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Background: Pediatric research is a diverse field that is constantly growing. Current machine learning advancements have prompted a technique termed text-mining. In text-mining, information is extracted from texts using algorithms. This technique can be applied to analyze trends and to investigate the dynamics in a research field. We aimed to use text-mining to provide a high-level analysis of pediatric literature over the past two decades., Methods: We retrieved all available MEDLINE/PubMed annual data sets until December 31, 2018. Included studies were categorized into topics using text-mining., Results: Two hundred and twenty-five journals were categorized as Pediatrics, Perinatology, and Child Health based on Scimago ranking for medicine journals. We included 201,141 pediatric papers published between 1999 and 2018. The most frequently cited publications were clinical guidelines and meta-analyses. We found that there is a shift in the trend of topics. Epidemiological studies are gaining more publications while other topics are relatively decreasing., Conclusions: The topics in pediatric literature have shifted in the past two decades, reflecting changing trends in the field. Text-mining enables analysis of trends in publications and can serve as a high-level academic tool., Impact: Text-mining enables analysis of trends in publications and can serve as a high-level academic tool. This is the first study using text-mining techniques to analyze pediatric publications. Our findings indicate that text-mining techniques enable better understanding of trends in publications and should be implemented when analyzing research., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The 113th Congress of the United States begins in January 2013. With each new Congress, there are many changes, not only in the faces of the newly elected, but also in the membership of committees and the staff serving the members. As agendas for the session are set, there is a resurgence of conflicting priorities. In the past, when these conflicts were resolved, children were rarely at the top of the list. Given the numerous pressing national issues, both domestic and foreign, the same trend will likely occur.

The goals of clinical research include comparing new and standard treatments, establishing treatment efficacy, defining risk factors for disease, elucidating pathophysiologic mechanisms of disease, and establishing causation. Although the randomized clinical trial has been the "gold standard" in clinical research and is the strongest study design to establish causation for many clinical research questions, an interventional study or "experiment" such as a randomized trial is often not possible. Observational study designs also demonstrate associations between exposures and outcome. To determine whether these associations are likely to be causal, one can assess a number of qualities, first outlined by the British epidemiologist Sir Austin Bradford Hill. These qualities include analogy to what is known; the plausibility, strength and specificity of the association; consistency and coherence across studies; the temporality of the putative cause and effect; and the presence of a biological gradient. The presence of these factors adds weight to the probability that a given association is causal. Systematic reviews and meta-analyses use these factors in combining studies to assess whether associations are cause and effect. Additionally, new methods in the analysis of longitudinal data collected in observational studies can help to determine causation. In this review, we will use recent literature and contemporary topics in pediatric nephrology to illustrate state-of-the-art research methods using classic epidemiological elements needed to establish causation.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort. METHODS: Hemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects. RESULTS: In 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p

PurposeWe determined the association between dietary zinc intake and incident calcium kidney stones in adolescents. We also examined the relationship between dietary zinc intake and urinary zinc excretion between cases and controls.Materials and methodsWe conducted a nested case-control study within a large pediatric health care system. Three 24-hour dietary recalls and spot urine chemistry analyses were obtained for 30 participants 12 to 18 years old with a first idiopathic calcium based kidney stone and 30 healthy controls matched for age, sex, race and month of enrollment. Conditional logistic regression models were used to estimate the association between daily zinc intake and incident calcium kidney stones, adjusting for dietary phytate, protein, calcium, sodium and oxalate. Multivariable linear regression was used to estimate the association between dietary and urine zinc, adjusting for urine creatinine and dietary phytate and calcium.ResultsCases had lower daily zinc intake (8.1 mg) than controls (10 mg, p = 0.029). Daily zinc intake of boys and girls with calcium stones was 2 mg and 1.2 mg less, respectively, than the daily intake recommended by the Institute of Medicine. Odds of incident stones were reduced by 13% for every 1 mg increase in daily zinc intake (OR 0.87, 95% CI 0.75-0.99). There was an estimated 4.5 μg/dl increase in urine zinc for every 1 mg increase in dietary zinc (p = 0.009), with weak evidence of a smaller increase in urine zinc in cases than in controls (interaction p = 0.08).ConclusionsDecreased dietary zinc intake was independently associated with incident calcium nephrolithiasis in this population of adolescents.

Background: Young age has been associated with poorer control of hypertension in children with chronic kidney disease (CKD). Using data from the CKiD Study (Chronic Kidney Disease in Children), we examined the relationship between age, hypertensive blood pressure (BP) recognition, and pharmacologic BP control in children with nondialysis-dependent CKD. Methods: Participants included 902 CKiD Study participants with CKD stages 2 to 4. A total of 3550 annual study visits met inclusion criteria and participants were stratified by age (0 to <7, ≥7 to <13, ≥13 to ≤18 years). Generalized estimating equations to account for repeated measures were applied to logistic regression analyses to evaluate the association of age with unrecognized hypertensive BP and medication use. Results: Children <7 years of age had a higher prevalence of hypertensive BP and a lower prevalence of antihypertensive medication use compared with older children. At visits where participants <7 years of age had hypertensive BP readings, 46% had unrecognized, untreated hypertensive BP compared with 21% of visits for children ≥13 years of age. The youngest age group was associated with higher odds of unrecognized hypertensive BP (adjusted odds ratio, 2.11 [95% CI, 1.37–3.24]) and lower odds of antihypertensive medication use among those with unrecognized hypertensive BP (adjusted OR, 0.51 [95% CI, 0.27–0.996]). Conclusions: Children younger than 7 years of age with CKD are more likely to have both undiagnosed and undertreated hypertensive BP. Efforts to improve BP control in young children with CKD are needed to minimize development of cardiovascular disease and slow CKD progression. [ABSTRACT FROM AUTHOR]

Background: Nocturnal hypertension is a risk factor for chronic kidney disease (CKD) progression among adults. In children, effects of nocturnal hypertension on CKD progression is less studied.Methods: We investigated the relationships between nocturnal, daytime, or sustained hypertension and progression to kidney replacement therapy in children using Cox proportional hazards models. Nocturnal and diurnal hypertension respectively defined as: mean blood pressure >95th percentile and/or load >25% for either systolic or diastolic blood pressure within sleep or wake periods.Results: One thousand five hundred seventy-seven ambulatory blood pressure monitoring studies from 701 CKiD participants were reviewed. Nighttime, daytime, and both types of hypertension were 19%, 7%, and 33%, respectively. Participants with both daytime and nocturnal hypertension had the highest risk of kidney replacement therapy. Among children with CKD, compared with those who were normotensive, those with isolated nocturnal hypertension had a hazard ratio of 1.49 ([CI, 0.97-2.28]; P=0.068) while those with both daytime and nocturnal hypertension had a HR of 2.23 ([CI, 1.60-3.11]; P<0.001) when adjusted for age, race, sex, and baseline proteinuria and glomerular filtration. Estimates for risk were similar among glomerular and nonglomerular participants but not significant in glomerular due to smaller sample size.Conclusions: The presence of both daytime and nocturnal hypertension is significantly associated with risk of kidney replacement therapy. Our study confirms the utility of ambulatory blood pressure monitoring in children with CKD. Identifying and controlling both daytime and nocturnal hypertension using ambulatory blood pressure monitoring may improve outcomes and delay CKD progression in this population. [ABSTRACT FROM AUTHOR]

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

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

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Introduction: The number of medications could serve as a surrogate for burden of care at home and may affect health-related quality of life (HRQoL) in children with chronic kidney disease (CKD). Methods: Using baseline data from the Chronic Kidney Disease in Children (CKiD) Study, we modeled HRQoL scores, self-reported by the child (if ≥ 8 years old) and/or caregiver (all children) on unique counts and administrations of CKD- and non-CKD-related medications, using multivariate linear regression. Heterogeneity of associations between HRQoL and medication burden by age group (≥ 8 vs. < 8 years old) were explored. Results: 734 participants median age 11 years, disease duration 8 years, median eGFR 53 mL/min/1.73 m2, 61% male, 22% African-American, 31% glomerular disease were prescribed median 3 unique CKD-related medications. Regarding HRQoL assessment, 201 children were < 8 years old and had only parent-proxy HRQoL score; 533 children ≥ 8 years of age had both child and parent-proxy scores. Overall, parents of children < 8 years old reported higher HRQoL scores than parents of older children: 84 vs. 76. However, in a unified multivariate regression model, HRQoL scores of children < 8 years showed greater decreases as the number of CKD-related medications increased compared to scores for children ≥ 8 years old. Conclusion: Average HRQoL scores reported by parents of younger CKD children were higher than those of older CKD children but decreased more with increased CKD medication counts than scores of older children. Considerations of HRQoL may be of particular importance for clinicians and caregivers when managing chronic disease comorbidities in younger children. [ABSTRACT FROM AUTHOR]

Background BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. Methods In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1–4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. Results We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1–4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. Conclusions Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication. [ABSTRACT FROM AUTHOR]

Background: Kidney transplant is the renal replacement therapy (RRT) of choice for children with end stage kidney disease (ESKD). Only 21.3% of children who initiate RRT receive a preemptive kidney transplant (PKT). We characterized the transition to RRT in children in the CKiD cohort including the prevalence of dialysis as first RRT vs. PKT and graft survival. Methods: 258 children enrolled in CKiD have initiated RRT, and 202 had post-RRT initiation data collected through phone or in-person follow-up. Characteristics by first RRT modality were compared using Chi-square and Kruskal-Wallis tests. Parametric-accelerated failure time models were fit for transplantation. Graft failure was characterized using Kaplan-Meier methods and log rank tests. Results: Sixty-one percent received dialysis as first RRT modality and 39% PKT. Those with PKT were less likely to have glomerular disease and to be African-American, and had higher household-income. African-American subjects were nearly twice as likely to undergo dialysis prior to transplant. Those with a living donor and a college-educated mother had 40%-decreased odds of being dialysis experienced. Children with PKT were more likely to receive a living donor transplant. Only 5% of PKT subjects had graft failure by 4 years compared to 16% of those initially treated with dialysis (p = 0.092); however, after adjustment the effect of dialysis exposure was attenuated (p = 0.206). Conclusion: CKiD subjects undergo PKT more often compared to nationally-reported rates, and are more likely to receive a kidney transplant within 1 year of starting dialysis. African-American race and lower household-income are associated with decreased access to PKT. [ABSTRACT FROM AUTHOR]

Background: The relationship between muscle strength and chronic kidney disease (CKD) in children is unknown. This study aims to quantify the association between grip strength (GS) and kidney function and to explore factors associated with grip strength in children and adolescents with CKD. Methods: We included 411 children (699 GS assessments) of the Chronic Kidney Disease in Children (CKiD) study. They were matched by age, sex, and height to a healthy control from the National Health and Nutrition Examination Survey to quantify the relationship between GS and CKD. Linear mixed models were used to identify factors associated with GS among CKD patients. Results: Median GS z-score was − 0.72 (IQR − 1.39, 0.11) among CKD patients with CKD stages 2 through 5 having significantly lower GS than CKD stage 1. Compared with healthy controls, CKiD participants had a decreased GS z-score (− 0.53 SD lower, 95% CI − 0.67 to − 0.39) independent of race/ethnicity and body mass index. Factors associated with reduced GS included longer duration of CKD, pre-pubertal status, delayed puberty, neuropsychiatric comorbidities, need of feeding support, need for alkali therapy, and hemoglobin level. Decreased GS was also associated with both a lower frequency and intensity of physical activity. Conclusions: CKD is associated with impaired muscle strength in children independent of growth retardation and BMI. Exposure to CKD for a prolonged time is associated with impaired muscle strength. Potential mediators of the impact of CKD on muscle strength include growth retardation, acidosis, poor nutritional status, and low physical activity. Additional studies are needed to assess the efficacy of interventions targeted at these risk factors. [ABSTRACT FROM AUTHOR]

Background: PROMIS Pediatric patient-reported outcome measures were developed with children from the general population, and their content validity has not been established in children with chronic disease. This study was done to evaluate the content validity of the PROMIS Pediatric Pain Interference and Fatigue measures in children 8–17 years-old with Crohn's disease and the PROMIS Pediatric Fatigue, Sleep Disturbance, and Sleep-related Impairment measures for children 8–17 years-old with chronic kidney disease. Methods: We conducted semi-structured interviews with individuals affected by Crohn's disease and chronic kidney disease. The interviews were done to elicit children's lived experiences of the PROMIS outcomes of interest. We used deductive content analysis to contrast the participants' reports of their symptoms and impacts on daily life with existing conceptual frameworks for the PROMIS measures, each of which was developed with input from children in the general population. Results: On average, we elicited an average of 7 pain interference and 7 fatigue concepts from Crohn's disease participants (n = 37), while chronic kidney disease participants (n = 26) provided 9 concepts for fatigue, 4 for sleep disturbance, and 7 for sleep-related impairment. Concept saturation was achieved after 16–19 interviews across the four PROMIS measures. Children with these two chronic health conditions reported the same breadth and types of lived experiences as children from the development samples drawn from the general population. Conclusion: The study supports the content validity of several PROMIS Pediatric measures for children with Crohn's disease and chronic kidney disease. These findings provide evidence that PROMIS Pediatric measures, developed as universally relevant patient-reported outcomes, may be more broadly applicable to children with chronic disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Obstructive uropathy (OU) is a common cause of end-stage renal disease (ESRD) in children. Children who escape the newborn period with mild-to-moderate chronic kidney disease (CKD) continue to be at increased risk. The predictive ability of clinically available markers throughout childhood is poorly defined.Methods: Patients with OU were identified in the Chronic Kidney Disease in Children Study. The primary outcome of interest was renal replacement therapy (RRT) (cases). Controls were age matched and defined as patients within the OU cohort who did not require RRT during study follow-up.Results: In total, 27 cases and 41 age-matched controls were identified. Median age at baseline and age at outcome measurement were 10 vs. 16 years, respectively. First available glomerular filtration rate (GFR) (36.9 vs. 53.5 mL/min per 1.73 m2), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO2 (20 vs. 22 mmol/L) and hemoglobin (12.4 vs. 13.2 g/dL) differed significantly between cases and controls, respectively. GFR declined 3.07 mL/min per 1.73 m2/year faster in cases compared to that in controls (p < 0.0001). Urine protein/Cr and microalbumin/Cr increased by 0.16 and 0.11 per year more in cases compared to those in controls, respectively (p ≤ 0.001 for both). Serum phosphate increased by 0.11 mg/dL and serum albumin and hemoglobin decreased by 0.04 (g/dL) and 0.14 (g/dL) per year more for cases compared to those for controls, respectively (p < 0.05 for all).Conclusions: Age-specific baseline and longitudinal measures of readily available clinical measures predict progression to ESRD in children with mild-to-moderate CKD from OU. [ABSTRACT FROM AUTHOR]

Background: In pediatric chronic kidney disease (pCKD), traditional factors (proteinuria, etiology, and race) do not fully explain disease progression. The levels of methylated arginine derivatives (MADs: asymmetric and symmetric dimethylarginine, respectively) rise in CKD and increase with CKD progression. The impact of MADs on glomerular filtration rate (GFR) decline has not been examined in pCKD. The aim of this study was to examine the additive impact of baseline (BL) levels of MADs on directly measured GFR (mGFR) decline per year (ml/min/1.73 m2/year) for a period of up to 4 years.Methods: Plasma and data, including mGFR by plasma iohexol clearance, were provided by the prospective, observational Chronic Kidney Disease in Children study. BL MADs were analyzed by high-performance liquid chromatography-tandem mass spectrometry.Results: For 352 pCKD subjects, the median [interquartile range] BL mGFR was 45 [35, 57] ml/min/1.73 m2. The levels of BL MADs were inversely related to the initial mGFR and its decline over time (p < 0.0005) but not to the rate of decline. Covariates, non-glomerulopathy and Tanner stage of ≥ 3 demonstrated weaker relationships between BL levels and beginning mGFR (p = 0.004 and p = 0.002, respectively).Conclusions: In pCKD, higher concentrations of BL MADs were inversely related to BL mGFR. MADs did not affect the CKD progression rate. Quantification of this relationship is novel to the pCKD literature. [ABSTRACT FROM AUTHOR]

Background: No controlled trials in children with end-stage kidney disease have assessed the benefits of more frequently administered hemodialysis (HD). Methods: We conducted a multicenter, crossover pilot trial to determine if short, more frequent (5 days per week) in-center HD was feasible and associated with improvements in blood pressure compared with three conventional HD treatments per week. Because adult studies have not controlled for the weekly duration of dialysis, we fixed the total treatment time at 12 h a week of dialysis during two 3-month study periods; only frequency varied from 5 to 3 days per week between study periods. Results: Eight children (median age 16.7 years) consented at three children's hospitals. The prespecified primary composite outcome was a sustained 10% decrease in systolic blood pressure and/or a decrease in antihypertensive medications relative to each study period's baseline. Among the six patients completing both study periods, five (83.3%) experienced the primary outcome during HD performed 5 days per week but not 3 days per week; one of the six (16.7%) achieved that outcome during 3-day but not 5-day ( p = 0.22) per week HD. During 5-day HD, all patients had significantly more treatments during which their pre-HD systolic ( p = 0.01) or diastolic ( p = 0.01) blood pressure was 10% lower than baseline. Conclusions: We observed that more frequent HD sessions per week was feasible and associated with improved blood pressure control, but barriers to changing thrice-weekly standard of care include financial reimbursement and the time demands associated with more frequent treatments. [ABSTRACT FROM AUTHOR]

Carotid-femoral pulse wave velocity (cfPWV) is a measure of arterial stiffness associated with cardiovascular events in the general population and in adults with chronic kidney disease. However, few data exist regarding cfPWV in children with chronic kidney disease. We compared observed cfPWV assessed via applanation tonometry in children enrolled in the CKiD cohort study (Chronic Kidney Disease in Children) to normative data in healthy children and examined risk factors associated with elevated cfPWV. cfPWV Z score for height/gender and age/gender was calculated from and compared with published pediatric norms. Multivariable linear regression was used to assess the relationship between cfPWV and age, gender, race, body mass index, diagnosis, urine protein-creatinine ratio, mean arterial pressure, heart rate, number of antihypertensive medications, uric acid, and serum low-density lipoprotein. Of the 95 participants with measured cfPWV, 60% were male, 19% were black, 46% had glomerular cause of chronic kidney disease, 22% had urine protein-creatinine ratio 0.5 to 2.0 mg/mg and 9% had >2.0 mg/mg, mean age was 15.1 years, average mean arterial pressure was 80 mm Hg, and median glomerular filtration rate was 63 mL/min per 1.73 m2 Mean cfPWV was 5.0 m/s (SD, 0.8 m/s); mean cfPWV Z score by height/gender norms was -0.1 (SD, 1.1). cfPWV increased significantly with age, mean arterial pressure, and black race in multivariable analysis; no other variables, including glomerular filtration rate, were independently associated with cfPWV. In this pediatric cohort with mild kidney dysfunction, arterial stiffness was comparable to that of normal children. Future research is needed to examine the impact of chronic kidney disease progression on arterial stiffness and associated cardiovascular parameters in children. [ABSTRACT FROM AUTHOR]

Purpose We determined the association between dietary zinc intake and incident calcium kidney stones in adolescents. We also examined the relationship between dietary zinc intake and urinary zinc excretion between cases and controls. Materials and Methods We conducted a nested case-control study within a large pediatric health care system. Three 24-hour dietary recalls and spot urine chemistry analyses were obtained for 30 participants 12 to 18 years old with a first idiopathic calcium based kidney stone and 30 healthy controls matched for age, sex, race and month of enrollment. Conditional logistic regression models were used to estimate the association between daily zinc intake and incident calcium kidney stones, adjusting for dietary phytate, protein, calcium, sodium and oxalate. Multivariable linear regression was used to estimate the association between dietary and urine zinc, adjusting for urine creatinine and dietary phytate and calcium. Results Cases had lower daily zinc intake (8.1 mg) than controls (10 mg, p = 0.029). Daily zinc intake of boys and girls with calcium stones was 2 mg and 1.2 mg less, respectively, than the daily intake recommended by the Institute of Medicine. Odds of incident stones were reduced by 13% for every 1 mg increase in daily zinc intake (OR 0.87, 95% CI 0.75–0.99). There was an estimated 4.5 μg/dl increase in urine zinc for every 1 mg increase in dietary zinc (p = 0.009), with weak evidence of a smaller increase in urine zinc in cases than in controls (interaction p = 0.08). Conclusions Decreased dietary zinc intake was independently associated with incident calcium nephrolithiasis in this population of adolescents. [ABSTRACT FROM AUTHOR]

Background: Children with chronic kidney disease (CKD) may have impaired caloric intake through a variety of mechanisms, with decreased appetite as a putative contributor. In adult CKD, decreased appetite has been associated with poor clinical outcomes. There is limited information about this relationship in pediatric CKD. Methods: A total of 879 participants of the Chronic Kidney Disease in Children (CKiD) study were studied. Self-reported appetite was assessed annually and categorized as very good, good, fair, or poor/very poor. The relationship between appetite and iohexol or estimated glomerular filtration rate (ieGFR), annual changes in anthropometrics z-scores, hospitalizations, emergency room visits, and quality of life were assessed. Results: An ieGFR < 30 ml/min per 1.73 m was associated with a 4.46 greater odds (95 % confidence interval: 2.80, 7.09) of having a worse appetite than those with ieGFR >90. Appetite did not predict changes in height, weight, or BMI z-scores. Patients not reporting a very good appetite had more hospitalizations over the next year than those with a very good appetite. Worse appetite was significantly associated with lower parental and patient reported quality of life. Conclusions: Self-reported appetite in children with CKD worsens with lower ieGFR and is correlated with clinical outcomes, including hospitalizations and quality of life. [ABSTRACT FROM AUTHOR]

Background. Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown. Methods. The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from >10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrolment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFRcrea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ⩾300 and ⩾500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD. Results. SNPs with suggestive association P-values <1×10-5 were identified in 10 regions for eGFRcrea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5×10-8). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/ UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD. Conclusions. Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations. [ABSTRACT FROM AUTHOR]

Background: Vitamin D plays an important role in the mineral and bone disorder seen in chronic kidney disease (CKD). Deficiency of 25-hydroxyvitamin D (25OHD) is highly prevalent in the adult CKD population. Methods: The prevalence and determinants of 25OHD deficiency (defined as a level <20 ng/ml) were examined longitudinally in 506 children in the CKiD cohort. Predictors of secondary hyperparathyroidism and the determinants of 1,25-dihydroxyvitamin D (1,25(OH)D) levels were also evaluated. Results: Deficiency of 25OHD was observed in 28 % of the cohort at enrollment. Significant predictors of 25OHD deficiency were older age, non-white race, higher body mass index, assessment during winter, less often than daily milk intake, non-use of nutritional vitamin D supplement and proteinuria. Lower values of glomerular filtration rate (GFR), serum 25OHD, calcium and higher levels of FGF23 were significant determinants of secondary hyperparathyroidism. Lower GFR, low serum 25OHD, nephrotic-range proteinuria, and high FGF23 levels were significant determinants of serum 1,25(OH) D levels. Conclusions: Deficiency of 25OHD is prevalent in children with CKD and is associated with potentially modifiable risk factors such as milk intake, nutritional vitamin D supplement use, and proteinuria. 25OHD deficiency is a risk factor for secondary hyperparathyroidism and decreased serum 1,25(OH)D in children with CKD. [ABSTRACT FROM AUTHOR]

Background: Studies in children with chronic kidney disease indicate a high prevalence of masked hypertension detected by ambulatory blood pressure monitoring (ABPM). However, it is not well known if the frequency of masked hypertension is related to the level of normal casual blood pressure (BP). Methods/Results: We hypothesized that lower levels of normal casual BP are associated with a lower prevalence of masked hypertension. Data from the chronic kidney disease (CKiD) cohort were analyzed cross-sectionally across multiple visits. The majority of children with normal casual BP also had normal wake and sleep ABP (60 %), even at the highest percentiles of casual BP. The frequency of masked hypertension was lower in children with casual BP ≤25th percentile versus those with casual BP in 26-50th percentile and casual BP in 51-90th percentile during both wake and sleep periods. In children with the lowest normal casual BP levels (≤25th percentile), the frequency of abnormal mean wake or sleep ABP was 2-7 %, and of abnormal BP load was 6-16 %. Conclusions: These data suggest that masked hypertension is unlikely if the casual BP is found to be in the low normal range. [ABSTRACT FROM AUTHOR]

At a recent meeting of international experts on clinical aspects of progressive chronic kidney disease (CKD), an extensive analysis of extant clinical trials was used to develop more effective and economical surrogate markers for CKD outcomes in adults. This article describes the reasons for this undertaking, the methods and conclusions of the meeting, and the relevance of these findings to pediatric nephrology. [ABSTRACT FROM AUTHOR]

Background: Growth failure is common among children with chronic kidney disease (CKD). We examined the relationship of growth parameters with glomerular filtration rate (GFR), CKD diagnosis, sex and laboratory results in children with CKD. Methods: Baseline data from 799 children (median age 11.0 years, median GFR 49.9 mL/min/1.73 m) participating in the Chronic Kidney Disease in Children Study were examined. Growth was quantified by age-sex-specific height, weight, body mass index (BMI-age), and height-age-sex-specific BMI (BMI-height-age) standard deviation scores (SDS). Results: Median height and weight SDS were −0.55 [interquartile range (IQR) −1.35 to 0.19] and 0.03 (IQR −0.82 to 0.97), respectively. Girls with non-glomerular CKD were the shortest (median height SDS −0.83; IQR −1.62 to −0.02). Compared to those with a serum bicarbonate (CO) level of ≥22 mEq/L, children with CO of <18 mEq/L had a height SDS that was on average 0.67 lower [95 % confidence interval (CI) −0.31 to −1.03]. Only 23 % of children with a height SDS of ≤−1.88 were prescribed growth hormone therapy. Forty-six percent of children with glomerular CKD were overweight or obese (BMI-height-age ≥85th percentile). Conclusions: Growth outcomes in a contemporary cohort of children with CKD remain suboptimal. Interventions targeting metabolic acidosis and overcoming barriers to recombinant human growth hormone usage may improve growth in this population. [ABSTRACT FROM AUTHOR]

Background: In adults with chronic kidney disease (CKD), protein-energy wasting (PEW) is a risk factor for hospitalization and death. However, PEW in children with CKD is not well characterized or defined. Methods: Using data from the Chronic Kidney Disease in Children study, we assessed three alternate definitions of PEW using biochemical parameters, body and muscle mass measurements, and reported appetite as described in adults: (1) a minimal PEW definition (≥2 of the four criteria); (2) a standard PEW definition (≥3 of the four criteria); (3) a modified PEW definition (≥3 of the four criteria plus a pediatric-focused criterion of short stature or poor growth). Results: Of the 528 children analyzed in this study (median age 12 years, median glomerular filtration rate 45 mL/min/1.73 m, 39 % female, 18 % African American), 7-20 % met the spectrum of definitions for PEW. The unadjusted incidence rates for incident hospitalizations were 1.9-, 2.1-, and 2.2-fold higher for those children diagnosed with PEW using the minimal, standard, and modified definitions, respectively ( P = 0.08, 0.09 and 0.03). Following adjustment, only the modified PEW definition, which added short stature or poor growth as a criterion, showed modest significance ( P = 0.06). Conclusions: The inclusion of a criterion based on growth may augment the definition of PEW and improve risk discrimination in children with CKD. [ABSTRACT FROM AUTHOR]

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that has deleterious consequences on skeletal and cardiovascular health. Nowhere is the morbidity of this disorder more telling than in children. During childhood and adolescence, CKD-MBD may result in poor growth and skeletal deformities, while the mineral dysregulation can manifest in cardiovascular disease in early adulthood, a development that places the patients at high risk for severe morbidity and early mortality. Unfortunately, management of CKD-MBD has been less than satisfactory in children despite recent advances and is limited by the lack of evidence-based treatment guidelines. More positive are ongoing research efforts, such as the Chronic Kidney Disease in Children and the Cardiovascular Comorbidity in Children with CKD (4C) studies that are currently providing important insights which should help better elucidate the pathogenesis and progression of mineral dysregulation and its clinical impact in children. Data from these studies and others will undoubtedly also help formulate clinical trials and the generation of evidence-based therapeutic options designed to provide more effective management of CKD-MBD in the pediatric population. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate the accuracy of four equations based on serum creatinine concentration-the original Schwartz equation and the Leger, Bedside Chronic Kidney Disease in Children ( CKiD), and Counahan-Barratt equations-for determining glomerular filtration rate ( GFR) in pediatric patients with chronic kidney disease. Design Retrospective, observational, cross-sectional study. Setting Single-center, academic, outpatient pediatric nephrology clinic. Patients Fifty-three pediatric patients with stages 2-5 chronic kidney disease who completed GFR assessment with 125I-iothalamate between January 2002 and January 2005. Measurement and Main Results Data were collected from each patient's medical record. Glomerular filtration rate data were analyzed using 59 evaluations from the 53 pediatric patients. 125I-iothalamate clearance was used as the index GFR. The Bedside CKiD and Counahan-Barratt equations outperformed the Schwartz and Leger equations when the index GFR was less than 60 ml/minute/1.73 m2; the Schwartz and Counahan-Barratt equations performed best for index GFRs of 60 ml/minute/1.73 m2 or greater. Overestimation was highest with the Schwartz and Leger equations (> 20% index GFR in 57.6% and 62.7% of patients, respectively). Underestimation was highest with the Bedside CKiD and Counahan-Barratt equations (> 20% index GFR in 30.5% and 28.8%, respectively). Conclusion The new Bedside CKiD equation performed well for pediatric patients with moderate-to-severe chronic kidney disease, but less well for pediatric patients with mild disease. Additional studies are needed to develop more precise GFR equations using serum creatinine concentration. [ABSTRACT FROM AUTHOR]

Purpose: Urological disorders are the most common cause of pediatric chronic kidney disease. We determined the characteristics of children with urological disorders and assessed the agreement between the newly developed bedside glomerular filtration rate estimating formula with measured glomerular filtration rate in 586 patients in the Chronic Kidney Disease in Children study. Materials and Methods: The Chronic Kidney Disease in Children study is a prospective, observational cohort of children recruited from 48 sites in the United States and Canada. Eligibility requirements include age 1 to 16 years and estimated glomerular filtration rate by original Schwartz formula 30 to 90 ml/min/1.73 m2. Baseline demographics, clinical variables and glomerular filtration rate were assessed. Bland-Altman analysis was conducted to assess agreement between estimated and measured glomerular filtration rates. Results: Of the 586 participants with at least 1 glomerular filtration rate measurement 348 (59%) had an underlying urological diagnosis (obstructive uropathy in 118, aplastic/hypoplastic/dysplastic kidneys in 104, reflux in 87 and other condition in 39). Among these patients median age was 9 years, duration of chronic kidney disease was 7 years and age at first visit with a urologist was less than 1 year. Of the patients 67% were male, 67% were white and 21% had a low birth weight. Median height was in the 24th percentile. Median glomerular filtration rate as measured by iohexol plasma disappearance was 44.8 ml/min/1.73 m2. Median glomerular filtration rate as estimated by the Chronic Kidney Disease in Children bedside equation was 44.3 ml/min/1.73 m2 (bias = −0.5, 95% CI −1.7 to 0.7, p = 0.44). Conclusions: Underlying urological causes of chronic kidney disease were present in 59% of study participants. These children were diagnosed early in life, and many had low birth weight and growth delay. There is good agreement between the newly developed Chronic Kidney Disease in Children estimating equations and measured glomerular filtration rate in this population. [Copyright &y& Elsevier]

The rate of decline of glomerular filtration rate (GFR) in children with chronic kidney disease (CKD) can vary, even among those with similar diagnoses. Classic regression methods applied to the log-transformed GFR (i.e., lognormal) quantify only rigid shifts in a given outcome. The generalized gamma distribution offers an alternative approach for characterizing the heterogeneity of effect of an exposure on a positive, continuous outcome. Using directly measured GFR longitudinally assessed between 2005 and 2010 in 529 children enrolled in the Chronic Kidney Disease in Children Study, the authors characterized the effect of glomerular CKD versus nonglomerular CKD diagnoses on the outcome, measured as the annualized GFR ratio. Relative percentiles were used to characterize the heterogeneity of effect of CKD diagnosis across the distribution of the outcome. The rigid shift assumed by the classic mixed models failed to capture the fact that the greatest difference between the glomerular and nonglomerular diagnosis’ annualized GFR ratios was in children who exhibited the fastest GFR declines. Although this difference was enhanced in children with an initial GFR level of 45 mL/minute/1.73 m2 or less, the effect of diagnosis on outcome was not significantly modified by level. Generalized gamma models captured heterogeneity of effect more richly and provided a better fit to the data than did conventional lognormal models. [ABSTRACT FROM PUBLISHER]

Summary: Racial and gender differences in the prevalence and treatment of chronic kidney disease in US children have been reported. Girls have lower rates of kidney transplantation than boys. Incidence of end-stage renal disease is twice as high among black patients compared with whites. African Americans are less likely than white patients to achieve hemoglobin targets on dialysis, are more likely to be treated with hemodialysis, and to wait longer for a transplant. Reasons for these disparities in disease burden and treatment choices are not known, but possible causes include genetic factors and socioeconomic and sociocultural influences on accessing medical care. [ABSTRACT FROM AUTHOR]