Search

Derek K Ng, Daniel A Antiporta, Matthew B Matheson, Alvaro Muñoz Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USACorrespondence: Alvaro MuñozDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 Wolfe Street Room E7648, Baltimore, MD 21205, USATel +1 410-955-2792Email amunoz@jhu.eduAbstract: Associations between an exposure and multiple competing events are typically described by cause-specific hazard ratios (csHR) or subdistribution hazard ratios (sHR). However, diagnostic tools to assess differences between them have not been described. Under the proportionality assumption for both, it can be shown mathematically that the sHR and csHR must be equal, so reporting different time-constant sHR and csHR implies non-proportionality for at least one. We propose a simple, intuitive approach using the ratio of sHR/csHR to nonparametrically compare these metrics. In general, for the non-null case, there must be at least one event type for which the sHR and csHR differ, and the proposed diagnostic will be useful to identify these cases. Furthermore, once standard methods are used to estimate the csHR, multiplying it with our nonparametric estimate for the sHR/csHR ratio will yield estimates of sHR which fulfill intrinsic linkages of the subhazards that separate analysis may violate. In addition, for non-null cases, at least one must be time dependent (i.e., non-proportional), and thus our tool serves as an indirect test of the proportionality assumption. We applied this proposed diagnostic tool to data from a cohort of children with congenital kidney disease to describe racial differences in the time to first dialysis or first transplant and extend methods to include adjustment for socioeconomic factors.Keywords: survival analysis, nonparametric methods, competing risk analysis, cause-specific hazard ratios, sub-distribution hazard ratios, chronic kidney disease

Background: Direct coronary arterial evaluation via computed tomography (CT) angiography is the most accurate noninvasive test for the diagnosis of coronary artery disease (CAD). However, diagnostic accuracy is limited in the setting of severe coronary calcification or stents. Ultra-high-resolution CT (UHR-CT) may overcome this limitation, but no rigorous study has tested this hypothesis., Methods: The CORE-PRECISION is an international, multicenter, prospective diagnostic accuracy study testing the non-inferiority of UHR-CT compared to invasive coronary angiography (ICA) for identifying patients with hemodynamically significant CAD. The study will enroll 150 patients with history of CAD, defined as prior documentation of lumen obstruction, stenting, or a calcium score ≥400, who will undergo UHR-CT before clinically prompted ICA. Assessment of hemodynamically significant CAD by UHR-CT and ICA will follow clinical standards. The reference standard will be the quantitative flow ratio (QFR) with <0.8 defined as abnormal. All data will be analyzed in independent core laboratories., Results: The primary outcome will be the comparative diagnostic accuracy of UHR-CT vs. ICA for detecting hemodynamically significant CAD on a patient level. Secondary analyses will focus on vessel level diagnostic accuracy, quantitative stenosis analysis, automated contour detection, in-depth plaque analysis, and others., Conclusion: CORE-PRECISION aims to investigate if UHR-CT is non-inferior to ICA for detecting hemodynamically significant CAD in high-risk patients, including those with severe coronary calcification or stents. We anticipate this study to provide valuable insights into the utility of UHR-CT in this challenging population and for its potential to establish a new standard for CAD assessment., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Children with chronic kidney disease (CKD) are at risk for abnormalities in pubertal development. We aimed to describe the timing of pubertal onset by luteinizing hormone (LH) levels and the association between hormonal onset of puberty with changes in GFR., Methods: Data from the Chronic Kidney Disease in Children (CKiD) study were collected prospectively. GFR was estimated at annual visits and measured by iohexol clearance every other year. LH was measured from stored repository serum samples in a nested sample of 124 participants. Hormonal onset of puberty was defined as LH level greater than or equal to 0.3 IU/L. A mixed effects model with random intercepts and slopes was used to compare the slope of decline of GFR before and after hormonal onset of puberty. The model was adjusted for age, glomerular disease diagnosis, baseline proteinuria on the log scale, and BMI., Results: Median age at hormonal onset of puberty was 9.9 years (IQR 8.1, 11.9) in girls and 10.2 years (IQR 9.2, 11.0) in boys. The mixed effects model showed faster decline in both estimated GFR and measured GFR in boys after hormonal onset of puberty (p < 0.001), and a similar but attenuated accelerated estimated GFR decline was observed for girls with no difference for measured GFR., Conclusions: LH levels in the post-pubertal range were observed prior to clinical manifestations of puberty in children with CKD. Hormonal onset of puberty was associated with faster decline in GFR, particularly among boys with CKD., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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.)

Background: Few longitudinal studies have evaluated the impact of chronic kidney disease (CKD) duration on health-related quality of life (HRQOL). The study's aim was to determine how HRQOL changes over time in childhood CKD., Methods: Study participants were children in the chronic kidney disease in children (CKiD) cohort who completed the pediatric quality of life inventory (PedsQL) on three or more occasions over the course of two or more years. Generalized gamma (GG) mixed-effects models were applied to assess the effect of CKD duration on HRQOL while controlling for selected covariates., Results: A total of 692 children (median age = 11.2) with a median of 8.3 years duration of CKD were evaluated. All subjects had a GFR greater than 15 ml/min/1.73 m 2 . GG models with child self-report PedsQL data indicated that longer CKD duration was associated with improved total HRQOL and the 4 domains of HRQOL. GG models with parent-proxy PedsQL data indicated that longer duration was associated with better emotional but worse school HRQOL. Increasing trajectories of child self-report HRQOL were observed in the majority of subjects, while parents less frequently reported increasing trajectories of HRQOL. There was no significant relationship between total HRQOL and time-varying GFR., Conclusions: Longer duration of the disease is associated with improved HRQOL on child self-report scales; however, parent-proxy results were less likely to demonstrate any significant change over time. This divergence could be due to greater optimism and accommodation of CKD in children. Clinicians can use these data to better understand the needs of pediatric CKD patients. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Our objective is to use computed tomography angiography (CTA) and computed tomography perfusion (CTP) to identify the ischemic significance of myocardial bridging (MB). We also seek to determine the long-term prognostication of MB in the presence or absence of obstructive coronary artery disease (CAD). The CORE320, a prospective, multicenter study including 381 patients with known or suspected CAD clinically referred for invasive coronary angiography who underwent combined (CTA-CTP) and single-photon emission computed tomography before conventional coronary angiography. The incidence of MB was identified in 135 patients (35.4%) with 93.9% identified in the left anterior descending artery. MB were divided as partially encased versus fully encased. There was no difference in ischemia identified between partially encased MB and fully encased MB (37 [40%] vs 25 [35%], p = 0.54]. Ischemia was identified at similar rates in partially versus fully encased MB by single-photon emission computed tomography at (8 [9%] vs 8 [11%], p = 0.57] and CTP (34 [37%] vs 21 [30%], p = 0.33]. There was no difference in the primary outcome of 5-year outcome of combined incidence of myocardial infarction or death. The restricted mean survival time in patients with CTA with <50% stenosis with or without a MB was 4.906 years (95% confidence interval 4.759 to 5.000) and 4.891 years (95% confidence interval 4.718 to 5.000), respectively (p = 0.824). Cardiac computed tomography perfusion imaging can assess both anatomic and functional significance of myocardial bridging with diagnostic accuracy similar to current standard imaging. Furthermore, 5-year cardiovascular events were not different with the presence of MB in both obstructive and non-obstructive CAD., Competing Interests: Declaration of Competing Interest Dr. George is an employee at AstraZeneca. Dr. Vavere is an employee at AstraZeneca. Dr. Chen is an employee of the Division of Intramural Research, Department of Health and Human Services, National Heart, Lung, and Blood Institute, National Institutes of Health. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinicians need improved prediction models to estimate time to kidney replacement therapy (KRT) for children with chronic kidney disease (CKD). Here, we aimed to develop and validate a prediction tool based on common clinical variables for time to KRT in children using statistical learning methods and design a corresponding online calculator for clinical use. Among 890 children with CKD in the Chronic Kidney Disease in Children (CKiD) study, 172 variables related to sociodemographics, kidney/cardiovascular health, and therapy use, including longitudinal changes over one year were evaluated as candidate predictors in a random survival forest for time to KRT. An elementary model was specified with diagnosis, estimated glomerular filtration rate and proteinuria as predictors and then random survival forest identified nine additional candidate predictors for further evaluation. Best subset selection using these nine additional candidate predictors yielded an enriched model additionally based on blood pressure, change in estimated glomerular filtration rate over one year, anemia, albumin, chloride and bicarbonate. Four additional partially enriched models were constructed for clinical situations with incomplete data. Models performed well in cross-validation, and the elementary model was then externally validated using data from a European pediatric CKD cohort. A corresponding user-friendly online tool was developed for clinicians. Thus, our clinical prediction tool for time to KRT in children was developed in a large, representative pediatric CKD cohort with an exhaustive evaluation of potential predictors and supervised statistical learning methods. While our models performed well internally and externally, further external validation of enriched models is needed., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Background: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD., Methods: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log 2 -transformed given its skewed distribution., Results: Among 677 CKiD participants, the median age was 11.8 years (8.2-15.3), the median eGFR was 49 ml/min/1.73 m 2 (37-63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045-0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log 2 (Umod/Cr) and 0.20 (13%) lower log 2 (Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively)., Conclusions: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The coronary atheroma burden drives major adverse cardiovascular events (MACE) in patients with suspected coronary heart disease (CHD). However, a consensus on how to grade disease burden for effective risk stratification is lacking. The purpose of this study was to compare the effectiveness of common CHD grading tools to risk stratify symptomatic patients., Methods: We analyzed the 5-year outcome of 381 prospectively enrolled patients in the CORE320 international, multicenter study using baseline clinical and cardiac computer-tomography (CT) imaging characteristics, including coronary artery calcium score (CACS), percent atheroma volume, "high-risk" plaque, disease severity grading using the CAD-RADS, and two simplified CAD staging systems. We applied Cox proportional hazard models and area under the curve (AUC) analysis to predict MACE or hard MACE, defined as death, myocardial infarction, or stroke. Analyses were stratified by a history of CHD. Additional forward selection analysis was performed to evaluate incremental value of metrics., Results: Clinical characteristics were the strongest predictors of MACE in the overall cohort. In patients without history of CHD, CACS remained the only independent predictor of MACE yielding an AUC of 73 (CI 67-79) vs. 64 (CI 57-70) for clinical characteristics. Noncalcified plaque volume did not add prognostic value. Simple CHD grading schemes yielded similar risk stratification as the CAD-RADS classification. Forward selection analysis confirmed prominent role of CACS and revealed usefulness of functional testing in subgroup with known CHD., Conclusion: In patients referred for invasive angiography, a history of CHD was the strongest predictor of MACE. In patients without history of CHD, a coronary calcium score yielded at least equal risk stratification vs. more complex CHD grading., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery calcium (CAC) scanning can be performed using non-contrast computed tomography to predict cardiovascular events, but has less value for risk stratification in symptomatic patients., Objective: To identify and validate predictors of significant coronary obstruction (SCO) in symptomatic patients without coronary artery calcification., Methods: A total of 4,258 participants were screened from the CORE64 and CORE320 studies that enrolled patients referred for invasive angiography, and from the Quanta Registry that included patients referred for coronary computed tomography angiography (CTA). Logistic regression models evaluated associations between cardiovascular risk factors, CAC, and SCO. An algorithm to assess the risk of SCO was proposed for patients without CAC. Significance level of 5% was used in the analyses., Results: Of the 509 participants of the CORE study, 117 (23%) had zero coronary calcium score; 13 (11%) patients without CAC had SCO. Zero calcium score was related to younger age, female gender, lower body mass index, no diabetes, and no dyslipidemia. Being a current smoker increased ~3.5 fold the probability of SCO and other CV risk factors were not significantly associated. Considering the clinical findings, an algorithm to further stratify zero calcium score patients was proposed and had a limited performance in the validation cohort (AUC 58; 95%CI 43, 72)., Conclusion: A lower cardiovascular risk profile is associated with zero calcium score in a setting of high-risk patients. Smoking is the strongest predictor of SCO in patients without CAC.

Background: Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction. The aim of this study was to investigate associations between executive functions (EF), anemia, and iron deficiency., Methods: A total of 688 children > 6 years of age enrolled in the Chronic Kidney Disease in Children (CKiD) study who underwent evaluation for EF were included. Hemoglobin (Hgb) was characterized as low (1 st -5 th percentile) or very low (< 1 st percentile) compared to normative values for age, sex, and race irrespective of erythropoiesis-stimulating agent (ESA) usage. Longitudinal analysis was conducted using consecutive visit pairs, with anemia status defined as new onset, resolved, or persistent. Linear mixed models with random intercept were used and adjusted for key covariates., Results: Anemia was present in 41% of children, and median Hgb was 11.8 gm/dl. New onset anemia was associated with lower digit span total score (- 0.75, 95% CI - 1.36, - 0.15, p = 0.01). Persistent anemia was associated with lower scores on color-word inhibition/switching (β =  - 0.98; 95% CI - 1.78, - 0.18, p = 0.02). Errors of omission were significantly higher (worse) in those with persistent anemia (β = 2.67, 95% CI 0.18, 5.17, p = 0.04). Very low Hgb levels were significantly associated with lower color-word inhibition/switching scores (β =  - 1.33, 95% CI - 2.16, - 0.51; p = 0.002). Anemia and low GFR were associated with lower category fluency scores compared to non-anemic subjects with higher GFR (β =  - 1.09, 95% CI - 2.09, - 0.10, p = 0.03)., Conclusions: The presence of anemia, in addition to its severity and duration in children with CKD, is associated with poorer scores on select measures of EF. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Cardiovascular disease (CVD) screening entails precise event prediction to orient risk stratification, resource allocation, and insurance policy. We used random survival forests (RSF) to identify markers of incident CVD among Japanese adults enrolled in an employer-mandated screening program. Methods and Results: We examined biomarker, health history, medication use, and lifestyle data from 155,108 adults aged ≥40 years. The occurrence of coronary artery disease (CAD) or atherosclerotic CVD (ASCVD) events was examined over 6 years of follow-up. The analysis used RSF to identify predictors, then investigated simplified RSF models with fewer predictors for individual-level risk prediction. Data were split into training (70%) and test (30%) datasets. At baseline, the median patient age was 47 years (interquartile range 41-56 years), with 65% males. In all, 1,642 CAD and 2,164 ASCVD events were observed. RSF identified history of heart disease, age, self-reported blood pressure medication, HbA1c, fasting blood sugar, and high-density lipoprotein as important markers of both endpoints. RSF analyses with only the top 20 predictors demonstrated good performance, with areas under the curve of >84% for CAD and >82% for ASCVD in test data across 6 years. Conclusions: We present a machine learning technique for accurate assessment of cardiovascular risk using employer-mandated annual health checkup information. The algorithm produces individual-level risk curves over time, empowering clinicians to efficiently implement prevention strategies in a low-risk population., Competing Interests: All authors report funding from Toshiba Corporation for the development and completion of this research. S.B. is an employee of Toshiba Corporation., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)

Background: Inflammation surrounding the coronary arteries can be non-invasively assessed using pericoronary adipose tissue attenuation (PCAT). While PCAT holds promise for further risk stratification of patients with low coronary artery disease (CAD) prevalence, its value in higher risk populations remains unknown., Methods: CORE320 enrolled patients referred for invasive coronary angiography with known or suspected CAD. Coronary computed tomography angiography (CCTA) images were collected for 381 patients for whom clinical outcomes were assessed 5 years after enrollment. Using semi-automated image analysis software, PCAT was obtained and normalized for the right coronary (RCA), left anterior descending (LAD), and left circumflex arteries (LCx). The association between PCAT and major adverse cardiovascular events (MACE) during follow up was assessed using Cox regression models., Results: Thirty-seven patients were excluded due to technical failure. For the remaining 344 patients, median age was 62 (interquartile range, 55-68) with 59% having ≥1 coronary artery stenosis of ≥50% by quantitative coronary angiography. Mean attenuation values for PCAT in RCA, LAD, and LCx were -74.9, -74.2, and -71.2, respectively. Hazard ratios and 95% confidence intervals (CI) for normalized PCAT in the RCA, LAD, and LCx for MACE were 0.96 (CI: 0.75-1.22, p ​= ​0.71), 1.31 (95% CI: 0.96-1.78, p ​= ​0.09), and 0.98 (95% CI: 0.78-1.22, p ​= ​0.84), respectively. For death, stroke, or myocardial infarction only, hazard ratios were 0.68 (0.44-1.07), 0.85 (0.56-1.29), and 0.57 (0.41-0.80), respectively., Conclusions: In patients referred for invasive coronary angiography with suspected CAD, PCAT did not predict MACE during long term follow up. Further studies are needed to understand the relationship of PCAT with CAD risk., (Copyright © 2022 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Uromodulin regulates activity of the sodium-potassium-two-chloride transporter in the loop of Henle. In adults, higher urine uromodulin levels are associated with greater rise in blood pressure (BP) in response to salt intake. We hypothesized that higher urine uromodulin levels would be associated with higher BP in children with chronic kidney disease, and that there would be an interaction of dietary sodium on this association., Methods: In the chronic kidney disease in children Cohort, we utilized univariable and multivariable linear regression models to evaluate the relationship between baseline spot urine uromodulin levels indexed to urine creatinine (Umod/Cr mg/g) and 24-hour mean systolic and diastolic BP, as well as baseline clinic BP. We also tested whether sodium intake (g/day) modified these relationships., Results: Among 436 participants, the median age was 12.4 years (8.9-15.2), median estimated glomerular filtration rate was 50 mL/min per 1.73 m 2 (36-62), and median 24-hour mean systolic BP was 112 mm Hg (104-119). The etiology of chronic kidney disease was glomerular disease in 27%. In univariable models, each 2-fold higher Umod/Cr ratio was associated with a 1.66 mm Hg (95% CI, -2.31 to -1.00) lower 24-hour mean systolic and a 1.71 mm Hg (-2.45 to -0.97) lower clinic systolic BP. However, there was no statistically significant association between Umod/Cr and either 24-hour or clinic BP in multivariable models. We did not find a significant interaction between uromodulin and sodium intake in their effect on BP ( P >0.05 in all models)., Conclusions: Urine uromodulin levels are not associated with BP in the chronic kidney disease in children cohort. Further studies are needed to confirm this finding in healthy pediatric cohorts.

Rationale & Objective: To examine the relationship between neighborhood poverty and deprivation, chronic kidney disease (CKD) comorbidities, and disease progression in children with CKD., Study Design: Observational cohort study., Setting & Participants: Children with mild to moderate CKD enrolled in the CKiD (Chronic Kidney Disease in Children) study with available US Census data., Exposure: Neighborhood poverty and neighborhood disadvantage., Outcome: 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., Analytical Approach: 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., Results: 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., Limitations: Limited generalizability, as only those with consistent longitudinal nephrology care were studied., Conclusions: 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., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Vegetable or plant-based sources of protein may confer health benefits in children with progressive kidney disease. Our aims were to understand the effect of the proportion of vegetable protein intake on changes in estimated GFR and to understand the effect of the proportion of vegetable protein intake on serum levels of bicarbonate, phosphorus, and potassium., Methods: Children with baseline eGFR between 30 and 90 mL/min/1.73 m 2 were recruited from 59 centers across North America as part of the chronic kidney disease in children (CKiD) study. The percentage of dietary vegetable protein (VP%) was gathered from annual Food Frequency Questionnaires. We performed longitudinal linear mixed models to determine the effect of VP% on eGFR and longitudinal logistic mixed models to determine the effect of VP% on electrolyte balance (potassium, phosphorus, bicarbonate)., Results: Two thousand visits from 631 subjects. Across all dichotomized groups of children (sex, African American race, Hispanic ethnicity, glomerular etiology of CKD, hypertension, anemia, hyperkalemia, hyperphosphatemia, acidosis, BMI < 95th percentile), the median VP% was 32-35%. The longitudinal mixed model analysis did not show any effect of VP% on eGFR electrolyte (bicarbonate, phosphorus, and potassium) abnormalities (p > 0.1)., Conclusions: A diverse cohort of children with CKD has a narrow and homogeneous intake of vegetable protein. Due to the low variability of plant-based protein in the cohort, there were no associations between the percentage of plant protein intake and changes in eGFR nor electrolyte balance. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Few data exist on long-term outcome in patients undergoing combined coronary CT angiography (CTA) and myocardial CT perfusion imaging (CTP) as well as invasive coronary angiography (ICA) and single photon emission tomography (SPECT)., Methods: At 16 centers, 381 patients were followed for major adverse cardiac events (MACE) for the CORE320 study. All patients underwent coronary CTA, CTP, and SPECT before ICA within 60 days. Prognostic performance according binary results (normal/abnormal) was assessed by 5-year major cardiovascular events (MACE) free survival and area under the receiver-operating-characteristic curve (AUC)., Results: Follow up beyond 2-years was available in 323 patients. MACE-free survival rate was greater among patients with normal combined CTA-CTP findings compared to ICA-SPECT: 85 vs. 80% (95% confidence interval [CI] for difference 0.1, 11.3) though event-free survival time was similar (4.54 vs. 4.37 years, 95% CI for difference: -0.03, 0.36). Abnormal results by combined CTA-CTP was associated with 3.83 years event-free survival vs. 3.66 years after abnormal combined ICA-SPECT (95% CI for difference: -0.05, 0.39). Predicting MACE by AUC also was similar: 65 vs. 65 (difference 0.1; 95% CI -4.6, 4.9). When MACE was restricted to cardiovascular death, myocardial infarction, or stroke, AUC for CTA-CTP was 71 vs. 60 by ICA-SPECT (difference 11.2; 95% CI -1.0, 19.7)., Conclusions: Combined CTA-CTP evaluation yields at least equal 5-year prognostic information as combined ICA-SPECT assessment in patients presenting with suspected coronary artery disease. Noninvasive cardiac CT assessment may eliminate the need for diagnostic cardiac catheterization in many patients., Clinical Trial Registration: NCT00934037., (Copyright © 2021 Society of Cardiovascular Computed Tomography. All rights reserved.)

Objective: To assess the incidence of contrast-associated acute kidney injury (CAAKI) after repeated exposure to contrast material for computed tomography (CT) and conventional coronary angiography within short intervals., Methods: We studied 651 patients enrolled in the CorE-64 (November 5, 2005-January 30, 2007) and CORE320 (October 21, 2009-August 17, 2011) multicenter studies. Participants with suspected obstructive coronary heart disease were referred for diagnostic cardiac catheterization and underwent coronary CT angiography for research before invasive angiography. Nonionic, low-osmolality iodinated contrast material was used for all imaging., Results: The median age of the patients was 62 years, and 190 (29%) were women. Major risk factors for acute kidney injury were present in 277 of 651 (43%) patients. The median interval between CT imaging and invasive angiography was 3.1 days (interquartile range, 0.9-8.0 days). The median volume of contrast material was 100 mL for each test. In 16 (2.5%) of 651 patients, CAAKI developed. Of these cases, 1 occurred after the CT scan, whereas 6 were documented after invasive angiography (compared with post-CT creatinine concentration assessment). In 9 patients, CAAKI was found in comparing creatinine concentration after completion of both tests with baseline values (but not compared with post-CT imaging)., Conclusion: Acute kidney injury after repeated exposure to iodinated contrast media within a few days is uncommon even in a population of patients with highly prevalent risk factors. Withholding of clinically indicated contrast-enhanced imaging may therefore not be justified in this setting., (© 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Purpose: To provide comparative prognostic information of coronary atherosclerotic plaque volume and stenosis assessment in patients with suspected coronary artery disease (CAD)., Methods: We followed 372 patients with suspected or known CAD enrolled in the CORE320 study for 2 years after baseline 320-detector row cardiac CT scanning and invasive quantitative coronary angiography (QCA). CT images were analyzed for coronary calcium scanning (CACS), semi-automatically derived total percent atheroma volume (PAV), segment stenosis score (SSS), in addition to traditional stenosis assessment (≥ 50%) by CT and QCA for (1) 30-day revascularization and (2) major adverse cardiac events (MACE). Area under the receiver operating characteristic curve (AUC) was used to compare accuracy of risk prediction., Results: Sixty percent of patients had obstructive CAD by QCA with 23% undergoing 30-day revascularization and 9% experiencing MACE at 2 years. Most late events (20/32) were revascularization procedures. Prediction of 30-day revascularization was modest (AUC range 0.67-0.78) but improved after excluding patients with known CAD (AUC range 0.73-0.86, p < 0.05 for all). Similarly, prediction of MACE improved after excluding patients with known CAD (AUC range 0.58-0.73 vs. 0.63-0.77). CT metrics of atherosclerosis burden performed overall similarly but stenosis assessment was superior for predicting 30-day revascularization., Conclusions: Angiographic and coronary atherosclerotic plaque metrics perform only modestly well for predicting 30-day revascularization and 2-year MACE in high risk patients but improve after excluding patients with known CAD. Atherosclerotic plaque metrics did not yield incremental value over stenosis assessment for predicting events that predominantly consisted of revascularization procedures., Clinical Trial Registration: NCT00934037.

Background: To evaluate impact of anemia on health-related quality of life (HRQOL) over time in a large pediatric cohort with mild-to-moderate chronic kidney disease (CKD)., Methods: Participants were enrolled in the Chronic Kidney Disease in Children Study (CKiD), a multicenter, longitudinal cohort. HRQOL was measured using the Pediatric Quality of Life Inventory (PedsQL). Anemia was defined as hemoglobin < 5th percentile for age, sex, and race. Two longitudinal analyses were conducted on consecutive visit pairs. Models examined effects of anemia status on both HRQOL score over time and change in HRQOL score between consecutive visits. The sample included 733 children with a median estimated GFR 54 ml/min/1.73 m 2 . Thirty percent of children had anemia at index visit., Results: Analysis of HRQOL scores revealed the presence of anemia was associated with significantly lower overall HRQOL (β = - 2.90 (95% CI = - 7.74, - 0.21), p = 0.04) and physical functioning (β = - 5.72 (- 9.49, - 2.25), p = 0.001) according to children. On parent ratings, the development of anemia was associated with lower emotional functioning scores (β = - 4.87 (- 8.72, - 0.11), p = 0.045). In the second model, children who developed anemia were rated by caregivers as having more decreased physical functioning than children who remained anemia-free (β = - 3.30 per year (- 5.83, - 0.76), p = 0.01). Caregivers did not observe declines in their children's other PedsQL subscales in the presence of developed anemia. Children with resolved or persistence did not show improvement or decline in any aspect of HRQOL functioning relative to non-anemic subjects., Conclusions: In children with CKD, anemia has an adverse effect on HRQOL which persists over time but does not appear to be progressive.

Background: 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., Methods: 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., Results: 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 < 0.05). Girls with delayed menarche had lower height and weight percentiles at the time of menarche (p < 0.05). Sixty-one percent of girls with delayed menarche had short stature compared with only 35% of girls without delayed menarche (p = 0.03)., Conclusion: Median age at menarche is similar among girls with CKD and healthy girls. Ten percent of girls with CKD had delayed menarche and may be at risk for short stature.

Background: This study aimed to determine stroke incidence and assess the association between stroke and neurocognitive functioning in children with chronic kidney disease (CKD)., Methods: Data was derived from the Chronic Kidney Disease in Children (CKiD) cohort study. Stroke incidence was calculated after confirming self-reports of stroke occurrence by chart review. Each participant with stroke was matched with three stroke-free participants and performance on selected neurocognitive measures was compared. Wilcoxon rank-sum tests were used to compare neurocognitive test scores. Effect size (ES) was estimated using a modified version of Cohen's U 3 metric that measures the excess percentage of the stroke group worse than the median of the control group., Results: Of 891 subjects, five (0.56%) had a confirmed stroke prior to study entry. Median time at risk was 15.7 years [interquartile range, 12.5-18.4]. Estimated incidence rate of history of stroke was 36.8 per 100,000 children per year (95% confidence interval 15.3, 88.5). Controls and subjects with stroke were similar in age, CKD duration, race, and maternal education. ES for many of the neurocognitive comparisons was moderate to large. Subjects in the CKID cohort with a history of stroke had lower scores on spatial span reverse, spatial span forward, and design fluency, and worse parent ratings on BRIEF Metacognition Index compared to a matched sample of children with CKD without stroke., Conclusions: Children with CKD have an increased incidence of prior ischemic stroke compared to the general pediatric population. A stroke history was associated with poorer performance on neurocognitive measures. Graphical abstract.

Background: Children with mild to moderate chronic kidney disease (CKD) are at increased risk for deficits in neurocognition. Less is known about how CKD affects emotional-behavioral functioning in this population., Methods: Parent ratings of emotional-behavioral functioning at baseline and over time were examined for 845 children with mild to moderate CKD using the Behavior Assessment System for Children, Second Edition Parent Rating Scales (BASC-2 PRS). Associations with demographic and disease-related predictors were also examined., Results: Children with mild to moderate CKD had parent-reported emotional-behavioral functioning largely within normal limits, at baseline and over time. The proportion with T-scores at least 1 SD above the mean was 24% for Internalizing Problems and 28% for Attention Problems. A greater proportion of participants scored lower than expected (worse) on scales measuring adaptive skills (25%). Persistent hypertension predicted attention problems (β = 1.59, 95% CI = 0.24 to 2.94, p < 0.02) and suggested worse behavioral symptoms (β = 1.36, 95% CI = - 0.01 to 2.73, p = 0.05). Participants with proteinuria at baseline, but not at follow-up, had fewer attention problems than participants whose proteinuria had not resolved (β = - 3.48, CI = - 6.79 to - 0.17, p < 0.04). Glomerular diagnosis was related to fewer (β = - 2.68, 95% CI = - 4.93 to - 0.42, p < 0.02) internalizing problems., Conclusions: Although children with CKD generally have average emotional-behavioral parent ratings, a notable percentage of the population may be at risk for problems with attention and adaptive behavior. Providers working with this population should facilitate psychosocial referrals when indicated.

Background: In adult chronic kidney disease (CKD), metabolic acidosis is associated with diminished cognition, notably executive function (EF). Data from the Chronic Kidney Disease in Children (CKiD) study demonstrate a risk for impairment of EF, a finding associated with heightened blood pressure variability (BPV). We sought to determine whether low serum bicarbonate is also associated with performance on tests of EF in pediatric CKD and to investigate potential interaction with BPV., Methods: CKiD participants with serum bicarbonate, blood pressure, and selected cognitive measurements available were evaluated. An EF summary score was derived from scores on the Delis-Kaplan Executive Function System, Conners' Continuous Performance Test, and Digit Span Backwards subtest from the Wechsler Intelligence Scale for Children-IV-Integrated. Parents completed the Behavioral Rating Inventory of Executive Function (BRIEF) to yield a Global Executive Composite (GEC) score. Linear mixed models with bicarbonate and hypertension as predictors and linear regression with bicarbonate and BPV were used to predict EF level., Results: Data were available for 865 children. Twenty-two percent had low bicarbonate (CO 2  ≤ 20 mmol/L) at baseline. On multivariate analysis, there was no relationship between bicarbonate, hypertension, and EF. There was no significant CO 2 ×hypertension interaction found. A significant interaction (p = 0.01) between high CO 2 (≥ 26 mmol/L) and BPV was detected in the model with GEC as the EF outcome, indicating that while higher BPV was associated with worse EF in the low and normal CO 2 groups, higher BPV was associated with better EF in the high CO 2 group., Conclusions: Our analyses revealed an interaction between one measure of BPV and low bicarbonate on neurocognition in pediatric CKD, suggesting a potential role for control of both bicarbonate and blood pressure in preserving cognition in early CKD. Further research is needed to confirm and further define this association.

Background CT allows evaluation of atherosclerosis, coronary stenosis, and myocardial ischemia. Data on the characterization of ischemia and no obstructive stenosis (INOCA) at CT remain limited. Purpose This was an observational study to describe the prevalence of INOCA defined at coronary CT angiography with CT perfusion imaging and associated clinical and atherosclerotic characteristics. The analysis was also performed for the combination of invasive coronary angiography (ICA) and SPECT as a secondary aim. Materials and Methods The prospective CORE320 study ( ClinicalTrials.gov : NCT00934037) enrolled participants between November 2009 and July 2011 who were symptomatic and referred for clinically indicated ICA. Participants underwent CT angiography, rest-adenosine stress CT perfusion, and rest-stress SPECT prior to ICA. For this ancillary study, the following three phenotypes were considered, using either CT angiography/CT perfusion or ICA/SPECT data: (a) participants with obstructive (≥50%) stenosis, (b) participants with no obstructive stenosis but ischemia (ie, INOCA) on the basis of abnormal perfusion imaging results, and (c) participants with no obstructive stenosis and normal perfusion imaging results. Clinical characteristics and CT angiography atherosclerotic plaque measures were compared by using the Pearson χ 2 or Wilcoxon rank-sum test. Results A total of 381 participants (mean age, 62 years [interquartile range, 56-68 years]; 129 [34%] women) were evaluated. A total of 31 (27%) of 115 participants without obstructive (≥50%) stenosis at CT angiography had abnormal CT perfusion findings. The corresponding value for ICA/SPECT was 45 (30%) of 151. The prevalence of INOCA was 31 (8%) of 381 (95% confidence interval [CI]: 5%, 11%) with CT angiography/CT perfusion and 45 (12%) of 381 (95% CI: 9%, 15%) with ICA/SPECT. Participants with CT-defined INOCA had greater total atheroma volume (118 vs 60 mm 3 , P = .008), more positive remodeling (13% vs 1%, P = .006), and greater low-attenuation atheroma volume (20 vs 10 mm 3 , P = .007) than participants with no obstructive stenosis and no ischemia. Comparisons for ICA/SPECT showed similar trends. Conclusion In CORE320, ischemia and no obstructive stenosis (INOCA) prevalence was 8% and 12% at CT angiography/CT perfusion and invasive coronary angiography/SPECT, respectively. Participants with INOCA had greater atherosclerotic burden and more adverse plaque features at CT compared with those with no obstructive stenosis and no ischemia. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by François in this issue.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Frailty is a condition of decreased physiologic reserve and increased vulnerability to stressors. Frailty in combination with inflammation has been associated with increased mortality risk in adults with advanced chronic kidney disease (CKD). This study aimed to investigate prevalence and outcomes associated with a frailty-inflammation phenotype, or "fragility," in children with CKD., Methods: We analyzed 557 children (age 6-19 years, eGFR 30-90 ml/min/1.73 m 2 ) from the Chronic Kidney Disease in Children (CKiD) study. Based on adult models, the CKiD fragility model included four indicators: (1) suboptimal growth/weight gain (BMI < 5th percentile-for-height-age, deceleration ≥ 10 BMI-for-height-age percentiles/1 year, height-for-age percentile < 3rd or deceleration ≥ 10 height percentiles/1 year); (2) low muscle mass (mid-upper-arm circumference < 5th percentile or deceleration ≥ 10 percentiles/1 year); (3) fatigue (parent/child report); (4) inflammation (CRP > 3 mg/l). Logistic regression was used to evaluate association of fragility indicators with three adverse outcomes: frequent infection (> 1 per year/3 years), hospitalization (any), and rapid CKD progression (decline in eGFR > 30% or initiation of renal replacement therapy within 3 years)., Results: Prevalence of fragility indicators 1 year after study entry were 39% (suboptimal growth/weight gain), 62% (low muscle mass), 29% (fatigue), and 18% (inflammation). Prevalence of adverse outcomes during the subsequent 3 years were 13% (frequent infection), 22% (hospitalization), and 17% (rapid CKD progression). Children with ≥ 3 fragility indicators had 3.16-fold odds of frequent infection and 2.81-fold odds of hospitalization, but did not have rapid CKD progression., Conclusions: A fragility phenotype, characterized by the presence of ≥ 3 indicators, is associated with adverse outcomes, including infection and hospitalization in children with CKD.

Background: There are limited data to describe academic achievement outcomes for children with mild to moderate pediatric chronic kidney disease (CKD). The objective of this study was to describe the prevalence of low academic achievement in patients with mild to moderate CKD., Methods: Wechsler Individual Achievement Test, Second Edition, Abbreviated (WIAT-II-A) data were collected at entry into the Chronic Kidney Disease in Children (CKiD) study. Achievement in basic reading, spelling, mathematics, and total achievement was evaluated with a focus on the effects of comorbid CKD-related variables, neurocognitive, and school-based characteristics on academic achievement., Results: WIAT-II-A data were available for 319 children in the CKiD cohort. Low total academic achievement was present in 34% percent of the sample. There was no significant effect of CKD-related medical variables on academic achievement. Mathematics had the lowest distribution of achievement scores. In univariate models, low achievement was significantly related to days of missed school (p = 0.006) and presence of individualized education plan (p < 0.0001)., Conclusions: Low academic achievement was seen in over one-third of children with CKD, with the most difficulty observed in the domain of mathematics. Providers and educators should monitor for academic difficulties in this population in order to facilitate early educational assistance and promote positive educational outcomes.

Background Ongoing advancements of coronary computed tomographic angiography (CTA) continue to challenge the role of invasive coronary angiography (ICA) as the gold standard for the evaluation of coronary artery disease (CAD). We sought to investigate the diagnostic accuracy of 320-slice CTA for detecting obstructive CAD in reference to ICA and nuclear myocardial perfusion imaging using single-photon emission computed tomography. Methods For the CORE320 study (Coronary Artery Evaluation Using 320-Row Multidetector Computed Tomography Angiography and Myocardial Perfusion), 381 patients at 16 centers underwent CTA, nuclear myocardial perfusion imaging by single-photon emission computed tomography, and ICA for the evaluation of CAD. Imaging studies were analyzed in blinded core laboratories, and a stenosis of ≥50% by quantitative coronary angiography was considered obstructive, whereas a stress difference score of ≥1 indicated inducible myocardial ischemia. The area under the receiver operating characteristic curve was used to evaluate diagnostic accuracy. Results Of 381 patients, 229 (60%) had obstructive CAD by quantitative coronary angiography. Diagnostic accuracy of CTA on a per-patient analysis revealed an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.87-0.93). Per-vessel and per-segment analysis revealed lower area under the receiver operating characteristic curve of 0.87 (0.84-0.90) and 0.81 (0.78-0.83), respectively. Median radiation dose was lower for CTA versus ICA: 3.16 (interquartile range, 2.82-3.59) versus 11.97 (interquartile range, 7.60-17.8) mSv ( P<0.001). Accuracy for identifying patients with inducible myocardial ischemia by SPECT-MPI was similar for CTA and ICA (area under the receiver operating characteristic curve, 0.68 versus 0.71 by quantitative coronary angiography and 0.68 by visual angiographic assessment; P>0.05). Furthermore, accuracy for identifying patients who subsequently underwent clinically driven coronary revascularization also was similar for CTA (0.76 [0.71-0.81]) and ICA (0.78 [0.74-0.83]; P=0.20). Conclusions Contemporary CTA accurately identifies patients with obstructive CAD by ICA at lower radiation exposure; however, agreement is lower in vessel- and segment-level analyses. Both CTA and ICA perform similarly for predicting clinically driven revascularization and for detecting myocardial ischemia by myocardial perfusion imaging using single-photon emission computed tomography, suggesting that limitations by both CTA and ICA contribute to variability of stenosis quantification. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00934037.

Aims: To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging., Methods: The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC)., Results: Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84-0.91) and 0.86 (0.83-0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82-0.88) and 0.84 (0.81-0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all)., Conclusion: Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objective: To identify factors contributing to cognitive impairment in children with lupus nephritis., Study Design: A cross-sectional analysis of a large multicenter national cohort of children with chronic kidney disease (CKD) using standardized measures to determine baseline neuropsychiatric function and health-related quality of life (HRQoL) in children with lupus nephritis (n = 34), and to compare baseline function with that in children with other forms of glomerular CKD (gCKD; n = 171). We used inverse probability weighting via a logistic model for propensity score analysis to achieve balance between children with lupus nephritis and those with other glomerular causes of CKD, adjusting for known confounders. We used linear regression models to compare neurocognitive outcomes between exposure groups, adjusting for current prednisone use and testing for an interaction between current prednisone use and lupus nephritis, and to test for an association between cognitive function and HRQoL., Results: Current prednisone use was independently associated with worse attention (P < .01) and better adaptive skills (P = .04), and there was a significant interaction between current prednisone use and lupus nephritis for internalizing problems, with worse parent-reported internalizing problems in children with lupus nephritis on prednisone (P = .047). Better parent-reported HRQoL was associated with better visual memory (P = .01), and better child-reported HRQoL was associated with better attention (P < .01) and inhibitory control (P < .01). Both parent and child HRQoL were associated with better measures of executive function (P = .02 and < .001, respectively)., Conclusion: Children with lupus nephritis have comparable or better cognitive function than their peers with other gCKDs, which is reassuring given the multiorgan and lifelong complications associated with lupus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose To compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined computed tomography (CT) angiography and CT myocardial stress perfusion imaging with that of combined invasive coronary angiography (ICA) and stress single photon emission CT myocardial perfusion imaging. Materials and Methods This study was approved by all institutional review boards, and written informed consent was obtained. Between November 2009 and July 2011, 381 participants clinically referred for ICA and aged 45-85 years were enrolled in the Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter diagnostic study. All images were analyzed in blinded independent core laboratories, and a panel of physicians adjudicated all adverse events. MACE was defined as revascularization (>30 days after index ICA), myocardial infarction, or cardiac death; hospitalization for chest pain or congestive heart failure; or arrhythmia. Late MACE was defined similarly, except for patients who underwent revascularization within the first 182 days after ICA, who were excluded. Comparisons of 2-year survival (time to MACE) used standard Kaplan-Meier curves and restricted mean survival times bootstrapped with 2000 replicates. Results An MACE (49 revascularizations, five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 of 379 patients (13.5%). The 2-year MACE-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD and were similar to combined ICA and single photon emission CT findings (93% negative for CAD vs 77% positive for CAD, P < .001 for both). Event-free rates for CT angiography and CT perfusion versus ICA and single photon emission CT for either positive or negative results were not significantly different for MACE or late MACE (P > .05 for all). The area under the receiver operating characteristic curve (AUC) for combined CT angiography and CT perfusion (AUC = 68; 95% confidence interval [CI]: 62, 75) was similar (P = .36) to that for combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79) in the identification of MACE at 2-year follow-up. Conclusion Combined CT angiography and CT perfusion enables similar prediction of 2-year MACE, late MACE, and event-free survival similar to that enabled by ICA and single photon emission CT. © RSNA, 2017 Online supplemental material is available for this article.

Background: Children with chronic kidney disease (CKD) and hypertension have increased blood pressure variability (BPV), which has been associated with lower neurocognitive test scores in adults. Children with CKD are at risk for decreased neurocognitive function. Our objective was to determine whether children with CKD and increased BPV had worse performance on neurocognitive testing compared with children with CKD and lower BPV., Methods: This was a cross-sectional and longitudinal analysis of the relation between BPV and neurocognitive test performance in children ≥6 years enrolled in the Chronic Kidney Disease in Children (CKiD) study. Visit-to-visit BPV was assessed by the standard deviation of visit BPs (BPV-SD) and average real variability (ARV). Ambulatory BPV was assessed by SD of wake and sleep periods on 24-h ambulatory BP monitoring., Results: We assessed 650 children with a mean follow-up period of 4.0 years. Children with systolic visit-to-visit BPV in the upper tertile had lower scores on Delis-Kaplan Executive Function System (D-KEFS) Verbal Category Switching than those with BPV in the lower tertile (BPV-SD, 8.3 vs. 9.5, p = 0.006; ARV, 8.5 vs. 9.6, p = 0.02). On multivariate analysis, the association between lower Category Switching score and increased BPV remained significant after controlling for mean BP, demographic characteristics, and disease-related variables [BPV-SD, β = -0.7, 95 % confidence interval (CI) -1.28 to -0.12; ARV, β = -0.54, CI -1.05 to -0.02). Ambulatory BPV was not independently associated with any cognitive measure., Conclusions: Higher systolic visit-to-visit BPV was independently associated with decreased D-KEFS Category Switching scores in children with mild-to-moderate CKD., Competing Interests: The authors report that they have no conflict of interest.

Objective: The negative impact of end-stage kidney disease on cognitive function in children is well established, but no studies have examined the neurocognitive, social-behavioral, and adaptive behavior skills of preschool children with mild to moderate chronic kidney disease (CKD)., Method: Participants included 124 preschool children with mild to moderate CKD, aged 12 to 68 months (median = 3.7 years), and an associated mean glomerular filtration rate (GFR) of 50.0 mL·min·1.73 m. In addition to level of function and percent of participants scoring ≥1 SD below the test mean, regression models examined the associations between biomarkers of CKD (GFR, anemia, hypertension, seizures, and abnormal birth history), and developmental level/IQ, attention regulation, and parent ratings of executive functions, social-behavior, and adaptive behaviors., Results: Median scores for all measures were in the average range; however, 27% were deemed at risk for a developmental level/IQ <85, 20% were at-risk for attention variability, and parent ratings indicated 30% and 37% to be at risk for executive dysfunction and adaptive behavior problems, respectively. Approximately 43% were deemed at risk on 2 or more measures. None of the disease-related variables were significantly associated with these outcomes, although the presence of hypertension approached significance for attention variability (p < .09). Abnormal birth history and lower maternal education were significantly related to lower developmental level/IQ; seizures were related to lower parental ratings of executive function and adaptive behavior; and abnormal birth history was significantly related to lower ratings of adaptive behavior. When predicting risk status, the logistic regression did evidence both higher GFR and the lack of anemia to be associated with more intact developmental level/IQ., Conclusion: These findings suggest relatively intact functioning for preschool children with mild to moderate CKD, but the need for ongoing developmental surveillance in this population remains warranted, particularly for those with abnormal birth histories, seizures, and heightened disease severity.

Background: Total atherosclerotic plaque burden assessment by CT angiography (CTA) is a promising tool for diagnosis and prognosis of coronary artery disease (CAD) but its validation is restricted to small clinical studies. We tested the feasibility of semi-automatically derived coronary atheroma burden assessment for identifying patients with hemodynamically significant CAD in a large cohort of patients with heterogenous characteristics., Methods: This study focused on the CTA component of the CORE320 study population. A semi-automated contour detection algorithm quantified total coronary atheroma volume defined as the difference between vessel and lumen volume. Percent atheroma volume (PAV = [total atheroma volume/total vessel volume] × 100) was the primary metric for assessment (n = 374). The area under the receiver operating characteristic curve (AUC) determined the diagnostic accuracy for identifying patients with hemodynamically significant CAD defined as ≥50% stenosis by quantitative coronary angiography and associated myocardial perfusion abnormality by SPECT., Results: Of 374 patients, 139 (37%) had hemodynamically significant CAD. The AUC for PAV was 0.78 (95% confidence interval [CI] 0.73-0.83) compared with 0.84 [0.79-0.88] by standard expert CTA interpretation (p = 0.02). Accuracy for both CTA (0.91 [0.87, 0.96]) and PAV (0.86 [0.81-0.91]) increased after excluding patients with history of CAD (p < 0.01 for both). Bland-Altman analysis revealed good agreement between two observers (bias of 280.2 mm(3) [161.8, 398.7])., Conclusions: A semi-automatically derived index of total coronary atheroma volume yields good accuracy for identifying patients with hemodynamically significant CAD, though marginally inferior to CTA expert reading. These results convey promise for rapid, reliable evaluation of clinically relevant CAD., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objective: To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL)., Study Design: Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Children's Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy., Results: A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P < .05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate., Conclusion: Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The combination of coronary CT angiography (CTA) and myocardial CT perfusion (CTP) is gaining increasing acceptance, but a standardized approach to be implemented in the clinical setting is necessary., Objectives: To investigate the accuracy of a combined coronary CTA and myocardial CTP comprehensive protocol compared to coronary CTA alone, using a combination of invasive coronary angiography and single photon emission CT as reference., Methods: Three hundred eighty-one patients included in the CORE320 trial were analyzed in this study. Flow-limiting stenosis was defined as the presence of ≥50% stenosis by invasive coronary angiography with a related perfusion defect by single photon emission CT. The combined CTA + CTP definition of disease was the presence of a ≥50% stenosis with a related perfusion defect. All data sets were analyzed by 2 experienced readers, aligning anatomic findings by CTA with perfusion defects by CTP., Results: Mean patient age was 62 ± 6 years (66% male), 27% with prior history of myocardial infarction. In a per-patient analysis, sensitivity for CTA alone was 93%, specificity was 54%, positive predictive value was 55%, negative predictive value was 93%, and overall accuracy was 69%. After combining CTA and CTP, sensitivity was 78%, specificity was 73%, negative predictive value was 64%, positive predictive value was 0.85%, and overall accuracy was 75%. In a per-vessel analysis, overall accuracy of CTA alone was 73% compared to 79% for the combination of CTA and CTP (P < .0001 for difference)., Conclusions: Combining coronary CTA and myocardial CTP findings through a comprehensive protocol is feasible. Although sensitivity is lower, specificity and overall accuracy are higher than assessment by coronary CTA when compared against a reference standard of stenosis with an associated perfusion defect., (Copyright © 2015 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) in childhood is associated with neurocognitive deficits. Affected children show worse performance on tests of intelligence than their unaffected siblings and skew toward the lower end of the normal range. Here we further assessed this association in 340 pediatric patients (ages 6-21) with mild-moderate CKD in the Chronic Kidney Disease in Childhood cohort from 48 pediatric centers in North America. Participants underwent a battery of age-appropriate tests including Conners' Continuous Performance Test-II (CPT-II), Delis-Kaplan Executive Function System Tower task, and the Digit Span Backward task from the age-appropriate Wechsler Intelligence Scale. Test performance was compared across the range of estimated glomerular filtration rate and duration of CKD with relevant covariates including maternal education, household income, IQ, blood pressure, and preterm birth. Among the 340 patients, 35% had poor performance (below the mean by 1.5 or more standard deviations) on at least one test of executive function. By univariate nonparametric comparison and multiple logistic regression, longer duration of CKD was associated with increased odds ratio for poor performance on the CPT-II Errors of Commission, a test of attention regulation and inhibitory control. Thus, in a population with mild-to-moderate CKD, the duration of disease rather than estimated glomerular filtration rate was associated with impaired attention regulation and inhibitory control.

OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study ( ClinicalTrials.gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA-perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA-perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion.

Purpose: To compare the diagnostic performance of myocardial computed tomographic (CT) perfusion imaging and single photon emission computed tomography (SPECT) perfusion imaging in the diagnosis of anatomically significant coronary artery disease (CAD) as depicted at invasive coronary angiography., Materials and Methods: This study was approved by the institutional review board. Written informed consent was obtained from all patients. Sixteen centers enrolled 381 patients from November 2009 to July 2011. Patients underwent rest and adenosine stress CT perfusion imaging and rest and either exercise or pharmacologic stress SPECT before and within 60 days of coronary angiography. Images from CT perfusion imaging, SPECT, and coronary angiography were interpreted at blinded, independent core laboratories. The primary diagnostic parameter was the area under the receiver operating characteristic curve (Az). Sensitivity and specificity were calculated with use of prespecified cutoffs. The reference standard was a stenosis of at least 50% at coronary angiography as determined with quantitative methods., Results: CAD was diagnosed in 229 of the 381 patients (60%). The per-patient sensitivity and specificity for the diagnosis of CAD (stenosis ≥50%) were 88% (202 of 229 patients) and 55% (83 of 152 patients), respectively, for CT perfusion imaging and 62% (143 of 229 patients) and 67% (102 of 152 patients) for SPECT, with Az values of 0.78 (95% confidence interval: 0.74, 0.82) and 0.69 (95% confidence interval: 0.64, 0.74) (P = .001). The sensitivity of CT perfusion imaging for single- and multivessel CAD was higher than that of SPECT, with sensitivities for left main, three-vessel, two-vessel, and one-vessel disease of 92%, 92%, 89%, and 83%, respectively, for CT perfusion imaging and 75%, 79%, 68%, and 41%, respectively, for SPECT., Conclusion: The overall performance of myocardial CT perfusion imaging in the diagnosis of anatomic CAD (stenosis ≥50%), as demonstrated with the Az, was higher than that of SPECT and was driven in part by the higher sensitivity for left main and multivessel disease.

Background: Daily oral hygiene and regular dental visits are important components of oral health care. The authors' objective in this study was to examine women's oral hygiene practices and use of dental services during pregnancy., Methods: The authors developed a written oral health questionnaire and administered it to 599 pregnant women. They collected demographic information, as well as data on oral hygiene practices and use of dental services during pregnancy. They used chi2 and multivariable logistic regression models to assess associations between oral hygiene practice and dental service use during pregnancy and to identify maternal predictor variables., Results: Of the 599 participants, 83 percent (n=497) reported brushing once or twice per day. Twenty-four percent (n=141) reported flossing at least once daily; Hispanic women were more likely to floss than were white or African American women (28 percent [52 of 183] versus 22 percent [54 of 248] versus 19 percent [23 of 121], respectively, P<.001). Seventy-four percent (n=442) of the participants reported having received no routine dental care during pregnancy. Hispanic women were significantly less likely than were black or white women to receive routine dental care during pregnancy (13 percent versus 21 percent versus 36 percent, respectively, P<.001). The authors found that being older than 36 years, being of Hispanic race or ethnicity, having an annual income of less than $30,000, flossing infrequently and receiving no dental care when not pregnant were significantly associated with lack of routine dental care during pregnancy (adjusted odds ratios, 95 percent confidence intervals: 2.56 [1.33-4.92]; 2.19 [1.11-4.29]; 2.02 [1.12-3.65]; 1.86 [1.13-3.07]; and 4.35 [2.5-7.69], respectively). A woman's lack of receiving routine dental care when not pregnant was the most significant predictor of lack of receiving dental care during pregnancy., Conclusion: Racial, ethnic and economic disparities related to oral hygiene practices and dental service utilization during pregnancy exist., Clinical Implications: Medical and dental care providers who treat women of reproductive age and pregnant women need to develop policy strategies to address this population's access barriers to, and use of, dental care services.