Mortality Risk Factors among Infants Receiving Dialysis in the Neonatal Intensive Care Unit.

OBJECTIVES: To identify risk factors associated with mortality for infants receiving dialysis in the neonatal intensive care unit (NICU). STUDY DESIGN: In this retrospective cohort study, we extracted data from the Pediatrix Clinical Data Warehouse on all infants who received dialysis in the NICU from 1999 to 2018. Using a Cox proportional hazards model with robust SEs we estimated the mortality hazard ratios associated with demographics, birth details, medical complications, and treatment exposures. RESULTS: We identified 273 infants who received dialysis. Median gestational age at birth was 35 weeks (interquartile values 33-37), median birth weight was 2570 g (2000-3084), 8% were small for gestational age, 41% white, and 72% male. Over one-half of the infants (59%) had a kidney anomaly; 71 (26%) infants died before NICU hospital discharge. Factors associated with increased risk of dying after dialysis initiation included lack of kidney anomalies, Black race, gestational age of <32 weeks, necrotizing enterocolitis, dialysis within 7 days of life, and receipt of paralytics or vasopressors (all P < .05). CONCLUSION: In this cohort of infants who received dialysis in the NICU over 2 decades, more than 70% of infants survived. The probability of death was greater among infants without a history of a kidney anomaly and those with risk factors consistent with greater severity of illness at dialysis initiation.

Variability in CKD Biomarker Studies: Soluble Urokinase Plasminogen Activator Receptor (suPAR) and Kidney Disease Progression in the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Biomarker studies are important for generating mechanistic insight and providing clinically useful predictors of chronic kidney disease (CKD) progression. However, variability across studies can often muddy the evidence waters. Here we evaluated real-world variability in biomarker studies using two published studies, independently conducted, of the novel plasma marker soluble urokinase-type plasminogen activator receptor (suPAR) for predicting CKD progression in children with CKD. STUDY DESIGN: A comparison of 2 prospective cohort studies. SETTING & PARTICIPANTS: 541 children from the Chronic Kidney Disease in Children (CKiD) study, median age 12 years, median glomerular filtration rate (GFR) of 54 mL/min/1.73m2. OUTCOME: The first occurrence of either a 50% decline in GFR from baseline or incident end-stage kidney disease. ANALYTICAL APPROACH: The suPAR plasma marker was measured using the Quantikine ELISA immunoassay in the first study and Meso Scale Discovery (MSD) platform in the second. The analytical approaches varied. We used suPAR data from the 2 assays and mimicked each analytical approach in an overlapping subset. RESULTS: We found that switching assays had the greatest impact on inferences, resulting in a 38% to 66% change in the magnitude of the effect estimates. Covariate and modeling choices resulted in an additional 8% to 40% variability in the effect estimate. The cumulative variability led to different inferences despite using a similar sample of CKiD participants and addressing the same question. LIMITATIONS: The estimated variability does not represent optimal repeatability but instead illustrates real-world variability that may be present in the CKD biomarker literature. CONCLUSIONS: Our results highlight the importance of validation, avoiding conclusions based on P value thresholds, and providing comparable metrics. Further transparency of data and equal weighting of negative and positive findings in explorations of novel biomarkers will allow investigators to more quickly weed out less promising biomarkers.

Streptococcus salivarius peritonitis in an infant receiving chronic peritoneal dialysis.

Peritonitis is the most common infectious complication of chronic peritoneal dialysis in children and the most common reason for hospitalization. Although the most common organisms responsible for peritonitis are gram-positive bacteria, peritonitis has not previously been reported secondary to Streptococcus salivarius, one of the 26 species in the Streptococcus viridians group. We describe a 4-month-old male who developed S. salivarius peritonitis while receiving automated peritoneal dialysis and who was successfully treated with a 14-day course of intraperitoneal vancomycin. Subtyping episodes of S. viridans-related infection is essential for the identification of S. salivarius.

Cardiometabolic Risk Factors, Metabolic Syndrome, and Chronic Kidney Disease Progression in Children.

OBJECTIVE: To estimate the prevalence of metabolic syndrome (MetS) and examine its association with chronic kidney disease progression in children enrolled in the Chronic Kidney Disease in Children study. STUDY DESIGN: MetS was defined as being overweight or obese and having ≥2 cardiometabolic risk factors (CMRFs). Incidence and prevalence of MetS were assessed using pairs of visits approximately 2 years apart. RESULTS: A total of 799 pairs of person-visits (contributed by 472 children) were included in the final analysis. Of these, 70% had a normal body mass index (BMI), 14% were overweight, and 16% were obese. At the first visit, the prevalence of MetS in the overweight group was 40% and in the obese group was 60%. In adjusted models, annual percent estimated glomerular filtration rate decline in those who had normal BMI and incident or persistent multiple CMRFs or those with persistent MetS was -6.33%, -6.46%, and -6.08% (respectively) compared with children who never had multiple CMRFs (-3.38%, P = .048, .045, and .036, respectively). Children with normal BMI and incident multiple CMRFs and those with persistent MetS had approximately twice the odds of fast estimated glomerular filtration rate decline (>10% per year) compared with those without multiple CMRFs and normal BMI. CONCLUSION: Children with chronic kidney disease have a high prevalence of MetS. These children as well as those with normal BMI but multiple CMRFs experience a faster decline in kidney function.

De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease.

BACKGROUND: Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naïve patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS: One-hundred sixteen pediatric ESA-naïve subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL™) in children ≥2 years. RESULTS: In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL™ scores showed modest increases. CONCLUSIONS: Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naïve pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.

Waist Circumference and Body Mass Index in Children with Chronic Kidney Disease and Metabolic, Cardiovascular, and Renal Outcomes.

OBJECTIVE: To describe the prevalence of obesity as estimated by waist circumference (WC) and body mass index (BMI) and compare associations of WC and BMI with indicators of metabolic, cardiovascular, and renal health in children with chronic kidney disease (CKD). STUDY DESIGN: Cross-sectional analysis stratified by CKD etiology (nonglomerular or glomerular) of 737 subjects. The kappa statistic was used to assess agreement between the 2 measures of obesity. Linear regression models were performed using WC and BMI as separate independent variables. Dependent variables included lipid measures, insulin resistance, blood pressure, left ventricular mass index, proteinuria, and estimated glomerular filtration rate. Associations were scaled to SD and interpreted as the change in dependent variable associated with a 1-SD change in WC or BMI. RESULTS: There was good agreement (kappa statistic = 0.68) between WC and BMI in identifying obesity. Approximately 10% of subjects had obesity by 1 measure but not the other. BMI was more strongly associated with estimated glomerular filtration rate than WC. BMI was more strongly associated with left ventricular mass index in the nonglomerular CKD group compared with WC, but both had significant associations. The associations between WC and BMI with the remainder of the dependent variables were not significantly different. CONCLUSIONS: Measurement of WC added limited information to BMI in this cohort. Further longitudinal study is needed to determine how WC and BMI compare in predicting outcomes, particularly for children with CKD identified as having obesity by 1 measure but not the other.

Cognitive Function in Children with Lupus Nephritis: A Cross-Sectional Comparison with Children with Other Glomerular Chronic Kidney Diseases.

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.

Kidney Disease Progression in Autosomal Recessive Polycystic Kidney Disease.

OBJECTIVE: To define glomerular filtration rate (GFR) decline, hypertension (HTN), and proteinuria in subjects with autosomal recessive polycystic kidney disease (ARPKD) and compare with 2 congenital kidney disease control groups in the Chronic Kidney Disease in Children cohort. STUDY DESIGN: GFR decline (iohexol clearance), rates of HTN (ambulatory/casual blood pressures), antihypertensive medication usage, left ventricular hypertrophy, and proteinuria were analyzed in subjects with ARPKD (n = 22) and 2 control groups: aplastic/hypoplastic/dysplastic disorders (n = 44) and obstructive uropathies (n = 44). Differences between study groups were examined with the Wilcoxon rank sum test. RESULTS: Annualized GFR change in subjects with ARPKD was -1.4 mL/min/1.73 m(2) (-6%), with greater decline in subjects age ≥ 10 years (-11.5%). However, overall rates of GFR decline did not differ significantly in subjects with ARPKD vs controls. There were no significant differences in rates of HTN or left ventricular hypertrophy, but subjects with ARPKD had a greater percent on ≥ 3 blood pressure medications (32% vs 0%, P < .0001), more angiotensin-converting enzyme inhibitor use (82% vs 27% vs 36%, P < .0005), and less proteinuria (urine protein: creatinine = 0.1 vs 0.6, P < .005). CONCLUSIONS: This study reports rates of GFR decline, HTN, and proteinuria in a small but well-phenotyped ARPKD cohort. The relatively slow rate of GFR decline in subjects with ARPKD and absence of significant proteinuria suggest that these standard clinical measures may have limited utility in assessing therapeutic interventions and highlight the need for other ARPKD kidney disease progression biomarkers.

Depressive Symptoms in Children with Chronic Kidney Disease.

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.

Correlates of leptin in children with chronic kidney disease.

OBJECTIVE: To investigate the relative associations of renal function, obesity, and inflammation with serum leptin levels in children with chronic kidney disease (CKD). STUDY DESIGN: This was a cross-sectional analysis of 317 children from the Chronic Kidney Disease in Children study, a large cohort of pediatric patients with stage II-IV CKD. Linear regression modeling was used to evaluate the association of serum leptin level with glomerular filtration rate calculated using the plasma iohexol disappearance curve, demographics, body mass index (BMI), and cardiovascular risk factors, including inflammatory cytokines, insulin resistance, and serum lipid levels. RESULTS: In univariate analyses, elevated serum leptin level was significantly associated with increased BMI, older age, and female sex (P < .001 for all). Leptin level also correlated positively with serum triglycerides and insulin resistance (P < .001) and negatively with serum high-density lipoprotein cholesterol (P = .002). Leptin level was not associated with glomerular filtration rate calculated using the plasma iohexol disappearance curve or inflammatory cytokines. In multivariate analysis, BMI, age, female sex, and serum triglyceride levels were significantly associated with serum leptin level. CONCLUSION: Increased leptin production was associated with female sex, older age, and adiposity in children with mild to moderate CKD. Renal function was not associated with serum leptin level, indicating that decreased clearance does not contribute to elevated leptin levels.

The effect of abnormal birth history on ambulatory blood pressure and disease progression in children with chronic kidney disease.

OBJECTIVE: To examine the associations between abnormal birth history (birth weight <2500 g, gestational age <36 weeks, or small for gestational age), blood pressure (BP), and renal function among 332 participants (97 with abnormal and 235 with normal birth history) in the Chronic Kidney Disease in Children Study, a cohort of children with chronic kidney disease (CKD). STUDY DESIGN: Casual and 24-hour ambulatory BP were obtained. Glomerular filtration rate (GFR) was determined by iohexol disappearance. Confounders (birth and maternal characteristics, socioeconomic status) were used to generate predicted probabilities of abnormal birth history for propensity score matching. Weighted linear and logistic regression models with adjustment for quintiles of propensity scores and CKD diagnosis were used to assess the impact of birth history on BP and GFR. RESULTS: Age at enrollment, percent with glomerular disease, and baseline GFR were similar between the groups. Those with abnormal birth history were more likely to be female, of Black race or Hispanic ethnicity, to have low household income, or part of a multiple birth. Unadjusted BP measurements, baseline GFR, and change in GFR did not differ significantly between the groups; no differences were seen after adjusting for confounders by propensity score matching. CONCLUSIONS: Abnormal birth history does not appear to have exerted a significant influence on BP or GFR in this cohort of children with CKD. The absence of an observed association is likely secondary to the dominant effects of underlying CKD and its treatment.

The impact of short stature on health-related quality of life in children with chronic kidney disease.

OBJECTIVES: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. STUDY DESIGN: Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. RESULTS: Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). CONCLUSION: The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results.

Correlates of resistin in children with chronic kidney disease: the chronic kidney disease in children cohort.

OBJECTIVE: To test the hypothesis that resistin is associated with insulin resistance and inflammation in pediatric patients with chronic kidney disease (CKD). STUDY DESIGN: This study is a cross-sectional analysis of 319 children in the Chronic Kidney Disease in Children cohort, a large cohort of children with stage II-IV CKD. Univariate and multivariate regression modeling was used to evaluate the association of serum resistin level with glomerular filtration rate (GFR), demographic data, and cardiovascular risk factors, including inflammatory cytokines, insulin resistance, and serum lipids. RESULTS: In univariate analyses, serum resistin level was negatively correlated with GFR (P < .01). Increased serum resistin was associated with elevated inflammatory cytokines, including interleukin (IL)-6 (P < .01), IL-10 (P < .01), and tumor necrosis factor-α (P < .01). Resistin level was not associated with insulin resistance, although it was positively correlated with serum triglycerides (P < .01) and negatively correlated with high-density lipoprotein cholesterol (P < .01). In multivariate analysis, GFR (ß = -0.01; P < .001), IL-6 (ß = 0.18; P < .001), IL-10 (ß = 0.09; P = .01), and pubertal status (ß = 0.18; P < .01) were significantly associated with serum resistin level. CONCLUSION: These results indicate that serum resistin level increases with GFR decline and is involved in the inflammatory milieu present in CKD.

Reliability of resting blood pressure measurement and classification using an oscillometric device in children with chronic kidney disease.

OBJECTIVE: To compare the reliability of blood pressure (BP) readings obtained with an oscillometric device with those obtained by auscultation and assess for differences in BP status classification based on the 2 techniques. STUDY DESIGN: Resting BP was measured by auscultation and with an oscillometric device at the same encounter in 235 subjects enrolled in the Chronic Kidney Disease in Children study. Resting auscultatory BP values were averaged and compared with averaged oscillometric readings. BP agreement by the 2 methods was assessed using Bland-Altman plots, and BP status classification agreement was assessed by calculation of kappa statistics. RESULTS: Oscillometric BP readings were higher than auscultatory readings, with a median paired difference of 9 mm Hg for systolic BP (SBP) and 6 mm Hg for diastolic BP (DBP). Correlation for mean SBP was 0.624 and for mean DBP was 0.491. The bias for oscillometric BP measurement was 8.7 mm Hg for SBP (P < .01) and 5.7 mm Hg for DBP (P < .01). BP status classification agreement was 61% for SBP and 63% for DBP, with Kappa values of .31 for SBP and .20 for DBP. CONCLUSIONS: Compared with auscultation, the oscillometric device significantly overestimated both SBP and DBP, leading to frequent misclassification of BP status.

Cardiac geometry in children receiving chronic peritoneal dialysis: findings from the International Pediatric Peritoneal Dialysis Network (IPPN) registry.

BACKGROUND AND OBJECTIVES: Left ventricular hypertrophy (LVH) is an independent risk factor and an intermediate end point of dialysis-associated cardiovascular comorbidity. We utilized a global pediatric registry to assess the prevalence, incidence, and predictors of LVH as well as its evolution in the longitudinal follow-up in dialyzed children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional echocardiographic, clinical, and biochemical data were evaluated in 507 children on peritoneal dialysis (PD), and longitudinal data were evaluated in 128 patients. The 95(th) percentile of LV mass index relative to height age was used to define LVH. RESULTS: The overall LVH prevalence was 48.1%. In the prospective analysis, the incidence of LVH developing de novo in patients with normal baseline LV mass was 29%, and the incidence of regression from LVH to normal LV mass 40% per year on PD. Transformation to and regression from concentric LV geometry occurred in 36% and 28% of the patients, respectively. Hypertension, high body mass index, use of continuous ambulatory peritoneal dialysis, renal disease other than hypo/dysplasia, and hyperparathyroidism were identified as independent predictors of LVH. The use of renin-angiotensin system (RAS) antagonists and high total fluid output (sum of urine and ultrafiltration) were protective from concentric geometry. The risk of LVH at 1 year was increased by higher systolic BP standard deviation score and reduced in children with renal hypo/dysplasia. CONCLUSIONS: Using height-adjusted left ventricular mass index reference data, LVH is highly prevalent but less common than previously diagnosed in children on PD. Renal hypo/dysplasia is protective from LVH, likely because of lower BP and polyuria. Hypertension, fluid overload, and hyperparathyroidism are modifiable determinants of LVH.

Defining left ventricular hypertrophy in children on peritoneal dialysis.

BACKGROUND AND OBJECTIVES: Left ventricular hypertrophy (LVH) is an important end point of dialysis-associated cardiovascular disease. The objective of this study was to evaluate the effect of different pediatric reference systems on the estimated prevalence of LVH in children on chronic peritoneal dialysis (CPD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Echocardiographic studies in 507 pediatric CPD patients from neonatal age to 19 years were collected in 55 pediatric dialysis units around the globe. We compared the prevalence of LVH on the basis of the traditional cutoff of left ventricular mass (LVM) index (>38.5 g/m(2.7)) with three novel definitions of LVH that were recently established in healthy pediatric cohorts. RESULTS: Application of the new reference systems eliminated the apparently increased prevalence of LVH in young children obtained by the traditional fixed LVM index cutoff currently still recommended by consensus guidelines. However, substantial differences of LVM distribution between the new reference charts resulted in a marked discrepancy in estimated LVH prevalence ranging between 27.4% and 51.7%. CONCLUSIONS: Although our understanding of the anthropometric determinants of heart size during childhood is improving, more consistent normative echocardiographic data from large populations of healthy children are required for cardiovascular diagnostics and research.