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Background: Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD., Methods: We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30-90 ml/min per 1.73 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR., Results: There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide-and with intelligence: γ -glutamyl amino acids and aconitate., Conclusions: Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;11&#95;17&#95;CJN0000000000000318.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10 years; 48% were men; mean eGFR was 96±16 ml/min/1.73 m 2 ; mean LVmvr was 0.93±0.18 g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04 g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria., Competing Interests: Disclosures Dr. Gutierrez receives grant funding and honoraria from Amgen and Akebia. He receives honoraria from AstraZeneca, Reata, and Ardelyx and serves on a Data Monitoring Committee for QED Therapeutics. Dr. Bonventre is cofounder and holds equity in Goldfinch Bio and Autonomous Medical Devices, is coinventor on KIM-1 patents assigned to Mass General Brigham, and has received consulting income and/or equity from Cadent, Renalytix, Sarepta, and Seagen and laboratory support from Kantum Pharma. He has equity in Pacific Biosciences, DxNow, and MediBeacon. Dr. Bonventre's interests were reviewed and are managed by BWH and MGB in accordance with their conflict-of-interest policies. Dr. Kimmel is a coeditor with Mark Rosenberg of Chronic Renal Disease Academic Press and a coeditor with Daniel Cukor and Scott D. Cohen of Psychosocial Aspects of Chronic Kidney Disease Academic Press. Dr. Shlipak is on advisory boards and receives honoraria from Bayer, Boehringer-Ingelheim, Astra-Zeneca. He receives grant support from Bayer. Dr. Ix has grant support from Baxter International. He is on advisory boards for Akebia, AstraZeneka, Ardelyx, Alpha Young, and Bayer. He serves on a Data and Safety Monitoring Board from Sanifit International. The remaining authors have no conflicts of interest to declare., (Published by Elsevier Inc.)

Background: The Revised Illness Perception Questionnaire (IPQ-R) measures individuals' unique perceptions of their illness. While psychometric properties of the IPQ-R have been demonstrated in many disease populations, its content validity has not been extensively studied in non-dialysis chronic kidney disease (CKD). Unique features of CKD (e.g., few symptoms in early stages) may impact the measurement of illness perceptions. The purpose of this study was to explore the IPQ-R content validity in a sample of CKD patients., Methods: Thirty-one participants completed the IPQ-R and were interviewed regarding their subscale scores (timeline, consequences, personal control, treatment control, coherence, cyclical, and emotions). Participants' agreement with their scores was tallied and assessed qualitatively for themes related to the content validity of the measure., Results: Individual participant agreement with their subscale scores averaged 79% (range: 29-100%). Subscale agreement varied: timeline (100%), consequences, coherence, and emotion (83% each), cyclical (75%), personal control (65%), and treatment control (64%). A qualitative exploration of disagreement responses revealed concerns with the relevance and comprehensibility of personal control and treatment control., Conclusions: Some IPQ-R subscales may pose content validity concerns in the non-dialysis CKD population. Item modification for comprehensibility (personal control) and relevance (treatment control) should be considered. Future studies should explore the impact of a patient's symptom experience on IPQ-R validity, especially in populations like CKD with a higher proportion of asymptomatic patients.

Background: Patients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome., Methods: Among 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage., Results: The mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death., Conclusions: More advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Slopes of eGFR have been associated with increased risks of death and cardiovascular events in a U-shaped fashion. Poor outcomes in individuals with rising eGFR are potentially attributable to sarcopenia, hemodilution, and other indicators of clinical deterioration., Methods: To investigate the association between eGFR slopes and risks of death or cardiovascular events, accounting for multiple confounders, we studied 2738 individuals with moderate to severe CKD participating in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used linear, mixed-effects models to estimate slopes with up to four annual eGFR assessments, and Cox proportional hazards models to investigate the association between slopes and the risks of death and cardiovascular events., Results: Slopes of eGFR had a bell-shaped distribution (mean [SD], -1.5 [-2] ml/min per 1.73 m 2 per year). Declines of eGFR that were steeper than the average decline associated with progressively increasing risks of death (hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 1.09 to 1.39; for a slope 1 SD below the average) and cardiovascular events (HR, 1.19; 95% CI, 1.03 to 1.38). Rises of eGFR or declines lower than the average decline were not associated with the risk of death or cardiovascular events., Conclusions: In a cohort of individuals with moderate to severe CKD, we observed steep declines of eGFR were associated with progressively increasing risks of death and cardiovascular events; however, we found no increased risks associated with eGFR improvement. These findings support the potential value of eGFR slopes in clinical assessment of adults with CKD., (Copyright © 2020 by the American Society of Nephrology.)

Background: Whether ambulatory BP monitoring is of value in evaluating risk for outcomes in patients with CKD is not clear., Methods: We followed 1502 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study for a mean of 6.72 years. We evaluated, as exposures, ambulatory BP monitoring profiles (masked uncontrolled hypertension, white-coat effect, sustained hypertension, and controlled BP), mean ambulatory BP monitoring and clinic BPs, and diurnal variation in BP-reverse dipper (higher at nighttime), nondipper, and dipper (lower at nighttime). Outcomes included cardiovascular disease (a composite of myocardial infarction, cerebrovascular accident, heart failure, and peripheral arterial disease), kidney disease (a composite of ESKD or halving of the eGFR), and mortality., Results: Compared with having controlled BP, the presence of masked uncontrolled hypertension independently associated with higher risk of the cardiovascular outcome and the kidney outcome, but not with all-cause mortality. Higher mean 24-hour systolic BP associated with higher risk of cardiovascular outcome, kidney outcome, and mortality, independent of clinic BP. Participants with the reverse-dipper profile of diurnal BP variation were at higher risk of the kidney outcome., Conclusions: In this cohort of participants with CKD, BP metrics derived from ambulatory BP monitoring are associated with cardiovascular outcomes, kidney outcomes, and mortality, independent of clinic BP. Masked uncontrolled hypertension and mean 24-hour BP associated with high risk of cardiovascular disease and progression of kidney disease. Alterations of diurnal variation in BP are associated with high risk of progression of kidney disease, stroke, and peripheral arterial disease. These data support the wider use of ambulatory BP monitoring in the evaluation of hypertension in patients with CKD., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2020&#95;09&#95;24&#95;JASN2020030236.mp3., (Copyright © 2020 by the American Society of Nephrology.)

Background: Data on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited., Objectives: This study examined rates of HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death., Methods: The prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death., Results: Among 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m 2 ); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m 2 (vs. >45 ml/min/1.73 m 2 ), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18)., Conclusions: Within a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Silica has been associated with end stage kidney disease and kidney dysfunction., Methods: Calculated glomerular filtration rate, history of kidney disease or chronic dialysis, elevated serum creatinine, and stages of chronic kidney disease among silicotics identified in Michigan's Silicosis Surveillance System from 1987 to 2009 were reviewed to determine the prevalence of kidney disease in confirmed cases of silicosis., Results: Twenty-four percent of 1,072 silicotics had a measure of kidney dysfunction (32.3% if diabetes or hypertension present vs. 20.2% if not). Sixty-nine percent of silicotics had Stage I or greater chronic kidney dysfunction versus 38.8% of the U.S. general population ≥60 years. No association was found between kidney function and measures of silica exposure., Conclusions: Individuals with silicosis have an increased prevalence of kidney disease. More work to define the pathological changes associated with silica exposure is needed to understand the cause of silica's adverse effect on the kidney., (© 2015 Wiley Periodicals, Inc.)

Background and Objectives: Initiation of dialysis on Sunday is limited by constraints that do not exist on other days of the week, which may lead to triaging of dialysis therapy. The study hypothesis was that patients with AKI on a Sunday would sustain higher mortality rates., Design, Setting, Participants, & Measurements: Study participants (n=4970) were part of the retrospective University of Pennsylvania Health AKI cohort, which is composed of patients with severe inpatient AKI (characterized by a doubling of admission creatinine) who were hospitalized from January 1, 2004, to August 31, 2010. Patient-days (n=15,995) were included if the patient had AKI severity of Acute Kidney Injury Network (AKIN) stage 2 or greater and had not yet begun receiving dialysis. The association of day of the week and inpatient mortality was assessed with logistic regression of data updated daily, using robust variance estimators., Results: The rate (95% confidence interval [CI]) of initiation of dialysis on Sunday was 2.5 (1.8 to 3.1) per 100 patient-days, compared with 3.8 (3.5 to 4.1) per 100 patient-days on other days of the week (P=0.001). Inpatient mortality (95% CI) among patients with severe AKI present on a Sunday was 30% (28% to 32%), compared with 31% (31% to 32%) on other days of the week (P=0.08). Inpatient mortality among patients who initiated dialysis on Sunday was 65% (52% to 79%), compared with 65% (61% to 70%) among those who initiated dialysis from Tuesday through Saturday (P=0.79). Patients who initiated dialysis on Monday had a lower mortality than those who initiated it on another day of the week (52% [40% to 64%] versus 65% [61% to 70%]; P=0.03)., Conclusions: Despite a lower frequency of dialysis, patients with severe AKI on Sunday have mortality similar to that of patients with severe AKI on other days of the week.

Some adolescents have differences, not of their own choosing, that require different approaches to clinical assessment and care. These adolescents are often marginalized from their peer group, and of-ten isolated in general. Awareness of the differences in health risks that these youth face, and their challenges in the successful mastery of developmental tasks is important to the clinician who serves them. Health care professionals must avoid three things in their efforts to help these groups of young people: judging, preaching, or becoming an agent of social control, even though such efforts maybe well meaning. This article addresses some of the unique needs of gay, lesbian, and bisexual youth; homeless adolescents; foster care youth; and youth who have disabilities.