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One of the puzzles to have emerged from the Kepler and TESS missions is the existence of unexplained dips in the light curves of a small fraction of rapidly rotating M dwarfs in young open clusters and star-forming regions. We present a theoretical investigation of one possible explanation – that these are caused by dust clouds trapped in the stellar magnetic fields. The depth and duration of the observed dips allow us to estimate directly the linear extent of the dust clouds and their distances from the rotation axis. The dips are found to be between 0.4 and 4.8 per cent. We find that their distance is close to the co-rotation radius: the typical location for stable points where charged particles can be trapped in a stellar magnetosphere. We estimate the charge acquired by a dust particle due to collisions with the coronal gas and hence determine the maximum grain size that can be magnetically supported, the stopping distance due to gas drag, and the time-scale on which dust particles can diffuse out of a stable point. Using the observationally derived magnetic field of the active M dwarf V374 Peg, we model the distribution of these dust clouds and produce synthetic light curves. We find that for 1μm dust grains, the light curves have dips of 1–3 per cent and can support masses of order of 1012 kg. We conclude that magnetically trapped dust clouds (potentially from residual disc accretion or tidally disrupted planetesimal or cometary bodies) are capable of explaining the periodic dips in the Kepler and TESS data. [ABSTRACT FROM AUTHOR]

Spectropolarimetric data allow for simultaneous monitoring of stellar chromospheric |$\log {R^{\prime }_{\rm {HK}}}$| activity and the surface-averaged longitudinal magnetic field, Bl , giving the opportunity to probe the relationship between large-scale stellar magnetic fields and chromospheric manifestations of magnetism. We present |$\log {R^{\prime }_{\rm {HK}}}$| and/or Bl measurements for 954 mid-F to mid-M stars derived from spectropolarimetric observations contained within the PolarBase database. Our magnetically active sample complements previous stellar activity surveys that focus on inactive planet-search targets. We find a positive correlation between mean |$\log {R^{\prime }_{\rm {HK}}}$| and mean log | Bl |, but for G stars the relationship may undergo a change between |$\log {R^{\prime }_{\rm {HK}}}\sim -4.4$| and −4.8. The mean |$\log {R^{\prime }_{\rm {HK}}}$| shows a similar change with respect to the |$\log {R^{\prime }_{\rm {HK}}}$| variability amplitude for intermediately active G stars. We also combine our results with archival chromospheric activity data and published observations of large-scale magnetic field geometries derived using Zeeman–Doppler Imaging. The chromospheric activity data indicate a slight under-density of late-F to early-K stars with |$-4.75\le \log {R^{\prime }_{\rm HK}}\le -4.5$|⁠. This is not as prominent as the original Vaughan–Preston gap, and we do not detect similar under-populated regions in the distributions of the mean | Bl |, or the Bl and |$\log {R^{\prime }_{\rm HK}}$| variability amplitudes. Chromospheric activity, activity variability, and toroidal field strength decrease on the main sequence as rotation slows. For G stars, the disappearance of dominant toroidal fields occurs at a similar chromospheric activity level as the change in the relationships between chromospheric activity, activity variability, and mean field strength. [ABSTRACT FROM AUTHOR]

We report results of a spectropolarimetric and photometric monitoring of the weak-line T Tauri star V410 Tau based on data collected mostly with SPIRou, the near-infrared (NIR) spectropolarimeter recently installed at the Canada-France-Hawaii Telescope , as part of the SPIRou Legacy Survey large programme, and with TESS between October and December 2019. Using Zeeman–Doppler Imaging (ZDI), we obtained the first maps of photospheric brightness and large-scale magnetic field at the surface of this young star derived from NIR spectropolarimetric data. For the first time, ZDI is also simultaneously applied to high-resolution spectropolarimetric data and very-high-precision photometry. V410 Tau hosts both dark and bright surface features and magnetic regions similar to those previously imaged with ZDI from optical data, except for the absence of a prominent dark polar spot. The brightness distribution is significantly less contrasted than its optical equivalent, as expected from the difference in wavelength. The large-scale magnetic field (⁠|${\sim}410$|  G), found to be mainly poloidal, features a dipole of |${\sim}390$|  G, again compatible with previous studies at optical wavelengths. NIR data yield a surface differential rotation slightly weaker than that estimated in the optical at previous epochs. Finally, we measured the radial velocity of the star and filtered out the stellar activity jitter using both ZDI and Gaussian Process Regression down to a precision of |${\sim}0.15$| and 0.08  |$\mathrm{km}\, \mathrm{s}^{-1}$| RMS, respectively, confirming the previously published upper limit on the mass of a potential close-in massive planet around V410 Tau. [ABSTRACT FROM AUTHOR]

Background: Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti-VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria; effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers., Methods: An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 mg/kg or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-to-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 mL/min/1.73m2. Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at Week 16., Results: In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at Week 16 (combined CSL346 group difference from placebo 95% confidence interval]: 4.0% [-14.7, 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 [SGLT2] inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic blood pressure was significantly higher with CSL346 16 mg/kg versus placebo from Week 2 onwards, with differences ranging from +3.8 to +5.3 mmHg (P = 0.002 at Week 16)., Conclusions: CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD, and was associated with an increase in diastolic blood pressure., (Copyright © 2024 by the American Society of Nephrology.)

Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg l -1 at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l -1 was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961 ., (© 2024. The Author(s).)

Background and Hypothesis: Heart failure is characterized as cardiac dysfunction resulting in elevated cardiac filling pressures with symptoms and signs of congestion. Distinguishing heart failure from other causes of similar presentations in patients with kidney failure is challenging but necessary, and is needed in randomized controlled trials (RCTs) to accurately estimate treatment effects. The objective of this study was to review heart failure events, their diagnostic criteria and adjudication in RCTs of patients with kidney failure treated with dialysis. We hypothesized that heart failure events, diagnostic criteria and adjudication were infrequently reported in RCTs in dialysis., Methods: We conducted a meta-epidemiologic systematic review of RCTs from high impact medical, nephrology and cardiology journals from 2000 to 2020. RCTs were eligible if they enrolled adults receiving maintenance dialysis for kidney failure and evaluated any intervention. Results. Of 561 RCTs in patients receiving dialysis, 36 (6.4%) reported heart failure events as primary (10, 27.8%) or secondary (31, 86.1%) outcomes. 10 of the 36 (27.8%) RCTs provided heart failure event diagnostic criteria and 5 of these 10 (50%) adjudicated heart failure events. These 10 RCTs included event diagnostic criteria for heart failure or heart failure hospitalizations, and their criteria included dyspnea (5/10), edema (2/10), rales/crackles (4/10), chest x-ray pulmonary edema or vascular redistribution (4/10), treatment in an acute setting (6/10) and ultrafiltration or dialysis (4/10). No study explicitly distinguished heart failure from volume overload secondary to non-adherence or underdialysis., Conclusion: Overall, we found that heart failure events are infrequently reported in RCTs in dialysis and are heterogeneously defined. Further research is required to develop standardized diagnostic criteria that are practical and meaningful to patients and clinicians., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity., Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge., Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021., Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke., Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition., Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge., Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Background: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established., Method: The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events., Results: At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30)., Conclusions: People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A., Clinical Trial: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791., Competing Interests: Disclosures Dr. Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; is a director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Drs. Tefera, Yavin, and Hansen are full-time employees of Jansen Research & Development, LLC. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor-A (VEGF-A) and may play a role in diabetic kidney disease (DKD). We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations., Methods: Two thousand five hundred sixty-five study participants with DKD and available plasma samples treated with canagliflozin or placebo in the Canagliflozin and Kidney Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial were included. Angiopoietin 2 and VEGF-A concentrations were measured at baseline, year 1, and year 3. The primary composite end point of the trial was a composite of kidney failure, doubling of the serum creatinine level, and kidney or cardiovascular death., Results: Patients with the highest baseline quartile of angiopoietin 2, but not VEGF-A, concentration had the highest risk clinical profile. Treatment with canagliflozin significantly lowered concentrations of angiopoietin 2 (adjusted geometric mean ratio: 0.94; 95% confidence interval, 0.92 to 0.95; P < 0.001), but not VEGF-A. In multivariable-adjusted modeling, each 50% increment in log baseline angiopoietin 2 concentrations was associated with a higher risk of primary composite outcome (hazard ratio, 1.27; 95% confidence interval, 1.13 to 1.43). Angiopoietin 2 change at year 1 compared with baseline explained 10% of the effect of canagliflozin on the primary composite outcome. VEGF-A concentrations were not associated with outcomes, alone or in combination with angiopoietin 2., Conclusions: Higher angiopoietin 2 levels were associated with cardiorenal risk among individuals with DKD independent of VEGF-A. Canagliflozin lowered angiopoietin 2 concentrations., Clinical Trial Registry Name and Registration Number: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy, NCT02065791 ., (Copyright © 2023 by the American Society of Nephrology.)

Significance Statement: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population., Background: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration., Methods: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status., Results: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables., Conclusions: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices., (Copyright © 2023 by the American Society of Nephrology.)

Background: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that has been shown to reduce cardiovascular events in diabetic patients with and without heart failure (HF). Whether the clinical benefits and safety profile of canagliflozin are different in those on a beta blocker and an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (BB + RAASi) is unknown., Methods: We pooled participants with HF at baseline from the CANVAS Program and CREDENCE trial and assessed major adverse cardiovascular events and its components; hospitalization for heart failure (HHF); HHF or CV death; all-cause mortality; a renal composite; and a combined renal and CV composite., Results: Of 14,543 participants, 2113 had HF at baseline, and 1280 were on BB + RAASi. In those with a history of HF, participants on BB + RAASi therapy were more likely to have coronary atherosclerotic disease (82 vs 72%, p < 0.001), history of myocardial infarction (42 vs 29%, p < 0.001), higher mean body mass index (34 vs 32 kg/m 2 , p < 0.001), and lower mean estimated glomerular filtration rate (67 vs 70 mL/min/1.73 m 2 , p < 0.01). They were also more likely to be on insulin, a statin, antithrombotic agent, and a diuretic (all p < 0.001). In unadjusted analysis and when adjusted for selected baseline factors, there was no heterogeneity in canagliflozin treatment effect except for HHF/CV death in those on baseline BB + RAASi vs. those not on baseline BB + RAASi (P heterogeneity  = 0.02)., Conclusion: Canagliflozin mostly improved CV and kidney outcomes in participants with a history of HF irrespective of use of BB + RAASi at baseline, with possible greater benefit on HHF/CV death in participants on BB + RAASi., Competing Interests: Declaration of Competing Interest S.S. Jain has no financial disclosures. J. Yu has no financial disclosures. C. Arnott is supported by a Medical Research Future Fund Priority Investigator Grant and NSW Health EMCR Grant. She has received honoraria from AstraZeneca and Amgen B. Neal has received grants for CANVAS and CREDENCE, advisory board, honoraria, travel reimbursement all from Janssen and all paid to his institution. He has received research support from the Australian National Health and Medical Research Council Principal Research Fellowship and from Janssen, and has served on advisory boards and/or has had involvement in continuing medical education programs for Janssen, with any consultancy, honoraria, or travel support paid to his institution. He also notes institutional relationships with AbbVie, Actelion and Janssen. V. Perkovic B. Neuen has received fees for advisory boards, steering committee roles and travel support from AstraZeneca, Bayer and Janssen, with all honoraria paid to his employer. M. Jardine is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro and MSD. She has received advisory, steering committee and/or speaker fees from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Medical, Chinook, CSL, Janssen, Medscape, MSD, Roche and Vifor; with any consultancy, honoraria or travel support are paid to her institution. K.W. Mahaffey's financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey., (Copyright © 2023. Published by Elsevier B.V.)

The global unmet need for kidney replacement therapy means that millions of people die every year as they cannot afford treatment. Peritoneal dialysis (PD) offers comparable survival to haemodialysis and is often more affordable, but one barrier to increasing access is that conventional manufacturing and distribution of PD fluid is costly. Here we report the results from a pilot proof-of-principal study demonstrating for the first time that the Ellen Medical Devices Point-of-Care system can be used by patients to produce sterile PD fluid at the point-of-care. With further development, this low-cost system could offer a solution to the many millions of people around the world who currently cannot afford treatment for kidney failure., Competing Interests: Declaration of conflicting interestThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BT, JB, VG, AB, NK and JK are employees of Ellen Medical Devices on secondment from the George Institute for Global Health. BT, VG, VP, MJ, MG and JK are employees or hold appointments at the George Institute for Global Health which is the majority owner of Ellen Medical Devices. These relationships are considered to be synergies rather than conflicts. SD receives research funding from Baxter HealthCare, lecture fees from Baxter and Fresenius Medical Care, Advisory Board Fees from Ellen Medical and is president of EuroPD. MJ is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro and MSD; has received fees for Advisory, Steering Committee and/or Scientific Presentations from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, MSD, Roche and Vifor; with any consultancy, honoraria or travel support paid to her institution.

Introduction: Autoantibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population., Methods: The CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular (CV) causes. Secondary outcomes included CV and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit, stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model., Results: Of 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (hazard ratio [HR] per 1-SD increase = 1.12, 95% confidence interval [CI] = 1.01-1.24, P  = 0.04), with CV death (HR = 1.27, 95% CI = 1.08-1.48, P  < 0.01) and all-cause mortality (HR = 1.26, 95% CI = 1.11-1.43, P  < 0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0 g/l (95% CI = 6.2-7.9) and 2.4% (2.2-2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies ( P -interaction = 0.24 and 0.36, respectively)., Conclusion: In patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and CV outcome, as well as CV and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes., Methods: Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes., Results: Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09-2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14-2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00-2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09-2.26; P; 0.01)., Conclusions: These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes., Trial Registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791., (© 2023. The Author(s).)

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: Participants in the CREDENCE trial., Intervention: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo., Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models., Results: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed., Limitations: This was a post hoc analysis with multiple comparisons., Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants., Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical., Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: How sex and gender concepts are incorporated into randomized controlled trials (RCTs) in adults with kidney failure receiving maintenance dialysis is largely unknown. We describe these practices in published journal articles as well as investigate the proportion of women and female participants in these studies., Study Design: Meta-epidemiologic study., Setting & Study Populations: RCTs in maintenance dialysis., Selection Criteria for Studies: Trials published in high-impact journals in 2000-2020., Data Extraction: Implemented in duplicate with conflicts resolved by a third reviewer., Analytical Approach: Meta-regression was performed to identify trial characteristics independently associated with the proportion of women and female participants., Results: Among 561 included RCTs, 69.7% were parallel and 28.0% were crossover in design; 80.6% were conducted in the hemodialysis population; and 25% of trials compared the treatment of interest with a placebo arm, 25% with a usual care treatment arm, and 50% with an active alternative therapy arm. Of the RCTS, 37.6% were masked. The median size was 60 (IQR, 26-151) participants, and the median follow-up period was 154 (IQR, 42-365) days. The mean proportion of women or female participants was 0.40±0.13 (SD): 39.0% of trials reported sex, and 26.6% reported the gender of the participants. Also, 56.2% referred to participants as females, 25.3% referred to participants as women, and 15.5% referred to both females and women. No trial characteristic other than region (β of 0.062 [95% CI, 0.007-0.117] for Asia) was associated with the proportion of women or female participants. Considering trial design and conduct, 2.7% of trials used sex and/or gender as an inclusion criterion, 26.6% as an exclusion criterion, 4.5% for randomization, 4.8% for subgroup analyses, and 15.7% for covariate adjustment., Limitations: Only high-impact journal articles were studied; and the included studies lacked pediatric trials, those addressing chronic kidney disease or kidney transplantation, any trials from Africa and underrepresentation of other regions, and missing data., Conclusions: RCTs in dialysis are representative of the general dialysis population with regard to sex and gender but they uncommonly report both and often do not include either in their reporting or analysis., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age., Methods and Analysis: We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 μL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent., Ethics and Dissemination: The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites., Trial Registration Number: NCT04904523., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Aim: This study examined whether survival and causes of death differed between participants enrolled from Australia (AUS), Malaysia (MYL), and New Zealand (NZ) in extended follow-up of the Study of Heart and Renal Protection (SHARP), a randomized controlled trial (RCT) of participants with moderate to severe chronic kidney disease comparing placebo to combination therapy with Simvastatin and Ezetimibe., Methods: All participants alive at final SHARP study visit in participating centres were eligible for inclusion. Consenting participants were re-enrolled following final SHARP Study visit and followed for 5 years. Data collection included: significant medical events, hospital admissions and requirement for kidney replacement therapy. Data linkage was performed to national kidney and mortality registries. The primary outcome was all-cause mortality compared across the three countries., Results: The SHARP trial randomized 2029 participants from AUS (1043/2029, 51%), MYL (701/2029, 35%), and NZ (285/2029, 14%), with 1136 participants alive and eligible for extended follow-up at the end of SHARP. In multivariable analysis, risk of death was increased for participants in MYL (HR 1.37, 95% CI 1.17-1.61, p < .001) and NZ (HR 1.28, 95% CI 1.04-1.57, p = .02) when compared to AUS participants. Adjustment for kidney transplantation as a competing risk did not explain the variation seen between countries., Conclusion: This study allows a better understanding of the differences in long-term mortality risk across participants from AUS, MYL, and NZ in extended follow-up of the SHARP study and demonstrates the feasibility and value of extended follow-up of participants enrolled in RCTs., (© 2022 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Background: The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trials have demonstrated significant kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitors are now standard of care for patients with diabetic kidney disease and have also been shown to be effective in those with albuminuric CKD with or without diabetes., Objective: We sought to determine how many patients in nephrology care in British Columbia, Canada, would have been eligible for those trials, to compare rates of outcomes, and to estimate cost avoidance arising from widespread use of SGLT2 inhibitors in this cohort., Study Design: Retrospective cohort study., Setting: British Columbia, Canada., Participants: CKD patients followed in the Kidney Care Clinics in British Columbia., Measurements: We compared the outcomes of kidney failure, sustained estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m 2 , dialysis, transplant, death from any cause, and doubling of serum creatinine. We also compared the composite outcome of kidney failure and doubling of serum creatinine., Methods: The cohort was derived using a provincial database by combining the inclusion criteria of CREDENCE and DAPA-CKD trials. We included adult patients aged ≥18 years, urine albumin to creatinine ratio (UACR) ≥20 mg/mmol, and eGFR between 25 and 90 mL/min/1.73 m 2 , between April 1, 2014 and March 31, 2017. The primary outcome was compared with the outcomes experienced in the placebo arms of CREDENCE and DAPA-CKD. The composite outcome stratified by eGFR categories were compared in the British Columbia cohort and the CREDENCE trial. Cost avoidance was estimated based on the number needed to treat to prevent one instance of kidney failure., Results: A total of 17.5% (3138/17 963) of patients were eligible, resulting in a cohort with a mean age of 69.7 years and 38% women. The eGFR slope of the British Columbia cohort was -4.21 ± 0.47 mL/min. The mean eGFR was 37.0 mL/min/1.73 m 2 , median UACR was 55.3 mg/mmol, and use of renin-angiotensin-aldosterone system inhibitors was 56.6%. The British Columbia cohort experienced nearly double the outcomes of kidney failure, death from any cause, and doubling of serum creatinine than the placebo arms of CREDENCE and DAPA-CKD. When stratified by eGFR, the British Columbia cohort and the CREDENCE placebo arm had similar event rates for those with an eGFR <45 mL/min but there were still higher rates of outcome in the greater than 45 mL/min eGFR groups in the British Columbia cohort. Treating the British Columbia cohort with canagliflozin could lead to net cost avoidance of $2.31 million over 2.6 years., Limitations: The database only captures those referred to the Kidney Care Clinics by nephrologists, which may lead to selection bias of higher risk patients in the British Columbia cohort. The cost avoidance analysis was a limited high-level analysis., Conclusions: The British Columbia cohort represents a high-risk group in whom implementation of the use of SGLT2 inhibitors may well improve outcomes and reduce health care system costs., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: No funding was provided for this work. B.S. is supported by The Jacquot Research Establishment Fellowship from the Royal Australasian College of Physicians. A.L. was a member of the Steering committee for canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) and has received grant support from Janssen. M.J. is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and MSD; has received Advisory, Steering Committee and/or speaker fees from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Lynx, Chinook, Medscape, CSL, Janssen, MSD, Roche, and Vifor; with any consultancy, honoraria, or travel support paid to her institution., (© The Author(s) 2022.)

Aim: To study the associations between baseline blood glucose levels (BGL), glycemic variability and clinical outcomes in patients with severe acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). Methods: We performed a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. A multivariate Cox regression model was used to assess the association between baseline BGL, glycemic variability and clinical outcomes. The primary outcome was all-cause mortality, and secondary outcomes were duration of hospital and intensive care unit (ICU) stay. Results: Baseline BGL data were available in 1404 out of 1508 patients from the RENAL study. Among them, 627 patients died within 90 days of randomization. Compared to patients in the second quartile (BGL 5.8−7.2 mmol/L), patients in the first quartile (BGL < 5.8 mmol/L) had increased mortality rate (90-day HR 1.48; p = 0.001; 28-day HR 1.47; p = 0.042). However, there were no significant differences in ICU and hospital length of stay (LOS) (p = 0.82 and p = 0.33, respectively). Glycemic variability data were from 1345 out of 1404 patients who had data for BG values within 28 days. Higher coefficient of variation (CV) (HR 1.02; P trend = 0.002) and standard deviation value (SD) (HR 1.29; P trend = 0.027) were associated with higher risk of death at day 90. Conclusions: We identified a low BGL within the normal physiological range at baseline and greater CV and SD values as significant modifiable risk factors for mortality in severe AKI patients in ICU, which may be a target for intervention.

Introduction In Aotearoa New Zealand, lead maternity carers (LMCs) provide maternity care through pregnancy and birth, until 6 weeks' postpartum. An early LMC connection in pregnancy is associated with better maternal and perinatal health outcomes. However, hapū māmā (pregnant women) may experience barriers to engaging with LMC, delaying screening, risk assessments, and education. These barriers contribute to inequitable health outcomes for Māori māmā and pēpi (Māori mothers and babies). A pro-equity approach to maternity care is warranted. Aim To investigate the LMC plan at the first point of contact with a primary care provider once pregnancy is confirmed, as well as selected risk factors to maternal and perinatal health for Māori and non-Māori hapū māmā. Methods Data entered by primary care providers into the Best Start-Pregnancy Tool were analysed for 482 pregnant women from November 2020 to December 2021. Results Most hapū māmā planned for midwifery care. About one-third of hapū māmā had engaged with a midwife before their first GP visit after a confirmed pregnancy. Māori hapū māmā were more likely to present with risk factors to maternal and perinatal health than non-Māori hapū māmā. Discussion Primary healthcare providers have an expectation to connect hapū māmā to a LMC by 10 weeks' gestation. More research is needed to identify how to best support Māori hapū māmā to access a LMC early in pregnancy. The Best Start Kōwae is an accessible online tool (currently in an implementation phase) for primary care providers and LMCs that promotes equitable health outcomes for Māori māmā and pēpi.

Non-adherence to medications is a critical challenge in the management of people with chronic kidney disease (CKD). This review explores the complexities of adherence in this population, the unique barriers and enablers of good adherence behaviours, and the role of emerging digital health technologies in bridging the gap between evidence-based treatment plans and the real-world standard of care. We present the current evidence supporting the use of digital health interventions among CKD populations, identifying the key research questions that remain unanswered, and providing practical strategies for clinicians to support medication adherence in a digital age., (© 2022 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Background: Consuming different food groups and nutrients can have differential effects on body weight, body composition, and insulin sensitivity., Objective: The aim was to identify how food group, nutrient intake, and diet quality change relative to usual-diet controls after 16 weeks on a low-fat vegan diet and what associations those changes have with changes in body weight, body composition, and measures of metabolic health., Design: Secondary analysis of a randomized clinical trial conducted between October 2016 and December 2018 in four replications., Participants/setting: Participants included in this analysis were 219 healthy, community-based adults in the Washington, DC, area, with a body mass index (BMI) between 28 and 40, who were randomly assigned to either follow a low-fat vegan diet or make no diet changes., Intervention: A low-fat, vegan diet deriving approximately 10% of energy from fat, with weekly classes including dietary instruction, group discussion, and education on the health effects of plant-based nutrition. Control group participants continued their usual diets., Main Outcome Measures: Changes in food group intake, macronutrient and micronutrient intake, and dietary quality as measured by Alternate Healthy Eating Index-2010 (AHEI-2010), analyzed from 3-day diet records, and associations with changes in body weight, body composition, and insulin sensitivity were assessed., Statistical Analyses Performed: A repeated-measure analysis of variance model that included the factors group, subject, and time was used to test the between-group differences throughout the 16-week study. Interaction between group and time was calculated for each variable. Within each diet group, paired comparison t tests were calculated to identify significant changes from baseline to 16 weeks. Spearman correlations were calculated for the relationship between changes in food group intake, nutrient intake, AHEI-2010 score, and changes in body weight, body composition, and insulin sensitivity. The relative contribution of food groups and nutrients to weight loss was evaluated using linear regression., Results: Fruit, vegetable, legume, meat alternative, and whole grain intake significantly increased in the vegan group. Intake of meat, fish, and poultry; dairy products; eggs; nuts and seeds; and added fats decreased. Decreased weight was most associated with increased intake of legumes (r = -0.38; P < 0.0001) and decreased intake of total meat, fish, and poultry (r = +0.43; P < 0.0001). Those consuming a low-fat vegan diet also increased their intake of carbohydrates, fiber, and several micronutrients and decreased fat intake. Reduced fat intake was associated with reduced body weight (r = +0.15; P = 0.02) and, after adjustment for changes in BMI and energy intake, with reduced fat mass (r = +0.14; P = 0.04). The intervention group's AHEI-2010 increased by 6.0 points on average, in contrast to no significant change in the control group (treatment effect, +7.2 [95% CI +3.7 to +10.7]; P < 0.001). Increase in AHEI-2010 correlated with reduction in body weight (r = 0.14; P = 0.04), fat mass (r = -0.14; P = 0.03), and insulin resistance as measured by the Homeostasis Model Assessment (HOMA-IR; r = -0.17; P = 0.02), after adjustment for changes in energy intake., Conclusions: When compared with participants' usual diets, intake of plant foods increased, and consumption of animal foods, nuts and seeds, and added fats decreased on a low-fat vegan diet. Increased legume intake was the best single food group predictor of weight loss. Diet quality as measured by AHEI-2010 improved on the low-fat vegan diet, which was associated with improvements in weight and metabolic outcomes. These data suggest that increasing low-fat plant foods and minimizing high-fat and animal foods is associated with decreased body weight and fat loss, and that a low-fat vegan diet can improve measures of diet quality and metabolic health., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Dementia is characterized by global cognitive dysfunction, which can cause difficulties in performing Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs), leaving people with dementia (PwD) who do not have the proper support extremely vulnerable. Dementia management should involve preventative methods, including during the stage of mild cognitive impairment (MCI). Lay-caregivers are found to have poorer health in all three domains of the biopsychosocial model, as a result of the burden of care. New assistive technologies (ATs) have been designed to help care for PwD. ATs aim to be more affordable and widely available than human workers, achieving greater health equity and quality of life for all., Methods: To identify relevant articles, a literature search using PubMed was undertaken by one independent reviewer: S.L.C. The keywords of "dementia", "technology", and "management" were used, with no date of publication limitations, which revealed 571 results., Results: 44 articles were included in this review. Articles regarding new technologies to diagnose dementia or MCI were not included. ATs aim to help facilitate aging-in-place, reduce medical costs, and rates of caregiver burnout, by helping maintain patient functioning., Discussion: Legal issues in the form of workplace safety laws, data privacy laws and regulations, and health care ethics are major barriers to implementation that need to be resolved. The hope is that artificial intelligence (AI) systems may be able to advance what they are able to perceive and help uncover new knowledge and management options for dementia and MCI., (Copyright © 2022 Elsevier B.V. All rights reserved.)