Kidney International Reports

Abstract Background Alport Syndrome (AS), caused by pathogenic variants in type IV collagen genes COL4A3/4/5, is a leading monogenic cause of Kidney Failure (KF). Clinical course varies widely, and disease specific predictors of progression relevant to clinical care and trial design remain incompletely defined. Methods In this retrospective cohort study of individuals with AS in the UK National Registry of Rare Kidney Diseases, patients were classified as having AS or heterozygous genotypes and followed to assess proteinuria progression, eGFR slope and kidney survival. Proteinuria and eGFR trajectories were analysed using mixed effects regression models; kidney survival using Kaplan Meier analysis. Results Among 1032 participants (median follow up 11.6 years; 47% female), 475 (46%) had AS genotypes (Male XLAS or autosomal recessive AS). eGFR decline accelerated with advancing CKD stage across all genotypes (p<0.001). Proteinuria increased as eGFR declined and occurred earlier in AS genotypes. After reaching proteinuria thresholds of more than 1.0 and 3.0g/g, kidney survival over the subsequent 5 years did not differ significantly between genotypes (logrank p=0.14, p=0.17, respectively), although modest differences emerged over longer follow-up. Across eGFR thresholds (90, 60, and 45mL/min/1.73m2), higher proteinuria was associated with shorter time to KF; for example, at eGFR 45mL/min/1.73m2, median time to KF was 3.0 years (IQR, 1.6-5.4) for above-median vs 6.5 years (5.1-not estimable) for below-median proteinuria (p<0.0001). Almost all patients who reached KF had developed proteinuria of more than 0.3g/g. Conclusion In this national cohort, eGFR decline accelerated with CKD stage and proteinuria was strongly associated with progression to KF across genotypes. The non linearity of eGFR decline may inform its interpretation in clinical practice and use as a trial endpoint. Once comparable proteinuria levels were reached, differences in outcomes by genotype were attenuated, supporting proteinuria as a key prognostic marker and strengthening rationale for its use as a surrogate endpoint in AS clinical trials

Background: ADTKD-MUC1 is one of the major entities of ADTKD caused by frameshift variants in the MUC1 VNTR that standard short-read sequencing fails to detect. Existing 59dupC-targeted probe-extension assays do not allow for broad screening and cannot detect atypical non-dupC variants. Recently, VNtyper, a Kestrel-based genotyping pipeline with optional code-adVNTR cross-validation for MUC1 VNTR genotyping from short-read sequencing data allowed to circumvent this diagnostic limitation, but needed further development for easy access and rapid sample processing. Methods: We developed VNtyper 2, by refactoring VNtyper into a modular, production-grade tool with a companion web platform, VNtyper-Online (https://vntyper.org), for freely available browser-based analysis with short turnaround time and without local bioinformatics infrastructure. We validated VNtyper 2 on 400 simulated samples generated with MucOneUp and 142 clinical exomes with independently confirmed genotypes. Results: In simulation, VNtyper 2 detected the canonical 59dupC variant with 96% sensitivity and 100% specificity. Reference-standard validation on 142 samples yielded 90.6% sensitivity and 98.2% specificity overall, with cohort-dependent performance across the Twist Exome v2 French-German cohort (98% sensitivity, 87.5% specificity) and the KAPA HyperExome V2 (Roche) Czech-US cohort (79.4% sensitivity, 100% specificity). Screening of 3582 exomes and targeted panels from international CKD referral programmes identified 51 positive individuals, including 9 with atypical non-dupC frameshift variants that would have been missed by 59dupC-targeted probe-extension assays. In unselected CKD cohorts, a descriptive random-effects summary estimated a detection rate of 1.4% (95% CI 0.6 to 3.1%). Conclusions: VNtyper 2 and VNtyper-Online are open-source tools for MUC1 VNTR genotyping from short-read data and can support locally validated workflows when VNTR coverage is adequate. By improving accessibility and turnaround time, these tools democratize MUC1 diagnostics at global scale. For its integration into routine diagnostics, we propose an expert-informed two-pathway workflow developed through European ADTKD-Net consortium consensus.

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.

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.

Chronic benign proteinuria (PROCHOB), caused by biallelic pathogenic variants in CUBN, presents in childhood as isolated, asymptomatic tubular proteinuria with preserved long-term kidney function. Because its clinical presentation closely mimics early stage glomerular diseases with moderate proteinuria and without increased urinary {beta}2-microglobulin (uBMG) and 1-microglobulin, numerous patients undergo unnecessary kidney biopsies and receive angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers before genetic testing is considered. Using high-throughput aptamer-based urinary proteomics (SomaScan(R)), we identified urinary myoglobin as a disease-specific biomarker for PROCHOB. We developed and confirmed a diagnostic approach in which the urinary myoglobin-to-creatinine (uMB/Cr) ratio robustly distinguishes PROCHOB from other moderate glomerular proteinuric kidney diseases. Although certain cases of Dent disease causing megalin dysfunction exhibit increased urinary myoglobin levels, PROCHOB and Dent disease can be clearly distinguished based on the uBMG-to creatinine ratio. This biomarker reflects impaired proximal tubular protein reabsorption because of cubilin dysfunction and remains normal in healthy individuals or those with typical glomerular diseases with moderate proteinuria. Our findings establish a noninvasive diagnostic tool for PROCHOB that prompts targeted genetic testing for CUBN variants using the uMB/Cr and urinary uBMG-to-creatinine ratios. This strategy has the potential to transform the clinical diagnostic pathway for isolated proteinuria.

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.

Introduction: APOL1 high-risk variants markedly increase susceptibility to kidney disease among individuals of African ancestry; however, only a subset of carriers develops clinically significant CKD or ESKD. This discrepancy highlights a gap between genetic risk and clinical trajectory. Current prognostic tools rely primarily on eGFR and albuminuria, which incompletely reflect the underlying biological processes driving APOL1-associated kidney injury. We hypothesized that plasma biomarkers reflecting inflammatory and tubular injury pathways could identify biologically active disease states within this genetically high-risk population and improve prognostic stratification. Methods: Participants from the Mount Sinai BioMe Biobank carrying two APOL1 high-risk alleles (G1, G1; G1, G2; or G2 G2) were followed for a median of 6 years. Baseline plasma biomarkers of inflammation and tubular injury (TNFR1, TNFR2, KIM-1, MCP-1, YKL-40, IL-18, suPAR) were measured. The composite outcome was sustained 40% decline in eGFR or ESKD. Multivariable Cox models assessed associations between biomarkers and outcomes. A weighted biomarker risk score was derived from tertile-based hazard ratios and categorized into low-, moderate-, and high-risk groups. Results: Among 498 participants (median eGFR 83 ml/min/1.73 m2), 80 (16.1%) reached the composite outcome. Higher concentrations of TNFR1, TNFR2, suPAR, KIM-1, and IL-18 were independently associated with kidney events after multivariable adjustment. Event rates were 7% in the low-risk group, 16% in the moderate-risk group, and 36% in the high-risk group. Conclusions: Plasma biomarkers reflecting inflammatory and tubular injury pathways reveal marked heterogeneity in kidney outcomes among individuals with high-risk APOL1 genotypes. Integration of these signals into a biology-weighted score identifies distinct prognostic phenotypes beyond genotype and traditional clinical measures, supporting multidomain biomarker frameworks for risk stratification and potential trial enrichment in APOL1-associated kidney disease.

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.

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.

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.

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 Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide including an estimated 30,000-70,000 in the United Kingdom (UK). Tolvaptan is the only disease-modifying therapy approved for rapidly progressing disease. Despite national guidance, prescribing rates were hypothesised to vary by kidney centre. Treatment may not always align with guidelines: some patients eligible for tolvaptan may not be initiated, while other patients initiated on tolvaptan may not meet eligibility criteria. This may have important consequences for healthcare costs and health-related quality of life. Methods The National Registry of Rare Kidney Diseases (RaDaR) collects longitudinal data from UK NHS kidney centres. This retrospective cohort study used routinely collected data (2016-2023) to examine tolvaptan prescribing across kidney centres. Kidney centre-level initiation patterns were described, assessed using mixed-effects logistic regression and visualised with funnel plots. Cost-effectiveness analyses combined observed prescribing practices under likely negotiated commercial discounts to estimate costs and quality-adjusted life year (QALY) consequences of prescribing at the national level. Results Our study included 3,609 people with ADPKD from 72 kidney centres. Patients eligible for tolvaptan who were not initiated accounted for 34.8% (292/839). Across centres, five (6.9%) initiated tolvaptan significantly more than expected among eligible participants, while one centre (1.4%) initiated significantly less. Nationally, this could result in up to {pound}53.7 million in lost savings (assuming a 60% medication price reduction) and result in up to 1,245 lost QALYs. Patients initiated on tolvaptan who were not eligible accounted for 26.1% (103/395). Only one centre had significantly fewer eligible patients than expected among initiated patients. Nationally, this could cost up to {pound}15.9 million (assuming a 60% medication price reduction). Conclusions There is evidence of variation in tolvaptan prescribing in the UK. A substantial proportion of patients eligible for tolvaptan were not initiated at the cohort-level, with evidence of variation between centres suggesting differences in treatment decision-making. A substantial proportion of patients initiated on tolvaptan were not eligible at the cohort-level, but there was limited evidence of variation between centres. Together, these findings raise questions regarding the potential consistency of clinical decision-making, equitable access to a sole disease-modifying therapy in a rare disease, alignment with national guidance, and effective use of healthcare resources.

BackgroundThe first 1000 days from conception to age 2 years represent a critical window for kidney development, during which nutritional exposures may have lifelong programming effects. Whether early-life sugar restriction reduces long-term kidney disease risk remains unknown. MethodsUsing the UK sugar rationing policy (1942-1953) as a natural experiment, we compared risks of chronic kidney disease (CKD) and acute kidney injury (AKI) among 64,942 UK Biobank participants born around the rationing period. Duration of early-life exposure was categorised. Cox proportional hazards models estimated hazard ratios (HRs). Negative control analyses included non-UK-born UK Biobank participants and the Chinese CHARLS cohort. Mediation analyses integrated clinical phenotypes and metabolomic profiles. FindingsCompared with never-exposed individuals, those exposed to sugar rationing throughout the first 1000 days (in utero to age 2 years) had lower risks of CKD (adjusted HR 0.78, 95% CI 0.66-0.93) and AKI (0.79, 0.69-0.90). Negative control analyses showed null associations. Mediation analyses indicated that metabolic efficiency (basal metabolic rate), body composition (fat-free mass), and lipid metabolism mediated 4-9% of the protective association. A distinct metabolomic signature characterised by higher polyunsaturated fatty acids and lower VLDL subfractions was identified. InterpretationSugar restriction during the first 1000 days is associated with lower risks of CKD and AKI in adulthood, partially mediated by favorable metabolic efficiency, body composition, and lipid profiles. These findings identify early-life sugar exposure as a modifiable developmental programming factor for lifelong kidney health and support public health strategies to reduce added sugar intake during pregnancy and early childhood. FundingNational Natural Science Foundation of China, and others

Non-HLA donor-recipient (D-R) genetic mismatches contribute to kidney allograft injury and long-term graft loss, but their clinical use is limited by the unavailability of donor DNA after transplantation. We tested whether non-invasively obtained, recipient-derived samples could be used to infer donor genotype and D-R mismatches. Genomic DNA (g-DNA) of 11 unselected kidney transplant recipients and donors underwent whole-exome sequencing (100x). Additional customized probes were added for intronic coverage (300x) of 55 targeted non-HLA genes of reported clinical relevance. Variants identified from sequencing results were compared with plasma cell-free DNA (cfDNA), urine cell-pellet DNA (U-DNA) obtained from the same recipients. Genome-wide-, exonic-, or non-synonymous exonic- mismatches in transmembrane or secreted proteins, and mismatches within target genes were benchmarked using donor g-DNA to generate mismatch scores for each D-R pair. Within each of these genomic scales of mismatch, U-DNA identified D-R mismatches significantly better than the corresponding cfDNA (P<0.001 for each comparison). U-DNA also identified gene-level mismatches in the LIMS1 gene, and correctly inferred established donor-origin risk alleles, including SHROOM3 and APOL1. Our findings demonstrate proof-of-concept that U-DNA in tandem with recipient genome, can non-invasively infer relevant non-HLA loci/mismatches circumventing the need for the donor genomic DNA.

Gabapentin and pregabalin are renally cleared gabapentinoids with markedly different pharmacokinetic profiles in chronic kidney disease: gabapentin half-life extends from 5-7 hours to 52-132 hours in advanced chronic kidney disease, while pregabalin accumulation is more predictable. In an active comparator new-user cohort of 33,791 adults aged [&ge;]40 years with hypertension initiating gabapentinoids (2018-2024) from the Rutgers Clinical Research Data Warehouse, chronic kidney disease substantially amplified gabapentin-associated dementia risk (hazard ratio 7.39, 95% confidence interval 3.43 to 15.92, P<0.001), whereas patients without chronic kidney disease showed near-null effect (hazard ratio 1.09, 95% confidence interval 0.89 to 1.34; P=0.41; interaction P<0.001). This effect was independent of prescribed dose: within the low-dose stratum, chronic kidney disease patients showed hazard ratio 5.06 versus 1.27 in patients without chronic kidney disease. Pre-existing chronic kidney disease conferred significantly elevated risk (hazard ratio 1.78; P=0.001), while incident chronic kidney disease showed a nonsignificant trend (hazard ratio 1.32; P=0.16), consistent with cumulative pharmacokinetic burden. Independent replication in the NIH All of Us Research Program Controlled Tier (N=47,079; hazard ratio 1.593, 95% confidence interval 1.349 to 1.882; P<0.001) confirmed the overall gabapentin-pregabalin signal; eGFR-staged analysis showed the expected pharmacokinetic pattern (mild CKD [eGFR [&ge;]45]: hazard ratio 1.15, not significant; severe CKD [eGFR <45]: hazard ratio 1.77, directionally elevated but underpowered with 51 events). Food and Drug Administration Adverse Event Reporting System data corroborated the renal mechanism (odds ratio 1.642 for renal events in elderly co-exposed patients). These converging findings suggest that chronic kidney disease is a clinically important modifier of gabapentin-associated cognitive risk, and that gabapentinoid selection in chronic kidney disease patients should integrate renal function status into prescribing decisions. Significance StatementGabapentin is the most prescribed gabapentinoid in the United States, with approximately 59 million annual prescriptions, and is entirely dependent on renal clearance. In this active comparator cohort study of 33,791 gabapentinoid initiators, chronic kidney disease amplified gabapentin-associated dementia risk nearly 7-fold compared with pregabalin, an effect that was independent of prescribed dose and persisted even among patients receiving low-dose gabapentin. External replication in the NIH All of Us Research Program and FDA pharmacovigilance data corroborated the signal. These findings suggest that current dose-adjustment guidelines for gabapentin in CKD may be insufficient to prevent cognitive harm, and that renal function status should be incorporated into gabapentinoid selection decisions.

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.

Secondary hyperparathyroidism persists in the majority of kidney transplant recipients and is associated with adverse graft and cardiovascular outcomes. The immunosuppressive drug class used post-transplant may modulate parathyroid hormone (PTH) levels through distinct mechanisms: calcineurin inhibitors (CNI) stabilize PTH mRNA, while mTOR inhibitors (mTORi) suppress parathyroid cell proliferation in experimental models. We report supporting evidence from two independent analyses. In a multinational real-world database analysis (TriNetX Global Collaborative Network), kidney transplant recipients with documented mTORi use and eGFR in the target range had lower PTH than those on CNI across eGFR strata examined (15-30, 30-45, 45-60, 60-75, >75 mL/min/1.73 m2), with risk ratios for PTH >130 pg/mL ranging from 0.47 to 0.67 in propensity-matched analyses (all p < 0.05). The known confounders - calcium (higher in CNI) and phosphate (higher in mTORi) - both act to oppose this pattern, strengthening the possibility of a drug effect. In a longitudinal single-center cohort (n = 118; 796 PTH measurements), a linear mixed-effects model with time-varying mTORi exposure confirmed a 42% lower PTH during on-mTORi periods after adjustment for eGFR, transplant vintage, diabetes, age, and sex (fold-change 0.58 [95% CI 0.50-0.68]; p < 0.0001). These findings suggest a direct PTH-lowering effect of mTORi. Immunosuppression choice may be considered in the management of post-transplant hyperparathyroidism in selected patients.

Rationale & ObjectivePeriodontal disease(PD), a chronic inflammatory condition, may contribute to chronic kidney disease(CKD) through systemic inflammation, but its impact on CKD outcomes and the potential protective effects of periodontal treatment and routine dental prophylaxis remain uncertain. This study evaluated associations between PD, dental interventions, and kidney outcomes in a large U.S. veteran cohort. Study DesignRetrospective cohort study. Setting & ParticipantsUsing Veterans Health Administration data(2009-2019), we identified 86,376 adults eligible for comprehensive dental care with baseline eGFR >60 mL/min/1.73m{superscript 2} and followed them from their initial dental examination. ExposurePatients with PD (Cohort-A) were divided into those who received periodontal treatment (PD-Treated), those who did not receive treatment but had [&ge;]1 dental prophylaxis visit/year (PD-Prophylaxis), and those who received neither (PD-Untreated). Those without PD (Cohort-B) were grouped by presence or absence of regular dental prophylaxis ([&ge;]1 visit/year). OutcomeIncident CKD (eGFR <60 mL/min/1.73 m{superscript 2} and >25% decline from baseline), [&ge;]40% eGFR reduction, and incident albuminuria (>30 mg/g), each confirmed with repeat labs [&ge;]90 days apart. Analytical ApproachMultivariable logistic regression model ResultsOf 86,376 veterans (mean age 57.17{+/-}12.59 years; 91.4% male), 37.6% had PD. Adjusted model showed significantly lower odds of incident CKD, [&ge;]40% eGFR decline, and incident albuminuria noted in both PD-Treated [OR(95%CI): 0.80(0.70-0.91), 0.69(0.56-0.84), 0.88 (0.79-0.99)] and PD-Prophylaxis groups [OR(95%CI): 0.81(0.66-0.98), 0.60(0.43-0.82), 0.79(0.67-0.94)] compared to the PD-Untreated. Similarly, among patients without PD, regular dental prophylaxis was associated with reduced odds of Incident CKD, [&ge;]40% eGFR decline, and incident albuminuria [OR(95%CI): 0.87(0.78-0.96), 0.76(0.65-0.90), 0.85(0.78-0.93)]. LimitationsRetrospective design, unmeasured confounders, and reliance on electronic health records. ConclusionsPD is associated with increased risks of incident CKD, accelerated eGFR decline, and new-onset albuminuria. Periodontal treatment and routine dental prophylaxis mitigate these risks. Even in individuals without PD, regular dental prophylaxis appears protective against CKD development and progression.

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.