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BACKGROUND AND OBJECTIVES: Performing adequately powered clinical trials in pediatric diseases, such as SLE, is challenging. Improved recruitment strategies are needed for identifying patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Electronic health record algorithms were developed and tested to identify children with SLE both with and without lupus nephritis. We used single-center electronic health record data to develop computable phenotypes composed of diagnosis, medication, procedure, and utilization codes. These were evaluated iteratively against a manually assembled database of patients with SLE. The highest-performing phenotypes were then evaluated across institutions in PEDSnet, a national health care systems network of >6.7 million children. Reviewers blinded to case status used standardized forms to review random samples of cases (n=350) and noncases (n=350). RESULTS: Final algorithms consisted of both utilization and diagnostic criteria. For both, utilization criteria included two or more in-person visits with nephrology or rheumatology and ≥60 days follow-up. SLE diagnostic criteria included absence of neonatal lupus, one or more hydroxychloroquine exposures, and either three or more qualifying diagnosis codes separated by ≥30 days or one or more diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 100% (95% confidence interval [95% CI], 99 to 100), specificity was 92% (95% CI, 88 to 94), positive predictive value was 91% (95% CI, 87 to 94), and negative predictive value was 100% (95% CI, 99 to 100). Lupus nephritis diagnostic criteria included either three or more qualifying lupus nephritis diagnosis codes (or SLE codes on the same day as glomerular/kidney codes) separated by ≥30 days or one or more SLE diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 90% (95% CI, 85 to 94), specificity was 93% (95% CI, 89 to 97), positive predictive value was 94% (95% CI, 89 to 97), and negative predictive value was 90% (95% CI, 84 to 94). Algorithms identified 1508 children with SLE at PEDSnet institutions (537 with lupus nephritis), 809 of whom were seen in the past 12 months. CONCLUSIONS: Electronic health record–based algorithms for SLE and lupus nephritis demonstrated excellent classification accuracy across PEDSnet institutions.

Diastolic dysfunction is one of the earliest cardiac abnormalities in patients with chronic kidney disease. We analyzed echocardiographic markers of left ventricular function from 786 children and adolescents (1658 person-visits) enrolled in the CKiD (Chronic Kidney Disease in Children) cohort, a large prospective observational study of children with chronic kidney disease. Primary outcome was early mitral inflow velocity-to-early mitral annular peak velocity (E/e′) ratio as a marker of left ventricular compliance. Abnormal diastolic function was defined as E/e′>8.0. Those with an abnormal E/e′ ratio were younger, had a lower estimated glomerular filtration rate and hemoglobin, and a higher prevalence of hypertension and left ventricular hypertrophy compared to children with a normal E/e′. In adjusted analysis, a higher E/e′ ratio was independently associated with ambulatory (sustained) hypertension (1.66 [95% CI, 1.15–2.42]). Other significant independent predictors were higher left ventricular mass index Z score, increased body mass index Z score, lower hemoglobin, higher phosphorus level, and younger age. Casual blood pressure was not significantly associated with higher E/e′. These data indicate that ambulatory blood pressure might better identify children with chronic kidney disease at risk for subclinical cardiac dysfunction than clinic blood pressure alone. Graphic Abstract: An online graphic abstract is available for this article.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Rationale & objective To identify differences in socioeconomic factors (SES) and subclinical CVD markers by race among CKiD participants and determine whether differences in CVD markers persist after adjusting for SES. Study design Analysis of 3103 visits with repeated measures from 628 children (497 Caucasian; 131 African American) enrolled in the CKiD study. Setting & participants Children with mild-moderate CKD with at least 1 CV parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured. Exposures African American race OUTCOMES: Ambulatory hypertension, LVMI, triglycerides, high-density lipoprotein-cholesterol. Analytical approach Due to increased CV risks of glomerular disease, the analysis was stratified by CKD etiology. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers. Results African American children were disproportionately affected by adverse SES. African Americans with non-glomerular CKD had more ambulatory hypertension and higher LVMI, but more favorable lipid profile; after adjustment for SES, age, and sex, the magnitude of differences in these CV markers attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES. Limitations Study design limits causal inference. Conclusion African American children with CKD are disproportionately affected by socioeconomic disadvantages compared with Caucasians. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with non-glomerular CKD have increased LVMI, more ambulatory hypertension and favorable lipid profile, but a trend towards attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD have increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.

Background More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care. Methods Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology—Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8–21 years) and caregivers (of children ages 0–21 years) pertaining to blood pressure. Results Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects). Conclusions For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD.

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.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

To evaluate the association between chronic diuretic exposures and enteral electrolyte use in infants developing severe bronchopulmonary dysplasia (sBPD). Retrospective longitudinal cohort study in infants admitted to United States children’s hospitals. We identified diuretic exposures and measured enteral NaCl and KCl use during pre-defined exposure risk-interval days. We used mixed-effects logistic regression to model the association between diuretic exposures and electrolyte use. We identified 442,341 subject-days in 3252 infants. All common diuretic classes and class combinations were associated with increased NaCl and KCl use. Thiazide monotherapy was associated with greater electrolyte use than loop monotherapy. The addition of potassium-sparing diuretics was associated with a limited reduction in KCl use compared to thiazide monotherapy. Chronic diuretic exposures are associated with increased NaCl and KCl use. Presumptions about the relative impact of different diuretic classes on electrolyte derangements may be inaccurate and require further study.

BACKGROUND: Control of hypertension delays progression of pediatric chronic kidney disease (CKD), yet few data are available regarding what office blood pressure (BP) levels may slow progression. METHODS: Longitudinal BP data from children in the Chronic Kidney Disease in Children cohort study who had hypertension or an auscultatory BP ≥90th percentile enrolled were studied. BP categories were defined as the maximum systolic or diastolic BP percentile (

Studies in healthy children have shown racial-ethnic differences in bone markers and bone outcomes including fractures. At present, limited studies have evaluated the impact of race and ethnicity on bone markers and fractures within the pediatric chronic kidney disease (CKD) population. In a cohort study of 762 children between the ages of 1.5 years and 18 years, with CKD stages 1 to 4 from the CKD in children (CKiD) cohort, the relationship between racial-ethnic group and bone markers (parathyroid hormone [PTH], 25-hydroxyvitamin D [25-OHD], 1,25-dihydroxyvitamin D [1,25(OH)2 D], and C-terminal fibroblast growth factor [FGF23]) was determined using linear mixed models. Additionally, logistic regression was used to evaluate racial-ethnic differences in prevalent fracture upon study entry. Black race was associated with 23% higher PTH levels (confidence interval [CI], 2.5% to 47.7%; p = .03), 33.1% lower 25-OHD levels (CI, -39.7% to -25.7%; p < .0001), and no difference in C-terminal FGF23 or 1,25(OH)2 D levels when compared to whites. Hispanic ethnicity was associated with 15.9% lower C-terminal FGF23 levels (CI, -28.3% to -1.5%; p = .03) and 13.8% lower 25-OHD levels (CI, -22.2% to -4.5%; p = .005) when compared to whites. Black and Hispanic children had 74% (odds ratio [OR] 0.26; CI, 0.14 to 0.49; p = .001) and 66% (OR 0.34; CI, 0.17 to 0.65; p < .0001) lower odds of any fracture than white children at study entry, respectively. Race and ethnicity are associated with differences in bone markers and despite lower 25-OHD levels, both black and Hispanic children with CKD reported a lower prevalent fracture history than white children. The current findings in the CKD population are similar to racial-ethnic differences described in healthy children. Additional studies are needed to better understand how these differences might impact the management of pediatric CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).

BACKGROUND The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology—Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

OBJECTIVES: To evaluate whether liver and spleen magnetic resonance elastography (MRE) can measure the severity of congenital hepatic fibrosis (CHF) and portal hypertension (pHTN) in individuals with autosomal recessive polycystic kidney disease (ARPKD), and to examine correlations between liver MRE and ultrasound (US) elastography. METHODS: Cross-sectional study of 9 individuals with ARPKD and 14 healthy controls. MRE was performed to measure mean liver and spleen stiffness (kPa); US elastography was performed to measure point shear wave speed (SWS) in both liver lobes. We compared: (1) MRE liver and spleen stiffness between controls vs. ARPKD; and (2) MRE liver stiffness between participants with ARPKD without vs. with pHTN, and examined correlations between MRE liver stiffness, spleen length, platelet counts, and US elastography SWS. Receiver operating characteristic (ROC) analysis was performed to examine diagnostic accuracy of liver MRE. RESULTS: Participants with ARPKD (median age 16.8 [IQR 13.3, 18.9] years) had higher median MRE liver stiffness than controls (median age 14.7 [IQR 9.7, 16.7 years) (2.55 vs. 1.92 kPa, p=0.008), but MRE spleen stiffness did not differ. ARPKD participants with pHTN had higher median MRE liver stiffness than those without (3.60 kPa vs 2.49 kPa, p=0.05). Liver MRE and US elastography measurements were strongly correlated. To distinguish ARPKD vs. control groups, liver MRE had 78% sensitivity and 93% specificity at a proposed cut-off of 2.48 kPa [ROC area 0.83 (95% CI: 0.63–1.00)]. CONCLUSION: Liver MRE may be a useful quantitative method to measure the severity of CHF and pHTN in individuals with ARPKD.

OBJECTIVE To reliably and quickly diagnose children with posterior urethral valves (PUV), we developed a multi-instance deep learning method to automate image analysis. METHODS We built a robust pattern classifier to distinguish 86 children with PUV from 71 children with mild unilateral hydronephrosis based on ultrasound images (3504 in sagittal view and 2558 in transverse view) obtained during routine clinical care. RESULTS The multi-instance deep learning classifier performed better than classifiers built on either single sagittal images or single transverse images. Particularly, the deep learning classifiers built on single images in the sagittal view and single images in the transverse view obtained area under the receiver operating characteristic curve (AUC) values of 0.796 ± 0.064 and 0.815 ± 0.071, respectively. AUC values of the multi-instance deep learning classifiers built on images in the sagittal and transverse views with mean pooling operation were 0.949 ± 0.035 and 0.954 ± 0.033, respectively. The multi-instance deep learning classifiers built on images in both the sagittal and transverse views with a mean pooling operation obtained an AUC of 0.961 ± 0.026 with a classification rate of 0.925 ± 0.060, specificity of 0.986 ± 0.032, and sensitivity of 0.873 ± 0.120, respectively. Discriminative regions of the kidney located using classification activation mapping demonstrated that the deep learning techniques could identify meaningful anatomical features from ultrasound images. CONCLUSION The multi-instance deep learning method provides an automatic and accurate means to extract informative features from ultrasound images and discriminate infants with PUV from male children with unilateral hydronephrosis.

Congenital obstructive uropathy (OU) is a leading cause of pediatric kidney failure, representing a unique mechanism of injury, in part from renal tubular stretch and ischemia. Tubular injury biomarkers have potential to improve OU-specific risk stratification. Patients with OU were identified in the Chronic Kidney Disease in Children (CKiD) study. “Cases” were defined as individuals receiving any kidney replacement therapy (KRT), while “controls” were age- and time-on-study matched and KRT free at last study visit. Urine and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) levels were measured at enrollment and annually and compared between cases and controls. Urine values were normalized to urine creatinine. In total, 22 cases and 22 controls were identified, with median (interquartile range) ages of 10.5 (9.0–13.0) and 15.9 (13.9–16.9) years at baseline and outcome, respectively. At enrollment there were no differences noted between cases and controls for any urine (u) or plasma (p) biomarker measured. However, the mean pNGAL and uL-FABP/creatinine increased throughout the study period in cases (15.38 ng/ml per year and 0.20 ng/ml per mg/dl per year, respectively, p = 0.01 for both) but remained stable in controls. This remained constant after controlling for baseline glomerular filtration rate (GFR). In children with OU, pNGAL and uL-FABP levels increased over the 5 years preceding KRT; independent of baseline GFR. Future studies are necessary to identify optimal cutoff values and to determine if these markers outperform current clinical predictors.

BACKGROUND: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants responded to the question “In the past year, have you discussed renal replacement therapy with your doctor or health care provider?” at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measures logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status and CKD diagnosis (glomerular vs. non-glomerular). RESULTS: 721 CKiD participants (median age= 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race and socioeconomic status. CONCLUSIONS: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.

Children with chronic kidney disease (CKD) have delays in normal growth and pubertal development. We describe factors associated with delayed menarche and the association of delayed menarche with short stature in girls with CKD. Two hundred eighty-seven girls with CKD onset prior to menarche within the Chronic Kidney Disease in Children (CKiD) cohort were studied. Delayed menarche was defined as menarche at age 15 years or older; short stature was defined as last available height 2 standard deviations below projected adult height. Kaplan-Meier cumulative incidence function was used to estimate median age at menarche. Chi-squared and Wilcoxon rank-sum tests were used to assess factors associated with delayed menarche. Chi-squared test was used to evaluate the association between delayed menarche and short stature. Among 287 girls, 68 enrolled with prevalent menarche, 131 were observed to have incident menarche, and 88 were pre-menarchal at their last study visit. Median age at menarche was 12 years. Ten percent had delayed menarche. African American race, lower estimated glomerular filtration rate, ever corticosteroid use, and longer CKD duration were associated with delayed menarche (p

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

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

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

The Chronic Kidney Disease in Children (CKiD) cohort study is a North American (USA and Canada) multicenter, prospective study of children with chronic kidney disease (CKD). The original aims of the study were (1) to identify novel risk factors for CKD progression; (2) to measure the impact of kidney function decline on growth, cognition, and behavior; and (3) to characterize the evolution of cardiovascular disease risk factors. CKiD has developed into a national and international resource for the investigation of a variety of factors related to CKD in children. This review highlights notable findings in the area of CKD progression and outlines ongoing opportunities to enhance understanding of CKD progression in children. CKiD's contributions to the clinical care of children with CKD include updated and more accurate glomerular filtration rate estimating equations for children and young adults, and resources designed to help estimate the CKD progression timeline. In addition, results from CKiD have strengthened the evidence that treatment of hypertension and proteinuria should continue as a primary strategy for slowing the rate of disease progression in children.

It is hypothesized that chronic kidney disease (CKD) induces oxidant stress which contributes to the decline in kidney function. However, few studies have incorporated longitudinal designs and no studies have investigated this association among children. Using data from the Chronic Kidney Disease in Children (CKiD) study, we examined longitudinal associations between urinary biomarkers of oxidant stress, 8-OH deoxyguanosine (8-OHdG) and F2-isoprostane, and measures of renal function and blood pressure among children with CKD. Baseline levels of 8-OHdG were positively associated with estimated glomerular filtration rate (eGFR) over time and a log-unit increase in baseline 8-OHdG predicted a 5.68 ml/min/1.73 m2 increase in eGFR (95% Confidence Interval (CI): 3.75, 7.61). This association was attenuated when longitudinal measures of 8-OHdG were analyzed in relation to longitudinal eGFR (per log-unit increase in 8-OHdG, β = 0.81, 95% CI: 0.22, 1.39). Baseline 8-OHdG concentrations were also associated with decreased proteinuria over time, as measured by urinary protein:creatinine ratio. In addition, F2-isoprostane concentrations were associated with increases in eGFR, but only when baseline levels (vs. longitudinal levels) were considered in relation to longitudinal eGFR. There were no significant associations between either 8-OHdG or F2-isoprostane and blood pressure over time. Urinary measures of oxidant stress are not associated with worsening GFR over time. Our findings suggest that excretion of these biomarkers may be influenced by changes in glomerular and tubular function in varying patterns, which would limit their value in evaluating the impact of oxidant stress on CKD progression in children.

Children with mild to moderate chronic kidney disease are at an increased risk for cardiovascular sequelae, the leading cause of death in children with end-stage renal disease. We aimed to establish the prevalence of aortic dilatation, a newly recognized cardiovascular sequelae of renal disease, within a cohort of pediatric patients with mild to moderate kidney disease. A total of 501 children enrolled in the Chronic Kidney Disease in Children study contributed imaging data between April 2011 and February 2015. Aortic dilatation was defined as a dimension exceeding a z-score of 2 at any of three locations: aortic root, sinotubular junction, or the ascending aorta. At baseline echocardiographic evaluation, 30 (6%) children were identified to have aortic dilatation in at least one of the three locations. Multivariate analysis demonstrated an increased odds ratio for the presence of aortic dilatation associated with the following variables: high diastolic blood pressure z-scores, low weight z-score, and low body mass index z-score. Presense of protein energy wasting (modified definition, OR 2.41, 95%CI 1.23, 4.70) was the strongest independent predictor of aortic dilatation. In conclusion, aortic dilatation does occur early in the course of chronic kidney disease and associates with markers of poor nutrition. Future studies should continue to evaluate these risk factors longitudinally as the kidney disease progresses.

Background Adolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults. Methods In this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively. Results Overall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4–5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8–3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure. Conclusion Overall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension. Graphical abstract

BACKGROUND AND OBJECTIVES: The physiologic nocturnal BP decline is often blunted in patients with CKD; however, the consequences of BP nondipping in children are largely unknown. Our objective was to determine risk factors for nondipping and to investigate if nondipping is associated with higher left ventricular mass index in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a cross-sectional analysis of ambulatory BP monitoring and echocardiographic data in participants of the Chronic Kidney Disease in Children study. Multivariable linear and spline regression analyses were used to evaluate the relationship of risk factors with dipping and of dipping with left ventricular mass index. RESULTS: Within 552 participants, mean age was 11 (±4) years, mean eGFR was 53 (±20) ml/min per 1.73 m(2), and 41% were classified as nondippers. In participants with nonglomerular CKD, female sex and higher sodium intake were significantly associated with less systolic and diastolic dipping (P≤0.05). In those with glomerular CKD, Black race and greater proteinuria were significantly associated with less systolic and diastolic dipping (P≤0.05). Systolic dipping and diastolic dipping were not significantly associated with left ventricular mass index; however, in spline regression plots, diastolic dipping appeared to have a nonlinear relationship with left ventricular mass index. As compared with diastolic dipping of 20%–25%, dipping of 25% was associated with 1.98-g/m(2.7)-higher left ventricular mass index (95% confidence interval, −0.77 to 4.73), although these relationships did not achieve statistical significance. CONCLUSIONS: Black race, female sex, and greater proteinuria and sodium intake were significantly associated with blunted dipping in children with CKD. We did not find a statistically significant association between dipping and left ventricular mass index. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_12_20_CJN09810721.mp3

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 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.

Introduction: In 2012, KDIGO released a guideline on BP management in CKD not receiving dialysis. The emergence of new trials and meta-analyses coupled with wider recognition of the importance of standardized BP measurement protocols have prompted a call to update the 2012 guideline. This summary will outline the changes to the prior recommendations and highlight similarities to guidelines from ACC/AHA and ESC/ESH. Methods: A systematic review was undertaken to formally assess the following issues: 1) BP measurement; 2) lifestyle interventions; BP management in 3) patients with CKD, with and without diabetes, 4) kidney transplant recipients, and 5) children with CKD. Results: A total of 6863 citations were screened. Of these, 290 RCTs, 14 observational studies, and 35 systematic reviews were included in the evidence review. A major addition to the KDIGO 2021 guideline is a chapter devoted to BP measurement. KDIGO recommends the use of standardized office BP over routine BP. Out-of-office measurements (ABPM, HBPM) can be used to complement standardized readings. This emphasis on standardized office BP measurement is similar to recommendations from ACC/AHA and ESC/ESH. A systolic BP target of Conclusions: KDIGO has revised its guideline for BP management in CKD based on a rigorous development process and emerging new evidence underscoring the importance of standardized office BP measurement and a lower systolic BP target of

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

Description The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline. Methods The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020. Recommendations The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.

The Chronic Kidney Disease in Children (CKiD) prospective cohort study was designed to address the neurocognitive, growth, cardiovascular, and disease progression of children and adolescents with mild to moderate CKD. The study has had continuous funding from NIDDK for 17 years and has contributed significant advances in pediatric CKD. The goals of this educational review are threefold: (1) to provide an overview of the neurocognitive and psychosocial studies from CKiD to date; (2) to provide best practice recommendations for those working with the neurocognitive and psychosocial aspects of pediatric CKD based on CKiD findings; and (3) to help chart future goals and directives for both research and clinical practice. This collection of 22 empirical studies has produced a number of key findings for children and adolescents with mild to moderate CKD. While various studies suggest a relatively positive presentation for this population as a whole, without evidence of significant impairment or deterioration, findings do indicate the presence of neurocognitive dysfunction, emotional-behavioral difficulties, and lower quality of life for many children with CKD. These findings support the promotion of best practices that are accompanied by additional future clinical and research initiatives with this patient population.

Consensus blood pressure guidelines vary in their recommended ambulatory blood pressure targets for children with chronic kidney disease (CKD) because of limited research in this area. We analyzed longitudinal ambulatory blood pressure monitoring data from 679 children with moderate CKD enrolled in the observational CKiD (Chronic Kidney Disease in Children) cohort by time-varying mean arterial pressure (MAP) percentile categories based on the highest wake or sleep MAP percentile. Analyses were stratified by nonglomerular and glomerular diagnoses, with 3 models constructed: unadjusted, adjusted for age, sex, and race, and additional adjustment for proteinuria. The outcome of interest was time to renal replacement therapy or 50% decline in baseline renal function. We found that among children with nonglomerular CKD, MAP percentile was not associated with accelerated disease progression risk until after 4 years of follow-up at which point a high MAP (>90th percentile) was associated with a higher risk of progression to the composite end point (HR, 1.88 [CI, 1.03–3.44]). Among those with glomerular CKD, differential risk for progression began from baseline with the highest risk in those with MAP >90th percentile (HR, 3.23 [CI, 1.34–7.79]). These relationships were attenuated somewhat after adjustment for level of proteinuria, but the trend for higher MAP being associated with higher risk of progression remained significant. Thus, in children with CKD, having ambulatory wake or sleep MAP >90th percentile was associated with higher risk of kidney disease progression with the highest levels of MAP associated with the greatest risk of progression. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00327860

Background The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. Methods The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (n=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (n=800) and nonglomerular cases (n=798). Results The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months. Conclusions The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.

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.

BACKGROUND: Frailty is a condition of decreased physiologic reserve and increased vulnerability to stressors. Frailty in combination with inflammation has been associated with increased mortality risk in adults with advanced chronic kidney disease (CKD). This study aimed to investigate prevalence and outcomes associated with a frailty-inflammation phenotype, or “fragility,” in children with CKD. DESIGN/METHODS: We analyzed 557 children (age 6-19 years, eGFR 30-90ml/min/1.73m(2)) from the Chronic Kidney Disease in Children (CKiD) study. Based on adult models, the CKiD fragility model included four indicators: (1) Suboptimal growth/weight gain (BMI3 mg/L). Logistic regression was used to evaluate association of fragility indicators with three adverse outcomes: frequent infection (>1 per year/3 years), hospitalization (any), and rapid CKD progression (decline in eGFR>30% or initiation of renal replacement therapy within 3 years). RESULTS: Prevalence of fragility indicators one year after study entry were 39% (suboptimal growth/weight gain), 62% (low muscle mass), 29% (fatigue), and 18% (inflammation). Prevalence of adverse outcomes during subsequent 3 years were 13% (frequent infection), 22% (hospitalization) and 17% (rapid CKD progression). Children with ≥3 fragility indicators had 3.16-fold odds of frequent infection and 2.81-fold odds of hospitalization, but didn’t have rapid CKD progression. CONCLUSIONS: A fragility phenotype, characterized by the presence of ≥3 indicators, is associated with adverse outcomes, including infection and hospitalization in children with CKD.

BACKGROUND: Environmental lead exposure is associated with cognitive impairment in healthy children, with deficits seen in intelligence quotient (IQ), attention, and behavior. Neurocognitive dysfunction is also a well-described complication among children with chronic kidney disease (CKD). The objective was to evaluate the association between blood lead levels (BLL) and performance on neurocognitive assessments in a cohort of children with CKD. METHODS: Cross-sectional study of children with mild to moderate CKD from the Chronic Kidney Disease in Children (CKiD) multicenter prospective cohort study. The primary exposure was BLL. The primary outcome was performance on age-specific neurocognitive assessments evaluating IQ, executive functioning, attention, hyperactivity, and behavior. Multivariable linear regression was used to evaluate the association between BLL and neurocognitive performance, adjusted for key sociodemographic and clinical variables. RESULTS: A total of 412 subjects were included with median age 15.4 years, median estimated GFR 39 mL/min/1.73(2), median BLL1.2 mcg/dL, and median IQ score 99. In multivariable linear regression, higher BLL was associated with significantly lower IQ score (− 2.1 IQ points for every 1-mcg/dL increase in BLL, p = 0.029). Higher BLL was associated with worse scores on the Conners’ Continuous Performance Test II Variability T-Score, a measure of inattention (+ 1.8 T-Score points for every 1-mcg/dL increase in BLL, p = 0.033). CONCLUSIONS: Low-level lead exposure is associated with significantly lower IQ and more inattention in children with CKD, a population already at high risk for neurocognitive dysfunction. Universal screening for elevated BLL should be considered for all children with CKD at age 12–24 months.

AIMS Current estimated glomerular filtration rate (eGFR) equations may be inaccurate in patients with spina bifida (SB) because of reduced muscle mass and stature. Cross-sectional and longitudinal variability of eGFR were analyzed in these patients across multiple equations, hypothesizing greater variability in creatinine-based than cystatin-C (Cys-C)-based equations. METHODS This retrospective cohort study included children (age, 1-17.9 years) and adults (≥18 years) with SB from 2002-2017 at a large SB clinic. Those without all data needed to calculate eGFR were excluded. Four pediatric and three adult eGFR equations were compared for cross-sectional outcomes of eGFR and elevated office blood pressures using chronic kidney disease (CKD) stage classification, and for longitudinal outcome of eGFR slope over time using covariance pattern models accounting for repeated measures. RESULTS One hundred and eighty two children and 75 adults had greater than or equal to 1 set of data measurements; 118 and 52, respectively, had greater than or equal to 2 sets. The pediatric bedside Schwartz equation had the highest median eGFR and coefficient of variation. CKD stage classification by eGFR showed large differences across equations in children, with rates of eGFR

Rationale & Objective: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers. Study Design: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities. Settings & Participants: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada. Analytical Approach: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically. Results: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations). Limitations: Only English-speaking participants were recruited. Conclusions: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.

To examine if parent illness uncertainty is indirectly associated with child depression, anxiety, and HRQOL in the CKD/SLE population. Parent-child dyads (N = 31) from outpatient rheumatology and nephrology clinics included children (ages 9-18) diagnosed with CKD (Stage 1, 2, or nephrotic syndrome) or SLE. Parents completed demographic and uncertainty measures and children completed uncertainty, depression, anxiety, and HRQOL measures. This cross-sectional study examined mediational models using the percentile bootstrapping method. Parent uncertainty had an indirect effect on child depression, anxiety, and HRQOL through the mediator, child uncertainty. In other words, parents' illness uncertainty regarding their child's condition correlates to the child's illness uncertainty, which then is associated with the child's mental health and wellbeing. Reverse mediations illustrated that parent uncertainty did not mediate child uncertainty and outcome variables. Results extend previous research by examining parent and child illness uncertainty in understudied conditions (CKD/SLE) and the relationship to outcome variables commonly related to depression (e.g., anxiety and HRQOL). Findings allow health psychologists and medical personnel to understand the impact of uncertainty on the child's wellbeing and HRQOL. Clinical implications, including using specialized interventions to address illness uncertainty, are discussed.

BACKGROUND: The aims were to compare the cardiovascular disease (CVD) risk among children with chronic kidney disease (CKD) secondary to focal segmental glomerulosclerosis (FSGS) with the CVD risk of children with CKD due to other diagnoses. METHODS: Casual blood pressure (BP), ambulatory blood pressure monitoring (APBM), echocardiogram, lipids, carotid intima medial thickness (cIMT) and uric acid obtained from participants in the Chronic Kidney Disease in Children (CKiD) cohort were analyzed longitudinally. Seventy-nine children with FSGS (FSGS-CKD) were compared to 196 children with non-FSGS glomerular disease (GDO-CKD) and 616 children with non-glomerular disease (NG-CKD). RESULTS: At baseline, FSGS-CKD (median 14 years) had ambulatory hypertension (24.6%), masked hypertension (46.2%), left ventricular hypertrophy (LVH) (26.3%) and dyslipidemia (60.0%). In adjusted models, FSGS-CKD had higher systolic BP z-score (0.52 vs 0.11 and 0.23, p=0.002 and 0.02), triglycerides (133 vs 109 and 102 mg/dl, p=0.007 and

Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury. We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest. This was a retrospective cohort study of children aged 30 days–17 years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24 h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2–3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR). Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7 mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29 mL/min/1.73 m2 [interquartile range (IQR) 23–47] vs. 52 [IQR 50–57]; p = 0.03) but well below normal in both. In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population.

BACKGROUND: Maintaining high water intake reduces kidney stone recurrence, but is difficult to do. Strategies to reduce stone recurrence among adolescents are lacking. METHODS: We conducted an ecological momentary assessment study to identify factors associated with water intake among 25 adolescents with nephrolithiasis. Over 7-days, participants used smart bottles to self-monitor water intake and received questionnaires randomly four times daily that were completed in real-time on mobile devices. The questionnaires ascertained awareness of water intake volume, awareness of water intake goals, perceived need to drink, access to water, alternative beverage consumption, and attitudes towards bathrooms. Linear mixed-effects models were fit to estimate the association between momentary responses and daily water intake. RESULTS: Over 175 person-days, 595 (85%) assessments were completed. Median daily water intake was 1304mL (IQR 848–1832); 20% of participants met their intake goal for ≥4 days. Unawareness of water intake volume was associated with drinking 690mL less water a day (p=0.04). A strong self-perceived need to drink more was associated with drinking 1954 mL less water each day compared to no need to drink more (p

Purpose To compare blood T1 estimation approaches used for quantifying cerebral blood flow (CBF) with arterial spin labeled (ASL) perfusion MRI in a developmental cohort of chronic kidney disease (CKD) patients with anemia and a control group. Methods 61 patients with CKD and 47 age-matched control subjects were studied. Blood T1 approaches included: (1) a fixed value, (2) estimation based on measured hematocrit (Hct), and (3) estimation based on Age + Sex using a published formula. Resulting T1 and CBF values were compared along with group, age and sex effects. Results Highly significant group differences in CBF using fixed blood T1 were reduced when Hct-corrected blood T1 was used, and were eliminated entirely when using the Age + Sex estimated approach. In the control cohort, fixed T1 method showed the strongest correlations of CBF with age and sex. Hct-corrected T1 preserved a significant correlation between CBF and age and sex, while Age + Sex estimated T1 produced a poor fit of CBF with age and sex. Conclusions Blood T1 estimation method can confound the interpretation of CBF changes measured using ASL MRI in patients with CKD. Blood T1 should ideally be corrected for hematocrit effects in clinical populations with anemia.

BACKGROUND: Among children who receive a kidney transplant, short stature is associated with a more complicated post-transplant course and increased mortality. Short stature prior to transplant may reflect the accumulated risk of multiple factors during chronic kidney disease (CKD); however, its relationship with post-transplant kidney function has not been well characterized. METHODS: In the Chronic Kidney Disease in Children (CKiD) cohort restricted to children who received a kidney transplant, short stature (i.e., growth failure) was defined as age-sex-specific height

Purpose of Review To summarize and explain the new guideline on blood pressure (BP) management in chronic kidney disease (CKD) published by Kidney Disease: Improving Global Outcomes (KDIGO), an independent global nonprofit organization which develops and implements evidence-based clinical practice guidelines in kidney disease. KDIGO issued its first clinical practice guideline for the Management of Blood Pressure (BP) in Chronic Kidney Disease (CKD) for patients not receiving dialysis in 2012 and now updated the guideline in 2021. Recent Findings Recommendations in this update were developed based on systematic literature reviews and appraisal of the quality of the evidence and strength of recommendation following the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. The updated guideline includes five chapters covering BP measurement techniques, lifestyle interventions for lowering BP, and management of BP in three target populations, namely adults (with and without diabetes), kidney transplant recipients, and children. A dedicated chapter on BP measurement emphasizing standardized preparation and measurement protocols for office BP measurement is a new addition, following protocols used in large randomized trials of BP targets with pivotal clinical outcomes. Summary Based on the available evidence, and in particular in the CKD subgroup of the SPRINT trial, the 2021 guideline suggests a systolic BP target of

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 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.

BACKGROUND: Hypertension is common among children with chronic kidney disease (CKD), and dihydropyridine calcium channel blockers (dhCCBs) are frequently used as treatment. The impact of dhCCBs on proteinuria in children with CKD is unclear. METHODS: Data from 722 participants in the Chronic Kidney Disease in Children (CKiD) longitudinal cohort with a median age of 12 years were used to assess the association between dhCCBs and log transformed urine protein/creatinine levels as well as blood pressure control measured at annual visits. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use was evaluated as an effect measure modifier. RESULTS: Individuals using dhCCBs had 18.8% higher urine protein/creatinine levels compared to those with no history of dhCCB or ACEi and ARB use. Among individuals using ACEi and ARB therapy concomitantly, dhCCB use was not associated with an increase in proteinuria. Those using dhCCBs had higher systolic and diastolic blood pressures. CONCLUSIONS: Use of dhCCBs in children with CKD and hypertension is associated with higher levels of proteinuria and was not found to be associated with improved blood pressure control.

Background and objectives Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. Design, setting, participants, & measurements We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. Results Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR Conclusions Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.