Clinical Journal of the American Society of Nephrology

Introduction: Kidney volume is associated with renal function, but conventional whole-organ measurements may miss regional changes in kidney substructures. We used magnetic resonance imaging (MRI) to test whether kidney substructure volumes and three-dimensional (3D) thickness phenotypes are associated with disease, adiposity, and incident outcomes. Methods: Automated abdominal MRI segmentations from 70,270 UK Biobank participants were used to quantify left and right kidney cortex, medulla, and parenchyma volumes and mesh-based thickness maps. Mass univariate regression generated statistical parametric maps linking regional thickness to anthropometric traits and disease (CKD, type-2 diabetes [T2D], hypertension). Bidirectional causal mediation analyses were performed using kidney substructure volumetric, thickness PCs and kidney adiposity. Longitudinal changes were assessed in 2,610 participants with repeat imaging. Cox proportional hazards models tested the associations between kidney volumes and principal component (PC) scores of thickness and incident CKD, T2D, hypertension, cardiovascular disease (CVD), and mortality. Results: CKD was associated with thinning of the parenchyma and most pronounced in the medulla (87.7% left, 72.8% right), whereas associations in the cortex were mixed. In contrast, T2D and hypertension were predominantly associated with increased thickness, most extensively in the cortex (T2D: 84.39% left, 96.35% right; hypertension: 94.8% left, 99.9% right). Age-disease interactions were associated with reduced thickness across all conditions. Smaller medulla volume and lower cortical thickness mediated the association between CKD and renal sinus fat. Kidney substructure volume was inversely associated with incident CKD across all substructures and both kidney sides (p<0.05), but positively associated with incident hypertension and mortality (p<0.05). Thickness PC scores also predicted outcomes independently of volume, with PC3 in the left cortex (HR 0.91 [0.84-0.98]), reflecting inferior pole/hilar thickness, associated with incident CKD. Conclusions: MRI-derived kidney substructure volumes and 3D thickness maps provide complementary, spatially-resolved markers of kidney morphology, that are mechanistically linked to renal adiposity and future disease risk.

Abstract Background. Enteric hyperoxaluria (EH) causes calcium oxalate kidney stones, oxalate nephropathy, and chronic kidney disease (CKD), and can progress to end-stage kidney disease. It occurs in Crohn's disease (CD), cystic fibrosis (CF), chronic pancreatitis, celiac disease, short bowel syndrome, and after bariatric surgery. Its prevalence in these populations has not been synthesized. Methods. PROSPERO CRD420261364424. PubMed and Embase were searched to 24 August 2026 for studies reporting 24-hour urinary oxalate. Prevalence was pooled using the Freeman-Tukey double arcsine transformation with a DerSimonian-Laird random-effects model; unweighted crude prevalence is also reported. Because heterogeneity was high, the narrative synthesis stratified by testing condition is the primary result. Prespecified subgroups addressed oxalate load before collection, diagnostic threshold, ileal resection, age, and urine collection format. Results. Forty-seven studies were included. In CD (17 studies, 471 patients; 204 with EH), crude prevalence was 43.3% and pooled prevalence 49.3% (95% CI 38.9-59.8; I^2 = 95.3%). With an oxalate load, prevalence was 64.7% (pooled 74.0%, 55.9-88.6) versus 38.6% without (pooled 39.1%, 28.7-50.0). Among CD patients, EH was more frequent with ileal resection (48.8% vs 31.7%; OR 1.62, 0.91-2.89) and with steatorrhea (62.5% vs 29.3%; OR 9.88, 3.81-25.61). In CF (7 studies, 348 patients; 179 with EH), pooled prevalence was 49.8% (40.5-59.1; I^2 = 91.9%). After bariatric surgery (15 studies, 849 patients; 474 with EH), pooled prevalence was 54.7% (45.4-63.9; I^2 = 96.7%). Conclusions. Roughly half of these patients have EH, but the proportion depends heavily on whether an oxalate load precedes urine collection (39% unprovoked vs 65%-74% provoked); because most studies do not state this condition, published prevalence estimates are not directly comparable. Ileal resection and steatorrhea identify those who should be screened.

Certain glomerulopathies (GN) feature impaired protein homeostasis in the endoplasmic reticulum (ER) of podocytes. Protein misfolding causing ER stress activates the unfolded protein response (UPR), a protective signaling network. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and ERdj3/DNAJB11 are ER chaperones that may be secreted from cells during the UPR. In rats with membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), secretion of MANF or ERdj3 from podocytes into urine identified glomerular ER stress/UPR activation. We address the biomarker potential of MANF and ERdj3 in human MN and FSGS. Glomerular gene expression of MANF and ERdj3 was increased in human MN and FSGS. Urinary MANF and ERdj3 were increased in proteinuric MN and FSGS compared to MN and FSGS in remission (low proteinuria), as well as other GNs, polycystic kidney disease, hypertension and healthy controls. In individuals with proteinuric MN or FSGS, amounts of urinary MANF and ERdj3 correlated weakly with proteinuria; correlation of MANF with ERdj3 was moderate. Males represented ~60% of persons in each group. eGFR in proteinuric MN and FSGS was >40 ml/min/1.73 m2. In MN, there were no significant differences in urinary MANF and ERdj3 between anti-PLA2R positive and negative individuals. In conclusion, proteinuric MN and FSGS show increased glomerular expression of MANF and ERdj3. High urinary levels of these ER chaperones correlate only weakly with proteinuria. In these GNs, urinary ER chaperones are thus non-invasive biomarkers of glomerular/podocyte ER stress. Such biomarkers may eventually be useful in identifying patients for therapies targeting ER protein misfolding.

Background: Chronic kidney disease (CKD) imposes persistent metabolic stress, yet whether metabolic organization can be preserved under sustained renal stress remains unclear. Essential trace elements support redox defense, mitochondrial function, and intermediary metabolism, and their homeostasis is disturbed in CKD; however, single-element supplementation has yielded heterogeneous results. We examined whether a defined multi-element formulation preserves metabolic resilience in CKD. Methods: In a randomized, double-blind, placebo-controlled trial, 80 maintenance dialysis patients received standard care alone (n = 40) or plus a trace element cocktail (TEX, 20 mL/day; n = 40). Longitudinal trajectories were analyzed with linear mixed-effects models; endpoint plasma metabolomics and fecal metagenomics were profiled in subsets. A 5/6 nephrectomy mouse model was used to quantify plasma tryptophan-pathway branches and renal spatial metabolism by MALDI imaging mass spectrometry. Results: TEX was well tolerated, with no treatment-related safety signal, and was associated with modestly more favorable creatinine and eGFR trajectories. Supplementation constrained, rather than erased, CKD-associated metabolic displacement (median |Cohen's d|, 0.25 versus 2.09 for disease effects), selectively realigning circulating metabolism toward the healthy state. The host kynurenine branch responded most strongly, whereas microbial indole metabolism and gut community structure changed little. Renal metabolic remodeling was region-specific, with preservation of selected tubular and antioxidant features. Conclusions: Trace element supplementation preserved metabolic resilience in CKD, limiting metabolic displacement without complete restoration. Preservation of metabolic organization may represent a complementary dimension of therapeutic response in CKD. Trial registration: International Traditional Medicine Clinical Trial Registry, ITMCTR2026000263 (registered 3 February 2026).

Background: Genomic reassessment may reveal clinically relevant diagnoses in patients with young-onset kidney failure despite established clinical diagnostic labels. We evaluated this approach after excluding clinically apparent polycystic kidney disease (PKD). Methods: Among 1,139 patients receiving maintenance dialysis at participating Japanese facilities, 355 had initiated dialysis at age [&le;]50 years. After excluding 17 patients with clinically apparent PKD, 108 of 338 eligible patients underwent whole-genome sequencing through voluntary, nonrandom enrollment. Analysis included 465 nuclear candidate genes, mitochondrial DNA, and copy-number/structural variants. Clinically concordant diagnoses were adjudicated using integrated clinical and genetic evidence, with a separate pathogenic/likely pathogenic (P/LP)-supported subset. Results: Diagnoses were identified in 10/108 participants (9.3%; 95% confidence interval, 5.1-16.2), comprising seven renal and three systemic/metabolic diagnoses. Nine diagnoses were P/LP-supported (8.3%; 95% confidence interval, 4.4-15.1). The remaining diagnosis was phenotype-based clinical Dent disease associated with a CLCN5 variant of uncertain significance. Diagnoses occurred across diabetic kidney disease, nephrosclerosis, chronic glomerulonephritis, unknown-cause, and other clinical categories. In a post hoc analysis excluding three participants with low target coverage, the integrated and P/LP-supported proportions were 9/105 (8.6%) and 8/105 (7.6%). Six exploratory findings were excluded from both diagnostic numerators. Gitelman syndrome was included as a clinically manifest renal disorder, although its contribution to kidney failure remained uncertain. Conclusions: Integrated genomic assessment can uncover renal and systemic/metabolic diagnoses across conventional labels in young-onset kidney failure after exclusion of clinically apparent PKD. Nonrandom enrollment and variable sequencing coverage limit generalizability and interpretation of negative results.

Background: Noninvasive biomarkers capable of detecting kidney allograft injury and distinguishing rejection from infection remain an important clinical need. Torque teno virus (TTV) reflects host immune status, but its utility in urine has not been well established. We evaluated urinary TTV, total cell-free DNA (cfDNA), cfDNA fragmentation, and BK polyomavirus (BKV) as potential biomarkers of kidney transplant rejection and BK polyomavirus-associated nephropathy (BKPyVAN). Methods: Urine samples from 334 kidney transplant recipients were analyzed in association with kidney biopsies performed within 30 days of sample collection. TTV and cfDNA were measured by multiplex quantitative PCR (qPCR), with a subset analyzed by digital PCR (dPCR), and BKV was quantified by qPCR. Associations with biopsy results were evaluated using group comparisons and nominal logistic regression. Changes associated with outcomes of consecutive biopsies were assessed by matched pairs analysis. Results: Among 544 unique urine samples, the urinary TTV/cfDNA ratio was significantly lower in rejection than in non-rejection samples (P<0.0001). Logistic regression adjusted for demographic factors confirmed an inverse association between the qPCR-derived TTV/cfDNA metric and rejection (adjusted odds ratio per delta Cq, 0.91; 95% CI, 0.88-0.94; P<0.00001). Significant differences were observed for all types of rejection. Association was confirmed by dPCR: higher TTV was associated with lower rejection odds, whereas higher cfDNA was associated with greater rejection odds. A nominal logistic model incorporating dPCR measurements achieved an AUROC of 0.76 (95% CI, 0.69-0.82). Matched pairs analysis showed a significant decrease in TTV/cfDNA when rejection developed and an increase following recovery from rejection, with no significant changes when biopsy status remained unchanged. BKV levels were strongly associated with BKPyVAN. No correlation between TTV and BKV was observed. Nominal logistic regression integrating TTV, cfDNA, and BKV measurements yielded AUROCs of 0.75, 0.97, and 0.73 for rejection, BKPyVAN, and non-rejection, respectively. Conclusions: A reduced urinary TTV/cfDNA ratio is associated with biopsy-defined kidney transplant rejection, and changes in the ratio correlate with transitions in biopsy results. Combined TTV, cfDNA, and BKV measurements showed differential associations with rejection and BKPyVAN, supporting further evaluation as complementary urinary biomarkers.

Background: Chronic kidney disease (CKD) may progress to stage 5 CKD (end-stage renal disease, ESRD), but stage-associated molecular alterations remain incompletely characterized. This study aimed to identify candidate biomarkers associated with CKD and ESRD. Methods: Two discovery datasets comparing CKD or ESRD with healthy controls were analyzed using differential expression analysis and weighted gene co-expression network analysis. Candidate genes were identified by intersecting differentially expressed genes with key co-expression modules, followed by protein-protein interaction network analysis using Degree, Closeness, and Maximal Clique Centrality algorithms. Candidate genes were evaluated in independent GEO validation datasets and further examined by quantitative real-time PCR and western blotting using clinical blood samples. Results: Ten hub genes were identified, among which EPB42, KLF1, and H3F3A were prioritized for further evaluation. EPB42 showed decreased expression in CKD but increased expression in ESRD, indicating an opposite-direction pattern between the two disease states. KLF1 showed no significant difference between healthy controls and CKD but was increased in ESRD, whereas H3F3A was increased in CKD and further increased in ESRD. Functional enrichment analysis highlighted processes related to oxygen transport, mitochondrial function, muscle-associated processes, and inflammation, suggesting possible involvement of hypoxia-associated oxidative injury and ferroptosis-related processes. Conclusions: Integrated transcriptomic and experimental analyses identified EPB42, KLF1, and H3F3A as candidate stage-associated biomarkers in CKD and ESRD. In particular, the opposite-direction expression pattern of EPB42 may provide additional molecular information for distinguishing CKD from ESRD.

Background Studies of the 2018 United Network for Organ Sharing (UNOS) policy revision suggest improved early transplantation access for the sickest patients. It remains unknown whether these benefits vary as a function of time on the waitlist. Thus, we evaluated potential time-dependent effects of the 2018 heart allocation policy revision on waitlist outcomes. Methods Using UNOS data, we analyzed adult heart transplant candidates listed five years before (pre-policy) and after (post-policy) policy change, categorized as high-acuity (Status 1-3 or 1A) or low-acuity (Status 4-6 or 1B/old 2). Landmark analysis at weeks 0, 1, 2, 4, 8, 16, 24 using a competing risks framework was performed to assess transplantation, death/deterioration, and myocardial recovery. Sub-distribution and cause-specific hazard ratios were calculated. Absolute number and proportion of far-away transplants (donor distance [&ge;]500 nautical miles) were calculated at each timepoint. Results High-acuity patients experienced significantly higher risk of transplantation within 2 weeks post-policy change but equivocal risk by week 16. Low-acuity patients exhibited increased rate/risk of myocardial recovery and equal or improved death/deterioration risk at all timepoints; early transplantation cumulative incidence was increased. At all timepoints, both groups experienced significantly increased far-away donor use, highest immediately after listing and progressively declining over time. Conclusions The 2018 heart allocation policy change resulted in an initial appearance of time-dependent benefits among high-acuity, post-policy patients, but this was likely due to rapid transplantation of Status 1 and 2 patients from broader geographic sharing rather than a true temporal phenomenon. Post-policy, low-acuity patients experience benefits in all waitlist outcomes.

Background. Fluid collections are common after kidney transplantation, but their prevalence at scheduled imaging and their management are inconsistent from canter to canter. We describe the cross sectional prevalence and management of perigraft collections, including an exploratory deepdrain subgroup. Methods. In this retrospective single center cohort, 146 consecutive adult kidney transplant recipients (Cleveland Clinic Weston Hospital, July 2024 to June 2025) were imaged on postoperative day 0/1 and at approximately 1 and 3 months. Routine deep drainage was avoided (n=124), 22 clinically selected recipients with perioperative anticoagulation received a deep drain. The primary outcome was cross sectional prevalence of a perigraft collection at each visit. Secondary outcomes were management among patients with a collection. Drain group comparisons were exploratory. Results. Collections were present in 29 of 146 recipients at postoperative day 0/1 (19.9%; 95% CI, 14.2 to 27.1), 71 of 146 at 1 month (48.6%; 95% CI, 40.7 to 56.7), and 34 of 146 at 3 months (23.3%; 95% CI, 17.2 to 30.8). Prevalence in the no drain group was 21.0%, 50.0%, and 23.4%, respectively; corresponding prevalence in the deep drain group was 13.6%, 40.9%, and 22.7%. Between group prevalence comparisons were not statistically significant at any time point. BMI was higher in the deep-drain group than in the no-drain group (30.04 vs 27.1 kg/m2; P=0.01). Among patients with a 1-month collection, management did not differ significantly between groups (any invasive management, 11.1% vs 16.1%; P=1.00). Among patients with a 3month collection, invasive management was more common in the deep drain group than in the no drain group (80.0% vs 13.8%; P=0.007). This comparison included only five deep-drain recipients and was confounded by clinical selection, perioperative anticoagulation, and BMI imbalance. Conclusions. Perigraft collection prevalence was highest at 1 month and lower at 3 months in this predominantly no drain cohort. Most collections were managed conservatively, and invasive treatment was uncommon in the no-drain group. The deep drain subgroup provides clinically relevant information about high risk recipients selected for drainage but cannot support causal conclusions regarding drain benefit or harm. Patient level linkage is required to distinguish persistence, resolution, and new collection formation.

Background Delayed graft function (DGF) is among the most used metrics in transplant medicine, yet its prevailing definition-dialysis requirement within the first seven postoperative days lacks granularity and fails to capture the dynamic nature of graft recovery. It reflects a treatment decision rather than graft biology, varies by centre practice, and offers no temporal information about the pace or pattern of recovery. This study proposes a trajectory-based framework using serial serum creatinine measurements across three biologically defined time windows to capture the dynamic nature of early renal recovery. Methods We retrospectively analysed 205 adult kidney transplant recipients at Cleveland Clinic Weston Hospital in 2025. Donor groups included living donors, donation after brain death (DBD), donation after circulatory death with normothermic regional perfusion (DCD-NRP), and DCD without NRP. Creatinine slopes were estimated for Days 1-7, 7-30, and 30-90 using ordinary least-squares regression. Logistic regression assessed the predictive performance of each trajectory window for DGF, adjusting for Kidney Donor Profile Index, cold ischemia time, BMI, and donor type. Results DCD non-NRP kidneys showed negligible early creatinine decline (slope +0.02) compared to DBD (-0.71) and DCD-NRP (-0.57) grafts during Days 1-7. During Days 7-30, DCD-NRP kidneys showed accelerated recovery and converged toward DBD-level trajectories, whereas DCD non-NRP grafts remained sluggish. Predictive modelling identified the Day 7-30 trajectory had the strongest discrimination for DGF, with AUC 0.83, pseudo-R2 0.25, and the lowest AIC (181.73), outperforming Days 1-7 (AUC 0.75) and 30-90 (AUC 0.79). DGF rates were 0% in living donors, 25.5% in DBD, 20.7% in DCD-NRP, and 58.9% in DCD non-NRP recipients. Conclusions A trajectory-based creatinine model provides more informative prognostic value than the conventional binary DGF definition The Day 7-30 window periods offers the highest discriminatory power, and normothermic regional perfusion appears to favourably shift DCD kidney recovery trajectories in a manner the binary definition fails to detect.

BackgroundLiving donor kidney transplantation improves outcomes for eligible patients with kidney failure, yet living donation remains limited. Public awareness about the possibility of living donation may not be sufficient to translate into willingness to donate. This study evaluated knowledge, attitudes, personal exposure, perceived barriers, motivators, and financial considerations associated with willingness to participate in living kidney donation among adults in San Antonio, Texas. MethodsA cross-sectional community-based survey was conducted among 346 adults. The survey assessed demographic characteristics, knowledge about kidney transplantation and living donation, personal exposure to dialysis, transplantation, and living kidney donation, misconceptions regarding donation, motivating and discouraging factors, financial considerations, and willingness to become a living donor. Associations with willingness were evaluated using multivariable logistic regression models. ResultsAlthough 83.8% of participants knew that a healthy person could donate one kidney while living, only 68 participants (19.8%) expressed general willingness to become a living donor. Only 40.0% identified kidney transplantation as the best treatment for eligible patients with kidney failure. Demographic and socioeconomic factors were not independently associated with willingness, and individual misconceptions were not independently associated with willingness. In the integrated model, knowing a living kidney donor was associated with greater willingness (OR 2.82, 95% CI 1.33-5.95), whereas knowing a transplant recipient was associated with lower willingness (OR 0.42, 95% CI 0.19- 0.96). Helping someone in need was associated with greater willingness (OR 2.48, 95% CI 1.39-4.44), while concern about long-term donor health complications was associated with lesser willingness to donate (OR 0.48, 95% CI 0.26-0.90). Nearly half of respondents who answered the compensation question selected a monetary amount that could motivate donation. ConclusionsIn this community-based sample, awareness that living donation is possible did not translate into broad willingness to donate. Willingness appeared to be shaped by personal exposure, altruistic motivation, donor safety concerns and financial considerations. Community education should move beyond basic awareness and address donor safety, financial protection, living donor experiences, and the benefits of kidney transplantation.

Abstract Background Health-related quality of life (HRQoL) is an important outcome in patients with chronic kidney disease (CKD) receiving kidney replacement therapy (KRT), but the relationship between comprehensive metabolic control and the Symptoms/Problems domain of kidney diseasespecific HRQoL remains uncertain. Objective To evaluate the association between composite metabolic control and the Symptoms/Problems domain of the Kidney Disease Quality of Life-36 (KDQOL-36) in patients with stage 5 CKD receiving KRT, and to explore the relationship between individual metabolic parameters and the continuous Symptoms/Problems score. Materials and Methods We conducted an observational, cross-sectional, analytical study of 177 adults receiving hemodialysis or peritoneal dialysis at a nephrology unit in Chihuahua, Mexico. Metabolic control included blood pressure, glycated hemoglobin (HbA1c), total cholesterol, and triglycerides. Adequate control was defined as achievement of at least three of four studydefined operational thresholds. The KDQOL-36 Symptoms/Problems score was analyze as a continuous variable and categorized as low, moderate, or high according to the study protocol. Group comparisons, Spearman correlations, Pearson chi-square tests, and ordinal logistic regression were performed. Results Adequate metabolic control was present in 106 patients (59.9%). No, statistically significant association was observed between achievement of at least three of four study-defined operational thresholds and Symptoms/Problems score category (x2=3.983; p=0.137; Cramers V=0.150). None of the individual metabolic parameters differed significantly across Symptoms/Problems score categories or showed significant correlations with the continuous score. In ordinal logistic regression, adequate metabolic control yielded an odds ratio of 1.81 (95% CI: 0.98-3.35; p=0.057) after adjustment for age, sex, time receiving KRT, and KRT modality. Conclusions No, statistically significant association was identified between the operational definition of metabolic control used in this study and the KDQOL-36 Symptoms/Problems domain in patients with stage 5 CKD receiving KRT. The findings support evaluating HRQoL multidimensionally and warrant confirmation in larger longitudinal studies. Categories: Family/General Practice, Internal Medicine, Nephrology Keywords: chronic kidney disease (ckd), hemodialysis, kdqol-36, kidney replacement therapy, metabolic control, peritoneal dialysis (pd)

Background Pediatric nephrotic syndrome (NS) significantly increases cardiovascular risk, primarily through activation of the renin-angiotensin-aldosterone system (RAAS) and chronic inflammation. This study aimed to evaluate the relationship between serum aldosterone and interleukin 6 (IL-6) levels with carotid intima-media thickness (CIMT) in children with steroid-sensitive (SSNS) and steroid-resistant NS (SRNS), both before and after combined treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Materials and methods A prospective cohort study enrolled 32 children aged 2-18 years with idiopathic NS at Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia (May-June 2024). Participants received lisinopril (ACEI) or valsartan (ARB) for 12 weeks. Serum aldosterone was quantified via liquid chromatography-tandem mass spectrometry, IL-6 via electrochemiluminescence immunoassay, and CIMT via high-resolution B-mode Doppler ultrasound. Data were analyzed using SPSS version 26.0, including Shapiro Wilk normality testing, Pearson/Spearman correlations, and multivariate linear regression (enter method, R2=0.022), with statistical significance set at p<0.05. Results CIMT decreased significantly post-treatment (0.13{+/-}0.04 cm to 0.06{+/-}0.01 cm; p<0.001). Serum aldosterone remained stable (5.15 to 4.0 ng/dL; p=0.933), as did IL-6 (3.5 pg/mL; p=0.156). Univariate analyses revealed weak correlations (aldosterone-CIMT: R2=0.075; IL-6-CIMT: R2=0.215). Multivariate regression (R2=0.022) identified SRNS as positively associated with CIMT change (p=0.047), while aldosterone and IL-6 showed no significant independent effects. Conclusion This study highlights that ACEI and ARB therapy improved CIMT regardless of steroid sensitivity, suggesting vascular benefits may occur through pathways independent of aldosterone and IL-6 modulation.

Background: The Lung Transplant Frailty Scale (LT-FS) is a validated binary measure of frailty in lung transplant candidates. We aimed to refine the LT-FS Base and Body Composition measures by developing a three-category classification to improve clinical risk stratification with serum albumin as a more clinically practical frailty biomarker. Methods: To develop the refined LT-FS, we applied a 4-step measure development method to a multicenter prospective cohort study of lung transplant candidates. Low albumin (<3.5 g/dL) replaced high serum C-reactive protein ([&ge;]10 mg/L) as the LT-FS biomarker. Cutpoints that balanced discrimination, risk prediction, and calibration were identified to define ''frail'', ''pre-frail'', and ''not frail'' categories. Next, we evaluated associations between the refined LT-FS and exercise capacity, patient-reported outcomes, and mortality using multivariate linear and Cox regression. Results: Among 419 participants, the refined LT-FS identified a graded increase in mortality risk across frailty categories. For example, compared with candidates who were not frail, pre-frailty and frailty by the LT-FS Body Composition were associated with a 2.9-fold (HR 2.9, 95% CI 1.2-6.9) and 7-fold (HR 6.9, 95% CI 2.6-18.2) higher risk of waitlist delisting or death, respectively. Pre-frailty and frailty by LT-FS Body Composition were associated with 2-fold (HR 2.1, 95% CI 1.2-3.8) and 3.6-fold (HR 3.6, 95% CI 1.8-7.3) higher risk of mortality after transplant. Relationships with exercise capacity and patient-reported disability were less consistent. Conclusions: A refined Lung Transplant Frailty Scale incorporating serum albumin demonstrates strong associations with waitlist and post-transplant mortality. The addition of a pre-frail category better captures the continuum of frailty and improves clinical risk stratification of lung transplant candidates.

Importance. Plasma phosphorylated tau 217 (p-tau217) is entering clinical use with fixed diagnostic threshold that do not account for kidney function. Chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2), raises plasma p-tau217 concentrations and can produce false positive results. It remains unclear whether milder reductions in kidney function, above the CKD threshold, have the same effect. Objective. To determine whether plasma p-tau217 is elevated with mildly reduced kidney function, above the chronic kidney disease threshold, in adults without neurological disease. Design. Cross-sectional analysis of a cohort enrolled between 2023 and 2025 and biomarker analysis blinded to clinical data. Setting. Two private psychiatric inpatient facilities in Australia. Participants. Adults admitted with psychiatric disorders and free of neurological disease. Exposures. eGFR calculated from serum creatinine using the CKD-EPI 2021 equation. Main Outcomes and Measures. Plasma p-tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured on the Simoa platform. Multivariable linear regression compared eGFR groups (< 60, 60 to 90, and [&ge;] 90 mL/min/1.73 m2), adjusted for age, BMI, and sex. Results. Among 180 participants (median age, 50.5 years [IQR, 38.0-61.5]; 94 [52%] female), eGFR was [&ge;] 90 mL/min/1.73 m2 in 106 (59%), 60 to 90 in 61 (34%), and < 60 in 13 (7.2%). Compared with an eGFR [&ge;] 90, plasma p-tau217 was 36% higher in both the 60 to < 90 group ({beta} = 0.42 [95% CI: 0.11, 0.74]; P = .008) and 116% higher in the < 60 group ({beta} = 1.05 [95% CI: 0.43, 1.72]; P = .002). Plasma NfL and GFAP were elevated in the < 60 group but differences in the 60 to < 90 group did not reach significance. Modelled continuously, plasma p-tau217 was 9.5% lower per 10 mL/min/1.73 m2 higher eGFR (95% CI: 3.3%, 15.4%). Conclusions and Relevance. Plasma p-tau217 was elevated in adults with mildly reduced kidney function, above the CKD threshold, in a cohort free of neurological disease. Kidney function across its full range should be incorporated into plasma p-tau217 reference ranges and clinical interpretation to reduce false positive and false negative results.

Kidney disease affects over 850 million people and leads to degradation of the kidney cortical compartments and kidney failure. Interstitial fibrosis and tubular atrophy (IFTA) is a universal feature of chronic kidney disease, yet the sequence of tubulointerstitial matrix protein (matrisome) changes that underlie the development and progression of IFTA are not fully understood. In particular, post-translational modifications which may stabilize key matrisome components and result in irreversible and functionally detrimental interstitial fibrosis or tubular basement membrane thickening, have yet to be characterized. Post-translational modifications (e.g., acetylation) have been shown to contribute to kidney diseases, yet they have not been investigated in chronic kidney disease progression. Herein, we established feasibility of matrisome protein quantification in the tubulointerstitium, with concurrent matrisome protein post-translational modification quantification, in archived diagnostic human kidney biopsies, using laser capture microdissection, liquid chromatography tandem mass spectrometry (LC-MS/MS), and bioinformatics analysis. In this pilot study, we focused on two conditions associated with IFTA progression: diabetic nephropathy and kidney transplantation. We examined both healthy and chronically damaged tubulointerstitium in two human kidney biopsies, one representing each condition. We identified signature protein markers of tubulointerstitium (e.g., UMOD, SLC12A1) in abundance, confirming sample composition, and observed uniformity in protein abundance across replicates from the same biopsies. We found increases in certain collagen isoforms (COL1A1, COL6A3) and other ancillary proteins in areas of IFTA. We also successfully quantified post-translational modifications, confirming that hydroxylproline was the most abundant modification in healthy tubulointerstitium from the kidney transplant biopsy, and that hydroxyllysine was also highly abundant and could be confidently quantitated on two collagen isoforms (COL1A1, COL4A2). Lastly, we performed power analysis to determine the required sample size to achieve significant power and false discovery rate. Several proteins exhibited large Hedge effect sizes in the tubulointerstitium (ANPEP, PRODH2), indicating their potential usefulness as fibrosis signatures. Our study is a first step toward comprehensive characterization of tubulointerstitial matrisome changes, including post-translational modifications seen with IFTA progression. Subsequent studies will potentially reveal new molecular markers of key early events in chronic kidney disease progression, and new therapeutic targets for mitigating this process. Data are available via ProteomeXchange identifier PXD079025.

Understanding the shared and disease-specific mechanisms that drive glomerular injury remains a major unmet need for developing more precise and effective treatments for glomerular diseases. Here, we integrate histology-guided spatial transcriptomics with trajectory inference and cell-state deconvolution to resolve glomerular injury across Membranous Nephropathy, Focal Segmental Glomerulosclerosis, and Lupus Nephritis. Herein, we show that glomerular diseases arising from distinct initiating mechanisms converge on common pathways during progressive loss of kidney function. We used spatial transcriptomics to analyze kidney biopsies from 59 individuals with glomerular diseases and controls and identified 792 glomeruli, including structurally injured glomeruli missed by transcriptomic clustering alone. Glomeruli shared interferon- and complement- associated inflammatory programs together with suppression of oxidative and lipid metabolic pathways, while retaining disease-preferential transcriptional features. Increased pseudotime correlated with lower estimated glomerular filtration rate, and cell- state deconvolution linked progression to podocyte loss and cellular remodeling. Parallel analysis of passive Heymann nephritis, a rat model of membranous nephropathy, recapitulated complement activation and localized complement activity to multiple renal cell populations extending into the periglomerular niche. These findings define a spatially resolved, cross-disease continuum of glomerular injury and identify coordinated local complement activation as a convergent feature of progressive glomerular damage.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSLung donor-recipient matching requires balancing recipient medical urgency with expected post-transplant benefit. Conventional prediction models estimate outcomes for historical donor-recipient pairs but do not directly compare alternative candidates for the same donor. We developed an offline contextual-bandit framework to assess the feasibility of learning donor-centered lung-matching policies from historical registry data. MethodsWe used linked United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) Standard Transplant Analysis and Research files to identify 8,529 lung transplant allocation events from 2023 through 2025. Each event included the historical recipient and nine date-matched, ABO-compatible pseudo-candidates. The reward combined 72-hour respiratory-support-free survival (weight, 0.75) with a normalized initial Composite Allocation Score waitlist medical-urgency score (weight, 0.25). We trained a pessimistic neural lower-confidence-bound contextual-bandit policy (NeuraLCB) and evaluated it on held-out donor events using matched-action evaluation and self-normalized inverse propensity scoring (SNIPS). ResultsThe reconstructed dataset contained 85,290 donor-candidate rows. In the held-out set of 1,706 allocation events, the observed clinician reward was 0.534 (95% CI, 0.518-0.549). NeuraLCB agreed with the historical recipient in 174 events (10.2%), with a matched-action reward of 0.616. The SNIPS-estimated value of the NeuraLCB policy was 0.649 (95% CI, 0.568-0.717), corresponding to a paired difference of +0.116 (95% CI, +0.035 to +0.181) relative to observed clinician reward. However, the effective sample size was 51.5 events, indicating limited overlap between the learned and estimated historical policies. ConclusionsThis study demonstrates the feasibility of constructing and evaluating an offline contextual-bandit framework for lung donor-recipient matching using registry data. The estimated policy value was higher than the observed historical reward, but this finding is exploratory because candidate sets were reconstructed and off-policy evaluation had limited overlap. Verified offer sets, time-stamped candidate data, explicit compatibility constraints, and prospective evaluation are required before clinical use.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular mortality and chronic kidney disease (CKD) progression in cardiovascular-kidney-metabolic (CKM) syndrome, but this benefit derives primarily from reductions in heart failure and cardiovascular mortality rather than in atherothrombotic events. Sotagliflozin, which inhibits both intestinal SGLT1 and renal SGLT2, is the only drug in this class shown to lower rates of myocardial infarction and stroke in CKD. However, its mechanism remains unclear, and its effectiveness in non-diabetic CKD has not been studied. We hypothesized that dual SGLT1/2 inhibition reprograms systemic substrate utilization toward fatty acid oxidation, which may partially account for this protective effect. Methods: CKD was induced in male low-density lipoprotein receptor-deficient mice by 5/6 nephrectomy. Sham and CKD mice received a high-fat diet and drinking water containing sotagliflozin, empagliflozin, or vehicle for 16 weeks, at doses that produced equivalent fractional excretion of glucose. We quantified atherosclerosis en face and in the aortic sinus. Indirect calorimetry, echocardiography, hepatic RNA sequencing, plasma acylcarnitine profiling, and in vivo deuterium labeling of palmitate were performed. Results: At matched levels of glucosuria and plasma total cholesterol, sotagliflozin decreased body mass, atherosclerosis burden, triglycerides, and TNF- more than empagliflozin, and raised postprandial total GLP-1 approximately 3-fold, while both drugs similarly improved albuminuria and diastolic function. Sotagliflozin increased energy expenditure independent of body mass and lowered respiratory exchange ratio despite compensatory hyperphagia. Sotagliflozin reduced hepatic lipogenic genes and de novo lipogenic flux, while increasing {beta}-oxidation and ketogenesis; empagliflozin only activated the oxidative pathway. Conclusions: In experimental CKM syndrome, dual SGLT1/2 inhibition reduces atherosclerosis and metabolic syndrome more effectively than selective SGLT2 inhibition and is associated with reprogramming of hepatic lipid metabolism. These results suggest that sotagliflozin could be an attractive candidate for mitigating atherosclerotic risk in non-diabetic CKD.

Background: Dietary sodium intake is a modifiable determinant of blood pressure, and impaired renal sodium handling is implicated in the pathogenesis of hypertension. Whether dietary sodium intake modulates renal tubular sodium transporter abundance among normotensive adults at risk for hypertension is unknown. Methods: Forty-six normotensive adults with normal kidney function at risk of developing hypertension were prospectively enrolled to complete a very low sodium (LS) diet followed by a high sodium (HS) diet. Urinary extracellular vesicle (uEV) proteins were quantified from a 24-hour urine collection at the end of each diet. We compared normalized uEV protein concentrations between diets and tested whether diet modified uEV protein associations with serum aldosterone, urinary aldosterone, and serum cortisol-cortisone ratio under either diet using Wilcoxon rank sums and linear mixed effects models, respectively. Results: Participants achieved median [IQR] urine sodium 13.2 [7.7-19.9] mEq/24h on the LS diet and 244.0 [197.1-297.0] mEq/24h on the HS diet. LS intake induced greater renin activity, greater plasma and urinary aldosterone, and lower urinary cortisol, when compared to HS intake. In parallel, NCC, ENaC, SGLT2, OXSR1, and Pendrin uEV concentrations were significantly higher during LS intake than HS intake (p<0.05 for all), whereas TRPV5 and AQP2 uEV concentrations were lower during LS intake than HS intake (p<0.001 for both). Conclusions: Controlled dietary sodium modulation induced nephron-segment specific changes in uEV protein abundance. These findings demonstrate the ability of uEVs to serve as a non-invasive tool to probe in vivo renal sodium, water, and electrolyte handling.