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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.sub.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.sup.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.sub.2(Umod/Cr) and 0.20 (13%) lower log.sub.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. Graphical abstract, Author(s): Sophia C. Faulkner [sup.1] , Matthew B. Matheson [sup.2] , Jason H. Greenberg [sup.1] [sup.3] , Pranav S. Garimella [sup.4] , Susan L. Furth [sup.5] , Joachim H. Ix [...]

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.sup.st-5.sup.th percentile) or very low (< 1.sup.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 ([beta] = - 0.98; 95% CI - 1.78, - 0.18, p = 0.02). Errors of omission were significantly higher (worse) in those with persistent anemia ([beta] = 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 ([beta] = - 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 ([beta] = - 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. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Nisha S. Singh [sup.1] , Rebecca J. Johnson [sup.2] , Matthew B. Matheson [sup.3] , Joann Carlson [sup.4] , Stephen R. Hooper [sup.5] , Bradley A. Warady [sup.1] Author [...]

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.sup.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., Author(s): Lokesh N. Shah [sup.1] [sup.2] , Matthew B. Matheson [sup.3] , Susan L. Furth [sup.4] [sup.5] , George J. Schwartz [sup.6] , Bradley A. Warady [sup.7] [sup.8] , Cynthia [...]

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.sup.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 ([beta] = - 2.90 (95% CI = - 7.74, - 0.21), p = 0.04) and physical functioning ([beta] = - 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 ([beta] = - 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 ([beta] = - 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., Author(s): Joann Carlson [sup.1] , Arlene C. Gerson [sup.2] , Matthew B. Matheson [sup.3] , Sharon Manne [sup.4] , Bradley A. Warady [sup.5] , Stephen R. Hooper [sup.6] , Marc [...]

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., Author(s): Hannah S. Kim [sup.1] , Derek K. Ng [sup.2] , Matthew B. Matheson [sup.2] , Meredith A. Atkinson [sup.1] , Bradley A. Warady [sup.3] , Susan L. Furth [sup.4] [...]

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.sub.2 [less than or equal to] 20 mmol/L) at baseline. On multivariate analysis, there was no relationship between bicarbonate, hypertension, and EF. There was no significant CO.sub.2xhypertension interaction found. A significant interaction (p = 0.01) between high CO.sub.2 ([greater than or equal to] 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.sub.2 groups, higher BPV was associated with better EF in the high CO.sub.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., Author(s): Lyndsay A. Harshman [sup.1] , Amy J. Kogon [sup.2] [sup.3] , Matthew B. Matheson [sup.4] , Rebecca J. Johnson [sup.5] , Shlomo Shinnar [sup.6] , Arlene C. Gerson [sup.7] [...]

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.sub.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., Author(s): Juan C. Kupferman [sup.1] , Matthew B. Matheson [sup.2] , Marc B. Lande [sup.3] , Joseph T. Flynn [sup.4] , Susan Furth [sup.5] , Bradley A. Warady [sup.6] , [...]

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 ([beta] = 1.59, 95% CI = 0.24 to 2.94, p < 0.02) and suggested worse behavioral symptoms ([beta] = 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 ([beta] = - 3.48, CI = - 6.79 to - 0.17, p < 0.04). Glomerular diagnosis was related to fewer ([beta] = - 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., Author(s): Rebecca J. Johnson [sup.1] , Arlene C. Gerson [sup.2] , Lyndsay A. Harshman [sup.3] , Matthew B. Matheson [sup.4] , Shlomo Shinnar [sup.5] , Marc B. Lande [sup.6] , [...]

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.sup.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 [greater than or equal to] 10 BMI-for-height-age percentiles/1 year, height-for-age percentile < 3rd or deceleration [greater than or equal to] 10 height percentiles/1 year); (2) low muscle mass (mid-upper-arm circumference 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 [greater than or equal to] 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 [greater than or equal to] 3 indicators, is associated with adverse outcomes, including infection and hospitalization in children with CKD., Author(s): Kristen Sgambat [sup.1] , Matthew B. Matheson [sup.2] , Stephen R. Hooper [sup.3] , Bradley Warady [sup.4] , Susan Furth [sup.5] , Asha Moudgil [sup.1] Author Affiliations: (Aff1) grid.239560.b, [...]

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., Author(s): Lyndsay A. Harshman [sup.1] , Rebecca J. Johnson [sup.2] , Matthew B. Matheson [sup.3] , Amy J. Kogon [sup.4] [sup.5] , Shlomo Shinnar [sup.6] [sup.7] [sup.8] , Arlene C. [...]

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 [greater than or equal to]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., Author(s): Marc B. Lande[sup.1] , Susan R. Mendley[sup.2] , Matthew B. Matheson[sup.3] , Shlomo Shinnar[sup.4] , Arlene C. Gerson[sup.5] , Joshua A. Samuels[sup.6] , Bradley A. Warady[sup.7] , Susan L. [...]

A study was conducted to investigate women's oral hygiene practices and use of dental services during pregnancy. Findings indicate that some racial, ethnic, and economic disparities related to oral hygiene practices and dental service utilization during pregnancy exist. Clinical implications are also discussed.