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.

BackgroundThe rising burden of chronic kidney disease (CKD) requires reinforcing of the current mechanisms for early detection and intervention. Although timely referral to a specialist nephrology service plays a crucial role for many patients in ensuring improved outcomes, the lack of widely accepted definitions of timely (and by implication, early and late) referral may limit such outcomes. Study aimTo evaluate referral patterns among CKD.QLD Registry participants, focusing on the timing and appropriateness of referrals and their association with clinical outcomes. MethodsWe conducted a retrospective cohort study of adults ([≥]18 years) enrolled in the CKD.QLD Registry from seven public nephrology clinics between May 2011 and June 2018. Participants were followed until kidney replacement therapy (KRT), death, or study closure. All CKD stages were included to assess demographic and clinical characteristics at referral and associated outcomes. Late referral was defined as initiation of KRT within 12 months of the first nephrology visit among those who progressed to KRT. ResultsAmong 3,775 participants (median age 65 years; 54.8% male; 8.7% Indigenous), hypertension (77.5%) and type 2 diabetes (44.9%) were the most common comorbidities. ESKD developed in 775 (20.5%) participants; 513 (66.2%) received KRT. Overall, 722 (19.1%) died, including 124 (17.2%) after starting KRT. Late referral occurred in 60 (11.7%) KRT participants, with 15 (25%) deaths, 3 within 12 months of KRT initiation. Most KRT patients (77.4%) and deaths (65.5%) were in the high-comorbidity group; among KRT-related deaths, 101 (81.5%) were high-comorbidity, and 351 (88.4%) were referred early. ConclusionLate referral rates were lower than previously reported. Comorbidity burden, rather than referral timing, was the stronger predictor of mortality. These findings highlight the need for a standardized definition of late referral that incorporates risk stratification.

IntroductionLifestyle interventions have been shown to produce favorable changes in some health outcomes in patients with chronic kidney disease (CKD). However, few such studies, employing "real world" methods have been completed in patients with CKD. ObjectiveThis study tested the effectiveness of a comprehensive, multicomponent, lifestyle intervention, delivered through individualized counseling on a variety of health outcomes in pre-dialysis CKD patients. MethodsEligible patients were assigned randomly to the intervention (TR) or usual care group (UC). A six-month home-based program involving personalized counseling to increase physical activity to recommended levels among stage G3a to G4 CKD patients while exchanging plant proteins for animal proteins was implemented. Physical function, cardiovascular function, dietary intake, medication use, and health-related quality of life (HRQOL) were assessed at baseline and after 1-month, 3-months (M3) and 6-months (M6). ResultsForty-two, patients (age 60.2 {+/-} 9.2, BMI 34.5 {+/-} 7.8) participated in this study (TR=27 UC=15). The intervention reduced (p<0.05) brachial (bSBP) and central systolic blood pressures (cSBP) at month 3 (M3) but both were attenuated at month 6 (M6). Scores on the effect of kidney disease subscale of the HRQOL measure improved in the intervention group at M3 and M6. There was no change in the other measures of HRQOL or in any physical function scores. ConclusionsThis personalized multi-component lifestyle intervention enabled CKD patients to self-report fewer concerns with how CKD affected their daily lives independent of changes in physical function.

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.

BackgroundPhysical function is severely compromised in people with chronic kidney disease (CKD) and worsens with continued decreases in kidney function. Neuromuscular force capacity is a key determinant of physical function in healthy older adults, though its importance in persons with CKD is less understood. MethodsThis study aimed to determine the relationships among rate of force development (RFD), muscle quality and physical function in a group of community-dwelling, middle-aged and older men (n=14; age=71.2{+/-}6.2 years) with CKD stages 3 and 4 (eGFR=37.5{+/-}10.4 ml/min per 1.73 m2). Force characteristics were determined from maximal knee extensor isometric contractions and muscle quality was estimated using ultrasound grayscale analysis. Physical function was assessed by the Short Physical Performance Battery (SPPB) and 5-repetition sit-to-stand (STS) test. ResultseGFR was directly related to SPPB (r=0.54, p=0.044) and inversely related to STS (r=-0.62, p=0.029). RFD was positively related to SPPB at time points 0-50 ms, 50-100 ms, and 0-300 ms (RFD0-50, r=0.73, p=0.010; RFD50-100, r=0.67, p=0.022 and RFD0-300 r=0.61, p=0.045); and inversely related to STS at time points 0-50 ms, 50-100 ms, and 0-300 ms (RFD0-50, r=-0.78, p=0.007; RFD50-100, r=-0.78, p=0.006 and RFD0-300 r=-0.76, p=0.009), respectively. RFD was positively associated with maximal voluntary force (MVF) at times 50-100 ms, 100-200 ms, and 0-300 ms (RFD50-100, r=0.72, p=0.011; RFD100-200, r=0.66, p=0.025; and RFD0-300 r=0.70, p=0.016), respectively. Neither MVF nor muscle quality was significantly associated with functional measures. ConclusionsRFD is an important determinant of physical function in middle-aged and older men with CKD stages 3 and 4.

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.

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.

Objective: To determine the absolute risk of starting dialysis versus mortality among adults with chronic kidney disease (CKD) treated at EsSalud from 2013 to 2022, utilizing data from the Renal Health Surveillance system (VISARE). Methods: This retrospective cohort study analyzed clinical records from the VISARE system (EsSalud). We estimated rates of dialysis initiation and death using Fine & Gray competitive risk models. Additionally, we calculated Restricted Mean Survival Time (RMST), adjusting for age, sex, clinical stage, and geographic region. Results: Among 142,770 adults with confirmed CKD and available glomerular filtration rate data, only 15.2% had albumin-to-creatinine ratio measurements, allowing KDIGO staging of 40,404 patients (28.3%). Mortality without having previously started dialysis exceeded the probability of starting renal replacement therapy (RRT) from G1, becoming more marked in G3 of chronic kidney disease (CKD); the possibility of dialysis is only greater, as expected, in G5. This outcome was most prevalent in regions with limited healthcare coverage. The combination of diabetes, hypertension, and age over 55 (the triad) was associated with reduced restricted mean survival time at both 5- and 10-year horizons across all enrollment cohorts. While Lima saw the highest rates of renal replacement therapy initiation, the Andean and Amazonian regions reported the lowest indicators. Conclusions Death without prior dialysis was the dominant outcome from G1 to G3 in this Peruvian cohort with national insurance, with direct implications for prognostic counseling, recalibration of renal failure risk equations, and equitable expansion of nephrology services in underserved regions. Keywords: Renal Insufficiency, Chronic; Competitive Risk; Diabetes Mellitus; Hypertension; Mortality; Mass Screening.

BackgroundChronic kidney disease (CKD) is associated with an increased risk for cardiovascular events, hospitalizations or mortality. In populations aged [&ge;]40 years, CKD is as prevalent as diabetes or coronary heart disease. Awareness for CKD though is generally low in public, patients and physicians, which hinders early diagnosis and treatment to decelerate disease progress. MethodWe analyzed baseline data collected in 2010 from 3,334 participants with CKD stages 1-5 from German CKD cohorts and registries. CKD unawareness and 95%-confidence intervals (CI) was estimated according to patients answer to the question whether they had ever been told to suffer from a CKD. Prevalence ratios (PR) with 95%-CI were estimated in categories of age, sex, CKD stages, BMI, hypertension, diabetes and other relevant comorbidities. ResultsCKD unawareness was high, reaching 82% (95% CI: 80%-84%) for CKD stages 1 or 2, 71% (68%-73%) in CKD 3a, 49% (45%-54%) in CKD 3b and still 30% (24%-36%) in CKD4, in each stage increasing with age. CKD unawareness was similarly high in patients with hypertension, diabetes or cardiovascular comorbidities. Women were more often unaware than men (PR=1.07 (1.02;1.12)), this sex difference increased with increasing CKD stage. Macroalbuminuria (PR=0.90 (0.82; 1.00)), anemia (PR=0.78 (0.73; 0.83)) and BMI [&ge;]40 (PR=0.88 (0.77; 1.00)) were associated with higher CKD awareness. ConclusionEven in older patients or in patients with comorbidities, CKD unawareness was high. Sex differences were largest in later stages. Guideline oriented treatment of patients with hypertension or diabetes could increase awareness. Patient-physician communication about CKD might be amendable.

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.

Rationale & Objective: People who live in rural areas with advanced chronic kidney disease (CKD) face well-documented structural barriers to receiving care, yet little is known about how they experience their illness or perceive interactions with their healthcare teams. We aimed to characterize the lived experiences and care perceptions of adults living in rural areas with advanced, pre-dialysis CKD. Study Design: We conducted semi-structured qualitative interviews with patients and care partners. Setting & Participants: We recruited patients with advanced CKD (stages 4-5, not on dialysis) and their care partners from a single hospital-based nephrology clinic in northern New England serving a predominantly rural population. Analytical Approach: We analyzed interview transcripts using participatory Practical Thematic Analysis (PTA), an inductive, stakeholder-engaged approach to qualitative analysis. Results: We interviewed 12 patients and 4 care partners. Four themes were identified: (1) logistical challenges of rural CKD care were pervasive but frequently normalized as an expected feature of rural life; (2) disease progression and future treatments were sources of uncertainty and concern, with expectations about dialysis often shaped by peer accounts rather than clinical discussion; (3) clinical conversations centered on laboratory results and medications, leaving emotional concerns and psychologic challenges unaddressed; and (4) physical symptoms and lifestyle changes were common but frequently attributed to comorbid conditions rather than to CKD. Limitations: Recruitment from a single clinic with a small, racially homogeneous sample limits transferability. While in-person recruitment may have excluded patients with greater transportation barriers, those who attended represent a population navigating substantial access challenges to receive care. Conclusions: Adults living in rural areas with advanced CKD experience logistical, emotional, and informational challenges broadly consistent with those reported in non-rural CKD populations. Patients normalized geographic barriers and did not consistently identify rurality as a source of disadvantage, even as structural barriers persisted. These findings support the development of structured communication approaches in nephrology care that invite discussion of disease trajectory, daily life impacts, and emotional concerns.

Background: Initiation of emergency dialysis, often requiring temporary catheter owing to unprepared definitive vascular access, is associated with infectious and vascular complications and suggests advanced chronic kidney disease (CKD) care gaps. Previous studies focused on kidney failure or dialysis timing. This study aimed to predict initiation of emergency dialysis using machine learning and baseline data. Methods: This retrospective cohort study used the Japan Medical Data Center claims data (2014-2022). Adults with an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 were included. The primary outcome was initiation of emergency dialysis (temporary catheter code without evidence of previous access preparation). Participants were randomly divided into derivation (80%) and validation (20%) cohorts. Logistic regression, support vector machine, XGBoost, LightGBM, and random forest models were evaluated using internal cross-validation, post-hoc calibration of the selected model, and bootstrap confidence intervals. Results: The cohort included 3,062 individuals (derivation; n=2,449, validation; n=613). Emergency dialysis was initiated in 237 participants (7.7%); 185 (7.6%) and 52 (8.5%) in the derivation and validation cohorts, respectively. Validation area under the receiver operating characteristic curve ranged from 0.781-0.799, with the highest value observed for random forest (0.799, 95% confidence interval; 0.740-0.850). Risk stratification showed clear event enrichment in higher predicted risk categories. SHAP analyses identified hemoglobin, proteinuria, baseline eGFR, diabetes history, and diuretic use as key predictors. Decision curve analysis showed greater net benefit than eGFR alone at lower threshold probabilities. Conclusions: Baseline machine learning models showed moderate discrimination for initiation of emergency dialysis and identified clinically plausible predictors. These findings support potential use for risk stratification, although external validation and evaluation within pre-specified care pathways are needed before implementation.

BackgroundPatient activation, defined as the knowledge, skills, and confidence to manage ones health, is associated with better outcomes in chronic disease. However, evidence on interventions that improve activation in people with end-stage kidney disease on hemodialysis remains limited. Methods and analysisThis single-centre, prospective, participant-blinded, randomised controlled trial conducted with adults undergoing chronic hemodialysis in an acute dialysis unit tests the hypothesis that adding tailored activation interventions to usual care improves patient activation and reduces complications in hemodialysis patients compared to usual care alone. A target sample size of 140 patients was recruited and randomised to iPAD interventions or usual care in a 1:1 ratio with an expected intervention period of at least 6 months. The primary outcome of iPAD was change in patient activation from baseline to 18 months. Ethics and disseminationThis study has been approved by all institutional ethics review boards involved in the study. Participants could only be enrolled following informed written consent. Results will be published in peer-reviewed journals and presented at scientific and clinical conferences. ConclusionRecruitment and enrolment targets were successfully achieved, with the cohort broadly representative of the dialysis population, including strong participation from culturally and linguistically diverse and socioeconomically disadvantaged groups. The careful planning and successful execution of the study in resource-constrained environments highlight its feasibility and flexibility, establishing it as a scalable and cost-efficient model for broad implementation in dialysis care globally.

Background and aimsHeart failure and chronic kidney disease (CKD) are closely linked, with iron deficiency being highly prevalent in both conditions. Yet, major cardiovascular and nephrology guidelines offer contrasting recommendations on the use of iron. We evaluated the effects of iron versus usual care/placebo on clinical outcomes in patients with CKD. MethodsWe conducted a systematic review and meta-analysis of randomised trials of intravenous or oral iron in CKD (PROSPERO CRD42023453468). We searched Medline, Embase and the Cochrane Register from database inception until February 1, 2024 to identify eligible trials. We determined results overall and stratified by dialysis- and non-dialysis-requiring CKD using random effects models, with certainty of evidence assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary composite endpoint was heart failure hospitalisation or cardiovascular death. ResultsWe identified 45 trials that met our inclusion criteria. Compared to usual care/placebo, iron reduced the risk of the primary composite endpoint (1659 events; RR 0.84, 95% CI 0.75-0.94; moderate certainty) an effect consistent across dialysis and non-dialysis requiring CKD (P-heterogeneity=0.70). The effect on the primary endpoint appeared driven by both components of hospitalisation for heart failure (RR 0.77; 95% CI 0.61-0.96; moderate certainty) and cardiovascular death (RR 0.81; 95% CI 0.65-1.02; low certainty). The incidence of serious adverse events was lower for iron compared to usual care/placebo (RR 0.90, 95% CI 0.82-0.98; moderate certainty; P-heterogeneity=0.09). ConclusionIron therapies may reduce the risk of heart failure or cardiovascular death in patients with CKD. Randomised rials evaluating effects of iron on clinical outcomes are needed, especially in non-dialysis CKD, with or without anaemia.

BackgroundAdaptive design methods are intended to improve efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to quantify the use of adaptive designs in dialysis clinical trials. MethodsWe completed a full text systematic review and adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Our review utilised a machine learning classifier and a novel full text systematic review method. We searched MEDLINE (Pubmed) and performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data. Results50 studies, available as 66 articles, were included after full text review. 31 studies were conducted in a dialysis population and 19 studies had renal replacement therapy as a primary or secondary outcome. While the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.1% in 2009 to 0.3% in 2019). Adaptive design methods impacted 52% of dialysis trials they were used in. Group sequential designs were the most common type of adaptive design method used. Acute Kidney Injury (AKI) was studied in 27 trails (54%), End Stage Kidney Disease (ESKD) was studied in 22 trials (44%) and Chronic Kidney Disease (CKD) was studied in 1 trial (2%). 26 studies (52%) were supported by public funding. 41 studies (82%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic. ConclusionsAdaptive design methods are employed in dialysis trials, but there has been a decline in their relative use over time. Registration NumberPROSPERO: CRD42020163946 Significance statementO_ST_ABSWhat was previously known about the specific topic of the manuscript?C_ST_ABSThe use of adaptive designs methods in dialysis trials is unquantified. What were the most important findings? If studies are animals, this should be specifiedAlthough absolute numbers of adaptive design trials have increased over time, the proportion of dialysis trials using an adaptive design has reduced. Among trials that employed an adaptive design, 52% of dialysis trials were revised due to the adaptive criteria. Group sequential designs were the most common type of adaptive design method used in dialysis randomized clinical trials. Acute Kidney Injury (AKI) was studied in 54% of trials and End Stage Kidney Disease (ESKD) was studied in 44% of trials, which used an adaptive design. How does the new information advance a new understanding of the kidney and its diseases?Adaptive design methods are effective in dialysis trials, but their relative use has declined over time.

Arteriovenous (AV) access choice has sparked controversy with recent evidence suggesting overestimation of benefits associated with AV fistula versus graft in certain populations. We assessed outcomes associated with first-line AV access type in patients who started hemodialysis with a catheter in France, overall and by subgroups of age, sex, and comorbidities. In this retrospective cohort study, we included incident patients who initiated hemodialysis with a catheter from 2010 through 2018, followed by the French REIN Registry. Our main exposure was the first-line (first-created) AV graft versus fistula, ascertained through the linkage with the French national health-administrative database. Outcomes were all-cause and cause-specific hospitalization, and all-cause mortality. We used joint frailty models to deal with recurrent hospitalizations and informative censoring by death, Cox proportional hazard (PH) models, and inverse probability weighting. From the 18,625 patients included (mean age was 68{+/-}15 years, 35% were women), 5% had a first-line AV graft. Patients with AV graft had an 11%-higher weighted hazard of all-cause hospitalization (95% CI 1.09 to 1.13), 16% higher weighted hazard of cardiovascular (95% CI 1.05 to 1.29) and infection-related (95% CI 1.01 to 1.33) hospitalization, 34% higher weighted hazard of vascular access-related hospitalization, and a 9%-higher weighted hazard of all-cause death (95% CI 0.97 to 1.23). Results were consistent for most subgroups, except that the highest hazard of hospitalization with AV graft was blunted in patients with comorbidities (i.e. diabetes, weighted HR of all-cause hospitalization 1.03, 95% CI 0.95-1.12).- To conclude, in patients starting hemodialysis with a catheter, first-line AV graft is associated with increased hazard of hospitalization vs. patients with AV fistula. This may, however, not be the case for patients with a poor vascular condition, i.e., those with diabetes, who have a similar hospitalization and mortality rates with either graft or fistula.

Withdrawal StatementThe authors have withdrawn their manuscript owing to uncorrectable data errors which were discovered after posting. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

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 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.