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A new study of mortality of children on renal replacement therapy in 32 European countries demonstrates that 67% of the variance between countries can be explained by disparities in public health expenditure. Investment in health care is critical and has demonstrable benefits for the most vulnerable populations.

Background Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Methods and findings Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: −0.75, −0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Conclusions Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels., Melanie H. Jacobson and colleagues investigate correlations between exposures to chemicals and kidney function in children., Author summary Why was this study done? The prevalence of chronic kidney disease has been steadily increasing over the last 40 years. While there are several known risk factors, such as diabetes and hypertension, few are potentially modifiable. Recent work has suggested kidney function may be affected by exposure to environmental chemicals such as bisphenols and phthalates, which are synthetic compounds used in the manufacturing of plastics and other consumer products. However, these chemicals are non-persistent, and no longitudinal studies to our knowledge have been conducted to investigate their potential impact on kidney function over time. What did the researchers do and find? In urine samples collected annually over 5 years from 618 children and adolescents with chronic kidney disease, we measured bisphenol A, phthalates, and biomarkers of tubular injury and oxidative stress. Clinical renal function outcomes were also monitored and collected over 5 years. We found that bisphenol A and phthalates were associated with increased tubular injury and oxidative stress biomarkers. Although phthalic acid was associated with lower estimated glomerular filtration rate over time, neither bisphenol A nor other phthalates were associated with clinical renal outcomes. What do these findings mean? Bisphenol A and phthalates were not associated with clinical renal function outcomes, but showed consistent positive associations with tubular injury and oxidative stress, which may signal the potential for clinical events to manifest with prolonged follow-up. These findings raise concern about the potential for clinically relevant changes to renal function to develop over time in relation to environmental exposures at current levels. This study suggests that exposure to environmental chemicals may be a potentially modifiable risk factor for the progression of chronic kidney disease.

This cohort study assesses whether time-varying vs baseline blood pressure measurements are associated with a higher risk of disease progression among children with chronic kidney disease., Key Points Question Are elevated longitudinal (time-varying) blood pressure measurements associated with a greater risk of disease progression when compared with baseline (time-fixed) blood pressure measurements in children with chronic kidney disease? Findings In this cohort study of 844 children with chronic kidney disease, those with baseline elevated systolic or diastolic blood pressure were at greater risk of disease progression. Elevated time-varying systolic and diastolic blood pressures were associated with increased risk among children with glomerular disease, even after adjustment for proteinuria and use of antihypertensives, and were more strongly associated with kidney disease progression than baseline blood pressure. Meaning These findings suggest that risk estimated using time-fixed blood pressure alone may underestimate the importance of updated blood pressure measurements in the assessment of chronic kidney disease progression., Importance Optimal blood pressure (BP) management in children with chronic kidney disease (CKD) slows progression to end-stage renal disease. Studies often base progression risk on a single baseline BP measurement, which may underestimate risk. Objective To determine whether time-varying BP measurements are associated with a higher risk of progression of CKD than baseline BP measurements. Design, Setting, and Participants The ongoing longitudinal, prospective cohort study Chronic Kidney Disease in Children (CKID) recruited children from January 19, 2005, through March 19, 2014, from pediatric nephrology centers across North America, with data collected at annual study visits. Participants included children aged 1 to 16 years with a diagnosis of CKD and a glomerular filtration rate (GFR) of 30 to 90 mL/min/1.73 m2. Data were analyzed from February 11, 2005, through February 13, 2018. Exposures Office BP measurement classified as less than 50th percentile, 50th to less than 90th percentile, or at least 90th percentile. Blood pressure categories were treated as time fixed (baseline) or time varying (updated at each visit) in models. Main Outcomes and Measures A composite renal outcome (50% GFR reduction from baseline, estimated GFR less than 15 mL/min/1.73 m2, or dialysis or transplant). Pooled logistic models using inverse probability weighting estimated the hazard odds ratio (HOR) of the composite outcome associated with each BP category stratified by CKD diagnosis. Results A total of 844 children (524 [62.1%] male; median age, 11 [interquartile range, 8-15] years; 151 [17.9%] black; 580 [68.7%] with nonglomerular CKD; and 264 [31.3%] with glomerular CKD) with complete baseline data and median follow-up of 4 (interquartile range, 2-6) years were included. One hundred ninety-six participants with nonglomerular diagnoses (33.8%) and 99 with glomerular diagnoses (37.5%) reached the composite outcome. Baseline systolic BP in at least the 90th percentile was associated with a higher risk of the composite outcome (HOR for nonglomerular disease, 1.58 [95% CI, 1.07-2.32]; HOR for glomerular disease, 2.85 [95% CI, 1.64-4.94]) compared with baseline systolic BP in less than the 50th percentile. Time-fixed estimates were substantially lower compared with time-varying systolic BP percentile categories (HOR among those with nonglomerular CKD, 3.75 [95% CI, 2.53-5.57]; HOR among those with glomerular diagnoses, 5.96 [95% CI, 3.37-10.54]) comparing those at or above the 90th percentile vs below the 50th percentile. Adjusted models (adjusted for proteinuria and use of antihypertensives) attenuated the risk in nonglomerular CKD (adjusted HOR for baseline measurement, 1.52 [95% CI, 0.98-2.36]; adjusted HOR for time-varying measurement, 2.25 [95% CI, 1.36-3.72]) and in glomerular CKD (adjusted HOR for baseline, 0.97 [95% CI, 0.39-2.36]; adjusted HOR for time-varying measurement, 1.41 [95% CI, 0.65-3.03]). Similar results were observed for diastolic BP. Conclusions and Relevance Among children with nonglomerular CKD included in this study, elevated time-varying BP measurements were associated with a greater risk of CKD progression compared with baseline BP measurement. This finding suggests that previous studies using only baseline BP likely underestimated the association between BP and CKD progression.

It remains challenging to automatically segment kidneys in clinical ultrasound (US) images due to the kidneys' varied shapes and image intensity distributions, although semi-automatic methods have achieved promising performance. In this study, we propose subsequent boundary distance regression and pixel classification networks to segment the kidneys automatically. Particularly, we first use deep neural networks pre-trained for classification of natural images to extract high-level image features from US images. These features are used as input to learn kidney boundary distance maps using a boundary distance regression network and the predicted boundary distance maps are classified as kidney pixels or non-kidney pixels using a pixelwise classification network in an end-to-end learning fashion. We also adopted a data-augmentation method based on kidney shape registration to generate enriched training data from a small number of US images with manually segmented kidney labels. Experimental results have demonstrated that our method could automatically segment the kidney with promising performance, significantly better than deep learning-based pixel classification networks.

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 m(2)), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO(2) (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 m(2)/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.

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

Background & Objectives Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. Study Design Qualitative study. Setting & Participants Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. Analytical Approach Transcripts were analyzed thematically. Results We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden). Limitations Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. Conclusions Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed.

In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.

The ambulatory arterial stiffness index (AASI) is a non-invasive measure of arterial stiffness derived from ambulatory blood pressure monitoring (ABPM) data. Studies in children have shown higher AASI is associated with obesity and hypertension, but there are no data examining AASI in children with chronic kidney disease (CKD). We used data from the Chronic Kidney Disease in Children (CKiD) Cohort Study to evaluate the association between AASI and hypertensive status on ABPM, and to identify predictors of AASI, including BMI, proteinuria, mineral metabolism and BP parameters from ABPM. Of 639 CKiD participants at their first successful ABPM visit, the mean age was 12 years, 60% (382/639) were male, 15% (96/639) were obese and the mean eGFR was 52 ml/min/1.73m 2 . Approximately two-thirds reported antihypertensive therapy use (66%, 422/639) yet 58% (368/639) met criteria for abnormal ABPM (elevated mean awake/sleep DBP/SBP or awake/sleep load >25%). Participants who met criteria for abnormal ambulatory BP had a higher mean AASI than those with a normal ambulatory BP (0.337 and 0.307, respectively, p=0.008). Masked hypertension (MH) was common (42.4%, 284/639) and those subjects had a significantly higher AASI compared to normotensive children (Table). Male sex, age and BMI category were all positively associated with AASI, but presence of proteinuria, abnormal serum calcium or phosphate were not. AASI is associated with hypertensive status and BMI in children with CKD and may be a useful non-invasive measure of vascular stiffness in this population. The relationship of AASI to other measures of vascular stiffness such as pulse wave velocity requires further study.

Objective: Adiposity, not blood pressure (BP), is associated with left ventricular hypertrophy (LVH) among hypertensive children without chronic kidney disease (CKD). We aimed to determine the longitudinal association of BMI z-score with LVH and left ventricular mass index (LVMI) among children with CKD. Methods: 696 participants of the Chronic Kidney Disease in Children study with echocardiography results who contributed a total of 1,300 visits were included. Mixed models, adjusting for repeated visits with a random subject effect, were used to determine the longitudinal association of body mass index (BMI) z-score with LVMI and LVH (LVMI> age-sex specific 95 th %ile). Models were adjusted for age, sex, race, systolic and diastolic BP z-score, glomerular diagnosis, time with CKD, glomerular filtration rate and calcium*phosphorus product and accounted for informative censoring. Results: Baseline characteristics are in the table. Among females, a 1 unit increase in BMI z-score was associated with an 8.5% increase in LVMI and 3.4 greater odds of LVH, whereas with boys, a 1 unit increase in BMI z-score was associated with a 5.2% increase in LVMI and a 1.4 greater odds of LVH (p Conclusions: Among children with mild-moderate CKD, adiposity is independently associated with LVMI and LVH over time. This association is greater among females, a finding that may have future clinical and research implications.

Background: No data are available regarding what office blood pressure (BP) is protective against progression of chronic kidney disease (CKD) in children. In this study, we examined the association between achieved office BP and CKD outcomes among 688 hypertensive children in the Chronic Kidney Disease in Children Cohort study. Methods: BP categories were defined as the maximum systolic/diastolic BP percentile ( Results: Median age was 11.3 years, 62% were male, median duration of CKD was 8y; 213 had glomerular [G] CKD and 475 had nonglomerular [NG] CKD. For both G and NG groups, the highest risk of CKD progression was observed for those with BP ≥90th percentile, and BP 50 to 75th percentile was associated with the lowest risk from 0 to 2 years for G (time-varying RH between 0.09 to 0.24, p Conclusion: Achieved office BP between the 50th-75th percentiles appeared to offer the greatest protection against CKD progression in this cohort. This observation should be confirmed prospectively.

Background Conventional magnetic resonance imaging (MRI) is limited for detection of clinically relevant brain changes in youth with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms. We aimed to examine structural brain abnormalities in youth with SLE compared to healthy controls, utilizing advanced MRI analysis. Methods We cross-sectionally compared images from clinically-obtained brain MRI for adolescents and young adults with SLE, to those from age and sex-matched healthy control subjects with research MRI. Images were obtained from 2007–2015 on the same 3T scanner using a T1-weighted MPRAGE (magnetization-prepared rapid, acquisition gradient echo) protocol. A neuroradiologist performed conventional MRI reads, and was blinded to subsequent structural MRI volumetric analysis. An advanced multi-atlas segmentation algorithm divided the brain into 154 anatomical regions of interest (ROIs). Calculated volumes for large brain structures and ROIs were corrected for average intracranial volume of the sample, then compared between SLE and control subjects using univariate paired t-tests, with Bonferroni correction for multiple comparisons. Results 29 SLE were compared to 29 control images. SLE subjects had a median disease duration of 1.1 years (interquartile range, 0.3–3.3) at brain MRI, with clinical indications including cognitive changes (31%), headache (24%), depression/anxiety (21%), and seizures (14%). Nonspecific findings on conventional MRI read were higher for SLE subjects compared to controls, including T1 hyperintensities/T2 hypointensities (48% vs 17%, p Conclusions Compared to healthy peers, youth with SLE early in their disease course have increased white matter and decreased regional gray matter volumes, possibly representing acceleration of normal age-related brain changes. Future study will examine the relationship between structural brain changes, disease-related factors and cognitive function in youth with SLE.

Summary Introduction Anatomic characteristics of kidneys derived from ultrasound images are potential biomarkers of children with congenital abnormalities of the kidney and urinary tract (CAKUT), but current methods are limited by the lack of automated processes that accurately classify diseased and normal kidneys. Objective The objective of the study was to evaluate the diagnostic performance of deep transfer learning techniques to classify kidneys of normal children and those with CAKUT. Study design A transfer learning method was developed to extract features of kidneys from ultrasound images obtained during routine clinical care of 50 children with CAKUT and 50 controls. To classify diseased and normal kidneys, support vector machine classifiers were built on the extracted features using (1) transfer learning imaging features from a pretrained deep learning model, (2) conventional imaging features, and (3) their combination. These classifiers were compared, and their diagnosis performance was measured using area under the receiver operating characteristic curve (AUC), accuracy, specificity, and sensitivity. Results The AUC for classifiers built on the combination features were 0.92, 0.88, and 0.92 for discriminating the left, right, and bilateral abnormal kidney scans from controls with classification rates of 84%, 81%, and 87%; specificity of 84%, 74%, and 88%; and sensitivity of 85%, 88%, and 86%, respectively. These classifiers performed better than classifiers built on either the transfer learning features or the conventional features alone (p Discussion The present study validated transfer learning techniques for imaging feature extraction of ultrasound images to build classifiers for distinguishing children with CAKUT from controls. The experiments have demonstrated that the classifiers built on the transfer learning features and conventional image features could distinguish abnormal kidney images from controls with AUCs greater than 0.88, indicating that classification of ultrasound kidney scans has a great potential to aid kidney disease diagnosis. A limitation of the present study is the moderate number of patients that contributed data to the transfer learning approach. Conclusions The combination of transfer learning and conventional imaging features yielded the best classification performance for distinguishing children with CAKUT from controls based on ultrasound images of kidneys.

BACKGROUND: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. METHODS: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n=112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n=96) and Novel therapies for resistant FSGS Trial (FONT) (n=30). Urinary α(1)-microglobulin (α(1)-M), albumin (A), total protein (TP) and creatinine (Cr) were assessed from CKiD subjects (n=104); DD1 patients (n=14) and DD1 carriers (DC; n=8). TP/Cr, α1M/Cr, α1M/TP and A/TP from the CKiD cohort were compared with DD1 and DC. RESULTS: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than DD1 and CKiD with glomerular disease (P < 0.002). α(1)M/Cr was higher in DD1 than CKiD and DC (P < 0.001). A/TP was lower in DD1, DC and CKiD with tubulointerstitial disease, higher in CKiD with glomerular disease (P < 0.001). Thresholds for A/TP of ≤ 0.21 and α(1)-M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. CONCLUSIONS: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cut off of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α(1)-M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

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.

Adolescent age at time of transplant has been recognized as a risk factor for renal allograft loss. Increased risk for graft failure may persist from adolescence to young adulthood. Transfer of care is hypothesized as a risk factor for non-adherence and graft loss. We explored whether kidney allograft function declined at an accelerated rate after transfer of care to adult transplant centers and whether coefficient of variation of tacrolimus (CV TAC) trough levels predicted allograft loss. Single-center, retrospective chart review was performed for pediatric kidney transplant recipients who received transplants between 1999 and 2011. Change in eGFR pre- and post-transfer was performed via a linear mixed-effects model. CV TAC was calculated in transplant recipients with TAC data pre- and post-transfer. t test was performed to determine the difference between means of CV TAC in subjects with and without allograft loss following transfer of care. Of the 138 subjects who transferred to adult care, 47 subjects with data pre- and post-transfer demonstrated a decrease in the rate of eGFR decline post-transfer from 8.0 mL/min/1.73 m2 per year to 2.1 mL/min/1.73 m2 per year, an ~80% decrease in eGFR decline post-transfer (P = 0.01). Twenty-four subjects had CV TAC data pre- and post-transfer of care. Pretransfer CV TAC for subjects with allograft loss post-transfer was significantly higher than in subjects without allograft loss (49% vs 26%, P < 0.05). Transfer of care was not independently associated with acceleration in eGFR decline. CV TAC may aid in identifying patients at risk for allograft loss post-transfer.

Cardiovascular (CV) risk is high in children with chronic kidney disease (CKD), and further compounded in those who are overweight. Children with CKD have a unique body habitus not accurately assessed by body mass index (BMI). Waist-to-height ratio (WHr), a better predictor of CV risk in populations with short stature, has not been investigated in children with CKD.Analysis of 1723 visits of 593 participants enrolled in the Chronic Kidney Disease in Children (CKiD) study was conducted. CKiD participants had BMI and WHr measured and classified as follows: (1) lean (WHr ≤ 0.49, BMI 85th percentile); (2) WHr-overweight (WHr 0.49, BMI 85th percentile); (3) BMI-overweight (WHr ≤ 0.49, BMI ≥ 85th percentile); or (4) overweight by both BMI and WHr. Left ventricular mass index (LVMI), fasting lipids, fibroblast growth factor 23 (FGF23), blood pressure, and glucose were measured as markers of CV risk. Linear mixed-effects regression was used to evaluate differences in CV markers between overweight and lean groups.Participants were 12.2 years old, 60% male, and 17% African-American. Approximately 15% were overweight by WHr but not by BMI. Overweight status by WHr-only or both WHr and BMI was associated with lower high-density lipoprotein (HDL) and higher LVMI, triglycerides, and non-HDL cholesterol compared to lean. CV markers of participants overweight by BMI-only were similar to those of lean children.WHr-adiposity is associated with an adverse CV risk profile in children with CKD. A significant proportion of children with central adiposity are missed by BMI. WHr should be utilized as a screening tool for CV risk in this population.

Uncontrolled hypertension in children with chronic kidney disease (CKD) has been identified as one of the main factors contributing to progression of CKD and increased risk for cardiovascular disease. Recent efforts to achieve better blood pressure (BP) control have been recommended. The primary objective of this analysis was to compare BP control over 2 time periods among participants enrolled in the CKiD study (Chronic Kidney Disease in Children). Casual BP and 24-hour ambulatory BP monitor data were compared among 851 participants during 2 time periods: January 1, 2005, through July 1, 2008 (period 1, n=345), and July 1, 2010, through December 31, 2013 (period 2, n=506). Multivariable logistic regression to model the propensity of a visit record being in period 2 as a function of specific predictors was performed. After controlling for confounding variables (age, sex, race, socioeconomics, CKD duration, glomerular filtration rate, proteinuria, body mass index, growth failure, and antihypertensives), no significant differences were detected between time periods with respect to casual BP status (prehypertension: 15% versus 15%; uncontrolled hypertension: 18% versus 17%; P =0.87). Analysis of ambulatory BP monitor data demonstrated higher ambulatory BP indices, most notably masked hypertension in period 2 (36% versus 49%; P P P

Importance The kidney failure risk equation (KFRE) has been shown to accurately estimate progression to kidney failure in adults with chronic kidney disease (CKD). Use of the KFRE in children with CKD, if accurate, would help to optimize planning for end-stage renal disease (ESRD) care. Objective To determine whether the KFRE adequately discriminates the risk of ESRD in children with CKD. Design, Setting, and Participants This retrospective cohort study included 603 children with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2in the Chronic Kidney Disease in Children study, a national multicenter observational study. Data were collected from January 1, 2005, through July 31, 2013, and analyzed from September 30, 2016, through September 8, 2017. Exposures The primary predictive factors were the 4-variable (age, sex, bedside Schwartz estimated glomerular filtration rate, and ratio of albumin to creatinine levels) and 8-variable (4 variables plus serum calcium, phosphate, bicarbonate, and albumin levels) KFREs, which provide 1-, 2-, and 5-year estimates of the risk of progression to ESRD. Main Outcomes and Measures Time to ESRD. The Cox proportional hazards model was used to examine the association between the KFRE score and time to ESRD. C statistics were used to discriminate ESRD risk by the KFRE, with a value of greater than 0.80 indicating strong discrimination. Results Of the 603 children included in the study, 378 were boys (62.7%) and 225 were girls (37.3%); median age at study entry was 12 years (interquartile range, 8-15 years). Median estimated glomerular filtration rate was 44 mL/min/1.73 m2. Four hundred fifty-seven participants (75.8%) had a nonglomerular cause of CKD. Median observation time was 3.8 years (interquartile range, 1.7-6.2 years); 144 (23.9%) developed ESRD within 5 years of enrollment. The 4-variable KFRE scores discriminated risk of ESRD, with C statistics of 0.90, 0.86, and 0.81 for the 1-, 2-, and 5-year risk scores, respectively. Results were similar using the 8-variable equation. Conclusions and Relevance The KFRE is a simple tool that provides excellent discrimination of the risk of ESRD. Results suggest that the KFRE could be incorporated into the clinical care of children with CKD to aid in anticipatory guidance, timing of referral for transplant evaluation, and planning for dialysis access.

OBJECTIVE To compare behavior ratings of executive functioning in individuals with chronic kidney disease (CKD), using the Behavior Rating Inventory for Executive Functions (BRIEF), with a typically developing comparison group and to examine the correlation between disease severity and ratings of executive functioning. METHODS Participants included 92 individuals with CKD (eGFR < 90 mL/min per 1.73 m), aged 8 to 25 years, recruited from nephrology clinics in both hospital and community settings. The disease severity ranged from CKD Stage II to V. The BRIEF was completed by parents for individuals younger than 18 years of age and the BRIEF-Adult was completed by individuals who were older than 18. RESULTS For individuals with CKD younger than 18 years of age, the parent-reported BRIEF revealed significant group differences when compared with controls on the Metacognition Index and the individual scales of Initiate, Working Memory, and Plan/Organize. A large proportion of individuals with CKD were rated as being at-risk for executive dysfunction. For the individuals of 18 years of age and older, there were no significant group differences. The relationship between BRIEF ratings and disease severity was limited to a few scales across both versions of the BRIEF. CONCLUSION This study supported the presence of executive dysfunction through a parent report, although the level of impairment was mild and its association with disease severity was related to select executive functions. Few difficulties were reported by older adolescents and young adults with CKD. It will be important for developmental-behavioral pediatricians to be cognizant of the level and pattern of executive function capabilities in their patients with CKD, and possible discrepancies with parent reports, so as to facilitate their management and transition planning.

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.The prevalence and determinants of 25OHD deficiency (defined as a level20 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)2D) levels were also evaluated.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)2 D levels.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)2D in children with CKD.

Background Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. Study Design Prospective multicenter observational cohort study. Setting & Participants 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Predictors Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. Outcomes Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). Results 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. Limitations Small number of events in glomerular patients and use of internal cross-validation. Conclusions Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.

IntroductionChildren with systemic lupus erythematosus (SLE) have an increased prevalence of kidney disease compared to their adult counterparts. Our goal was to identify potential clinical and laboratory predictors of renal disease.MethodsWe performed a cohort study of incident and prevalent patients with SLE aged ≤19 years. Retrospective data from initial presentation until study enrollment was also collected. Laboratory and clinic data were recorded from each clinic visit including disease activity indices, autoantibodies, urinalyses, blood counts, and metabolic profile. Kidney disease was defined as the presence of abnormal renal biopsy or by American College of Rheumatology case definition for lupus nephritis. Logistic regression analyses were used to determine the association between clinical and laboratory data with kidney disease in those who had renal involvement within 30 days of SLE diagnosis. We also performed a time to event analysis to identify antecedents of renal disease.ResultsForty-seven children and adolescents with SLE were followed in the cohort, 91% female and 68% black. All of the males in the cohort developed renal disease, and all within one month of the diagnosis of SLE. In logistic regression, low serum albumin (odds ratio (OR): 4.8, 95% CI: 1.9–12.5) and positive dsDNA antibodies (OR: 3.2, 95% CI: 1.7–5.9) were associated with kidney disease. In longitudinal analyses, isolated sterile pyuria (hazard ratio (HR): 3, 95% CI: 1.1–6.4) and low serum albumin (HR: 3.4, 95% CI: 1.7–6.9) were predictors of future kidney disease. The presence of antibodies against Ro were protective against renal disease (HR: 0.2, 95% CI: 0.05–0.5).ConclusionWe identified variables associated with kidney disease, both at initial diagnosis of SLE and in longitudinal follow-up in a cohort of children with SLE. The recognition of these abnormal laboratory values may help clinicians identify patients at risk for kidney disease before its onset thus preventing long-term complications.

BackgroundAnorexia and malnutrition are associated with poor outcomes in children with chronic kidney disease (CKD).Study designObservational cohort study.Setting & participantsWe assessed changes in body mass index (BMI) as kidney function declines and its association with risk for end-stage renal disease (ESRD) among 854 participants followed between 2005 to 2013 in the CKD in Children (CKiD) Study.PredictorsRepeated measurements of estimated glomerular filtration rate (eGFR) by serum creatinine concentration in our trajectory analysis using mixed models; change in BMI z score (per year) after eGFR decreased to 0.2 per year) after eGFR decreased to&nbsp

Background and objectives Our objective was to determine whether clinic BPs (taken at either a single visit or two sequential visits) are inferior to ambulatory BPs in their ability to discriminate risk of adverse outcomes in children with CKD. Design, setting, participants, & measurements We included 513 participants of the CKD in Children Study who had clinic BPs and 24-hour ambulatory BP monitoring performed during similar timeframes. Predictors of interest were systolic BPs taken at a single visit or two repeated visits within a 1-year period compared with mean wake and sleep systolic ambulatory BPs. Outcomes were left ventricular hypertrophy and ESKD. We determined the ability for each BP parameter to provide risk discrimination using c statistics. Results During mean follow-up of 3.5 years, 123 participants developed ESKD. In cross-sectional unadjusted analysis, every 0.1 increase in systolic BP index was associated with a 2.0 times higher odds of left ventricular hypertrophy (95% confidence interval, 1.5 to 2.8) by clinic BPs versus 1.8 times higher odds (95% confidence interval, 1.3 to 2.4) by ambulatory wake BP. The c statistic was highest for clinic BP ( c =0.65; 95% confidence interval, 0.58 to 0.73) but similar to ambulatory wake BP ( c =0.64; 95% confidence interval, 0.57 to 0.71) for the discrimination of left ventricular hypertrophy. In longitudinal unadjusted analysis, every 0.1 increase in systolic BP index was associated with a higher risk of ESKD using repeated clinic (hazard ratio, 1.5; 95% confidence interval, 1.3 to 1.8) versus ambulatory wake BP (hazard ratio, 1.6; 95% confidence interval, 1.3 to 2.0). Unadjusted c statistics were the same for wake ( c =0.61; 95% confidence interval, 0.56 to 0.67) and clinic systolic BPs ( c =0.61; 95% confidence interval, 0.55 to 0.66) for discriminating risk of ESKD. Conclusions Clinic BPs taken in a protocol-driven setting are not consistently inferior to ambulatory BP in the discrimination of BP-related adverse outcomes in children with CKD.

Background. Optimal immunosuppression after organ transplant should balance the risks of rejection, infection, and malignancy while minimizing barriers to adherence including frequent or time-sensitive dosing. There is currently no reliable immune function assay to directly measure the degree of immunosuppression after transplantation. Methods. We developed an immune function assay to mea//sure T-cell proliferation after exposure to immunosuppression in vivo. We tested the assay in mice, and then piloted the approach using single time point samples, 11 pediatric kidney transplant recipients prescribed tacrolimus, mycophenolate, and prednisone 6 months to 5 years posttransplant, with no history of rejection, opportunistic infection, or cancer. Twelve healthy adults were controls. Results. We demonstrated that our assay can quantify suppression of murine T-cell proliferation after tacrolimus treatment in vivo. In humans, we found a mean 25% reduction in CD4 and CD8 T-cell proliferation in pediatric renal transplant recipients on triple immunosuppression compared with adult healthy controls, but the pilot results were not statistically significant nor correlated with serum tacrolimus levels. We observed that cell processing and washing reduced the effects of tacrolimus on T-cell proliferation, as did discontinuation of tacrolimus treatment shortly before sampling. Conclusions. T-cell proliferation is currently not suitable to measure immunosuppression because sample processing diminishes observable effects. Future immune function testing should focus on fresh samples with minimal washing steps. Our results also emphasize the importance of adherence to immunosuppressive treatment, because T-cell proliferation recovered substantially after even brief discontinuation of tacrolimus.

Chronic kidney disease (CKD) has become a significant public health concern as it is associated with substantial morbidity. Prior research has evaluated multiple novel CKD biomarkers to supplement serum creatinine and proteinuria. The ultimate goal of this research is to find biomarkers that can be used to accurately predict CKD progression and to better time outpatient follow-up, and referral for transplant. Also, an optimal panel of biomarkers can augment the predictive value of proteinuria and serum creatinine by enriching patient enrollment in clinical trials. In this review, we discuss salient findings on 12 candidate plasma and urine biomarkers and their reported association with CKD. We explore the common pathways of CKD progression and the pathophysiologic processes of tubulointerstitial injury, inflammation, repair, and fibrosis that are potentially classified by specific biomarkers. We describe both pediatric and adult findings and highlight the paucity of pediatric research in CKD progression. It will be important for future research in cohorts with longitudinal follow-up to evaluate these CKD biomarkers in children for use in pediatric clinical trials and routine CKD management.

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. 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. 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

No controlled trials in children with end-stage kidney disease have assessed the benefits of more frequently administered hemodialysis (HD). 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. 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. 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.

Variability in measures of mineral metabolism has not been studied in pediatric end stage kidney disease. We sought to determine the intra-individual variability in measures of mineral metabolism in children on hemodialysis (HD) and its impact on clinical decision-making. We conducted a prospective single-center study of children (3.6–17.3 years old) on chronic HD. Serial twice weekly measures of serum calcium, phosphate and intact parathyroid hormone (PTH), as well as weekly measures of fibroblast growth factor 23 (FGF23) and vitamin D metabolites, were obtained over a 12-week period in 10 children. Samples (n = 226) were assayed in a single batch at the end of the study. The median intra-individual coefficient of variation (CV) calculated by 4-week blocks was 5.1–6.5% for calcium, 9.5–14.9% for phosphate and 32.7–33.4% for PTH. The median overall CV for FGF23 was 44.4%. Using the first value of each block as a reference, subsequent values would dictate a discrepant management decision 33–56%, 19–28%, and 30–33% of the time for calcium, phosphate, and PTH, respectively. Adjusting for sex and age, most of the variability in phosphate and PTH was attributable to within-participant variability. For calcium, 49% of the variability was attributable to day of blood collection (Monday vs. Friday). The median (range) of an individual participant’s values within clinical target ranges was 55% (26–86%) for calcium, 58% (0–96%) for phosphate, and 21% (0–64%) for PTH. There is considerable intra-individual variability in measures of mineral metabolism that serve as surrogate markers for bone health in children on HD. Within a 4-week period, at least 20–30% of measures would dictate a discrepant decision from the referent measure of that month. These findings have important implications for clinical decision-making and underscore the need to base therapeutic decisions on trends rather than single measurements.

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for Chronic Kidney Disease. A high body mass index is one of the strongest risk factors for new-onset Chronic Kidney Disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing Chronic Kidney Disease in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that makes preventive behaviors an affordable option. Resumen La obesidad se ha convertido en una epidemia mundial, y se ha proyectado que su prevalencia se incrementará en un 40% en la próxima década. Esta creciente prevalencia supone implicaciones tanto para el riesgo de desarrollo de diabetes y enfermedades cardiovasculares como para el desarrollo de Enfermedad Renal Crónica. Un elevado índice de masa corporal es uno de los factores de riesgo más importantes para el desarrollo de Enfermedad Renal Crónica. En individuos afectados por la obesidad, tiene lugar una hiperfiltración compensatoria necesaria para alcanzar la alta demanda metabólica secundaria al aumento del peso corporal. El incremento de la presión intraglomerular puede generar daño renal y elevar el riesgo de desarrollar Enfermedad Renal Crónica a largo plazo. La incidencia de glomerulopatía asociada a obesidad se ha incrementado 10 veces en los últimos años. Así mismo se ha demostrado que la obesidad es un factor de riesgo para el desarrollo de nefrolitiasis y un número de neoplasias, incluyendo cáncer renal. Este año, el Día Mundial del Riñón promueve la educación a cerca de las consecuencias nocivas de la obesidad y su asociación con la enfermedad renal, abogando por un estilo de vida saludable y la implementación de políticas públicas de salud que promuevan medidas preventivas alcanzables.

International audience; Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

To identify factors contributing to cognitive impairment in children with lupus nephritis.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.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).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.

Hepcidin, a key iron regulatory protein, is elevated in patients with chronic kidney disease (CKD). Its role in the development and progression of the anemia of CKD in children remains poorly defined.Cross-sectional and longitudinal study in children aged 1-16 years with stage 2-4 CKD in the Chronic Kidney Disease in Children (CKiD) cohort (n = 133) with hepcidin measured at baseline and hemoglobin (HGB) measured annually at follow-up. Anemia was defined as HGB5th percentile for age/sex OR treatment with an erythropoiesis-stimulating agent (ESA).Hepcidin levels correlated negatively with glomerular filtration rate (GFR; r = -0.22, p = 0.01) and positively with ferritin (r = 0.67, p 0.001). At the lower end of the GFR spectrum at baseline (10th percentile, 27.5 mL/min/1.73 m(2)), higher hepcidin was associated with a 0.87 g/dL decrease in HGB during follow-up (95 % CI -1.69, -0.05 g/dL, p = 0.038). At higher GFR percentiles there was no significant association between baseline hepcidin and HGB during follow-up. Among 90 non-anemic subjects at baseline, 23.3 % developed incident anemia. In subjects with GFR ≤ the median, a higher hepcidin level was associated with an increased risk of incident anemia (at the 10th percentile GFR, HR 3.471, 95 % CI 1.228, 9.810, p = 0.019; at the 25th percentile GFR, HR 2.641, 95 % CI 1.213, 5.750, p = 0.014; at the 50th percentile GFR, HR 1.953, 95 % CI 1.011, 3.772, p = 0.046). Among subjects with GFR at the 75th percentile or above, incrementally higher baseline hepcidin was not associated with increased anemia risk.Higher hepcidin levels are associated with a decreased HGB and an increased risk of incident anemia, and this association is most significant among subjects with lower GFR.

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.

The National Institute of Diabetes and Digestive and Kidney Diseases–supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease; >1600 participants from >30 countries posted >300 ideas and >500 comments covering all areas of kidney research. Smaller groups of investigators interrogated the postings and published a series of commentaries in CJASN. Additional review of the entire series identified six cross-cutting themes: (1) increase training and team science opportunities to maintain/expand the nephrology workforce, (2) develop novel technologies to assess kidney function, (3) promote human discovery research to better understand normal and diseased kidney function, (4) establish integrative models of kidney function to inform diagnostic and treatment strategies, (5) promote interventional studies that incorporate more responsive outcomes and improved trial designs, and (6) foster translation from clinical investigation to community implementation. Together, these cross-cutting themes provide a research plan to better understand normal kidney biology and improve the prevention, diagnosis, and treatment of kidney disease, and as such, they will inform future research efforts supported by the National Institute of Diabetes and Digestive and Kidney Diseases through workshops and initiatives.

Background and objectives Poor growth is a consequence of CKD, but can often be partially or fully prevented or corrected with the use of a number of medications. The extent of nonadherence with medications used to treat or mitigate growth failure in CKD has not been examined prospectively in children with CKD. Design, setting, participants, & measurements The prevalence of both prescription of and nonadherence to recombinant human growth hormone (rhGH), phosphate binders, alkali, active vitamin D, nutritional vitamin D, iron, and erythrocyte-stimulating agents was summarized over the first seven visits of the Chronic Kidney Disease in Children cohort study. The association between self-reported nonadherence to each medication group and the mean annual change in age- and sex-specific height z score was quantified using seven separate linear regression models with generalized estimating equations. Results Of 834 participants, 597 reported use of at least one of these medication groups and had adherence data available. Nonadherence ranged from 4% over all visits for erythrocyte-stimulating agents to 22% over all visits for nutritional vitamin D. Of the study participants, 451 contributed data to at least one of the analyses of adherence and changes in height z score. Children nonadherent to rhGH had no change in height z score, whereas those adherent to rhGH had a significant improvement of 0.16 SDs (95% confidence interval, 0.05 to 0.27); the effect size was slightly larger and remained significant after adjustment. Among participants with height≤3rd percentile and after adjustment, adherence to rhGH was associated with a 0.33 SD (95% confidence interval, 0.10 to 0.56) greater change in height z score. Nonadherence with other medication groups was not significantly associated with a change in height z score. Conclusions Self-reported nonadherence to rhGH was associated with poorer growth velocity in children with CKD, suggesting an opportunity for intervention and improved patient outcome.

The National Institute of Diabetes and Digestive and Kidney Diseases conducted the Kidney Research National Dialogue as an interactive means to formulate and prioritize research goals necessary to address the needs of patients with renal disease. This commentary summarizes the discussion and priorities arising from the training domain of the dialogue and posits three overall strategies to broaden the nephrology research workforce pipeline. The community needs to recruit and provide support for mentors in nephrology, target medical and graduate students earlier in their education for exposure to renal research, and expand the research workforce to include basic scientists from many disciplines as well as under-represented minorities.

Background and objectives The hospital admission rate for children receiving chronic dialysis has been increasing over the last decade. Approximately one third of patients with ESRD age 0–19 years are readmitted to the hospital within 30 days of discharge. The objective of this study was to examine hospital readmissions among a cohort of children receiving chronic dialysis to identify factors associated with higher rates of 30-day readmission. Design, settings, participants, & measurements A retrospective cohort of index admissions was developed among chronic dialysis patients age 3 months to 17 years at free-standing children’s hospitals reporting information to the Pediatric Hospital Information System between January 2006 and November 30, 2010, and followed until December 31, 2010. The primary outcome was any-cause 30-day readmission, and the secondary outcome was 30-day readmission for a cause similar to that of the index hospitalization. Results In this cohort, 25% of hospital admissions were followed by a readmission within 30 days. Children older than 2 years of age had a lower odds of readmission (odds ratio [OR], 0.6; 95% confidence interval [95% CI], 0.5 to 0.8). Those receiving hemodialysis had a higher risk of readmission (OR, 1.2; 95% CI, 1.0 to 1.4), and admissions >14 days were also more likely to be followed by a readmission (OR, 1.5; 95% CI, 1.1 to 2.0). Approximately 50% of the readmissions were for a similar diagnosis as the index admission; however, the specific admitting diagnosis was not associated with readmission. Conclusions A significant number of admissions among children receiving long-term dialysis are followed by readmission within 30 days. Further investigation is required to reduce the high rate of readmissions in these children.

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.

Summary Background and objectives In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. Design, setting, participants, & measurements Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1–16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. Results Median GFR for the cohort was 45 ml/min per 1.73 m2 (interquartile range=33–57; range=15–109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60–69 ml/min per 1.73 m2 than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR Conclusion In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Chronic kidney disease (CKD) is associated with increased incidence of cardiac dysfunction. Recent animal studies have demonstrated that elevated levels of ceramides cause dilated lipotoxic cardiomyopathy. We hypothesized ceramides are increased in children with CKD and associated with abnormal cardiac structure and function.Ceramide levels were determined in 93 children aged 1-16 years enrolled in the Chronic Kidney Disease in Children (CKiD) study and compared to levels from 24 healthy controls. Complete demographic, clinical, and laboratory information, and ceramide measurements were analyzed cross-sectionally. Echocardiography was performed to determine cardiac structure and function.Very long-chain C24:0 ceramides were the most abundant species in both control (56 %) and CKD subjects (55 %), followed by C24:1 (controls 19 %, CKD 23 %) and C22:0 (controls 19 %, CKD 13 %). Total serum ceramide levels were significantly higher in CKD children versus controls (p0.001). Ceramide metabolites lactosylceramide, C24:0L, and C16:0L were significantly higher in CKD subjects than controls (p0.001). The proportion of C24:0L was dramatically higher in CKD (59 %) versus control (17 %) subjects (p0.001). In adjusted multivariate analyses, higher log10C24:0L and log10C16:0L were significant predictors of lower shortening fraction and mid-wall shortening.Ceramide levels are increased in children with CKD. Our study identified lactosylceramides as an independent predictor of lower systolic function in these children.

Background: Arterial stiffness is a natural consequence of aging, accelerated in certain chronic conditions, and predictive of cardiovascular events in adults. Emerging research suggests the importance of arterial stiffness in pediatric populations. Methods: There are different indices of arterial stiffness. The present manuscript focuses on carotid-femoral pulse wave velocity and pulse wave analysis, although other methodologies are discussed. Also reviewed are specific measurement considerations for pediatric populations and the literature describing arterial stiffness in children with certain chronic conditions (primary hypertension, obesity, diabetes, chronic kidney disease, hypercholesterolemia, genetic syndromes involving vasculopathy, and solid organ transplant recipients). Conclusions: The measurement of arterial stiffness in children is feasible and, under controlled conditions, can give accurate information about the underlying state of the arteries. This potentially adds valuable information about the functionality of the cardiovascular system in children with a variety of chronic diseases well beyond that of the brachial artery blood pressure.

Background This was a retrospective study to determine whether lack of furosemide responsiveness (LFR) predicts acute kidney injury (AKI) after cardiopulmonary bypass surgery in infants. Methods Infants (less than 1 year of age) undergoing cardiopulmonary bypass surgery, receiving routine postoperative furosemide (0.8 to 1.2 mg/kg per dose between 8 and 24 hours after surgery) were included. Urine output was measured 2 and 6 hours after furosemide dose. Lack of furosemide responsiveness was defined a priori as urine output less than 1 mL · kg −1 · h −1 after furosemide. Serum creatinine was corrected for fluid balance. Acute kidney injury was determined using changes in uncorrected and corrected serum creatinine. The predictive utility of LFR was assessed using receiver-operating characteristics curve analysis. Results We analyzed 568 infants who underwent cardiopulmonary bypass. Eighty-one (14.3%) had AKI using uncorrected serum creatinine; AKI occurred in 41 (7.2%) after correcting for fluid overload. Patients with AKI had a lower response to furosemide (median urine output 2 hours: 1.2 versus 3.4 mL · kg −1 · h −1 , p = 0.01; median urine output 6 hours: 1.3 versus 2.9 mL · kg −1 · h −1 , p = 0.01). After creatinine correction, LFR predicts AKI development (area under receiver-operating characteristics curve of 0.74 at 2 hours and 0.77 at 6 hours). After adjusting for surgical complexity using The Society of Thoracic Surgeons/European Association for Cardiothoracic Surgery mortality categories, the area under the receiver-operating characteristics curve was 0.74 at 2 hours and 0.81 at 6 hours. Patients with urine output greater than 1 mL · kg −1 · h −1 were unlikely to have AKI (negative predictive value, 97%). Conclusions After correcting serum creatinine for fluid balance and adjusting for surgical complexity, LFR performs fairly at 2 hours, whereas at 6 hours, LFR is a good AKI predictor. Prospective studies are needed to validate whether diuretic responsiveness predicts AKI.