Kidney360

Background: Clinical LLM benchmarks rarely test whether algorithmic rankings agree with expert clinical judgment. We developed a trap-embedded peritoneal dialysis (PD) benchmark comparing multiple scoring constructs with blinded nephrologist ratings. Methods: We generated 125 synthetic PD cases containing 13 ISPD-aligned trap types. Five LLMs (Claude Sonnet 4.5, GPT-5.4, Gemini 3.1 Pro, DeepSeek-R1, Grok 4.1 Fast) evaluated each case three times at temperature 0 (1,875 calls). Primary outcome was must-identify TDR_must, analyzed with GEE and case-clustered bootstrap. Secondary analyses included a verbosity-sensitive alarm-burden proxy, WCS, relaxed-match scoring, WCS sensitivity analyses, and a 25-output blinded expert adequacy substudy. Must-identify kappa was 0.89 in Stage 1 and 0.92 in Stage 2. Results: Rankings were discordant. Recall ranked Claude (0.977) and GPT-5.4 (0.955) above the other models (0.86-0.90, p<0.0001). The alarm-burden proxy favored concise models (Grok 0.689; 21.6 vs 2.4 issues/case), while WCS produced a third ordering. In the expert substudy, inter-rater concordance was strong (rho 0.977), but WCS did not show a positive association with expert adequacy (rho -0.17, p=0.41). Conclusion: Clinical LLM rankings in PD prescription review depend strongly on scoring construct. Algorithmic metrics should be reported alongside blinded expert adequacy ratings and should not alone determine deployment.

Background: Lower urine pH has been associated with reduced kidney function and an increased risk of kidney disease; however, its prognostic and pathological significance in biopsy-proven kidney disease remains unclear. A recent study demonstrated that medullary cast formation is independently associated with adverse renal outcomes beyond established predictors such as interstitial fibrosis and tubular atrophy (IFTA), yet its clinical determinants are not fully elucidated. Urine pH reflects the intratubular acid-base microenvironment and may contribute to tubular obstruction through cast formation. In this study, we examined kidney outcomes in patients undergoing native kidney biopsy, and the associations of urine pH with medullary cast formation. Methods: Among 1167 adults who underwent native kidney biopsy between 2011 and 2024, 503 patients with evaluable medullary tissue were included in this retrospective observational cohort study. Urine pH was analyzed in relation to clinical and histological variables and kidney outcomes. The primary outcome was a 40% decline in estimated glomerular filtration rate (eGFR) or initiation of renal replacement therapy. Results: The mean baseline eGFR was 54.3 mL/min/1.73 m2, the mean urine pH was 6.15, and the median urinary protein excretion was 1.1 g/gCr. During a median follow-up of 2.11 years, 113 patients (22.5%) reached the kidney outcome. Kaplan-Meier analysis showed that lower urine pH was associated with a higher risk of kidney outcomes. In Cox proportional hazards models adjusted for proteinuria, baseline eGFR, and IFTA score, urine pH remained independently associated with kidney outcomes (hazard ratio, 0.69; 95% confidence interval, 0.51-0.91). Inclusion of urine pH improved prognostic discrimination beyond established risk factors (Harrell C-index, 0.642 to 0.654). Lower urine pH was also associated with greater medullary cast formation. Conclusion: In patients undergoing native kidney biopsy, lower urine pH was independently associated with adverse kidney outcomes and greater medullary cast formation.

BackgroundPolycystic kidney disease (PKD) is the leading genetic cause of renal failure, resulting in the accumulation of fluid filled cysts and gross enlargement of the kidney. Mutations in PKD1 or PKD2, which encode ciliary polycystin proteins, are the most common cause of PKD. These proteins function in a cilia-dependent cyst activation (CDCA) pathway-one that requires cilia for its pro-cystic function-yet the molecular driver(s) of this pathway are unknown. ARL13B is a regulatory GTPase enriched in cilia and links to renal cystogenesis. ARL13B possesses guanine nucleotide exchange factor (GEF) activity for ARL3, another ARL with links to cilia. MethodsWe used two distinct Arl13b mouse alleles to investigate whether ARL13B is a component of the CDCA pathway: Arl13bV358Aencodes for enzymatically normal ARL13B that is undetectable in cilia, and Arl13bR79Qencodes for cilia-localized ARL13B lacking a residue critical for its ARL3 GEF activity. We used these alleles in a Pkd1-deficient adult mouse model and investigated renal morphology (H&E and cystic index analysis), physiology (blood urea nitrogen measurements), renal fibrosis (picrosirius staining and -smooth muscle actin levels), renal injury (SOX9 immunofluorescent staining and quantification), and Wnt signaling ({beta}-catenin and cyclin D1 protein levels). ResultsWe found that loss of ciliary ARL13B or mutation of a single residue critical for its ARL3 GEF activity suppressed Pkd1-dependent cysts. We observed reductions in kidney size, cystic index, and blood urea nitrogen. We also observed suppression of renal fibrosis, renal injury, and {beta}-catenin and cyclin D1 protein levels. ConclusionsOur results identified a subcellular location and mechanism driving Pkd1-dependent renal cystogenesis. We demonstrated that expression of a critical residue for ARL13Bs GEF activity specifically in cilia is a key mechanism of the CDCA pathway driving renal cystogenesis. Key PointsO_LILoss of ciliary ARL13B suppressed renal cystogenesis in an adult mouse model of polycystic kidney disease (PKD) without ablating cilia C_LIO_LILoss of ciliary ARL13B or mutation of the residue critical for its GEF activity did not affect renal morphology or physiology in a PKD mouse model C_LIO_LIMutation of a residue critical for ARL13B activation of ARL3 suppressed cystic phenotypes in Pkd1-dependent cysts C_LI

BackgroundMicrovascular dysfunction is a key contributor to the development and progression of chronic kidney disease (CKD), yet direct and reproducible assessment of microvascular function in clinical CKD populations remains limited. Laser Doppler flowmetry (LDF) provides a noninvasive, dynamic assessment of skin microvascular blood flow and may serve as a surrogate measure of systemic microvascular health. However, the extent to which LDF-derived measures relate to kidney function, proteinuria, and kidney histopathology in CKD remains unclear. MethodsWe assessed cutaneous microvascular function in 150 participants with CKD (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m{superscript 2}) using a standardized forearm LDF protocol. Baseline perfusion was recorded at [~]30{degrees}C, followed by local heating to 44 {degrees}C to induce hyperemia. The percentage change in perfusion unit (PU) was calculated and used to define microvascular functional reserve. Associations between LDF-derived measures with eGFR and urine protein-to-creatinine ratio (uPCR) were assessed using multivariable linear regression adjusted for demographic and clinical covariates. Unsupervised k-means clustering was performed to identify microvascular phenotypes based on resting PU and microvascular function reserve. Associations of LDF measures with glomerulosclerosis (GS) and interstitial fibrosis and tubular atrophy (IFTA) were evaluated in a subset of participants (n = 20) who underwent clinically indicated kidney biopsies. ResultsAmong 150 CKD participants, the mean (SD) age was 64 (14) years, 46% were female, 38% had diabetes, and 83% had hypertension. The mean eGFR was 42 (21) mL/min/1.73 m{superscript 2} and median uPCR was 0.21 (interquartile range (IQR) 0.11 to 1.20) mg/mg. Higher baseline PU ({beta} = -12; 95% CI, -24 to -1) and reduced percentage change in PU ({beta} = 7; 95% CI, 2 to 13) was associated with lower eGFR, independent of covariates. Baseline PU or percentage change in PU were not associated with uPCR. Unsupervised clustering identified four distinct microvascular phenotypes characterized by graded differences in resting perfusion and microvascular function reserve. Among participants with biopsy data, higher baseline PU and lower percentage change in PU were associated with greater severity of GS and IFTA. ConclusionIn persons with CKD, elevated resting perfusion and impaired microvascular functional reserve were associated with lower eGFR. These findings suggest that LDF-derived measures capture clinically relevant alterations in systemic microvascular function and may serve as a noninvasive biomarker of kidney function and underlying histopathologic injury in CKD.

Background and hypothesis: Sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) slow chronic kidney disease progression, but evidence in non-diabetic kidney transplant recipients is limited. We evaluated associations between SGLT2-inhibitor use and major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality. Methods: In this retrospective cohort study using the TriNetX federated research network, adult non-diabetic kidney transplant recipients transplanted between January 2015 and January 2022 were identified. SGLT2-inhibitor users initiating therapy [&ge;]1000 days post-transplant were compared with non-users after 1:1 propensity score matching. The primary outcome was MAKE, defined as dialysis initiation or death. Secondary outcomes included all-cause mortality and MACE. Results: Propensity score matching yielded 867 pairs of SGLT2-inhibitor users and non-users. SGLT2-inhibitor use was associated with lower risks of MAKE (adjusted hazard ratio [aHR] 0.64, 95% CI 0.45-0.91) and all-cause mortality (aHR 0.55, 95% CI 0.36-0.85). No significant association was observed for MACE (aHR 0.86, 95% CI 0.64-1.17). No increased risk of urinary tract infections was observed among SGLT2-inhibitor users. Conclusion: SGLT2-inhibitor use was associated with lower risks of MAKE and all-cause mortality in non-diabetic kidney transplant recipients.

Background: Chronic kidney disease (CKD) affects approximately 850 million individuals worldwide and remains a leading cause of morbidity, premature mortality, and escalating healthcare costs. Despite the availability of clinical biomarkers, CKD progression to end stage renal disease (ESRD) is frequently identified late, limiting opportunities for preventive intervention. Conventional predictive models have relied predominantly on static cross sectional laboratory values, failing to capture the temporal dynamics of disease trajectory that longitudinal claims data can provide. Objective: This study proposes a novel hybrid machine learning framework: XGBoost LSTM Attention (XLA), that integrates gradient boosted feature selection with long short-term memory (LSTM) networks and a temporal attention mechanism to improve early prediction of CKD progression from Stage 3 to Stages 4/5 or ESRD using longitudinal claims based features. Methods: We conducted two complementary analyses. Primary analysis: a cross sectional validation using real NHANES 2015 to 2018 data (n=701 CKD Stage 3 adults) predicting significant proteinuria (UACR greater than or equal to 30 mg/g) from clinical features excluding UACR. Supplementary analysis: an NHANES-calibrated longitudinal cohort (n=8,412) with simulated quarterly measurements demonstrated XLA performance under real world longitudinal data conditions. All models were evaluated using 5-fold stratified cross-validation. Results: In the primary NHANES cross sectional analysis, the XLA framework achieved AUC ROC of 0.684 (95% CI: 0.641 to 0.727), with all models performing comparably (AUC 0.684 to 0.710), confirming that cross sectional clinical features alone provide limited signal for proteinuria prediction and underscoring the necessity of UACR measurement. In the longitudinal supplementary analysis, XLA achieved AUC ROC of 0.994 versus 0.939 for the best cross-sectional baseline (+5.5%), demonstrating that temporal trajectory features particularly eGFR slope and RAAS adherence trends: confer substantial incremental predictive value when longitudinal data are available. Conclusion: The XLA framework demonstrates meaningful advantages over traditional approaches when applied to longitudinal claims data. Cross sectional findings highlight the irreplaceable role of direct UACR measurement in CKD risk stratification. Together, these results provide actionable evidence for both the limitations of static prediction and the promise of trajectory based approaches in value based care programs managing large CKD populations. Keywords: chronic kidney disease, CKD progression, machine learning, XGBoost, LSTM, temporal attention, claims data, NHANES, proteinuria, healthcare informatics, value based care.

Background.Renoprotective therapies - SGLT2 inhibitors, finerenone, and renin-angiotensin system inhibitors (RASi) - remain underutilisedin chronic kidney disease (CKD). Large language models (LLMs) may detect therapy omissions, but their performance acrossCKD severity strata and at clinical decision boundaries has not been evaluated.Methods.We constructed 100 synthetic CKD vignettes (G3a-G5D; 75 with prespecified omissions, 25 decoys) and queried four LLMsthree times each at temperature 0 (1,200 calls). Omission criteria were adapted from KDIGO 2024, including an investigator-defined gray-zone RASi initiation criterion at eGFR<15. Two nephrologists independently classified a stratified 20-casesubset.Results.For SGLT2 inhibitor and finerenone omissions, all models achieved near-ceiling sensitivity (97-100%). For RASi, performancediverged at the eGFR<15 boundary: Grok 4.1 Fast 85% versus GPT-5.4 55%, Gemini 10%, DeepSeek 10%. Gap-detectioninter-rater agreement was perfect (kappa = 1.000). Clinically incorrect reasoning rates ranged from 0% (GPT-5.4) to 27%(DeepSeek R1); of 52 instances, 31 were factual pharmacology errors and 21 reflected conservative boundary-discordantreasoning. Reproducibility (Jaccard) ranged from 0.74 to 0.93.Conclusions.This boundary-aware synthetic benchmark showed that aggregate sensitivity can conceal clinically important operational-rulediscordance. Rule-based SGLT2 inhibitor and finerenone omissions were detected with near-ceiling sensitivity, whereas aninvestigator-defined gray-zone RASi criterion at eGFR<15 exposed model-specific boundary behaviour. Evaluation of LLM-based CKD decision support should report boundary-specific performance, reproducibility, and clinically incorrect reasoningalongside aggregate metrics.

BackgroundPatients with kidney failure undergoing maintenance hemodialysis suffer high rates of major adverse cardiovascular events(MACE) that are not accurately predicted by traditional cardiovascular risk models. There is an urgent need to identify novel, modifiable cardiovascular risk factors for these patients. MethodsWe analyzed associations of 6287 circulating proteins with MACE among 1048 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort(CRIC) (14-year follow-up) with validation in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study(PACE) (7-year follow-up). In both cohorts, proteins were measured shortly after dialysis initiation and one year later. We compared protein-based risk models derived by elastic net regression to the Pooled Cohort Equations(PCE) optimized for these cohorts(Refit PCE), and to an Expanded Refit PCE that included Troponin T and N-terminal pro-B-type natriuretic peptide. ResultsIn CRIC, 149 proteins were associated with MACE at false discovery rate<0.05. Among 22 proteins significant at Bonferroni p<8x10-6, proteins that validated in PACE included Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), Complement component C7, R-spondin 4, Tenascin, Fibulin-3 and Fibulin-5. Complement pathways were prominent in network analyses. SVEP1 surpassed other markers by statistical significance, with CRIC HR per log2 1.8 (p=2.1x10-12) and HR per annual doubling 1.6 (p=6.8x10-6). For 2-year MACE, AUC(95%CI) for SVEP1 alone was 0.72(0.59, 0.84) in CRIC, and 0.73(0.63, 0.81) in PACE. SVEP1 surpassed the Expanded Refit PCE in CRIC (0.61 (0.48, 0.73)) (p=0.038). In the pooled CRIC + PACE cohort, SVEP1 AUC(95%CI) (0.79(0.70, 0.88)) surpassed Refit PCE (0.61(0.51, 0.72)) (p=0.004). ConclusionsSVEP1, a 390 kDa protein unlikely to be renally cleared, surpassed over 6000 other proteins and by itself outperformed traditional clinical risk models in predicting MACE in two populations of patients undergoing maintenance hemodialysis. Future studies should provide mechanistic insights behind these findings. Key PointsO_LIPatients with kidney failure undergoing hemodialysis have 20-fold higher cardiovascular mortality compared to the general population, and conventional risk factors have low prognostic utility for these patients. C_LIO_LIBy applying large-scale circulating proteomics in two independent hemodialysis cohorts, we have discovered >20 novel proteins that predict major adverse cardiovascular events(MACE). C_LIO_LISushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1) surpassed >6000 individual proteins and clinical factors for predicting MACE. C_LI

BackgroundSingle-nephron glomerular filtration rate (GFR) represents a nephron-level functional index that may reveal key pathophysiological mechanisms driving progression in patients with diabetic nephropathy. However, its clinical relevance remains incompletely understood. This cross-sectional study assessed single-nephron estimated GFR (eGFR) across different chronic kidney disease (CKD) stages in patients with advanced diabetic nephropathy. MethodsNephron number was estimated as the number of nonglobally sclerotic glomeruli per kidney using computed tomography-derived cortical volume combined with biopsy stereology. Single-nephron eGFR was calculated by dividing eGFR by the nephron number of both kidneys. Patients were stratified according to CKD stage at kidney biopsy. Associations between CKD stages and single-nephron eGFR were evaluated using multivariable linear regression models adjusted for age, sex, urinary protein excretion, and eGFR. ResultsThe study included 105 patients with biopsy-proven diabetic nephropathy and overt proteinuria (median age 59 years, 83% male, HbA1c 6.6%, 57% had nephrotic range proteinuria). The percentage of globally sclerotic glomeruli, mesangial expansion score, and prevalence of nodular lesions increased significantly with advancing CKD stage. Median nephron number declined from 529,178 to 224,458 per kidney, whereas glomerular volume remained constant. Single-nephron eGFR decreased markedly with CKD stage and remained significantly inversely associated with CKD stage after adjustment for clinicopathologic covariates (P for trend <0.001). ConclusionIn overt diabetic nephropathy, single-nephron eGFR decreased with advancing CKD stage, despite relatively preserved glomerular volume. At this stage of disease, structural alterations specific to diabetic nephropathy may impair effective single-nephron filtration capacity.

Chronic kidney disease is a progressive condition characterized by the accumulation of nitrogenous waste products, including urea, creatinine, and uric acid, leading to significant morbidity in advanced stages. Current management strategies, such as dialysis, are effective but associated with substantial clinical and socioeconomic burdens, highlighting the need for alternative approaches to reduce circulating toxins. In this study, we evaluated a novel formulation of psyllium-based granules functionalized with specific antibody combinations targeting urea, creatinine, and uric acid. The aim was to assess the biochemical effects, as well as the binding and sequestration efficiency, of these formulations under controlled experimental conditions. A randomized, double blind controlled in vitro study was conducted using serum samples obtained from twenty patients with uremia undergoing dialysis. Three formulations, labeled S1, S2, and S3, were evaluated. All tested formulations resulted in statistically significant reductions in urea, creatinine, and uric acid concentrations compared with baseline values. Among them, the S1 formulation demonstrated the highest binding efficiency, reducing urea by 70% {+/-} 7%, creatinine by 80% about 4%, and uric acid by 52% about 11%. Linear regression analysis confirmed a statistically significant association between the S1 formulation and reductions in these biochemical parameters. These findings suggest that antibody functionalized granules can effectively bind and sequester nitrogenous waste products under in vitro conditions. This approach may represent a potential strategy for reducing uremic toxin burden, either as a complementary method or as a future alternative to existing renal replacement therapies. Further studies, including in vivo validation, dose optimization, and controlled clinical trials, are required to establish safety, efficacy, and translational applicability.

IntroductionThe mitochondrial citrate carrier (CiC), which mediates the transport of citrate across mitochondria, has been implicated in various diseases, but its role in kidney tubules is unclear. Here, we unraveled a novel role of CiC in tubular metabolism in the context of antibiotics-induced acute tubular injury (ATI). MethodsATI was induced by administration of vancomycin and gentamycin for 48 hours in mice (V+G-ATI). Tubular-specific CiC knockout (KO) was induced by adeno-associated virus (AAV) serotype 9 encoding Cre recombinase driven by KSP promoter (AAV9-Ksp-Cre) injection. Unbiased proteomic and metabolomic analyses were performed in CiC KO mouse kidneys. We performed in vivo 13C metabolic flux analysis to elucidate metabolic alterations in ATI and the effect of CiC KO. ResultsIn this study, V+G-induced ferroptosis, oxidative damage, and extensive ATI in mice were alleviated by CiC KO. Metabolic reprogramming induced by CiC KO increased mitochondrial TCA cycle intermediates, including alpha ketoglutarate (AKG), and elevated levels of the endogenous antioxidant glutathione (GSH). Supplementation with AKG or GSH attenuated V+G-ATI in mice. Tracking of the 13C pyruvate / lactate revealed an increased flux of glucose oxidation pathway in V+G-ATI. Interestingly, tubular-specific CiC KO expands the effective TCA cycle pool reserve space, which may contribute to mitigation of ROS. The beneficial metabolic alteration in CiC KO requires AKG and glutamate, as simultaneous inhibition of mitochondrial transporters of AKG and glutamate attenuated the cytoprotective effects of CiC KO against antibiotic-induced oxidative damage. ConclusionsThis is the first study to demonstrate the role of mitochondrial CiC in kidney tubular epithelial cells, showing that it induces metabolic alterations that protect against antibiotic-induced ATI.

Poor outcomes in proteinuric kidney diseases are challenging to successfully manage therapeutically due to the heterogeneity of underlying disease pathogenesis and associated risk for progression. The role of cytoskeleton-associated proteins, including the scaffolding protein Anillin (ANLN), are of specific interest in kidney disease given the importance of actin dynamics in the kidneys specialized epithelial cell types. In this study, we identify the prevalence of genetic variants in ANLN, the gene encoding ANLN, in a cohort of deeply phenotyped individuals with non-diabetic proteinuric kidney disease. Thirty-one individuals (of 864 genotyped) harbor heterozygously expressed variants in ANLN; 7 unrelated individuals shared the same variant (I1109V) in the C-terminal pleckstrin homology (PH) domain, a region necessary for interaction with the plasma membrane. Kidney organoids generated from I1109V induced pluripotent stem cells from 1 of these individuals showed increased epithelial cell mitogen-activated protein kinase 8 network activity and apoptosis, which was enhanced by tumor necrosis factor alpha (TNF-) and phenocopied by actin polymerization inhibition. TNF--treated I1109V organoids also exhibited tubular lumen expansion. Knockdown and re-expression of the analogous ANLN variant in Xenopus laevis embryonic epithelia resulted in defects in cell-cell junction dynamics including wavy cell membranes exhibiting increased transverse movements as well as abnormal junctional F-actin remodeling in response to mechanical stress and leaky barrier function. Taken together, these results indicate that enhanced tubular epithelial cell death, perturbed cell-cell contacts and barrier function defects are associated with a novel ANLN variant discovered in individuals with non-diabetic proteinuric kidney disease. ONE SENTENCE SUMMARYEnhanced tubular epithelial cell death and perturbed cell-cell junction integrity and barrier function are associated with a novel Anillin coding variant discovered in a cohort of individuals with proteinuric kidney disease.

Importance: Recently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD). Methods: Real world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg/g (PCR~0.9 g/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes. Results: In the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL/min/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg/g, mean eGFR slope was -4.67[-6.00, -3.33] mL/min/1.73m2/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL/min/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001). Conclusions and relevance: Changes in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.

BackgroundKidney cell lines are widely used to model kidney physiology and disease; however, their gene expression profiles may differ from primary cells due to immortalization, culture conditions, or experimental treatments. Determining whether a cell line resembles its native cell type is critical for interpreting in vitro findings. We developed a transcriptome-based approach that matches bulk RNA-seq data from kidney cell lines, primary cells, or tissues to reference cell types derived from single-cell RNA-seq (scRNA-seq) datasets. MethodsReference transcriptomic profiles were generated from two human and two murine kidney scRNA-seq datasets by pseudobulk aggregation. Bulk RNA-seq data from microdissected kidney tissue, non-kidney negative controls, and kidney cell lines were matched to these references using three statistical similarity measures (Spearman correlation, Euclidean distance, Poisson distance) and three machine learning classifiers (Random Forest, XGBoost, TabPFN). Each was assessed with global gene expression, curated kidney marker gene lists, and the most variable genes. Matching accuracy was evaluated through a three-step validation strategy: within-dataset matching, cross-reference comparison, and validation against primary kidney tissue and negative controls. ResultsGene expression rank-based Spearman correlation and TabPFN, a foundation model for tabular data, emerged as the most accurate and specific approaches, particularly with curated kidney marker gene lists. Both methods correctly identified microdissected kidney tubule segments and were robust against non-kidney negative controls. Applied to commonly used kidney cell lines, OK cells retained proximal tubule identity, particularly under shear stress, while other proximal tubule lines (HK-2, HKC-8, HKC-11) showed inconsistent matching. Collecting duct-derived mIMCD-3 maintained stable similarity across passages, culture conditions, and genetic modifications. ConclusionWe provide two complementary implementations: CellMatchR, an accessible web-based tool using Spearman correlation for routine use, and comprehensive scripts for TabPFN-based matching (link will be added after peer reviewed publication). Together, these resources enable researchers to make informed decisions about kidney cell culture model selection, interpretation, and stability. Translational StatementKidney cell lines are fundamental tools in nephrology research, yet their transcriptomic similarity to native cell types is rarely validated systematically. We demonstrate that combining bulk RNA-seq data with single-cell reference datasets enables robust assessment of cell line identity using gene expression-rank-based correlation and machine learning approaches. By providing a comprehensive evaluation of matching methods, curated kidney marker gene lists, and reference datasets, our study serves as both a practical resource and a methodological framework for the kidney research community, facilitating informed selection of cell culture models, quality control of experimental conditions, developing new experimental cell culture models, and more reliable translation of in vitro findings to kidney physiology and disease.

Introduction: Podocyte injury is central to the pathogenesis of most glomerulonephritides (GN) and causes segmental glomerulosclerotic lesions that predict progression in IgA Nephropathy (IgAN). Recent advances in high-resolution microscopy and AI-assisted image analysis have enabled detailed quantification of podocyte foot process (FP) morphology. However, whether nanoscale podocyte morphometrics can predict disease progression or treatment response in GN has not been investigated. Aim: To evaluate whether nanoscale podocyte morphometric parameters predict clinical characteristics, disease progression, and treatment response in GN, with a focus on IgAN. Method: Podocyte morphometrics were analyzed in kidney biopsies from patients with GN using high-resolution microscopy and the deep learning-based tool Automatic Morphometric Analysis of Podocytes (AMAP). Four morphometric parameters were quantified: slit diaphragm length (SDL), FP area, FP circularity and FP perimeter. These parameters were correlated with clinical characteristics, conventional electron microscopy (EM) findings and longitudinal follow-up data. Results: The study included 37 patients with GN from Danderyd University Hospital (Stockholm, Sweden), with IgAN representing the largest diagnostic subgroup (n = 19). The median follow-up for the cohort was 3.0 years. SDL correlated significantly with urine albumin-to-creatinine ratio (uACR; p = 0.021), whereas conventional EM measurements did not (p = 0.22). Within the IgAN subgroup, lower SDL was associated with a steeper decline in eGFR, higher FP area with increased long-term proteinuria, and higher FP circularity with improvement in uACR during the first year. The association between lower SDL and eGFR decline remained as a trend in IgAN patients not treated with corticosteroids (p = 0.068) but was absent in the treatment group (p = 0.59). Conclusion: In this proof-of-concept study, nanoscale podocyte morphometrics demonstrated greater sensitivity than conventional EM in quantifying podocyte injury and predicting progression in IgAN. These findings suggest that high-resolution morphometrics may improve risk stratification in IgAN but require validation in larger, independent cohorts before clinical implementation.

There is an epidemic of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low-and-middle income countries (LMICs). Although it is currently unclear whether there is a common underlying cause, these conditions have been collectively termed CKD of unknown cause (CKDu). CKDu is estimated to have led to the premature deaths of tens to hundreds of thousands of young adults in LMICs over the last two decades. Thus, there is an urgent need to understand the aetiology and pathophysiology of these conditions and to develop preventive interventions. We have now established that CKDu exists in Central America (Nicaragua) and South Asia (India, Sri Lanka), but not in some other tropical countries. It is not clear yet whether the epidemics in Central America and South Asia have common causes or different causes, which is why it is important to conduct research using the same protocols and methods in these different regions. We have therefore established prospective studies in affected communities in Nicaragua, South India, and Sri Lanka to investigate the causes of the epidemics of CKDu, and factors which affect prognosis. The underlying hypothesis is that CKDu is caused by unknown factors to which the populations have become exposed, due to changes in agricultural practice or other environmental changes (e.g. water supply), over recent decades. The objectives of the collaboration are to investigate the environmental causes of renal decline in these high-risk populations, using standardised instruments capturing occupational and environmental exposures. We will address four proposed causes of CKDu: (i) metals and metaloids; (ii) agrochemicals; (iii) infections by organisms that affect the kidney; and (iv) heat/dehydration.

BackgroundLife-sustaining hemodialysis (HD) is onerous for patients, especially those with multiple co-morbidities and advanced age. A standard HD prescription is 720 minutes per week. Alternative HD regiments have been proposed in attempt to maintain quality of life (QOL). Studies are needed to investigate the efficacy and safety of less frequent HD prescriptions in this population. This is an institution-wide observational study in New Brunswick, Canada to compare HD prescriptions and the impact on QOL and mortality. ObjectiveThe purpose of this study is to assess the current HD prescribing practices at a provincial healthcare institution in relation to patient QOL. DesignProspective Observational Study. SettingSingle centre hospital and satellite hemodialysis units. PatientsVoluntarily consented patients undergoing in-centre hemodialysis treatment. MeasurementsObservational clinical data was collected for each study participant from their hospital and dialysis electronic medical records. The KDQOL-36TM questionnaire was used to assess patient-reported quality of life at the time of consent. MethodsAdults undergoing in-centre or satellite site HD for at least 3 months were eligible to participate. Consenting patient participants were grouped by HD prescription whether they were prescribed 720 minutes or more per week or less than 720 minutes per week. All participants completed the KDQOL-36 TM questionnaire to estimate QOL and groups were compared using the Mann-Whitney U statistical test. Emergency department visits, hospitalizations, and mortality were analyzed using a negative binomial regression or a logistic regression. ResultsWe enrolled 140 patient participants; 41 were undergoing less than 720 minutes per week of HD and 99 were undergoing 720 minutes or more of HD per week. Patients who were undergoing less than 720 minutes per week of HD were older [Median (IQR): 76 (72- 81) yrs. vs. 64 (55 - 75) yrs.; p < 0.001], had higher median (IQR) QOL scores on the Symptoms/ Problems List scale on the KDQOL-36 TM questionnaire [79.2 (70.8 - 88.5 vs. 70.8 (62.5 - 81.3); p = 0.0022], and were less likely to present to the emergency department (incident rate ratio 0.52, 95% confidence interval [CI] 0.33-0.81). Mortality was similar between groups, even when adjusted for age and comorbidity score (odds ratio 1.62, 95% CI 0.59-4.49). LimitationsPatient participant enrollment was limited by the single centre nature of this study. As this was an observational study, we did not account for how long the patients had been prescribed less than 720 minutes of hemodialysis. We did not include a frailty assessment of the study participants. A higher number of study participants may have identified significant trends in mortality. ConclusionsThe results of this study show that patients undergoing less than 720 minutes of weekly HD had a higher QOL score for the KDQOL-36 TM Symptoms/ Problems List scale, were less frequently in the emergency department and were not more likely to die than patients undergoing 720 minutes or more of weekly HD. Further studies are required to assess the feasibility and safety of a conservative model of HD prescribing to improve QOL of patients with palliative care treatment goals.

Background and objectiveKidney stone disease (KSD) is common and distinct monogenic forms with well-defined treatment pathways exist. However, it is unclear which patients should undergo genetic testing and the significance of monoallelic variants in SLC34A1, SLC34A3, CYP24A1, SLC7A9, and SLC3A1. We aimed to define monogenic KSD inheritance patterns, determine the diagnostic yield of genetic testing in selected and unselected cohorts, and establish the utility of standard serum biochemistry in highlighting those at risk of monogenic KSD. MethodsWe compared genetic and phenotypic data from individuals with and without KSD in the UK Biobank to determine inheritance patterns. We established the "number needed to test" (NNTT) to identify monogenic KSD in the UK Biobank and a specialist adult kidney stone nephrology clinic where patients had genetic testing based on age, recurrence, and family history. We examined the utility of standard serum biochemistry in identifying monogenic KSD in both settings. Key findings and limitationsMonogenic KSD associated with SLC34A3, SLC7A9, and SLC3A1 is inherited in an autosomal dominant manner and monogenic KSD associated with SLC34A1 and CYP24A1 in an autosomal recessive manner. A monogenic diagnosis was made in [~]1% of KSD in the UK Biobank (NNTT[~]90) and 15% of KSD in a specialist nephrology clinic (NNTT[~]7). In both settings, standard serum biochemistry failed to identify individuals at risk of monogenic KSD. Conclusions and clinical implicationsGenetic testing for monogenic KSD has utility in specialist settings where there is clinical suspicion of an inherited disorder even in the absence of biochemical abnormalities.

Background: Renal effects of statins in type 2 diabetes mellitus (T2DM) remain uncertain. We evaluated whether statin exposure is associated with time to dialysis initiation. Methods: We conducted a retrospective cohort study of adults with T2DM, indexing follow-up at diagnosis during first hospital admission (day 0) between january 2017 and march 2025. Statin use was modeled as time-varying from statin days; (classified in 3 categories: baseline users, new users, and never users). The primary outcome was dialysis. Analysis estimated cause-specific hazards, censoring deaths; proportional hazards were checked with prespecified windows of statin exposure (0?1, 1?3, > 3 years). Competing-risk analyses (Fine?Gray) assessed the sub-distribution hazard of dialysis with death as a competing event in two models: (i) prevalent users at baseline and (ii) new-users with post-initiation intervals of 30 and 90 days. An Observational Medical Outcomes Partnership Common Data Model standardized dataset of a Brazilian quaternary hospital, and the Real-World Data tool MD Clone were used in the study. Results: Of 36,246 adults identified, 32,125 entered the time-varying cohort (39,943 risk intervals; 656 dialysis events); median follow-up among censored patients was 753 days. At baseline, 70.3% never used statins, 5.5% were users (? 0 days), and 24.2% initiated after diagnosis. Crude dialysis incidence was 4.51 vs. 12.31 per 1,000 patient-years during unexposed vs. exposed time. In the adjusted time-varying Cox model, current statin exposure was associated with a modestly higher hazard of dialysis (HR = 1.043, 95% CI 1.011?1.077). In the new-users analysis, HRs were 0.83 (95% CI 0.66?1.05), and 0.73 (95% CI 0.57?0.92) with a 30-day and 90-day intervals, respectively. Conclusions: In this retrospective cohort of hospitalized diabetic patients at baseline, statin initiation at least 90-days in advance is associated with reduced indication of renal replacement therapy.

BackgroundWithin the kidney, (pro) renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and modulate physiological and pathophysiological processes. We have recently reported that activation of CD PRR mediates obstructive renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). The current study addresses the underlying mechanisms by examining the profibrotic pathway mediated by soluble PRR (sPRR)-dependent alternative macrophage activation. MethodsWe performed UUO or sham surgery on mice with CD-specific deletion of PRR (CD PRR KO) and floxed controls. After 7 days, we assessed fibrosis-related parameters, inflammatory cytokines, M1/M2 macrophage markers, other gene expression markers of kidney injury, and the concentration of plasma sPRR. We also administered vehicle or site-1 protease (S1P) inhibitor PF-429242 (PF) to C57BL/6 mice with UUO to determine the role of sPRR. Experiments were performed in vitro to examine the mechanism of sPRR-His-mediated macrophage M2 polarization and activation of potential target genes in bone-marrow-derived macrophages (BMDMs). ResultsCompared with the floxed control, CD PRR KO decreased macrophage accumulation, M2 polarization, and Yap/Taz expression while improving renal fibrosis and suppressing plasma sPRR levels following UUO. In BMDMs, sPRR-His treatment promoted macrophage M2 polarization, fibrosis, and Yap/Taz expression, which was dependent on angiotensin type 1 receptor (AT1R). ConclusionCD PRR-derived sPRR acts via ATR to promote macrophage M2 polarization and stimulates the AT1R/Yap/Taz axis, which leads to renal fibrosis during UUO.