BMC Nephrology

Introduction With limited treatment options, identifying risk factors for chronic kidney disease (CKD) disease progression is an important aspect of CKD management. Novel approaches for correcting case-only genome-wide association studies (GWAS) for index event bias and the availability of large GWAS conducted in people with CKD may allow us to identify such risk factors. Methods We applied Mendelian randomization (MR) using European ancestry data from CKDGen consortium to estimate the causal effect of 74 putative risk factors for CKD progression on annual decline in estimated glomerular filtration rate (eGFR) among people with CKD (N=26,653) and in the general population (N=343,339). Additionally, we examined the effect of the same risk factors on incident CKD (N=480,698). We accounted for index event bias using the Dudbridge et.al. and SlopeHunter methods in CKD case-only analyses. Results Type-2 diabetes (T2D) and high thyroid-stimulating hormone (TSH) increased annual decline in eGFR in CKD population of 0.102 (0.035,0.168) and 0.353 (0.108,0.598) ml/min/1.73 m2 per 1 log-odds higher exposure respectively. These effects were consistent after index event bias adjustment. In unadjusted analysis, pulse pressure (PP) (CKD population: 0.221 (0.041,0.402); general population: 0.059 (0.028,0.091) ml/min/1.73 m2 per SD increase); and serum uric acid level (CKD population: 0.252 (0.081,0.423); general population: 0.041 (0.007,0.075) ml/min/1.73 m2 per SD increase) also increased annual eGFR decline. Conversely, educational attainment decreased annual eGFR decline (CKD population: -0.051 (-0.102,-0.001); general population: -0.016 (-0.025,-0.007)). Conclusion We applied novel methodological approaches to correct for index event bias in CKD case-only GWAS, enabling investigation of putative risk factors for CKD progression. Cardiometabolic traits showed suggestive effects on kidney function decline and there was evidence of a causal effect of T2D and high TSH on annual decline in eGFR. These findings highlight potential targets to slow CKD progression.

ABSTRACT Importance: The prevalence of chronic kidney disease (CKD) is increasing, with aging being a major contributor. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are well established therapies for CKD; however, adults aged 80 years or older have been underrepresented in previous large-scale trials. Consequently, evidence regarding effects of SGLT2i therapy in this cohort remains limited. Objective: To evaluate the association of SGLT2i initiation with mortality, kidney outcomes and cardiovascular outcomes among patients over 80 years of age and CKD. Design, Setting, Participants: This retrospective cohort study used data from TriNetX Research Network, a multicenter electronic health record database. To ensure comparable standard of care and SGLT2i eligibility, the period for the occurrence of the index event was restricted to January 1, 2021, until January 1, 2025. Propensity score matching was performed to balance comorbidities, laboratory parameters, concomitant medications, and frailty-associated factors between groups. Exposures: Initiation of SGLT2i therapy vs. non-use Main Outcomes and Measures: Outcome analysis focused on all-cause mortality, major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE). Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals; following propensity score matching, results were considered as adjusted hazard ratios (aHR). Results: After propensity score matching, 5,038 patients were included in each group. During two years of follow-up, SGLT2i initiation was associated with lower all-cause mortality (aHR 0.818; 95% CI 0.746 - 0.896, p<0.0001) and fewer MAKE events (aHR 0.779; 95% CI 0.0.715 - 0.850, p<0.0001). No significant difference in MACE was observed (aHR 1.007; 95%CI 0.938 - 1.082, p=0.84). Results were generally consistent across subgroups. Risk of acute kidney injury was higher in the SGLT2i group, while incident dialysis and end-stage renal disease were significantly reduced. Acute myocardial infarction and acute heart failure were increased in the SGLT2i group. Conclusion and Relevance: Regarding survival and kidney endpoints, even the oldest CKD patients seem to benefit from SGLT2i treatment, which was associated with reduced mortality as well as improved long-term renal outcomes. MACE showed no significant differences, while specific cardiac events were increased, reflecting possible safety concerns requiring further investigation in this specific age group.

Vitamin D sterols, phosphorus binders and calcimimetics are used to treat chronic kidney disease mineral and bone disorder (CKD-MBD) in hemodialysis. With few randomized trials, providers may titrate agents differently reflecting equipoise and opportunities for clinical trials. We studied patients initiating in-center hemodialysis at Dialysis Clinic, Inc facilities from 2006-2015 and who remained on hemodialysis for [&ge;]90 days (n=23,549). Multinomial logit models assessed titration among users of each medication at the start of the month considering static and dynamic CKD-MBD laboratories. Similarly parameterized logistic models assessed treatment initiation. Differences across facilities were quantified as random effects and corresponding median odds ratios. We observed patterns of titration associated with CKD-MBD laboratories including albumin-corrected serum calcium (Ca), serum phosphorus and parathyroid hormone (PTH) and minimal impact of patient characteristics. Best fit models incorporated 3 months of lagged Ca and phosphorus values and linear splines for current Ca, phosphorus and PTH values. Absolute titration probabilities for vitamin D sterols and calcimimetics were influenced by all three CKD-MBD parameters, such that Ca and phosphorus values altered the threshold PTH at which escalation and de-escalation probabilities crossed. Median odds ratios indicated the greatest facility variation for vitamin D sterol titration. Providers titrate CKD-MBD medications based largely on the full CKD-MBD laboratory phenotype, including the recent serum Ca, phosphorus and PTH history. Facility variation suggests equipoise in titration of vitamin D sterols with opportunities for clinical trials.

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.

Background Acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition is associated with dynamic changes in tubular cell state. However, conventional single-cell transcriptomic analyses primarily identify genes differentially expressed between disease states and do not directly evaluate genes associated with directional transitions between cellular states. Methods We developed REN-former by fine-tuning Geneformer using the GSE183276 single-cell RNA-sequencing dataset from 45 participants representing Normal Reference, AKI, and CKD states. In silico gene deletion and overexpression analyses were used to estimate directional transcriptomic shifts, with a focus on proximal tubular cells. Selected genes were evaluated using summary-data-based Mendelian randomization (SMR), colocalization and expression analysis in additional KPMP participants not included in GSE183276. Results REN-former achieved recall values of 0.99, 0.80, and 0.79 for Normal Reference, AKI, and CKD, respectively. In silico perturbation analyses identified distinct gene programs associated with transitions from Normal Reference to AKI, from Normal Reference to CKD, from AKI to CKD, and from CKD to Normal Reference. Conventional analysis showed metabolic suppression and increased inflammatory and stress-response activation. SMR identified IFITM3, CALR, TTR, CALM1, MUC13, and RPL13, and colocalization supported IFITM3, CALR, TTR, and CALM1. In additional KPMP data, IFITM3 was higher, whereas TTR and CALM1 were lower, in CKD proximal tubules; CALR did not differ significantly. The observed expression changes were concordant with the REN-former-predicted directions for TTR and CALM1 but discordant for IFITM3. Conclusion REN-former provides a framework for prioritizing candidate regulators of kidney disease-associated cell states by integrating predicted perturbation effects with human genetic and transcriptomic evidence.

Background: The dietary approaches to stop hypertension (DASH) diet is often recommended to patients with chronic kidney disease, although evidence regarding its efficacy in this population is limited. Our study tested the hypothesis that increased adherence to the dietary approaches to stop hypertension (DASH) diet score would be associated with longer time to kidney function decline among Veterans. Methods: We conducted a retrospective cohort study of 251,921 Veterans enrolled in the Million Veteran Program (MVP). The DASH diet score was calculated from the food frequency questionnaire and categorized into tertiles. The primary outcome was a composite of: Kidney event or death, where a kidney event was defined as a sustained 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Cox regression models compared the hazard for both outcomes by DASH score tertiles. We examined modification by ancestry, sex and other clinical characteristics Results: The median age was 67 years and 90% of Veterans were men. There were 59,269 (23.5%) who experienced the primary composite outcome, during the maximum follow-up of 10 years (median 6.1 years). Crude incidence rates for the kidney event and death outcome were 43.3, 40.4, and 36.8 per 1000 person-years of DASH score by tertiles. DASH score was associated with a lower hazard ratio (HR) for the primary composite outcome; third vs first tertile 0.81 (95% Confidence Interval (CI) 0.80 - 0.83) and second vs first tertile HR 0.90 [95% CI 0.88 - 0.92]. In subgroup analysis for individuals of African ancestry, Admixed American, and Females, only the third tertile of the DASH score was associated with a statistically significant reduction in composite outcome. Conclusion: Beneficial associations of the DASH diet were observed across subgroups. Future research is needed to understand gene and environmental factors that influence the observed subgroup differences

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).

Introduction: Red blood cell distribution width (RDW) and intra-individual variability (IIV) of biomarkers are different types of variation. Although their high levels are commonly associated with high mortality risks and poor clinical outcomes, the reason for this remains unclear. Methods: We explored the significance of this similarity using time-series data (from 143,475 samples) collected over a 9-year period from 1,216 patients on long-term hemodialysis. The IIV of each of the 22 blood-based biomarkers was assessed using the moving coefficient of variation (mCV). Non-linear longitudinal/temporal changes of the variables and their mutual relationships were analyzed using generalized additive (mixed) models. Results: RDW and all of the IIVs showed similar trends throughout the entire period of dialysis treatment: a rapid decrease after hemodialysis initiation followed by an increase that accelerated prior to death. The slopes of these downward and upward trends during each one-year period were statistically different from zero for RDW and the majority of the IIVs. Given the reported increase in the RDW and IIVs of several biomarkers in the pre-dialysis stages of chronic kidney disease, these shared changes might reflect alterations in homeostatic capacity. The RDW exhibited positive correlations with the mCVs of all 22 biomarkers (all p-values < 0.0009), suggesting that it represents dysregulation of the overall physiological system. Furthermore, the levels of the biomarkers showed a specific (nearly linear or U-shaped) relationship with the RDW, analogous to their reported relationship to all-cause mortality in the hemodialysis population. Conclusion: Increased RDW could serve as a marker of physiological dysregulation, and measurement of the RDW can be an effective tool for assessing the overall health status and identifying optimal ranges for various health indicators.

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: 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: Current understanding of acute kidney injury (AKI) risk factors remains largely descriptive, offering limited precision into how specific biomarker values or physiologic thresholds influence susceptibility. We aimed to synthesize knowledge from machine learning models trained across multiple health systems to identify generalizable, value-specific risk drivers and biomarker interactions contributing to AKI risk. Methods: We analyzed electronic health records (EHRs) from 785,497 adult inpatients between 2010 and 2019 across nine U.S. academic medical centers within PCORnet. Interpretable gradient boosting machine models were independently developed at each health system to quantify predictor-outcome associations. Meta-regression was applied to integrate these site-level results, characterize nonlinear value-risk relationships, and identify bivariate interactions between predictors. Results: Meta-analysis revealed consistent, value-specific risk drivers across health systems. An increase in glucose from 100 mg/dL to 140 mg/dL was associated with a 1.46-fold higher risk of AKI. Chloride and anion gap also demonstrated elevated AKI risk with risk increases overlapping portions of their reference ranges, with anion gap showing a 1.14-fold increase across 4-12 mmol/L and chloride a 1.28-fold increase across 96-100 mEq/L. Electrolytes including potassium, calcium, and sodium showed quadratic associations with AKI risk. Bivariate meta-regression identified interactions between key predictors, highlighting pathways that jointly modulate AKI risk. Conclusion: This cross-system meta-analysis synthesizes machine learning-derived evidence into clinically interpretable knowledge, revealing how specific biomarker ranges and interactions modulate AKI risk. By moving beyond surface-level associations to quantitative, generalizable physiologic thresholds, these findings provide actionable insights to enhance risk stratification and personalized prevention in hospital care.

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.

Nutritional status and immune function have a significant impact on the prognosis of patients undergoing maintenance hemodialysis (MHD). Previous studies have shown that the Geriatric Nutritional Risk Index (GNRI) and the Prognostic Nutritional Index (PNI) at the initiation of dialysis can be used to assess the prognosis of MHD. However, as the physical status of patients are usually unstable in the early stage of dialysis, we hypothesized that the nutritional status and immune function after a certain period of stable dialysis might be more closely related to the prognosis. This study conducted a retrospective analysis of patients who started MHD between January 1, 2019 and December 31, 2021. A total of 200 patients were included, with 66 patients succumbing during follow-up. Both initial PNI and initial GNRI exhibited a negative correlation with all-cause mortality (p=0.019 and p=0.046, respectively). After three months of MHD, both PNI and GNRI increased in most patients; however, only the PNI measured after three months was significantly associated with prognosis and higher PNI was associated with a better prognosis (p<0.001). Multivariate Cox regression analyses indicated that only PNI after three months of MHD was linked to prognosis (p=0.004). Kaplan-Meier curves demonstrated patients experiencing a decrease in PNI following three months of MHD had poorer prognoses compared to those whose PNI increased (p=0.004). Furthermore, the predictive value of PNI after three months of MHD was evident in both younger (<60 years old; p=0.024) and older (>60 years old; p=0.022) patient groups. Both the PNI and GNRI showed a downward trend before death, but only PNI had a significant decline (p=0.03, compared with PNI after three months of MHD). In conclusion, for patients undergoing MHD, the correlation between PNI and prognosis is closer than that of GNRI, and the PNI after three months of MHD is a statistically significant but moderate predictor of long-term outcomes.

Cognitive and psychological difficulties are frequently reported by patients undergoing haemodialysis, yet these experiences are rarely explored within routine clinical assessments. The aim of this study was to examine self-perceived cognition and psychological well-being as patient-reported outcomes in adults with chronic kidney disease undergoing maintenance haemodialysis, and to explore the relationships between these outcomes and sociodemographic, clinical, and biochemical variables. Adults receiving maintenance haemodialysis were recruited from a hospital-based dialysis unit as part of the GoodRENal project, which focuses on developing educational approaches for people on haemodialysis. Participants completed self-report measures assessing perceived cognitive functioning and psychological well-being. Sociodemographic, clinical, and biochemical data routinely collected in dialysis care were obtained from medical records. Associations were examined between self-perceived cognition, psychological well-being, and the available data. Seventy-eight patients took part in the study. Perceived cognitive difficulties were more closely related to indicators of kidney disease severity and metabolic imbalance, whereas psychological well-being showed stronger associations with social and emotional factors. The patients' subjective experiences could not be fully explained by objective clinical indicators alone, suggesting a gap between physiological measures and patient-reported outcomes. Self-perceived cognition and psychological well-being provide clinically relevant information that could complement routine clinical indicators in haemodialysis care.

Background: Data from National Health and Nutrition Examination Survey (NHANES) cycles 1988-1994 and 1999-2004 show a declining trend in the adherence to Dietary Approaches to Stop Hypertension (DASH) among adults. Since then, DASH evidence, dietary guidelines, and public-facing dietary resources have advanced, but whether national DASH adherence has improved is uncertain. Methods: We extended the Mellen et al. NHANES analysis among 14,163 adults with self-reported hypertension (N=6,914, 2003-2010, N=7,249, 2011-2018). DASH score included 9 nutrient components: total fat, saturated fat, protein, cholesterol, fiber, calcium, magnesium, potassium, and sodium, with adherence defined as a score 4.5. Survey-weighted multivariable models compared DASH score, adherence, and nutrient-threshold attainment across periods. Results: In 2011-2018, U.S. adults with self-reported hypertension represented 76.2 million individuals (33.8%). Multivariable-adjusted DASH adherence declined from 22.1% in 2003-2010 to 18.6% in 2011-2018 (p=0.003), and mean DASH score declined from 2.98 to 2.85 (p=0.007). Adjusted odds of adherence were lower in 2011-2018 compared with 2003-2010 (OR, 0.78; 95% CI, 0.67-0.91; p=0.002). Adherence was lower among non-Hispanic Black adults (OR, 0.70; 95% CI, 0.59-0.84), adults with BMI 30 kg/m2 (OR, 0.61; 95% CI, 0.51-0.73), and adults with prior stroke (OR, 0.71; 95% CI, 0.56-0.89). Total fat and sodium threshold attainment declined from 20.9% to 18.7% and 13.8% to 11.8%, respectively. Conclusions: DASH adherence among U.S. adults with self-reported hypertension declined from 2003-2011 to 2011-2018. Implementation strategies should identify barriers to adoption and address the full DASH dietary pattern.

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Introduction: Mitochondrial DNA (mtDNA) is not routinely analyzed in inherited kidney disease. We evaluated mtDNA variation in families who remained genetically unresolved despite extensive testing. Methods: We reviewed pedigrees from the Wake Forest-Charles University Rare Inherited Kidney Disease Registry to identify genetically unresolved families with suspected maternal inheritance, performed mtDNA genotyping, clinically characterized variant carriers, and functionally evaluated disease-associated mitochondrial variants. Results: Among 33 families with evidence of maternal inheritance, 18 (55%) carried one of seven disease-associated mtDNA variant types, including homoplasmic recurrent single-nucleotide insertions in the second light-strand promoter (LSP2; 9 families), novel MT-TW and MT-TL2 variants (2 and 1 families, respectively), and previously reported MT-TF and heteroplasmic MT-ND5 variant (5 and 1 families, respectively). In 16 families, variants occurred on distinct haplotypes, consistent with independent mutational events and rapid enrichment to homoplasmy across generations. Maternal transmission was strongly supported, with below-normal kidney function observed in 54/60 (90%) offspring of affected mothers versus 1/17 (6%) offspring of affected fathers (p = 1.23 x 10e-11). Pathogenicity was further supported by predicted deleterious structural effects and functional evidence of impaired mitochondrial transcription and translation, respiratory chain deficiency, and CoQ10 depletion. Affected individuals predominantly presented with chronic tubulointerstitial kidney disease, occasionally accompanied by gout and only sporadically with extrarenal manifestations. The rate of kidney disease progression appeared to vary both between and within families. Overall, 109/119 genetically affected individuals or obligate at-risk carriers were clinically affected; most unaffected carriers were younger than 45 years of age. Clinical status was unavailable for an additional 66 obligate at-risk carriers. Conclusions: These findings establish the physiological relevance of the LSP2 promoter, support routine assessment of the mitochondrial genome in inherited kidney disease, and highlight mtDNA variants as an important cause of familial and sporadic tubulointerstitial kidney disease of previously unexplained etiology.

Introduction: Depression is common among people receiving haemodialysis and is associated with adverse outcomes, but the biological pathways underlying this relationship remain uncertain. We examined associations between depressive symptoms, mortality, immune-metabolic markers and stress-related transcriptional profiles, including potential sex differences in routine biomarkers. Methods: We studied 297 adults receiving maintenance haemodialysis across North and East London and Essex. Moderate/severe depressive symptoms were defined as a 17-item Hamilton Depression Rating Scale score >18. Cox regression examined all-cause mortality from enrolment until death or administrative censoring on 24 March 2026. Linear regression assessed associations between depressive-symptom severity and routinely measured immune-metabolic markers, overall and by sex. In a laboratory subset, inflammatory proteins and transcriptional profiles were examined overall only. Results: Moderate/severe depressive symptoms were associated with higher mortality in the adjusted model, although the association was attenuated after full adjustment (HR= 1.49; 95% CI 1.00-2.23; p=0.055). Higher white-cell count was associated with greater depressive-symptom severity before, but not after, adjustment for body mass index. Diastolic blood pressure was the only routine marker showing evidence that its association with depressive symptoms differed by sex (interaction p=0.022). Exploratory analyses did not provide convincing evidence that the measured biomarkers accounted for the depression-mortality association. In the laboratory subset, no inflammatory protein or transcriptional measure was significantly associated with depressive symptoms in fully adjusted analyses. Conclusion: Depression may identify a clinically relevant risk state among people receiving haemodialysis. The exploratory biological findings require validation in larger, prospectively sampled cohorts.

Background: Fibrosis, characterised by excessive accumulation of collagen type I (COL1), is a common feature of chronic diseases, including liver diseases (LDs), chronic kidney disease (CKD) and heart failure (HF). COL1 degradation products can be detected in urine by proteomics/ peptidomics analyses and may serve as non-invasive biomarkers of fibrosis. We aimed to identify a common molecular signature of fibrosis across these diseases that may ultimately guide interventions to slow disease progression and prevent organ damage. Methods: Using capillary electrophoresis coupled to mass spectrometry (CE-MS), naturally occurring COL1 degradation products (peptides) in the urine of patients with fibrotic disease, LDs (n=127), CKD (n=263) or HF (n=187), were investigated and compared with the same number of matched controls. Disease-associated COL1 peptides were identified separately for each condition, and peptides showing consistent associations across the three diseases were selected to define a common fibrosis signature. A support vector machine model based on the selected peptides was developed and validated in independent cohorts of patients with LDs (n=110), CKD (n=93), HF (n=32) and controls (n=643). Results: We identified a common fibrotic signature consisting of 50 COL1 degradation products, mainly downregulated in fibrosis. A model based on these peptides achieved a strong performance, with an area under the receiver operating characteristic curve (AUC) of 0.935 (95% confidence interval (CI) 0.917-0.953, p<0.0001) in an external validation cohort comprising pooled disease groups (LDs, CKD, and HF) and controls. Performance was maintained in LDs, CKD and HF, with AUCs of 0.917 (95% CI 0.890-0.944, p<0.0001), 0.951 (95% CI 0.931-0.971, p<0.0001) and 0.950 (95% CI 0.903-0.997, p<0.0001), respectively. The model scores were significantly associated with fibrosis stage in LDs (p=0.0097) and with interstitial fibrosis and tubular atrophy in CKD (p=0.045). Conclusion: A model of urinary COL1 peptides captures a shared collagen degradation signature across organs and diseases, enabling the non-invasive assessment of fibrosis irrespective of its origin. As these peptides exclusively reflect collagen degradation, the findings suggest impaired collagen degradation as a driver in fibrosis. Future clinical studies are warranted to evaluate the utility of this model for early fibrosis detection and earlier implementation of anti-fibrotic interventions.

Background: Whether benchmark performance reflects robust clinical reasoning rather than surface-level pattern recognition remains uncertain. We evaluated the robustness of state-of-the-art large language models (LLMs) on nephrology board renewal questions using "None of the other answers" (NOTA) substitution. Methods: From 210 Japanese Society of Nephrology board renewal questions (2014-2023), two nephrologists independently reviewed all items. Questions in which NOTA became the sole correct answer after replacement were included, yielding 145 validated questions. GPT-5, GPT-4o, Gemini 2.5 Pro, and Gemini 2.0 Flash were evaluated via application programming interfaces under default settings. The primary endpoint was accuracy, and paired differences were assessed using the exact two-sided McNemar test. Results: Accuracy was significantly lower after NOTA substitution for all models: GPT-4o, 66.21% to 19.31% (drop, 46.90 percentage points [pp]); GPT-5, 87.59% to 73.10% (14.48 pp); Gemini 2.0 Flash, 58.62% to 31.03% (27.59 pp); and Gemini 2.5 Pro, 86.90% to 55.86% (31.03 pp); all P < .001. GPT-5 showed the smallest decline and the highest accuracy in both versions. Conclusions: All evaluated LLMs showed a significant robustness gap after NOTA replacement. Newer models may be more robust, but multiple-choice accuracy remains an incomplete measure of clinical reasoning robustness.