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Rationale & Objective: Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric nephrotic syndrome, and African Americans exhibit an increased risk for developing FSGS compared with other populations. Predisposing genetic factors have previously been described in adults. Here we performed genomic screening of primary FSGS in a pediatric African American population., Study Design: Prospective cohort with case-control genetic association study design., Setting & Participants: 140 African American children with chronic kidney disease from the Chronic Kidney Disease in Children (CKiD) cohort, including 32 cases with FSGS., Predictors: Over 680,000 common single-nucleotide polymorphisms (SNPs) were tested for association. We also ran a pathway enrichment analysis and a human leucocyte antigen (HLA)-focused association study., Outcome: Primary biopsy-proven pediatric FSGS., Analytical Approach: Multivariate logistic regression models., Results: The genome-wide association study revealed 169 SNPs from 14 independent loci significantly associated with FSGS (false discovery rate [FDR]<5%). We observed notable signals for genetic variants within the APOL1 (P=8.6×10 -7 ; OR, 25.8 [95% CI, 7.1-94.0]), ALMS1 (P=1.3×10 -7 ; 13.0% in FSGS cases vs 0% in controls), and FGFR4 (P=4.3×10 -6 ; OR, 24.8 [95% CI, 6.3-97.7]) genes, all of which had previously been associated with adult FSGS, kidney function, or chronic kidney disease. We also highlighted novel, functionally relevant genes, including GRB2 (which encodes a slit diaphragm protein promoting podocyte structure through actin polymerization) and ITGB1 (which is linked to renal injuries). Our results suggest a major role for immune responses and antigen presentation in pediatric FSGS through (1) associations with SNPs in PTPRJ (or CD148, P=3.5×10 -7 ), which plays a role in T-cell receptor signaling, (2) HLA-DRB1∗11:01 association (P=6.1×10 -3 ; OR, 4.5 [95% CI, 1.5-13.0]), and (3) signaling pathway enrichment (P=1.3×10 -6 )., Limitations: Sample size and no independent replication cohort with genomic data readily available., Conclusions: Our genetic study has identified functionally relevant risk factors and the importance of immune regulation for pediatric primary FSGS, which contributes to a better description of its molecular pathophysiological mechanisms., Plain-Language Summary: We assessed the genetic risk factors for primary focal segmental glomerulosclerosis (FSGS) by simultaneously testing over 680,000 genetic markers spread across the genome in 140 children, including 32 with FSGS lesions. Fourteen independent genetic regions were significantly associated with pediatric FSGS, including APOL1 and ALMS1-NAT8, which were previously found to be associated with FSGS and chronic kidney diseases in adults. Novel genes with relevant biological functions were also highlighted, such as GRB2 and FGFR4, which play a role in the kidney filtration barrier and in kidney cell differentiation, respectively. Finally, we revealed the importance of immune regulation in pediatric FSGS through associations involving cell surface proteins presenting antigens to the immune system and interacting with T-cell receptors., (Copyright © 2023 National Kidney Foundation, Inc. All rights reserved.)

Rationale & Objective: Accurate detection of hypertension is crucial for clinical management of pediatric chronic kidney disease (CKD). The 2017 American Academy of Pediatrics (AAP) clinical practice guideline for childhood hypertension included new normative blood pressure (BP) values and revised definitions of BP categories. In this study, we examined the effect of applying the AAP guideline's normative data and definitions to the Chronic Kidney Disease in Children (CKiD) cohort compared with use of normative data and definitions from the 2004 Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents., Study Design: Observational cohort study., Setting & Participants: Children and adolescents in the CKiD cohort., Exposure: Clinic BP measurements., Outcome: BP percentiles and hypertension stages calculated using the 2017 AAP guideline and the Fourth Report from 2004., Analytical Approach: Agreement analysis compared the estimated percentile and prevalence of high BP based on the 2017 guideline and 2004 report to clinic and combined ambulatory BP readings., Results: The proportion of children classified as having normal clinic BP was similar using the 2017 and 2004 systems, but the use of the 2017 normative data classified more participants as having stages 1-2 hypertension (22% vs 11%), with marginal reproducibility (κ=0.569 [95% CI, 0.538-0.599]). Those identified as having stage 2 hypertension by the 2017 guideline had higher levels of proteinuria compared with those identified using the 2004 report. Comparing use of the 2017 guideline and the 2004 report in terms of ambulatory BP monitoring categories, there were substantially more participants with white coat (3.5% vs 1.5%) and ambulatory (15.5% vs 7.9%) hypertension, but the proportion with masked hypertension was lower (40.2% vs 47.8%, respectively), and the percentage of participants who were normotensive was similar (40.9% vs 42.9%, respectively). Overall, there was good reproducibility (κ=0.799 [95% CI, 0.778-0.819]) of classification by ambulatory BP monitoring., Limitations: Relationship with long-term progression and target organ damage was not assessed., Conclusions: A greater percentage of children with CKD were identified as having hypertension based on both clinic and ambulatory BP when using the 2017 AAP guideline versus the Fourth Report from 2004, and the 2017 guideline better discriminated those with higher levels of proteinuria. The substantial differences in the classification of hypertension when using the 2017 guideline should inform clinical care., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Recent reassessment of the use of race in estimated glomerular filtration rate (eGFR) in adults has instigated questions about the role of race in eGFR expressions for children. Little research has examined the associations of self-reported race with measured GFR (mGFR) adjusting for serum creatinine or cystatin C in children and young adults with chronic kidney disease (CKD). This study examined these associations and evaluated the performance of the previously published "U25" (under the age of 25 years) eGFR equations in a large cohort of children and young adults with CKD., Study Design: Observational cohort study., Setting & Participants: Participants in the Chronic Kidney Disease in Children (CKiD) study including 190 Black and 675 non-Black participants contributing 473 and 1,897 annual person-visits, respectively., Exposure: Self- or parental-reported race (Black, non-Black). Adjustment for serum creatinine or cystatin C, body size, and socioeconomic status., Outcome: mGFR based on iohexol clearance., Analytical Approach: Linear regression with generalized estimating equations, stratified by age (<6, 6-12, 12-18, and ≥18 years) incorporating serum creatinine or serum cystatin C. Contrasting performance in different self-reported racial groups of the U25 eGFR equations., Results: Self-reported Black race was significantly associated with 12.8% higher mGFR among children in regression models including serum creatinine. Self-reported Black race was significantly associated with 3.5% lower mGFR after adjustment for cystatin C overall but was not significant for those over 12 years. The results were similar after adjustment for body size and socioeconomic factors. The average of creatinine- and cystatin C-based U25 equations was unbiased by self-reported race groups., Limitations: Small number of children < 6 years; lean body mass was estimated., Conclusions: Differences in the creatinine-mGFR relationship by self-reported race were observed in children and young adults with CKD and were consistent with findings in adults. Smaller and opposite differences were observed for the cystatin C-mGFR relationship, especially in the younger age group. We recommend inclusion of children for future investigations of biomarkers to estimate GFR. Importantly, for GFR estimation among those under 25 years of age, the average of the new U25 creatinine and cystatin C equations without race coefficients yields unbiased estimates of mGFR., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: To examine the relationship between neighborhood poverty and deprivation, chronic kidney disease (CKD) comorbidities, and disease progression in children with CKD., Study Design: Observational cohort study., Setting & Participants: Children with mild to moderate CKD enrolled in the CKiD (Chronic Kidney Disease in Children) study with available US Census data., Exposure: Neighborhood poverty and neighborhood disadvantage., Outcome: Binary outcomes of short stature, obesity, hypertension, and health care utilization for cross-sectional analysis; a CKD progression end point (incident kidney replacement therapy [KRT] or 50% loss in estimated glomerular filtration rate), and mode of first KRT for time-to-event analysis., Analytical Approach: Cross-sectional analysis of health characteristics at time of first Census data collection using logistic regression to estimate odds ratios. Risk for CKD progression was analyzed using a Cox proportional hazard model. Multivariable models were adjusted for race, ethnicity, sex, and family income., Results: There was strong agreement between family and neighborhood socioeconomic characteristics. Risk for short stature, hospitalization, and emergency department (ED) use were significantly associated with lower neighborhood income. After controlling for race, ethnicity, sex, and family income, the odds of hospitalization (OR, 1.71 [95% CI, 1.08-2.71]) and ED use (OR, 1.56 [95% CI, 1.02-2.40]) remained higher for those with lower neighborhood income. The hazard ratio of reaching the CKD progression outcome for participants living in lower income neighborhoods was significantly increased in the unadjusted model only (1.38 [95% CI, 1.02-1.87]). Likelihood of undergoing a preemptive transplant was decreased with lower neighborhood income (OR, 0.47 [95% CI, 0.24-0.96]) and higher neighborhood deprivation (OR, 0.31 [95% CI, 0.10-0.97]), but these associations did not persist after controlling for participant characteristics., Limitations: Limited generalizability, as only those with consistent longitudinal nephrology care were studied., Conclusions: Neighborhood-level socioeconomic status (SES) was associated with poorer health characteristics and CKD progression in univariable analysis. However, the relationships were attenuated after accounting for participant-level factors including race. A persistent association of neighborhood poverty with hospitalizations and ED suggests an independent effect of SES on health care utilization, the causes for which deserve additional study., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: The current clinical guidelines for vascular access do not have specific recommendations for older hemodialysis patients. Our study aimed to determine the association of age with arteriovenous fistula (AVF) placement, maturation, and primary and secondary patency loss among older hemodialysis recipients., Study Design: Retrospective cohort study., Setting & Participants: A US national cohort of incident hemodialysis patients 67 years or older (N = 43,851) assembled from the US Renal Data System., Exposure: Age at dialysis initiation., Outcomes: AVF placement, maturation, primary patency loss, and abandonment., Analytical Approach: Cause-specific and subdistribution proportional hazards models were used to examine the association of age and AVF outcomes, with kidney transplantation, peritoneal dialysis, and death treated as competing events. Age cutoff was identified by restricted cubic splines. We compared crude and inverse probability-weighted cumulative incidence functions using Gray's test., Results: As compared with those aged 67-<77 years, patients 77 years or older had significantly lower probabilities of AVF placement (adjusted cause-specific HR [cHR], 0.96 [95% CI, 0.92-0.99]; adjusted subdistribution HR [sHR], 0.92 [95% CI, 0.89-0.95]; Gray's test P < 0.001) and maturation (adjusted cHR, 0.95 [95% CI, 0.91-0.99]; adjusted sHR, 0.93 [95% CI, 0.90-0.97]; P < 0.001). However, age was not associated with AVF primary (adjusted cHR, 1.05 [95% CI, 1.00-1.11]; adjusted sHR, 1.04 [95% CI, 0.99-1.09]; P = 0.09) or secondary (adjusted cHR, 1.06 [95% CI, 0.94-1.20]; adjusted sHR, 1.05 [95% CI, 0.93-1.18]; P = 0.4) patency loss., Limitations: Reliance on administrative claims to ascertain AVF outcomes., Conclusions: The likelihood of AVF maturation is an important consideration for vascular access planning. Age alone should not be the basis for excluding older dialysis patients from AVF creation because maintenance of fistula patency was not reduced with older age despite a modest reduction in fistula maturation., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: 2 valid and reliable estimated glomerular filtration rate (GFR) equations for the pediatric population have been developed from directly measured GFR data in the Chronic Kidney Disease in Children (CKiD) cohort: the full CKiD and bedside CKiD equations. Although adult GFR estimating equations replicate relationships of measured GFR with biomarkers, it is unclear whether similar patterns exist among children and adolescents with chronic kidney disease (CKD)., Study Design: Prospective cohort study in children and adolescents., Settings & Participants: 730 participants contributed 1,539 study visits., Predictors: Measured GFR by plasma iohexol disappearance (mGFR), estimated GFR by the full CKiD equation (eGFR CKiDfull ; based on serum creatinine, cystatin C, serum urea nitrogen, height, and sex), and estimated GFR by the bedside CKiD equation (eGFR CKiDbed ; calculated as 41.3 × height [m]/serum creatinine [mg/dL]) were predictors of CKD-related biomarkers. Deviations of mGFR from eGFR CKiDfull and deviations of eGFR CKiDfull from eGFR CKiDbed from linear regressions (ie, residuals) were included in bivariate analyses., Outcomes & Measurements: CKD-related biomarkers included values for urine protein-creatinine ratio, blood hemoglobin, serum phosphate, bicarbonate, potassium, systolic and diastolic blood pressure z scores, and height z scores., Results: The median age of 730 participants with CKD was 12.5 years, with median mGFR, eGFR CKiDfull , and eGFR CKiDbed of 51.8, 54.0, and 53.2mL/min/1.73m 2 , respectively. eGFR CKiDfull demonstrated as strong or stronger associations with CKD-related biomarkers than mGFR; eGFR CKiDbed associations were significantly attenuated (ie, closer to the null). Residual information in mGFR did not substantially increase explained variability. eGFR CKiDbed estimated faster GFR decline relative to mGFR and eGFR CKiDfull ., Limitations: Simple linear summaries of biomarkers may not capture nonlinear associations., Conclusions: eGFR CKiDfull closely approximated mGFR to describe relationships with CKD-severity indicators and progression in this pediatric CKD population. eGFR CKiDbed offered similar inferences, but associations were attenuated and rate of progression was overestimated. The eGFR CKiDfull equation from 2012 is preferred for pediatric research purposes., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Among adults, lower socioeconomic status (SES) is a risk factor for chronic kidney disease (CKD), progression to end-stage renal disease, and poor health outcomes; but its impact on young people with CKD is not established., Study Design: Prospective cohort study., Settings & Participants: 572 children and adolescents aged 1-16 years with mild to moderate CKD residing in the United States and Canada who were enrolled in the Chronic Kidney Disease in Children (CKiD) Study., Predictor: Self-reported annual household income category as a proxy measure for SES: ≥$75,000 (high income), $30,000 to <$75,000 (middle income) and <$30,000 (low income)., Outcomes & Measurements: Clinical characteristics and CKD severity at baseline (glomerular filtration rate [GFR] and comorbid conditions related to disease severity and management) and longitudinally (GFR decline and changes in blood pressure z scores and height z scores per year)., Results: At baseline, low and middle household incomes, compared to high income, were associated with minority race (39% and 20% vs. 7%), lower maternal education (28% and 5% vs. 1%), abnormal birth history (34% and 32% vs. 21%), and having at least one clinical comorbid condition (66% and 64% vs. 55%). Baseline median GFRs were similar across income categories (43-45 mL/min/1.73 m2). After adjusting for baseline differences, average GFR declines per year for the low-, middle-, and high-income categories were -2.3%, -2.7%, and -1.9%, respectively, and were not statistically significantly different among groups. Blood pressure control tended to improve in all groups (z score, -0.10 to -0.04) but higher income was associated with a faster improvement. Each group showed similar deficits in height at baseline. Height deficits diminished over time for participants from high-income families, but not among those from low-income families (z scores for height per year, 0.05 and -0.004, respectively; P = 0.03 for comparison of high and low income)., Limitations: Income is an imperfect measure for SES; CKiD participants are not representative of children and adolescents with CKD who are uninsured or not receiving care; statistical power to detect associations by income level is limited., Conclusions: GFR decline was similar across income groups but better improvement in BP was observed among those with high income. Children and adolescents with CKD from lower income households are at higher risk of impaired growth., (Copyright © 2013 National Kidney Foundation, Inc. All rights reserved.)