in mouse model in which glycine at position 105 is replaced by arginine, recapitulating the most common pathogenic mutation in human SLC7A9. Disease onset and progression were assessed using micro-CT imaging, fecal metagenomics, and urine and serum metabolomics and proteomics. RESULTS: Both male and female Slc7a9G105R mice developed a cystinuria phenotype by nine weeks of age, characterized by substantial cystine stone formation and increased urinary cystine, lysine, arginine, and ornithine. Slc7a9G105R mice displayed distinct serum and urinary metabolite profiles, mapped to dibasic amino acid pathways, and serum protein profiles, mapped to disease progression. Fecal metagenomics revealed that Slc7a9G105R mice had a heterogeneous microbiota with altered functional pathways, including increased L-cysteine biosynthesis. Antibiotic-induced depletion of the microbiota did not affect cystine stone burden but reduced urinary tract inflammation. Prophylactic or therapeutic dietary supplementation with alpha-lipoic acid reduced stone burden and inflammation, but it also caused urothelial damage. Untargeted metabolomics analysis following alpha-lipoic acid supplementation identified metabolites that can increase cystine solubility, reduce inflammation, and damage epithelial cells. Correlation analysis revealed novel serum metabolite biomarkers of stone burden, including 2-hydroxybutyric acid and 2-amino-2-thiazoline-4-carboxylic acid, which were also detected in human serum. CONCLUSIONS: Collectively, the Slc7a9G105R mutant mouse model offers a precise, rapid-onset, and translational platform for investigating cystinuria pathogenesis and evaluating potential therapeutic strategies.

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PubMed2026

Clinical Validation of a Multiplex Urine Biomarker Assay for Surveillance of Recurrent Bladder Cancer.

PURPOSE: More than 50% of patients with non-muscle-invasive bladder cancer experience recurrence, requiring lifelong surveillance with repeated cystoscopy. Given the invasive nature and cost of cystoscopy, accurate noninvasive tools are needed to support risk-adapted monitoring. We evaluated the ability of Oncuria-Monitor, a multiplex urine biomarker assay, to detect recurrent bladder cancer during surveillance. PATIENTS AND METHODS: Between February 2017 and August 2020, six medical centers in the United States and Japan prospectively enrolled 300 patients with a history of bladder cancer, generating 1,248 serial urine samples. Participants were divided into training and validation cohorts. At each surveillance visit over 2 years, urine samples were analyzed in a blinded manner using Oncuria-Monitor and BladderChek, alongside urine cytology. Test performance was compared with cystoscopy and histopathology-confirmed recurrence. RESULTS: Recurrent bladder cancer was identified in 31% (93/300) of participants, with 143 total recurrences during follow-up, including 90 tumors in the validation cohort. In the validation cohort, Oncuria-Monitor achieved a sensitivity of 85.6% [95% confidence interval (CI), 78.1%-92.2%] and a negative predictive value (NPV) of 93% (95% CI, 89.2%-96.4%). In comparison, BladderChek demonstrated a sensitivity of 20.0% and an NPV of 88%, whereas urine cytology showed a sensitivity of 36.9% and an NPV of 91.6%. The number needed to evaluate to detect one recurrence was 3 for both cystoscopy and Oncuria-Monitor, compared with 15 for BladderChek and 8 for cytology. CONCLUSIONS: In this large prospective longitudinal study, Oncuria-Monitor demonstrated clinically actionable performance, enabling a rule-out strategy that could safely reduce cystoscopy in approximately 25% of surveillance visits. These findings support a paradigm shift toward biomarker-guided, risk-adapted surveillance in bladder cancer that reduces unnecessary invasive procedures while maintaining oncologic safety.

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PubMed2025

Absolute Quantification of Cellular and Cell-Free Mitochondrial DNA Copy Number from Human Blood and Urinary Samples Using Real Time Quantitative PCR.

Mitochondrial DNA copy number (mtDNA-CN) in human body fluids is widely used as a biomarker of mitochondrial dysfunction in common metabolic diseases. Here we describe protocols to measure cellular and/or cell free (cf)-mtDNA-CN in human peripheral blood and urine. Cellular mtDNA is located inside the mitochondria where it encodes key subunits of the respiratory complexes in mitochondria and is usually normalized with reference to the nuclear genome as the mitochondrial genome to nuclear genome ratio (Mt/N) in either whole blood, peripheral blood mononuclear cells (PBMCs), or whole urine. Cf -mtDNA is usually found outside of the mitochondria, often released following mitochondrial damage, can trigger inflammatory pathways, and is usually measured as mtDNA-CN per volume of the starting material. Here we describe how to (1) separate whole blood into PBMCs, plasma, and serum fractions and whole urine into urinary supernatant and pellet, (2) prepare DNA from each of these fractions, (3) prepare reference standards for absolute quantification, (4) carry out qPCR for either relative or absolute quantification from test samples, (5) analyze qPCR data, and (6) calculate the sample size to adequately power studies. The protocol presented here is suitable for high throughput use and can be modified to quantify mtDNA from other body fluids, human cells, and tissues.

Humans↗

PubMed2025

Exploring the Genetic Landscape of Primary Marginal Zone Lymphoma of the Urinary Bladder.

Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 women and 6 men) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed the literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a and negative for CD5 (except 1), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ and 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of 1 patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B, and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a point mutation-driven disease rather than gene fusion-driven disease and that E coli is present in approximately one-third of tumor biopsies. These tumors frequently harbor pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which was unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma; however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.

Humans↗