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

KEY POINTS: Higher plasma and urine kidney injury molecule-1, urine monocyte chemoattractant protein-1, and lower urine alpha-1-microglobulin were associated with left ventricular hypertrophy, even after adjustment for confounders. Biomarkers of tubular injury, dysfunction, and inflammation may indicate the severity of kidney pathology and are associated with left ventricular hypertrophy. BACKGROUND: Left ventricular hypertrophy (LVH) is common in children with CKD and is associated with an increased risk of cardiovascular disease and mortality. We have shown that several plasma and urine biomarkers are associated with increased risk of CKD progression. As CKD is associated with LVH, we sought to investigate the association between the biomarkers and LVH. METHODS: In the CKD in Children Cohort Study, children aged 6 months to 16 years with an eGFR of 30–90 ml/min per 1.73 m2 were enrolled at 54 centers in the United States and Canada. We measured plasma biomarkers kidney injury molecule-1 (KIM-1), tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase-type plasminogen activator receptor and urine KIM-1, monocyte chemoattractant protein-1 (MCP-1), YKL-40, alpha-1-microglobulin (alpha-1m), and epidermal growth factor in stored plasma and urine collected 5 months after enrollment. Echocardiograms were performed 1 year after enrollment. We assessed the cross-sectional association between the log2 biomarker levels and LVH (left ventricular mass index greater than or equal to the 95th percentile) using a Poisson regression model, adjusted for age, sex, race, body mass index, hypertension, glomerular diagnosis, urine protein-to-creatinine ratio, and eGFR at study entry. RESULTS: Among the 504 children, LVH prevalence was 12% (n=59) 1 year after enrollment. In a multivariable-adjusted model, higher plasma and urine KIM-1 and urine MCP-1 concentrations were associated with a higher prevalence of LVH (plasma KIM-1 prevalence ratio [PR] per log2: 1.27, 95% confidence interval [CI], 1.02 to 1.58; urine KIM-1 PR: 1.21, 95% CI, 1.11 to 1.48; and urine MCP-1 PR: 1.18, 95% CI, 1.04 to 1.34). After multivariable adjustment for covariates, lower urine alpha-1m was also associated with a higher prevalence of LVH (PR: 0.90, 95% CI, 0.82 to 0.99). CONCLUSIONS: Higher plasma and urine KIM-1, urine MCP-1, and lower urine alpha-1m were each associated with LVH prevalence in children with CKD. These biomarkers may better inform risk and help elucidate the pathophysiology of LVH in pediatric CKD.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Background Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. Methods Unrelated children < 18 years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR [less than or equal to] 90 ml/min/1.73 m.sup.2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. Results A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. Conclusions Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Michelle N. Rheault [sup.1] , Heather M. McLaughlin [sup.2] , Asia Mitchell [sup.2] , Lauren E. Blake [sup.2] , Prasad Devarajan [sup.3] , Bradley A. Warady [sup.4] , Keisha [...]

Background Comprehensive training of children on peritoneal dialysis (PD) and their caregivers is crucial to minimize peritonitis risk. Few studies have evaluated the impact of training on infection, so many published recommendations rely on expert opinion. This study uses data from the SCOPE collaborative to examine the impact of compliance with 4 components of PD training on the risk for peritonitis. Methods A retrospective cohort study of children enrolled in the SCOPE collaborative between 2011 and 2021 who received training prior to initiating PD. Compliance with 4 training components were assessed: performance of a home visit, 1:1 training, delaying training [greater than or equal to] 10 days after PD catheter insertion and average individual training session length [less than or equal to] 3 h. Univariate and multivariable generalized linear mixed modeling were used to assess relationships between peritonitis [less than or equal to] 90 days after PD training and median days to peritonitis and compliance with each component as well as all-or-none compliance. Results Among 1450 trainings, 51.7% had median session length [less than or equal to] 3 h, 67.1% delayed training [greater than or equal to] 10 days after catheter insertion, 74.3% had a home visit and 94.6% had 1:1 training. Only 333 trainings (23%) were compliant with all 4 training components. There was no statistically significant association between compliance with individual components, or all-or-none compliance and either the percentage of catheters with peritonitis [less than or equal to] 90 days after training end or median days to peritonitis. Conclusion No associations between 4 PD training components and risk for peritonitis were found. SCOPE requires monthly review of PD catheter practices which may have decreased the impact of training non-compliance. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Brandy Begin [sup.1] , Troy Richardson [sup.2] , Jennifer Ehrlich [sup.3] , Bradley A. Warady [sup.4] , Alicia M. Neu [sup.5] Author Affiliations: (1) grid.5288.7, 0000 0000 9758 5690, [...]

Background While hyperkalemia is well described in adult chronic kidney disease (CKD), large studies evaluating potassium trends and risk factors for hyperkalemia in pediatric CKD are lacking. This study aimed to characterize hyperkalemia prevalence and risk factors in pediatric CKD. Methods Cross-sectional analysis of Chronic Kidney Disease in Children (CKiD) study data evaluated median potassium levels and percentage of visits with hyperkalemia (K [greater than or equal to]5.5 mmoL/L) in relation to demographics, CKD stage, etiology, proteinuria, and acid-base status. Multiple logistic regression was used to identify risk factors for hyperkalemia. Results One thousand and fifty CKiD participants with 5183 visits were included (mean age 13.1 years, 62.7% male, 32.9% self-identifying as African American or Hispanic). A percentage of 76.6% had non-glomerular disease, 18.7% had CKD stage 4/5, 25.8% had low CO.sub.2, and 54.2% were receiving ACEi/ARB therapy. Unadjusted analysis identified a median serum potassium level of 4.5 mmol/L (IQR 4.1-5.0, p Conclusions Hyperkalemia was observed more frequently in children with advanced stage CKD, glomerular disease, low CO.sub.2, and ACEi/ARB use. These data can help clinicians identify high-risk patients who may benefit from earlier initiation of potassium-lowering therapies. Graphical Abstract, Author(s): Katherine L Kurzinski [sup.1] , Yunwen Xu [sup.2] , Derek K Ng [sup.2] , Susan L Furth [sup.3] , George J Schwartz [sup.4] , Bradley A Warady [sup.1] Author [...]

Background Hospitalization costs for treatment of hemodialysis (HD) catheter-associated blood stream infections (CA-BSI) in adults are high. No studies have evaluated hospitalization costs for HD CA-BSI in children or identified factors associated with high-cost hospitalizations. Methods We analyzed 160 HD CA-BSIs from the Standardizing Care to Improve Outcomes in Pediatric End-stage Kidney Disease (SCOPE) collaborative database linked to hospitalization encounters in the Pediatric Health Information System (PHIS) database. Charge-to-cost ratios were used to convert hospitalization charges reported in PHIS database to estimated hospital costs. Generalized linear mixed modeling was used to assess the relationship between higher-cost hospitalization (cost above 50.sup.th percentile) and patient and clinical characteristics. Generalized linear regression models were used to assess differences in mean service line costs between higher- and lower-cost hospitalizations. Results The median (IQR) length of stay for HD CA-BSI hospitalization was 5 (3-10) days. The median (IQR) cost for HD CA-BSI hospitalization was $18,375 ($11,584-$36,266). ICU stay (aOR 5.44, 95% CI 1.62-18.26, p = 0.01) and need for a catheter procedure (aOR = 6.08, 95% CI 2.45-15.07, p < 0.001) were associated with higher-cost hospitalization. Conclusions Hospitalizations for HD CA-BSIs in children are often multiple days and are associated with substantial costs. Interventions to reduce CA-BSI may reduce hospitalization costs for children who receive chronic HD. Graphical abstract, Author(s): Heather L. Wasik [sup.1] , Alicia Neu [sup.2] , Bradley Warady [sup.3] , Brendan Crawford [sup.4] , Troy Richardson [sup.5] , Heidi G. De Souza [sup.5] , Diana Cardwell [...]

BackgroundAdolescents 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.MethodsIn 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.ResultsOverall, 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.ConclusionOverall, 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.

Background Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. Methods We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan-Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. Results Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m.sup.2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. Conclusion Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Amy J. Kogon [sup.1] , Jennifer Roem [sup.2] , Michael F. Schneider [sup.2] , Mark M. Mitsnefes [sup.3] , Babette S. Zemel [sup.4] , Bradley A. Warady [sup.5] , [...]

Background Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction. The aim of this study was to investigate associations between executive functions (EF), anemia, and iron deficiency. Methods A total of 688 children > 6 years of age enrolled in the Chronic Kidney Disease in Children (CKiD) study who underwent evaluation for EF were included. Hemoglobin (Hgb) was characterized as low (1.sup.st-5.sup.th percentile) or very low (< 1.sup.st percentile) compared to normative values for age, sex, and race irrespective of erythropoiesis-stimulating agent (ESA) usage. Longitudinal analysis was conducted using consecutive visit pairs, with anemia status defined as new onset, resolved, or persistent. Linear mixed models with random intercept were used and adjusted for key covariates. Results Anemia was present in 41% of children, and median Hgb was 11.8 gm/dl. New onset anemia was associated with lower digit span total score (- 0.75, 95% CI - 1.36, - 0.15, p = 0.01). Persistent anemia was associated with lower scores on color-word inhibition/switching ([beta] = - 0.98; 95% CI - 1.78, - 0.18, p = 0.02). Errors of omission were significantly higher (worse) in those with persistent anemia ([beta] = 2.67, 95% CI 0.18, 5.17, p = 0.04). Very low Hgb levels were significantly associated with lower color-word inhibition/switching scores ([beta] = - 1.33, 95% CI - 2.16, - 0.51; p = 0.002). Anemia and low GFR were associated with lower category fluency scores compared to non-anemic subjects with higher GFR ([beta] = - 1.09, 95% CI - 2.09, - 0.10, p = 0.03). Conclusions The presence of anemia, in addition to its severity and duration in children with CKD, is associated with poorer scores on select measures of EF. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Nisha S. Singh [sup.1] , Rebecca J. Johnson [sup.2] , Matthew B. Matheson [sup.3] , Joann Carlson [sup.4] , Stephen R. Hooper [sup.5] , Bradley A. Warady [sup.1] Author [...]

Background Elevated serum uric acid concentration is a risk factor for CKD progression. Its change over time and association with CKD etiology and concomitant changes in estimated glomerular filtration rate (eGFR) in children and adolescents are unknown. Methods Longitudinal study of 153 children/adolescents with glomerular (G) and 540 with non-glomerular (NG) etiology from the CKD in Children (CKiD) study. Baseline serum uric acid, change in uric acid and eGFR over time, CKD etiology, and comorbidities were monitored. Adjusted linear mixed-effects regression models quantified the relationship between within-person changes in uric acid and concurrent within-person changes in eGFR. Results Participants with stable uric acid over follow-up had CKD progression which became worse for increased baseline uric acid (average annual percentage changes in eGFR were - 1.4%, - 7.7%, and - 14.7% in those with G CKD with baseline uric acid 7.5 mg/dL, respectively; these changes were - 1.4%, - 4.1%, and - 8.6% in NG CKD). Each 1 mg/dL increase in uric acid over follow-up was independently associated with significant concomitant eGFR decreases of - 5.7% (95%CI - 8.4 to - 3.0%) (G) and - 5.1% (95%CI - 6.3 to - 4.0%) (NG) for those with baseline uric acid < 5.5 mg/dL and - 4.3% (95%CI - 6.8 to - 1.6%) (G) and - 3.3% (95%CI - 4.1 to - 2.6%) (NG) with baseline uric acid between 5.5 and 7.5 mg/dL. Conclusions Higher uric acid levels and increases in uric acid over time are risk factors for more severe progression of CKD in children and adolescents. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information., Author(s): George J. Schwartz [sup.1] , Jennifer L. Roem [sup.2] , Stephen R. Hooper [sup.3] , Susan L. Furth [sup.4] , Donald J. Jr. Weaver [sup.5] , Bradley A. Warady [...]

Background Survival to hospital discharge in neonates born with kidney failure has not been previously described. Methods This was a retrospective, observational analysis of the Pediatric Health Information System (PHIS) database from 2005 to 2019. Primary outcome was survival at discharge; secondary outcomes were hospital and ICU length of stay (LOS). Univariate analysis was performed to describe the population by birth weight (BW) and characterize survival; multivariable generalized liner mixed modeling assuming a binomial distribution and logit link was performed to identify mortality risk factors. Results Of 213 neonates born with kidney failure (median BW 2714 g; GA 35 weeks; 68% male), 4 (1.9%) did not receive dialysis or peritoneal dialysis (PD) catheter placement, 152 (72.9%) received PD only, 49 (23.4%) received PD plus extracorporeal dialysis (ECD), and 8 (3.4%) were treated with an undocumented dialysis modality. Median age at dialysis initiation was 7 days; median hospital LOS and ICU LOS were 84 and 69 days, respectively. One-hundred and sixty-two patients (76%) survived to discharge. Non-survivors (n = 51) were more likely to have received ECD and mechanical ventilation, and had a longer duration of mechanical ventilation. Every day of mechanical ventilation increased the mortality odds by 2% (n = 189; adjusted OR 1.02; 1.01, 1.03); in addition, the odds of mortality were 2 times higher in those who received ECD vs. only PD (adjusted OR 2.25; 1.04, 4.86). Conclusions Survival to initial hospital discharge occurs in the majority of neonates born with kidney failure. Predictors of increased mortality included longer duration of mechanical ventilation, as well as the requirement for ECD. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Donna J. Claes [sup.1] , Troy Richardson [sup.2] , Matthew W. Harer [sup.3] , Mahima Keswani [sup.4] , Alicia Neu [sup.5] , Allison C. Redpath Mahon [sup.6] , Michael [...]

Peritoneal dialysis is the most commonly prescribed dialysis modality for infants and young children with kidney failure worldwide. Provision of high-quality care for the pediatric patient on chronic peritoneal dialysis requires a multidisciplinary approach and a strong collaboration with the patient and their caregiver. This article not only reviews current recommendations and advances in the care of pediatric patients on peritoneal dialysis with a focus on the provision of high-quality care and improvement in outcomes, but it also draws attention to health care disparities that exist locally and globally., Author(s): Annabelle N. Chua [sup.1] , Reeti Kumar [sup.1] , Bradley A. Warady [sup.2] Author Affiliations: (1) grid.26009.3d, 0000 0004 1936 7961, Division of Pediatric Nephrology, Department of Pediatrics, Duke [...]

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

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.