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Dementia algorithms are often developed in cross-sectional samples but implemented in longitudinal studies to ascertain incident dementia. However, algorithm performance may be higher in cross-sectional settings, and this may impact estimates of risk factor associations.We used data from the Religious Orders Study and the Memory and Aging Project (N = 3460) to assess the performance of example algorithms in classifying prevalent dementia in cross-sectional samples versus incident dementia in longitudinal samples. We used an applied example and simulation study to characterize the impact of varying sensitivity, specificity, and unequal sensitivity or specificity between exposure groups (differential performance) on estimated hazard ratios from Cox models.Using all items, algorithm sensitivity was higher for prevalent (0.796) versus incident dementia (0.719); hazard ratios had slight bias. Sensitivity differences were larger using a subset of items (0.732 vs. 0.600) and hazard ratios were 13%-19% higher across adjustment sets compared to estimates using gold-standard dementia status. Simulations indicated specificity and differential algorithmic performance between exposure groups may have large effects on hazard ratios.Algorithms developed using cross-sectional data may be adequate for longitudinal settings when performance is high and non-differential. Poor specificity or differential performance between exposure groups may lead to biases.

Patient selection for pediatric extracorporeal membrane oxygenation (ECMO) support has broadened over the years to include children with pre-existing neurologic morbidities. We aimed to determine the prevalence and nature of pre-ECMO neurologic disorders or disability and investigate the association between pre-ECMO neurologic disorders or disability and mortality and unfavorable neurologic outcome.Multicenter retrospective observational cohort study.Eight hospitals reporting to the Pediatric ECMO Outcomes Registry between October 2011 and June 2019.Children younger than 18 years supported with venoarterial or venovenous ECMO.The primary exposure was presence of pre-ECMO neurologic disorders or moderate-to-severe disability, defined as Pediatric Cerebral Performance Category (PCPC) or Pediatric Overall Performance Category (POPC) 3-5. The primary outcome was unfavorable outcome at hospital discharge, defined as in-hospital mortality or survival with moderate-to-severe disability (discharge PCPC 3-5 with deterioration from baseline).Of 598 children included in the final cohort, 68 of 598 (11%) had a pre-ECMO neurologic disorder, 70 of 595 (12%) had a baseline PCPC 3-5, and 189 of 592 (32%) had a baseline POPC 3-5. The primary outcome of in-hospital mortality ( n = 267) or survival with PCPC 3-5 with deterioration from baseline ( n = 39) was observed in 306 of 598 (51%). Overall, one or more pre-ECMO neurologic disorders or disability were present in 226 of 598 children (38%) but, after adjustment for age, sex, diagnostic category, pre-ECMO cardiac arrest, and ECMO mode, were not independently associated with increased odds of unfavorable outcome (unadjusted odds ratio [OR], 1.34; 95% CI, 1.07-1.69; multivariable adjusted OR, 1.30; 95% CI, 0.92-1.82).In this exploratory study using a multicenter pediatric ECMO registry, more than one third of children requiring ECMO support had pre-ECMO neurologic disorders or disability. However, pre-existing morbidities were not independently associated with mortality or unfavorable neurologic outcomes at hospital discharge after adjustment for diagnostic category and other covariates.

Background: Ambulatory blood pressure monitoring (ABPM) is routinely performed in children with chronic kidney disease to identify masked hypertension, a risk factor for accelerated chronic kidney disease progression. However, ABPM is burdensome, and developing an accurate prediction of masked hypertension may allow using ABPM selectively rather than routinely. Methods: To create a prediction model for masked hypertension using clinic blood pressure (BP) and other clinical characteristics, we analyzed 809 ABPM studies with nonhypertensive clinic BP among the participants of the Chronic Kidney Disease in Children study. Results: Masked hypertension was identified in 170 (21.0%) observations. We created prediction models for masked hypertension via gradient boosting, random forests, and logistic regression using 109 candidate predictors and evaluated its performance using bootstrap validation. The models showed C statistics from 0.660 (95% CI, 0.595–0.707) to 0.732 (95% CI, 0.695–0.786) and Brier scores from 0.148 (95% CI, 0.141–0.154) to 0.167 (95% CI, 0.152–0.183). Using the possible thresholds identified from this model, we stratified the dataset by clinic systolic/diastolic BP percentiles. The prevalence of masked hypertension was the lowest (4.8%) when clinic systolic/diastolic BP were both Conclusions: ABPM could be used selectively in those with low clinic BP, for example, systolic BP

To examine the relationship between neighborhood poverty and deprivation, chronic kidney disease (CKD) comorbidities, and disease progression in children with CKD.Observational cohort study.Children with mild to moderate CKD enrolled in the CKiD (Chronic Kidney Disease in Children) study with available US Census data.Neighborhood poverty and neighborhood disadvantage.Binary outcomes of short stature, obesity, hypertension, and health care utilization for cross-sectional analysis; a CKD progression end point (incident kidney replacement therapy [KRT] or 50% loss in estimated glomerular filtration rate), and mode of first KRT for time-to-event analysis.Cross-sectional analysis of health characteristics at time of first Census data collection using logistic regression to estimate odds ratios. Risk for CKD progression was analyzed using a Cox proportional hazard model. Multivariable models were adjusted for race, ethnicity, sex, and family income.There was strong agreement between family and neighborhood socioeconomic characteristics. Risk for short stature, hospitalization, and emergency department (ED) use were significantly associated with lower neighborhood income. After controlling for race, ethnicity, sex, and family income, the odds of hospitalization (OR, 1.71 [95% CI, 1.08-2.71]) and ED use (OR, 1.56 [95% CI, 1.02-2.40]) remained higher for those with lower neighborhood income. The hazard ratio of reaching the CKD progression outcome for participants living in lower income neighborhoods was significantly increased in the unadjusted model only (1.38 [95% CI, 1.02-1.87]). Likelihood of undergoing a preemptive transplant was decreased with lower neighborhood income (OR, 0.47 [95% CI, 0.24-0.96]) and higher neighborhood deprivation (OR, 0.31 [95% CI, 0.10-0.97]), but these associations did not persist after controlling for participant characteristics.Limited generalizability, as only those with consistent longitudinal nephrology care were studied.Neighborhood-level socioeconomic status (SES) was associated with poorer health characteristics and CKD progression in univariable analysis. However, the relationships were attenuated after accounting for participant-level factors including race. A persistent association of neighborhood poverty with hospitalizations and ED suggests an independent effect of SES on health care utilization, the causes for which deserve additional study.

Most cognitive assessments have been developed in high-income countries but are used in diverse contexts. Differences in culture and context may affect the performance of cognitive items.We used the Harmonized Cognitive Assessment Protocol (HCAP) surveys in the United States, Mexico, India, England, and South Africa (combined N = 11,364) to quantify associations across countries between cognitive items and cognitive impairment status using age- and sex-adjusted logistic regression.Associations were stronger in the United States (median odds ratio [OR] across items = 0.17) and England (median OR = 0.19), compared to South Africa (median OR = 0.23), India (median OR = 0.29), and Mexico (median OR = 0.28). Items assessing memory (e.g., delayed recall tasks) had the most consistent associations of the largest magnitudes across contexts.Transporting cognitive items among countries and cultures warrants caution. Our results can guide the design of future instruments by identifying items that performed well either in individual contexts or across the range of contexts considered.Little quantitative evidence exists to guide the design of cognitive assessments in cross-national studies. The performance of cognitive items for the measurement of dementia varied across countries. Items with lower variation across countries (e.g., delayed word recall) should be used in future cross-national assessments. Across countries, there was variability in the performance of language assessments, with the exception of the animal naming task. Results can be used to design future cross-national or location-specific cognitive assessments.

BACKGROUND Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO. METHODS We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course. RESULTS All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition. CONCLUSIONS High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO. IMPACT The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.

Diastolic dysfunction is one of the earliest cardiac abnormalities in patients with chronic kidney disease. We analyzed echocardiographic markers of left ventricular function from 786 children and adolescents (1658 person-visits) enrolled in the CKiD (Chronic Kidney Disease in Children) cohort, a large prospective observational study of children with chronic kidney disease. Primary outcome was early mitral inflow velocity-to-early mitral annular peak velocity (E/e′) ratio as a marker of left ventricular compliance. Abnormal diastolic function was defined as E/e′>8.0. Those with an abnormal E/e′ ratio were younger, had a lower estimated glomerular filtration rate and hemoglobin, and a higher prevalence of hypertension and left ventricular hypertrophy compared to children with a normal E/e′. In adjusted analysis, a higher E/e′ ratio was independently associated with ambulatory (sustained) hypertension (1.66 [95% CI, 1.15–2.42]). Other significant independent predictors were higher left ventricular mass index Z score, increased body mass index Z score, lower hemoglobin, higher phosphorus level, and younger age. Casual blood pressure was not significantly associated with higher E/e′. These data indicate that ambulatory blood pressure might better identify children with chronic kidney disease at risk for subclinical cardiac dysfunction than clinic blood pressure alone. Graphic Abstract: An online graphic abstract is available for this article.

BACKGROUND: Chronic kidney disease (CKD) is associated with many comorbidities requiring complex management. We described treatment patterns for common modifiable CKD complications (high blood pressure, anemia, hyperphosphatemia, and acidosis) according to severity of CKD and examined factors associated with the absence of drug therapy, among participants with a persistent comorbidity, for 1 year in children enrolled in the CKiD study. METHODS: A total of 703 CKiD participants contributed 2849 person-visits over a median 3.5 years of follow-up. Using pairs of annual visits, we examined whether participants with abnormal biomarker levels at the first (index) visit persisted in the abnormal levels 1 year later according to CKD risk stage. Multivariate analyses identified demographic and clinical factors associated with the absence of drug therapy among those with persistent comorbid conditions for 1 year. RESULTS: The overall proportions of person-visits prescribing therapy at 1-year follow-up for treating anemia, acidosis, hyperphosphatemia, and high blood pressure were 54%, 45%, 29%, and 81%, respectively. The frequency of therapy increased with advanced CKD risk stage for all comorbidities; however, 19–23% of participants with acidosis, 24–27% with anemia, and 30–39% with hyperphosphatemia at high-risk stages (E and F) were not prescribed appropriate therapy despite the persistence of abnormal levels of these biomarkers for at least 1 year. The resolution of comorbidities at advanced CKD stages without treatment was unlikely. CONCLUSIONS: Many children with CKD in the CKiD cohort did not receive pharmacological treatment for common and persistent modifiable comorbidities, even in severe CKD risk stages.

Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer– N -acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo ( n = 7 patients) or OP-101 at 2 ( n = 6), 4 ( n = 6), or 8 mg/kg ( n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101–treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.

Measurement error, although ubiquitous, is uncommonly acknowledged and rarely assessed or corrected in epidemiologic studies. This review offers a straightforward guide to common problems caused by measurement error in research studies and a review of several accessible bias-correction methods for epidemiologists and data analysts. Although most correction methods require criterion validation including a gold standard, there are also ways to evaluate the impact of measurement error and potentially correct for it without such data. Technical difficulty ranges from simple algebra to more complex algorithms that require expertise, fine tuning, and computational power. However, at all skill levels, software packages and methods are available and can be used to understand the threat to inferences that arises from imperfect measurements.

BACKGROUND: Control of hypertension delays progression of pediatric chronic kidney disease (CKD), yet few data are available regarding what office blood pressure (BP) levels may slow progression. METHODS: Longitudinal BP data from children in the Chronic Kidney Disease in Children cohort study who had hypertension or an auscultatory BP ≥90th percentile enrolled were studied. BP categories were defined as the maximum systolic or diastolic BP percentile (

BACKGROUND: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants responded to the question “In the past year, have you discussed renal replacement therapy with your doctor or health care provider?” at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measures logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status and CKD diagnosis (glomerular vs. non-glomerular). RESULTS: 721 CKiD participants (median age= 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race and socioeconomic status. CONCLUSIONS: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.

Children with chronic kidney disease (CKD) have delays in normal growth and pubertal development. We describe factors associated with delayed menarche and the association of delayed menarche with short stature in girls with CKD. Two hundred eighty-seven girls with CKD onset prior to menarche within the Chronic Kidney Disease in Children (CKiD) cohort were studied. Delayed menarche was defined as menarche at age 15 years or older; short stature was defined as last available height 2 standard deviations below projected adult height. Kaplan-Meier cumulative incidence function was used to estimate median age at menarche. Chi-squared and Wilcoxon rank-sum tests were used to assess factors associated with delayed menarche. Chi-squared test was used to evaluate the association between delayed menarche and short stature. Among 287 girls, 68 enrolled with prevalent menarche, 131 were observed to have incident menarche, and 88 were pre-menarchal at their last study visit. Median age at menarche was 12 years. Ten percent had delayed menarche. African American race, lower estimated glomerular filtration rate, ever corticosteroid use, and longer CKD duration were associated with delayed menarche (p

Accurate detection of hypertension is crucial for clinical management of pediatric chronic kidney disease (CKD). The 2017 American Academy of Pediatrics childhood hypertension guidelines included new normative blood pressure (BP) values and revised definitions of BP categories. In this study, we examined the effect of applying these changes to the Chronic Kidney Disease in Children (CKiD) cohort compared to use of the 2004 Fourth Report normative data and definitions.Observational cohort study.Children and adolescents in the CKiD cohort.Clinic blood pressure measurements.Blood pressure percentiles and hypertension stages calculated using the 2017 and 2004 guidelines.Agreement analysis compared the estimated percentile and prevalence of high blood pressure based on the 2017 and 2004 guidelines to clinic and combined ambulatory blood pressure readings.The proportion of children classified as having normal clinic blood pressure was similar using the 2017 and 2004 guidelines, but the use of the 2017 normative data classified more participants as having hypertensive-range blood pressure (22% vs. 11%) with marginal reproducibility (kappa= 0.569, 95%CI: 0.538, 0.599). Those identified as hypertensive by the 2017 guidelines had higher levels of proteinuria compared to those identified using the 2004 guidelines. There were substantially more participants with white coat and ambulatory hypertension when using the 2017 guidelines (3.5% vs. 1.5%; and 15.5% vs. 7.9%, respectively). The proportion with masked hypertension was lower using the 2017 guidelines (40.2% vs. 47.8%, respectively) with good reproducibility (kappa= 0.799, 95%CI: 0.778, 0.819), and the percentage of participants with normal ambulatory blood pressure was similar (40.9% vs. 42.9%, respectively), LIMITATIONS: Relationship with long-term progression and target organ damage was not assessed.A greater percentage of children with CKD were identified as hypertensive based on both clinic and ambulatory blood pressure when using the 2017 vs. the 2004 guidelines, and the 2017 guidelines better discriminated those with higher levels of proteinuria. The substantial differences in the classification of hypertension when using the 2004 vs. 2017 guidelines should inform clinical care.

Because dementia is progressive, incident cases are on average milder than prevalent cases, affecting the performance of cognitive tests and questions on functional limitations (i.e., cognition/functional limitation items) used for dementia assessment. Longitudinal studies assess incident cases, while cross-sectional studies assess prevalent cases, but differences are not typically considered when researchers select items to include in studies. We used longitudinal data from the Religious Orders Study and Memory and Aging Project (ROSMAP) (n = 3,446) collected between 1994 and 2021 to characterize differences in associations between items (cognition: 35 items; functional limitations: 14 items) and incident or prevalent dementia using multinomial regression models with generalized estimating equations, controlling for ROSMAP cohort (Religious Orders Study or Memory and Aging Project), age, sex, race, and education. The association between a given item and incident dementia was significantly weaker than the association between the same item and prevalent dementia for 46 of 49 items. However, there was variability, with larger differences for some items, including naming a pencil (prevalence odds ratio = 0.02 (95% confidence interval: 0.02, 0.03); incidence odds ratio = 0.10 (95% confidence interval: 0.06, 0.17); P for difference

We conducted a systematic review to assess outcomes in Hispanic donors and explore how Hispanic ethnicity was characterized. We searched PubMed, EMBASE, and Scopus through October 2021. Two reviewers independently screened study titles, abstracts, and full texts; they also qualitatively synthesized results and independently assessed quality of included studies. Eighteen studies met our inclusion criteria. Study sample sizes ranged from 4007 to 143,750 donors and mean age ranged from 37 to 54 years. Maximum follow-up time of studies varied from a perioperative donor nephrectomy period to 30 years post-donation. Hispanic donors ranged between 6% and 21% of the donor populations across studies. Most studies reported Hispanic ethnicity under race or a combined race and ethnicity category. Compared to non-Hispanic White donors, Hispanic donors were not at increased risk for post-donation mortality, end-stage kidney disease, cardiovascular disease, non-pregnancy-related hospitalizations, or overall perioperative surgical complications. Compared to non-Hispanic White donors, most studies showed Hispanic donors were at higher risk for diabetes mellitus following nephrectomy; however, mixed findings were seen regarding the risk for post-donation chronic kidney disease and hypertension. Future studies should evaluate cultural, socioeconomic, and geographic differences within the heterogeneous Hispanic donor population, which may further explain variation in health outcomes.

Summary Background Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals. Methods We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology. Findings Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83–0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10–2·69) and for cancer (2·57, 1·86–3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions. Interpretation Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. Funding None.

Background Placing an arteriovenous fistula (AVF) in older hemodialysis patients at great risk of primary failure leads to prolonged dependency on central venous catheter (CVC). A model which accurately predicts AVF maturation can facilitate better clinical determination for AVF placement. Methods We assembled a retrospective cohort of 14 892 patients aged 67 years and older who started hemodialysis with a CVC between 7/1/2010 and 6/30/2012 and had a subsequent, incident AVF placement from the United States Renal Data System (USRDS). We used random survival forests (RSF) with competing risks to identify important predictors for AVF maturation. Results Approximately 49.7% patients achieved AVF maturation and 13.6% had a competing event. The median time to maturation was 4 (IQR: 3-5) months. Patient's gender had the highest variable importance (VIMP, 0.0027), followed by race, being institutionalized, days on hemodialysis without an AVF, estimated glomerular filtration rate, and body mass index with borderline importance (VIMP ≥0.0005). The out-of-bag (OOB) error rate of the RSF was 45.3% and 45.8% for AVF maturation in the training and validation data sets, respectively. Conclusions Predictors in USRDS data have limited ability to predict AVF maturation. Patient's gender might be considered as the most important predictor for AVF maturation.

The Chronic Kidney Disease in Children (CKiD) cohort study is a North American (USA and Canada) multicenter, prospective study of children with chronic kidney disease (CKD). The original aims of the study were (1) to identify novel risk factors for CKD progression; (2) to measure the impact of kidney function decline on growth, cognition, and behavior; and (3) to characterize the evolution of cardiovascular disease risk factors. CKiD has developed into a national and international resource for the investigation of a variety of factors related to CKD in children. This review highlights notable findings in the area of CKD progression and outlines ongoing opportunities to enhance understanding of CKD progression in children. CKiD's contributions to the clinical care of children with CKD include updated and more accurate glomerular filtration rate estimating equations for children and young adults, and resources designed to help estimate the CKD progression timeline. In addition, results from CKiD have strengthened the evidence that treatment of hypertension and proteinuria should continue as a primary strategy for slowing the rate of disease progression in children.

Children with mild to moderate chronic kidney disease are at an increased risk for cardiovascular sequelae, the leading cause of death in children with end-stage renal disease. We aimed to establish the prevalence of aortic dilatation, a newly recognized cardiovascular sequelae of renal disease, within a cohort of pediatric patients with mild to moderate kidney disease. A total of 501 children enrolled in the Chronic Kidney Disease in Children study contributed imaging data between April 2011 and February 2015. Aortic dilatation was defined as a dimension exceeding a z-score of 2 at any of three locations: aortic root, sinotubular junction, or the ascending aorta. At baseline echocardiographic evaluation, 30 (6%) children were identified to have aortic dilatation in at least one of the three locations. Multivariate analysis demonstrated an increased odds ratio for the presence of aortic dilatation associated with the following variables: high diastolic blood pressure z-scores, low weight z-score, and low body mass index z-score. Presense of protein energy wasting (modified definition, OR 2.41, 95%CI 1.23, 4.70) was the strongest independent predictor of aortic dilatation. In conclusion, aortic dilatation does occur early in the course of chronic kidney disease and associates with markers of poor nutrition. Future studies should continue to evaluate these risk factors longitudinally as the kidney disease progresses.

Background: Choice of vascular access for older hemodialysis patients presents a special challenge since the rate of arteriovenous fistula (AVF) primary failure is high. The Lok’s risk equation predicting AVF primary failure has achieved good prediction accuracy and holds great potential for clinical use, but it has not been validated in the United States older hemodialysis patients. Methods: We assembled a validation data set of 14,892 patients aged 67 years and older who initiated hemodialysis with a central venous catheter between July 1, 2010, and June 30, 2012, and had a subsequent, incident AVF placement from the United States Renal Data System. We examined the external validity of Lok’s model by applying it to this validation data set. The discriminatory accuracy and calibration were evaluated by the concordance index (C-statistics) and calibration plot, respectively. Results: The observed frequency of AVF primary failure varied from 0.45 to 0.53 in hemodialysis patients in the validation data set. The predicted probabilities of AVF primary failure calculated by using the Lok’s risk equation ranged from 0.08 to 0.61, and 77.8, 40.5, and 51.7% of patients were categorized as having high, intermediate, and low risk of AVF primary failure, respectively. The C-statistics of the Lok’s risk equation in the validation data set was 0.53 (95% CI 0.52–0.54). The predicted probabilities of AVF primary failure corresponded poorly with the observed proportions in the calibration plot. Conclusions: When externally applied to a cohort of U.S. older hemodialysis patients, the Lok’s risk equation exhibited poor discrimination and calibration accuracy. It is invalid to use it to predict AVF primary failure. A more complex model with strong predictors is expected to better serve clinical determination for AVF placement in this population.

Objective Persistent organic pollutants (POPs) are lipophilic environmental toxicants that accumulate in adipose tissue. Weight loss leads to mobilization and increased redistribution of these toxicants. Many are obesogens and endocrine disruptors. Increased exposure could pose long-term health risks. The study objective was to measure the changes in serum concentrations of lipophilic POPs during significant weight loss. Methods This study enrolled 27 patients at a university hospital in a longitudinal, 6-month, observational study examining changes in POP blood levels after bariatric surgery. The primary outcome was the changes in the concentrations of 24 polychlorinated biphenyls (PCBs), 9 organochlorine pesticides (OCPs), 11 polybrominated diphenyl ethers, 2,2',4,4',5,5'-hexabromobiphenyl, and 4 perfluorochemicals (PFCs). Results Older adults (those born before 1976) had baseline levels of PCBs, OCPs, and PFCs that were two- to fivefold higher than younger adults (those born after 1976). Older adults had greater increases in PCBs, OCPs, and polybrominated diphenyl ethers associated with weight loss. Conversely, younger adults had greater increases in PFCs associated with weight loss. On average, blood POP levels increased as weight loss occurred. Conclusions Although weight loss is considered beneficial, the release and redistribution of POPs to other lipid-rich organs such as the brain, kidneys, and liver warrant further investigation. Interventions should be considered to limit organ exposure to POPs when weight loss interventions are planned.

BackgroundChronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression through their cholesterol-lowering and pleiotropic effects.MethodsAmong 850 HIV-infected men from the Multicenter AIDS Cohort Study with stored urine samples (2009-2011), we evaluated cross-sectional associations of statin use with urine biomarkers of kidney damage [albumin-to-creatinine ratio (ACR), alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, and procollagen type III N-terminal propeptide] using multivariable linear regression. We evaluated the longitudinal associations of statin use with annual change in estimated glomerular filtration rate by creatinine (eGFR) using linear mixed models, and with incident proteinuria and incident CKD (eGFR

The Chronic Kidney Disease in Children Study, a prospective cohort study with data collected from 2003 to 2018, provided the first opportunity to characterize the incidence of renal replacement therapy (RRT) initiation over the life course of pediatric kidney diseases. In the current analysis, parametric generalized gamma models were fitted and extrapolated for RRT overall and by specific treatment modality (dialysis or preemptive kidney transplant). Children were stratified by type of diagnosis: nonglomerular (mostly congenital; n = 650), glomerular–hemolytic uremic syndrome (HUS; n = 49), or glomerular–non-HUS (heterogeneous childhood onset; n = 216). Estimated durations of time to RRT after disease onset for 99% of the nonglomerular and glomerular–non-HUS groups were 42.5 years (95% confidence interval (CI): 31.0, 54.1) and 25.4 years (95% CI: 14.9, 36.0), respectively. Since onset for the great majority of children in the nonglomerular group was congenital, disease duration equated with age. A simulation-based estimate of age at RRT for 99% of the glomerular population was 37.9 years (95% CI: 33.6, 63.2). These models performed well in cross-validation. Children with glomerular disease received dialysis earlier and were less likely to have a preemptive kidney transplant, while the timing and proportions of dialysis and transplantation were similar for the nonglomerular group. These diagnosis-specific estimates provide insight into patient-centered prognostic information and can assist in RRT planning efforts for children with moderate-to-severe kidney disease who are receiving regular specialty care.

Objectives Adipose tissue (AT) density measurement may provide information about AT quality among people living with HIV. We assessed AT density and evaluated relationships between AT density and immunometabolic biomarker concentrations in men with HIV. Design Cross-sectional analysis of men enrolled in the Multicenter AIDS Cohort Study. Methods Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density (Hounsfield units, HU; less negative = more dense) were quantified from computed tomography (CT) scans. Multivariate linear regression models described relationships between abdominal AT density and circulating biomarker concentrations. Results HIV+ men had denser SAT (−95 vs −98 HU HIV−, P s.d. greater SAT or VAT density was associated with higher levels of adiponectin, leptin, HOMA-IR and triglyceride:HDL cholesterol ratio and lower hs-CRP concentrations in HIV− men. Conversely, in HIV+ men, each s.d. greater SAT density was not associated with metabolic parameter improvements and was significantly (P s.d. greater VAT density were also observed among HIV+ men. Conclusions Among men living with HIV, greater SAT density was associated with greater systemic inflammation independent of SAT area. AT density measurement provides additional insight into AT density beyond measurement of AT quantity alone, and may have implications for metabolic disease risk.

Background A simple equation for glomerular filtration rate (GFR) measurement based on only plasma samples during the slow compartment after injection of iohexol was previously developed among children with chronic kidney disease and adult men with or at risk of HIV infection [Chronic Kidney Disease in Children (CKiD)-Multicenter AIDS Cohort Study (MACS) equation], but has not been externally validated. We aimed to evaluate the performance of the CKiD-MACS equation among elderly participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who underwent directly measured iohexol GFR. Methods Using data from 287 participants of the MESA-Kidney study who underwent a five-sample measured iohexol GFR (two and three samples in the fast and slow compartments, respectively), we assessed the performance of the CKiD-MACS equation using only plasma samples in the slow compartment by sex, race and age. Agreement was assessed by bias, correlation, proportion within 5 and 10%, and the root mean square error (RMSE). Results The average age and GFR of the participants were 71 years and 70.8 mL/min/1.73 m2, respectively, and 46% were black. The equation yielded excellent agreement within stratified groups with high correlation (>0.96), low bias (≤1.2 mL/min/1.73 m2) and low RMSE ( Conclusions The CKiD-MACS equation demonstrated valid GFR measurement using only samples in the slow compartment in this racially diverse, elderly population. While the equation yielded practically the same results as the original Brochner-Mortensen equation, the CKiD-MACS equation conforms to theoretical principles embedded in the two-compartment model of direct GFR measurement.

Chronic kidney disease (CKD) progression is typically characterized as either time to a clinically meaningful event (such as dialysis or transplant), or longitudinal changes in kidney function. This review describes pediatric kidney disease progression using these two distinct frameworks by reviewing and discussing data from the Chronic Kidney Disease in Children study. We first describe new equations to estimate glomerular filtration rate (GFR) for patients younger than age 25 years, and how the average of serum creatinine-based and cystatin C-based GFR equations yield valid estimates than either alone. Next, we present a life course description of CKD onset to kidney replacement therapy, prediction models based on clinical measurements, and show the importance of diagnosis (broadly classified as nonglomerular and glomerular in origin), GFR level, and proteinuria on progression. Literature on longitudinal GFR in children and young adults are reviewed and new data are presented to characterize nonlinear changes in estimated GFR in patients younger than age 25 years. These models showed accelerated progression associated with glomerular diagnosis, lower GFR level, and higher proteinuria, which was congruent with time-to-event analyses. Descriptions of online tools for GFR estimation and risk stratification for clinical applications are presented and we offer key epidemiologic considerations for the analysis of longitudinal pediatric CKD studies.

Consensus blood pressure guidelines vary in their recommended ambulatory blood pressure targets for children with chronic kidney disease (CKD) because of limited research in this area. We analyzed longitudinal ambulatory blood pressure monitoring data from 679 children with moderate CKD enrolled in the observational CKiD (Chronic Kidney Disease in Children) cohort by time-varying mean arterial pressure (MAP) percentile categories based on the highest wake or sleep MAP percentile. Analyses were stratified by nonglomerular and glomerular diagnoses, with 3 models constructed: unadjusted, adjusted for age, sex, and race, and additional adjustment for proteinuria. The outcome of interest was time to renal replacement therapy or 50% decline in baseline renal function. We found that among children with nonglomerular CKD, MAP percentile was not associated with accelerated disease progression risk until after 4 years of follow-up at which point a high MAP (>90th percentile) was associated with a higher risk of progression to the composite end point (HR, 1.88 [CI, 1.03–3.44]). Among those with glomerular CKD, differential risk for progression began from baseline with the highest risk in those with MAP >90th percentile (HR, 3.23 [CI, 1.34–7.79]). These relationships were attenuated somewhat after adjustment for level of proteinuria, but the trend for higher MAP being associated with higher risk of progression remained significant. Thus, in children with CKD, having ambulatory wake or sleep MAP >90th percentile was associated with higher risk of kidney disease progression with the highest levels of MAP associated with the greatest risk of progression. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00327860

Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO.We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course.All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition.High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO.The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.

The aim of this study was to determine if plasma cyclohexanone and metabolites are associated with clinical outcomes of children on extracorporeal membrane oxygenation (ECMO) support. We performed a secondary analysis of a prospective observational study of children on ECMO support at two academic centers between July 2010 and June 2015. We measured plasma cyclohexanone and metabolites on the first and last days of ECMO support. Unfavorable outcome was defined as in-hospital death or discharge Pediatric Cerebral Performance Category score > 2 or decline ≥ 1 from baseline. Among 90 children included, 49 (54%) had unfavorable outcome at discharge. Cyclohexanediol, a cyclohexanone metabolite, was detected in all samples and at both time points; concentrations on the first ECMO day were significantly higher in those with unfavorable versus favorable outcome at hospital discharge (median, 5.7 ng/µl; interquartile range [IQR], 3.3-10.6 ng/µl vs. median, 4.2 ng/µl; IQR, 1.7-7.3 ng/µl; p = 0.04). Twofold higher cyclohexanediol concentrations on the first ECMO day were associated with increased risk of unfavorable outcome at hospital discharge (multivariable-adjusted hazard ratio [HR], 1.24 [95% CI, 1.05-1.48]). Higher cyclohexanediol concentrations on the first ECMO day were not significantly associated with new abnormal neuroimaging or 1-year Vineland Adaptive Behavior Scales-II score < 85 or death among survivors.

BACKGROUND: We investigated the putative associations of alcohol, cigarette, e-cigarette and marijuana use with kidney function and proteinuria among adolescents and young adults (AYA) with pediatric-onset chronic kidney disease (CKD) enrolled in the Chronic Kidney Disease in Children (CKiD) study. METHODS: Participants responded to questions about past year and 30-day substance use. Associations between each substance and kidney function, proteinuria, nephrotic range proteinuria and high blood pressure were separately estimated using repeated measures regression models, adjusting for sociodemographic characteristics. Models controlled for covariates at the present visit (contemporaneous), and additionally controlled for disease severity at the year prior to reporting substance use (lagged). RESULTS: A total of 441 participants ≥16 years contributed 1,245 person-visits with 39% reporting alcohol and 16%, 17% and 15% reporting cigarette, e-cigarette and marijuana use, respectively, over the previous year. In adjusted lagged models, past year and 30-day cigarette use were significantly associated with higher levels of proteinuria (+18.6%, 95%CI: +2.8%, +36.9%; and +20.0%, 95%CI: +0.7%, +43.1%, respectively). Inferences were similar when controlling for secondhand smoke exposure. CONCLUSIONS: In a cohort of AYA with pediatric kidney diseases, substance use was non-trivial, and cigarette use was associated with higher proteinuria, although the prevalence was low. Occasional alcohol, e-cigarette and marijuana use were not associated with proteinuria, disease progression, or elevated blood pressure. Pediatric nephrologists as specialty care providers are well-positioned to discuss substance use and should encourage tobacco prevention/treatment efforts among AYA at high risk for use in order to preserve kidney function and promote well-being.

Outdoor air pollution, a spatially and temporally complex mixture, is a human carcinogen. However, ambient measurements may not reflect subject-level exposures, personal monitors do not assess internal dose, and spot assessments of urinary biomarkers may not recapitulate chronic exposures. Nucleophilic sites in serum albumin – particularly the free thiol at Cys(34) – form adducts with electrophiles. Due to the 4-week lifetime of albumin in circulation, accumulating adducts can serve as intermediate- to long-residence biomarkers of chronic exposure and implicate potential biological effects. Employing nanoflow liquid chromatography-high resolution mass spectrometry (nLC-HRMS) and parallel reaction monitoring (PRM), we have developed and validated a novel targeted albumin adductomics platform capable of simultaneously monitoring dozens of Cys(34) adducts per sample in only 2.5 μL of serum, with on-column limits of detection in the low femtomolar range. Using this platform, we characterized the magnitude and impact of ambient outdoor air pollution exposures with three repeated measurements over 84 days in n=26 non-smoking women (n=78 total samples) from Qidong, China, an area with a rising burden of lung cancer incidence. In concordance with seasonally rising ambient concentrations of NO(2), SO(2), and PM(10) measured at stationary monitors, we observed elevations in concentrations of Cys(34) adducts of benzoquinone (p

Recent reassessment of the use of race in estimated glomerular filtration rate (eGFR) in adults has instigated questions about the role of race in eGFR expressions for children. Little research has examined the associations of self-reported race with measured GFR (mGFR) adjusting for serum creatinine or cystatin C in children and young adults with chronic kidney disease (CKD). This study examined these associations and evaluated the performance of the previously published "U25" (under the age of 25 years) eGFR equations in a large cohort of children and young adults with CKD.Observational cohort study.Participants in the Chronic Kidney Disease in Children (CKiD) study including 190 Black and 675 non-Black participants contributing 473 and 1,897 annual person-visits, respectively.Self- or parental-reported race (Black, non-Black). Adjustment for serum creatinine or cystatin C, body size, and socioeconomic status.mGFR based on iohexol clearance.Linear regression with generalized estimating equations, stratified by age (6, 6-12, 12-18, and ≥18 years) incorporating serum creatinine or serum cystatin C. Contrasting performance in different self-reported racial groups of the U25 eGFR equations.Self-reported Black race was significantly associated with 12.8% higher mGFR among children in regression models including serum creatinine. Self-reported Black race was significantly associated with 3.5% lower mGFR after adjustment for cystatin C overall but was not significant for those over 12 years. The results were similar after adjustment for body size and socioeconomic factors. The average of creatinine- and cystatin C-based U25 equations was unbiased by self-reported race groups.Small number of children 6 years; lean body mass was estimated.Differences in the creatinine-mGFR relationship by self-reported race were observed in children and young adults with CKD and were consistent with findings in adults. Smaller and opposite differences were observed for the cystatin C-mGFR relationship, especially in the younger age group. We recommend inclusion of children for future investigations of biomarkers to estimate GFR. Importantly, for GFR estimation among those under 25 years of age, the average of the new U25 creatinine and cystatin C equations without race coefficients yields unbiased estimates of mGFR.

BACKGROUND: Hypertension is common among children with chronic kidney disease (CKD), and dihydropyridine calcium channel blockers (dhCCBs) are frequently used as treatment. The impact of dhCCBs on proteinuria in children with CKD is unclear. METHODS: Data from 722 participants in the Chronic Kidney Disease in Children (CKiD) longitudinal cohort with a median age of 12 years were used to assess the association between dhCCBs and log transformed urine protein/creatinine levels as well as blood pressure control measured at annual visits. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use was evaluated as an effect measure modifier. RESULTS: Individuals using dhCCBs had 18.8% higher urine protein/creatinine levels compared to those with no history of dhCCB or ACEi and ARB use. Among individuals using ACEi and ARB therapy concomitantly, dhCCB use was not associated with an increase in proteinuria. Those using dhCCBs had higher systolic and diastolic blood pressures. CONCLUSIONS: Use of dhCCBs in children with CKD and hypertension is associated with higher levels of proteinuria and was not found to be associated with improved blood pressure control.

BACKGROUND: Recombinant growth hormone (rGH) is an efficacious therapy for growth failure in children with chronic kidney disease (CKD). We described rGH use and estimated its relationship with growth and kidney function in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants included those with growth failure, prevalent rGH users, and rGH initiators who did not meet growth failure criteria. Among those with growth failure, height z-scores and GFR were compared between rGH initiators and non-initiators across 42 months. Inverse probability weights accounted for differences in baseline variables in weighted linear regressions. RESULTS: Among 148 children with growth failure and no previous rGH therapy, 42 (28%) initiated rGH therapy. Of the initiators, average age was 8.9 years, height z-score was 2.50 standard deviations (SDs) (0.6(th) percentile) and GFR was 44 ml/min/1.73m(2). They were compared to 106 children with growth failure who never initiated therapy (8.8 years, −2.33 SDs, and 51 ml/min/1.73m(2)). At 30 and 42 months after rGH, height increased +0.26 (95%CI: −0.11, +0.62) and +0.35 (95%CI: −0.17, +0.87) SDs, respectively, relative to those who did not initiate rGH. rGH was not associated with GFR. CONCLUSIONS: Participants with growth failure receiving rGH experienced significant growth, although this was attenuated relative to RCTs, and were more likely to have higher household income and lower GFR. A substantial number of participants, predominantly boys, without diagnosed growth failure received rGH and had highest achieved height relative to mid-parental height. Since rGH was not associated with accelerated GFR decline, increasing rGH use in this population is warranted.